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Therapeutic strategy in unresectable metastatic colorectal cancer: an updated review:

Therapeutic strategy in unresectable metastatic colorectal cancer: an updated review: 572343 TAM0010.1177/1758834015572343Therapeutic Advances in Medical OncologyB Chibaudel, C Tournigand research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Therapeutic strategy in unresectable 2015, Vol. 7(3) 153 –169 DOI: 10.1177/ metastatic colorectal cancer: an updated © The Author(s), 2015. Reprints and permissions: review http://www.sagepub.co.uk/ journalsPermissions.nav Benoist Chibaudel, Christophe Tournigand, Franck Bonnetain, Hubert Richa, Magdalena Benetkiewicz, Thierry André and Aimery de Gramont Abstract: Systemic therapy is the standard care for patients with unresectable advanced colorectal cancer (CRC), but salvage surgery of metastatic disease should be considered in the case of adequate tumor shrinkage. Several drugs and combinations are now available for use in treating patients with advanced CRC, but the optimal sequence of therapy remains unknown. Moreover, the administration of antitumor therapy can be modulated by periods Correspondence to: of maintenance or treatment breaks rather than delivered as full therapy until disease Benoist Chibaudel, MD Department of Medical progression or unacceptable toxicity, followed by reintroduction of prior full therapy when Oncology, Institut required, before switching to other drugs. Consequently, randomized strategy trials are Hospitalier Franco- Britannique, 4, rue Kléber, needed to define the optimal treatment sequences. Molecular testing for Kirsten rat sarcoma 92300, Levallois-Perret, viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) France benoist.chibaudel@ihfb. is mandatory but not sufficient to select appropriate patients for epidermal growth factor org receptor (EGFR) monoclonal antibody (MoAb) therapy. Christophe Tournigand, MD Hôpitaux de Paris, Créteil, France Franck Bonnetain, MD Keywords: chemotherapy, colorectal cancer, maintenance, molecular targeted agents, Methodology and strategy, treatment biostatistics Unit, Hôpital Besançon, Besançon, France Hubert Richa, MD Department of Surgery, Institut Hospitalier Franco-Britannique, Levallois-Perret, France Introduction oncologists, gastroenterologists, and radiologists. Magdalena Benetkiewicz, The theoretical definition of potentially resecta- PhD Colorectal cancer ble tumors and patient classification has been GERCOR, Groupe Coopérateur Colorectal cancer (CRC) is the third most com- proposed, but mainly depends on the experience Multidisciplinaire en mon cancer in men and the second most common of each individual surgeon [Adams et al. 2013]. In Oncologie, Paris, France and Fondation ARCAD, cancer in women worldwide but with a geograph- the case of initially unresectable disease, systemic Aide et Recherche en ical variation in incidence and mortality. The therapy is the standard care, but the evaluation Cancérologie Digestive, Paris, France highest mortality rates present in both sexes in for conversion to resectable disease should be Thierry André, MD Central and Eastern Europe [Globocan, 2012]. considered at each tumor assessment. Department of Medical Metastatic disease can occur at the same time as Oncology, Hôpital Saint- Antoine, Assistance the diagnosis of primary tumor (synchronous Publique – Hôpitaux de metastatic disease) or subsequently (metachro- Tumor biology Paris, Paris, France and INSERM U938, Hôpital nous metastatic disease) after surgery of primary Half of the patients with advanced CRC harbor a Saint-Antoine, Paris, tumor followed or not by adjuvant chemotherapy. Kirsten rat sarcoma viral oncogene homolog France The prognosis of patients with metachronous dis- (KRAS) or neuroblastoma N-Ras (NRAS) tumor Aimery de Gramont, MD Department of ease is usually more favorable. gene mutation, which is a negative predictive bio- Medical Oncology, marker for anti-epidermal growth factor receptor Institut Hospitalier Franco-Britannique, Resectability of the metastatic disease should be (EGFR) monoclonal antibodies (MoAbs) therapy Levallois-Perret, assessed at the time of first diagnosis of involve- in these patients [Lièvre et  al. 2006]. Thus, only France and GERCOR, Groupe Coopérateur ment of one or several metastatic sites in a multi- patients with RAS wild-type metastatic CRC Multidisciplinaire en disciplinary approach with surgeons, medical (mCRC) are eligible for MoAbs EGFR inhibitors Oncologie, Paris, France http://tam.sagepub.com 153 Therapeutic Advances in Medical Oncology 7(3) RAS/RAF wild-type KRAS exon 2 (40%) (40%) KRAS exon 3-4 BRAF exon 15 NRAS exon 2-3-4 (10%) (10%) Major effect of EGFRi (21%) Uncertain or minimal effect of EGFRi (11%) RAS mutant (50%) Mutant « like» (17.5%) Figure 1. Colon cancer biology: focus on epidermal growth factor (EGF) pathway and sensitivity to epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs). (A) Frequency of KRAS, NRAS, and BRAF tumor genes mutations in patients with advanced colorectal cancer (CRC). (B) Role of tumor biology for the estimated sensitivity to EGFR MoAbs in metastatic CRC. therapy. When adding patients with serine/threo- was associated with a near-doubling median sur- nine-protein kinase B-Raf (BRAF) mutant vival, which surpassed 2 years with the addition of tumors (10%), the RAS/RAF mutant population molecular-targeted agents. Vascular endothelial represents 60% of previously untreated mCRC growth factor (VEGF) inhibition with MoAbs patients (Figure 1A). increased survival in combination with chemo- therapy in first- or second-line treatment of patients with mCRC. Anti-EGFR MoAbs (i.e. Drugs cetuximab, panitumumab) also improved patient Until the 2000s, 5-fluorouracil (5-FU) was the outcomes, but only in the absence of RAS tumor only approved drug for the treatment of advanced gene mutations. More recently, regorafenib, an CRC, which administration was producing orally active inhibitor of angiogenic, stromal and median overall survival (OS) of less than 1 year. oncogenic kinases, improved survival in heavily Other orally active 5-FU prodrugs (capecitabine, pretreated CRC patients. But the optimal strategy tegafur-uracil, S1) are also available. Patient out- or the best way to combine and sequence all of comes were improved with the use of irinotecan, these drugs available in routine practice has not an inhibitor of topoisomerase I, and oxaliplatin, yet been established. which were approved by the United States (US) Food and Drug Administration (FDA) in 1998 In the case of initially unresectable metastatic and 2002, respectively. The combination of fluo- disease, the association of chemotherapy (single- ropyrimidine with either irinotecan or oxaliplatin agent to three-drug regimen) and a molecular 154 http://tam.sagepub.com B Chibaudel, C Tournigand et al. targeted agent, either antiangiogenic (i.e. bevaci- irinotecan/oxaliplatin), followed by maintenance zumab) or EGFR inhibitor monoclonal antibody therapy with fluoropyrimidine-bevacizumab (cetuximab, panitumumab), is the standard prac- [Loupakis et al. 2014]. The addition of oxaliplatin tice for first-line therapy. Of note, the combina- to FOLFIRI-bevacizumab significantly increased tion of chemotherapy with both the EGFR and PFS (primary endpoint) from 9.7 to 12.1 months VEGF MoAbs inhibitors led to adverse outcomes (HR = 0.75; p = 0.003) and RR from 53% to in two large randomized phase III trials (PACCE, 65% (p = 0.006), but neither R0 salvage surgery CAIRO2) [Hecht et al. 2009; Tol et al. 2009]. rate (12% versus 15%, p = 0.33) nor OS were improved (HR = 0.79; p = 0.054). First-line therapy Fluoropyrimidine-bevacizumab in elderly patients. The international Australasian Gastro- Chemotherapy with antiangiogenic drugs intestinal Trials Group (AGITG) MAX study In the first-line setting, bevacizumab can be com- [Tebbutt et  al. 2010] randomized 471 patients bined with an oxaliplatin-based (NO16966) with unresectable mCRC considered suitable for [Saltz et  al. 2008], an irinotecan-based initial monotherapy. Patients received low-inten- (AVF2107g) [Hurwitz and Kabbinavar, 2005] sity chemotherapy including capecitabine alone, chemotherapy doublet, chemotherapy triplet capecitabine plus bevacizumab, or capecitabine- (GONO TRIBE) [Loupakis et al. 2014], or even mitomycin C plus bevacizumab. The median age with fluoropyrimidine monochemotherapy of patients was 68 years. After a median follow up (MAX, AVF2192, AVEX) [Tebbutt et  al. 2010; of 31 months, median PFS (primary endpoint) Kabbinavar et al. 2005; Cunningham et al. 2013] was improved from 5.7 months in the capecitabine group to 8.5 months in the capecitabine–bevaci- Irinotecan-based chemotherapy with bevaci- zumab group (HR = 0.63, p < 0.001). Median zumab. In the AVF2107g study, the addition of survival was not statistically different between bevacizumab to an irinotecan-based chemother- these patients (18.9 months in both groups). The apy resulted in statistically significant improve- triplet combination arm was not superior to the ment in OS (primary endpoint) among 813 capecitabine–bevacizumab doublet arm neither patients with previously untreated mCRC [haz- for PFS nor OS. The MAX study results were ard ratio (HR) = 0.66; p < 0.001] [Hurwitz consistent with an earlier phase II study OS et al. 2004]. Secondary endpoints of progression- (AVF2192) performed in patients over the age of free survival (PFS; HR = 0.54) and response 65 years and considered unfit for first-line irinote- PFS rate (RR) were also improved. can [Kabbinavar et al. 2005]. Oxaliplatin-based chemotherapy with bevaci- AVEX. In the AVEX randomized phase III trial, zumab. The NO16966 study included 1401 280 patients with previously untreated, unre- patients with previously untreated mCRC with a sectable mCRC, and not eligible to oxaliplatin- median age of 60 years [Saltz et  al. 2008]. The based or irinotecan-based chemotherapy addition of bevacizumab to either FOLFOX regimens were randomly assigned to receive the (leucovorin/5-FU/oxaliplatin regimen) or XELOX bevacizumab–capecitabine combination or (capecitabine plus oxaliplatin regimen) led to a capecitabine only [Cunningham et  al. 2013]. 17% improvement of PFS (primary endpoint, The median age of patients was 76 years. PFS HR = 0.83; p = 0.0023). This benefit was higher (primary endpoint) was significantly longer with when censoring patients at the time of drug dis- bevacizumab and capecitabine than with continuation (‘on-treatment PFS’, HR = 0.63). capecitabine alone (9.1 versus 5.1 months, Unlike other trials, RR was similar with or without HR = 0.53; p < 0.0001). Thus, the combination bevacizumab. of bevacizumab and fluoropyrimidine can be considered as the treatment of choice in elderly Triplet chemotherapy (irinotecan- and oxaliplatin- patients with mCRC. based) with bevacizumab. In the GONO TRIBE study, 508 patients with unresectable mCRC Chemotherapy with anti-EGFR MoAbs. Anti- were randomized to receive 6 months of bevaci- EGFR MoAbs can be combined with a doublet of zumab-based induction therapy with either FOL- chemotherapy that is either FOLFOX (PRIME) FIRI (regimen of leucovorin/5-FU/irinotecan) or [Douillard et  al. 2010, 2014a] or FOLFIRI FOLFOXIRI (regimen of leucovorin/5-FU/ (CRYSTAL) [Van Cutsem et al. 2009, 2011]. http://tam.sagepub.com 155 Therapeutic Advances in Medical Oncology 7(3) Anti-EGFR MoAbs with an oxaliplatin-based che- German or Austrian centers [Heinemann et  al. motherapy. The addition of panitumumab to 2014]. The RR (primary endpoint) and PFS were FOLFOX has been evaluated in the PRIME similar in the two treatment arms. Unexpectedly, study [Douillard et al. 2010, 2014a]. The primary a prolongation of OS (secondary endpoint), was endpoint was PFS. In the ‘all RAS wild-type’ pop- observed in favor of the cetuximab arm from 25.0 ulation (N = 512), which represented 43% of the to 28.7 months, corresponding to a HR of 0.77. randomized population (N = 1183), the median In an exploratory analysis of RAS wild-type PFS and OS were significantly higher (HR = patients excluding 42% of the primary population PFS 0.70; p = 0.004 and HR = 0.78; p = 0.04) in (N = 342), there was still no difference in PFS OS the combination arm [Douillard et al. 2013]. (HR = 0.97; p = 0.770), but the benefit in OS was amplified with an absolute difference in The addition of cetuximab to an oxaliplatin-based median OS of 8.1 months (from 25.0 to 33.1 chemotherapy was evaluated in two randomized months, HR = 0.70; p = 0.006). This unexpected phase III studies [Maughan et al. 2011; Tveit et al. discrepancy between an OS advantage without 2012]. In both studies, the addition of cetuximab any benefit during treatment period could be led to a detrimental effect on survival, whatever partly explained by a high number of active cen- KRAS mutational status. Of note, the chemother- ters and the absence of predefined post-protocol apy regimen used was either FOLFOX or XELOX treatment, leading to significant heterogeneity of in the COIN study [Maughan et  al. 2011], and post-progression therapy. Graphically, the OS FLOX (leucovorin/5-FU bolus/oxaliplatin regi- Kaplan–Meier curves appear similar in 25% of men) in the NORDICVII study [Tveit et al. 2012]. patients, widely different in favor of cetuximab in 55% of patients, and slightly different in 20% in Anti-EGFR MoAbs with an irinotecan-based chemo- favor of cetuximab (Figure 2A). therapy. FOLFIRI in combination with cetuximab is a standard first-line regimen for patients with First-line oxaliplatin- or irinotecan-based ther- RAS wild-type tumors, based on a retrospective apy. The CALGB/SWOG 80405 study random- analysis of the prospective CRYSTAL study limited ized patients with mCRC to receive chemotherapy to patients with KRAS exon 2 wild-type tumors and with cetuximab, or bevacizumab, or both agents including 89% of the overall population [Van Cut- [Lenz et  al. 2014]. The chemotherapy regimen sem et al. 2011]. This combination yielded positive (FOLFIRI or mFOLFOX6) was selected by phy- results in terms of RR (overall response (OR) = sician. The main changes during the study 2.07; p < 0.001), PFS (HR = 0.70; p = 0.001), and included discontinuation of the study arm com- OS (HR = 0.80; p = 0.009) in favor of cetuximab bining both targeted-MoAbs agents after the containing arm [Van Cutsem et al. 2009, 2011]. results of the PACCE and CAIRO2 trials [Hecht et al. 2009; Tol et al. 2009], and the limitation of Conclusions. Overall, if the preferred targeted eligibility to patients with KRAS exon 2 wild-type agent is an anti-EGFR MoAb in first-line treat- tumors. Of 1137 patients with KRAS exon 2 ment of patients with RAS wild-type mCRC, two wild-type tumors, 526 (46.3%) were analyzed in combinations can be recommended: either an expanded RAS wild-type population (KRAS FOLFOX–panitumumab or FOLFIRI–cetux- and NRAS exons 2, 3, and 4). No significant dif- imab until progression or limiting toxicity. The ference was observed between the cetuximab combination of oral fluoropyrimidine (capecitabine (N = 270) and the bevacizumab arms (N = 256) or UFT) to oxaliplatin and cetuximab should defi- in combination with chemotherapy, both for OS nitely not be used [Maughan et  al. 2011; Douil- (32.0 versus 31.2 months, HR 0.90; p = 0.40) and lard et al. 2014b]. PFS (11.3 versus 11.4 months, HR = 1.10; p = 0.310). However, there was higher RR achieved in the cetuximab arm in the expanded Dilemma for treatment-naïve mCRC patients: RAS population than in the bevacizumab arm choice between antiangiogenics and anti-EGFR (68.6% versus 53.6%, p < 0.01). Graphically, the agents, two options OS Kaplan–Meier curves appear similar in 45% First-line irinotecan-based therapy. In the AIO of patients, widely different in favor of cetuximab FIRE-3 randomized study, 592 patients with in 30% of patients, and slightly different in 25% KRAS exon 2 wild-type mCRC were treated with of patients (10% in favor of cetuximab and 15% FOLFIRI in combination with either cetuximab in favor of bevacizumab) (Figure 2B). Subgroup (N = 297) or bevacizumab (N = 295) in 150 analysis of patients treated with FOLFIRI did not 156 http://tam.sagepub.com B Chibaudel, C Tournigand et al. Figure 2. Proportion of patients (%) with graphical overall survival (OS) superiority (green), uncertain difference (orange) and absence of superiority (red) of cetuximab over bevacizumab in the AIO FIRE-3 study (A), in the CALGB/SWOG 80405 study (B), and estimation (mean) from both (C). http://tam.sagepub.com 157 Therapeutic Advances in Medical Oncology 7(3) confirm the results of the AIO FIRE-3 study. Nei- therapy for improving survival [de Gramont et al. ther PFS (HR = 1.10) nor OS (HR = 1.10) was 2007]. The sensitivity to oxaliplatin reintroduc- different between the cetuximab and the bevaci- tion increases with the duration of oxaliplatin-free zumab arms when combined with FOLFIRI. interval [Chibaudel et al. 2013]. Based on a graphical analysis of both CALGB/ Maintenance with antiangiogenic agent only. Main- SWOG 80405 and AIO FIRE-3 studies, the supe- tenance with bevacizumab alone after a bevaci- riority of the MoAbs EGFR inhibitors over beva- zumab-based induction therapy is equivalent to cizumab can be considered as probably maintenance with bevacizumab-fluoropyrimidine unquestionable in 20% of all patients with previ- (AIO KRK 0207) [Hegewisch-Becker et al. 2014] ously untreated mCRC (40% of actual definition or continuous therapy (TTD MACRO) [Diaz- of ‘all RAS wild-type’ patients), and roughly 70% Rubio et al. 2012], but is superior to a complete may not have any benefit of adding anti-EGFR stop of therapy (AIO KRK 0207, SAKK 41/06) MoAbs to chemotherapy. An uncertain or limited [Hegewisch-Becker et  al. 2014; Koeberle et  al. effect of anti-EGFR therapy is observed in further 2013]. 10% of patients (Figures 1B and 2C). MACRO: maintenance bevacizumab as efficient as continuous therapy. In the TTD MACRO trial, Maintenance therapy the bevacizumab maintenance therapy was initi- The aim of maintenance therapy (Table 1 and ated after an induction therapy with XELOX–bev- Figure 3) is to decrease the frequency and severity acizumab, and compared with the continuation of of adverse events induced by antitumor therapy, this regimen until progression or severe toxicity to improve health-related quality of life (HRQoL) [Diaz-Rubio et  al. 2012]. The primary endpoint while maintaining as long as possible the effects was PFS. This trial could not formally conclude to achieved with induction therapy, leading to lower a statistical noninferiority of the maintenance arm treatments costs and decreased rates of drug over the continuous arm, but the absolute differ- resistance by stopping one or more drugs before ence in median PFS was only 0.7 months (9.7 disease progression. versus 10.4 months) and the HR for the observed PFS difference between the two arms was 1.10 [95% Several modalities have been evaluated in pro- confidence interval (CI) 0.89–1.35]. Of note, the spective trials, using chemotherapy alone (e.g. HR for OS was 1.05 (95% CI 0.85–1.29). fluoropyrimidine), molecular-targeted agents only (e.g. antiangiogenics or EGFR inhibitors or AIO KRK 0207: maintenance bevacizumab as effi- both), or chemotherapy with targeted agents. cient as bevacizumab–fluoropyrimidine. The AIO KRK 0207 study investigated whether a complete In addition to maintenance therapy drugs, the main stop of treatment or maintenance with bevaci- differences between those trials are the induction zumab alone was noninferior to maintenance with therapy used (chemotherapy regimen, duration) fluoropyrimidine plus bevacizumab following and the post-progression strategy (reintroduction 4-month oxaliplatin-based induction therapy in of induction therapy, switch to second line). 852 patients with previously untreated mCRC [Hegewisch-Becker et al. 2014]. The primary end- point was time to failure of strategy (TFS), defined Single-agent maintenance as the time from randomization (starting mainte- Maintenance with fluoropyrimidine alone: the nance) to progression after oxaliplatin reintroduc- oxaliplatin stop-and-go strategy. The oxaliplatin tion. The median age of patients was 65 years. The stop-and-go strategy was validated in the OPTI- trial found bevacizumab maintenance until pro- MOX1 and OPTIMOX2 studies [Tournigand gression with or without fluoropyrimidine supe- et  al. 2006; Chibaudel et  al. 2009]. The optimal rior to stopping therapy in terms of PFS and TFS duration of induction therapy is 3 months (6 fort- (maintenance fluoropyrimidine plus bevacizumab, nightly cycles), corresponding to a cumulative HR = 2.05, HR = 1.27; maintenance with PFS TFS dose of oxaliplatin below or equal to 600 mg/m² bevacizumab alone, HR = 1.53, HR not PFS TFS which is a way to reach the maximal tumor reported). The results in both maintenance arms response without severe sensory neuropathy. The were similar, despite a trend for PFS superiority in oxaliplatin stop-and-go strategy has also shown the fluoropyrimidine plus bevacizumab arm the importance of reintroduction of induction (HR = 1.26, HR = 1.03). Finally, the OS PFS TFS 158 http://tam.sagepub.com B Chibaudel, C Tournigand et al. Table 1. PFS and OS in maintenance and TFI trials. Post-IT Strategy Trials Phase N IT mPFS PFS mOS OS Trial result strategy duration (months) Complete TFI after chemo COIN [Adams et al. III 815 3 - - - 14.4 TFI < stop alone 2011] continuous OPTIMOX2 IIR 104 3 - 6.6 - 19.5 TFI < FU [Chibaudel et al. 2009] TFI after CAIRO3 [Koopman III 279 4.5 4.1 - 18.2 - TFI < bev/FU chemo-bev et al. 2013] AIO KRK 0207 III 158 6 3.6 - 23.3 - TFI < bev = [Arnold et al. 2014] bev/FU SAKK 41/06 III 123 4-6 3.1* 8.5 - 22.8 TFI < bev [Koeberle et al. 2013] TFI after COIN-B [Wasan IIR 64 3 3.1 - - 16.8 TFI < cetux chemo-cetux** et al. 2014] Maint. 1 FU maint. after OPTIMOX1 III 309 3 - 8.7 - 21.2 FU = agent chemo alone [Tournigand et al. continuous 2006] OPTIMOX2 IIR 98 3 - 8.6 - 23.8 FU > TFI [Chibaudel et al. 2009] Bev maint. after TTD MACRO [Diaz- III 241 4.5 - 9.7 - 20.0 bev = chemo-bev Rubioet al. 2012] continuous AIO KRK 0207 III 156 6 4.6 - 22.6 - Bev > TFI [Arnold et al. 2014] SAKK 41/06 III 124 4-6 4.5* 9.5 - 24.9 Bev > TFI [Koeberle et al. 2013] DREAM [Chibaudel III 228 3-6 4.9 9.3 22.1 27.0 Bev < bev/ et al. 2014b] erlo ACT-1 [Johnsson III 79 4.5 4.2 - 22.8 - bev = bev/ et al. 2013] erlo Cetux maint. NORDIC VII [Tveit III 109 4 - 7.5 - 21.4 cetux = after chemo- et al. 2012] IIR 129 4 - 8.9 - 23.6 continuous cetux** MACRO-2 [Alfonso cetux < et al. 2014] continuous COIN-B [Wasan IIR 66 3 5.8 - - 22.2 cetux > TFI et al. 2014] Maint. 2 Bev/FU maint CAIRO3 [Koopman III 279 4.5 8.5 - 21.7 - bev/FU > TFI agents after chemo- et al. 2013] III 158 6 6.2 - 23.4 - bev/FU = bev AIO KRK 0207 bev [Arnold et al. 2014] Bev/ DREAM [Chibaudel III 224 3-6 5.9 10.0 24.9 30.0 bev/erlo > erlotinibmaint. et al. 2014b] III 80 4.5 5.7 - 21.5 - bev after chemo- ACT-1 [Johnsson bev/erlo = bev et al. 2013] bev *TTP; **KRAS wild-type population. Abbreviations: TTP, time to progression; PFS, progression-free survival; OS, overall survival; TFI, treatment-free interval; IT, induction therapy; m, median; chemo, chemotherapy; bev, bevacizumab; cetux, cetuximab; FU, fluoropyrimidine; erlo, erlotinib; maint., maintenance. from maintenance was similar in all three arms, reintroduction in the maintenance arm with fluo- ranging from 22.6 to 23.4 months (p = 0.870). Of ropyrimidine plus bevacizumab, compared with note, only 24% of patients received an oxaliplatin 47% of patients in the other arms. http://tam.sagepub.com 159 Therapeutic Advances in Medical Oncology 7(3) SAKK 41/06: maintenance bevacizumab better than OS did not differ significantly between the two treatment-free interval. The SAKK 41/06 phase III arms (HR = 0.87; p = 0.156). Of note, the oxali- trial investigated a complete stop of treatment rather platin reintroduction rate was 47% after mainte- than maintaining bevacizumab until progression fol- nance and 76% after TFI. lowing 4–6 months bevacizumab-based induction therapy [Koeberle et al. 2013]. The primary objective Maintenance with antiangiogenic agent and EGF was to demonstrate a noninferiority of treatment-free receptor agent. Of the 701 patients registered in interval (TFI) over maintenance in terms of time to the GERCOR DREAM phase III trial across three progression (TTP). The median TTP from random- countries (France, Canada, Austria), 452 were ization (i.e. starting maintenance or TFI) was 4.5 and randomized to receive a maintenance therapy with 3.2 months in the maintenance and TFI arms, bevacizumab (7.5 mg/kg, every 3 weeks) or bevaci- respectively (HR = 0.74). The noninferiority of TFI zumab (same dose) and erlotinib (150 mg/day in terms of TTP could not be statistically demon- continuously), an EGFR tyrosine kinase inhibitor strated. The median OS from starting induction ther- [Chibaudel et al. 2014b]. After a median follow up apy was 25.1 and 22.8 months in the maintenance of 50 months, the combination therapy led to an and TFI arms, respectively (HR = 0.83), without any improvement of maintenance PFS (primary end- statistical difference between the arms. point), maintenance OS, and RR. The mainte- nance PFS and OS were prolonged to 1 and 3 Maintenance with EGF receptor only. Maintenance months, respectively, for a maintenance treatment cetuximab alone after a cetuximab-based induc- duration lasting less than 4 months. This effect was tion therapy is equivalent to continuing chemo- observed whatever the KRAS mutational status therapy until progression or limiting toxicity and the subsequent therapy used. (NORDICVII, MACRO-2) [Tveit et  al. 2012; Alfonso et  al. 2014], but might be superior to a This activity was previously suggested in the neg- complete stop of therapy (COIN-B) [Wasan et al. ative ACT-1 study [Johnsson et  al. 2013] that 2014] Further randomized phase III studies are reported similar HR for maintenance PFS or OS. needed to evaluate the role of EGFR inhibitors The trial, however, was underpowered to demon- MoAbs as maintenance therapy. strate any statically significant benefit. Conclusions. Bevacizumab with or without low- Double agents maintenance dose capecitabine is the standard maintenance Maintenance with antiangiogenic agent and fluoro- therapy. However, the association of bevacizumab pyrimidine. In the AIO KRK 0207 study, mainte- with a short period of erlotinib can be considered nance therapy with bevacizumab and capecitabine as a new treatment option after a bevacizumab- prolonged PFS (HR = 2.05; p < 0.0001) but not based induction first-line therapy in patients with OS (HR = 0.94) over a complete stop of therapy unresectable mCRC. [Hegewisch-Becker et al. 2014]. However, there is no evidence of survival benefit over bevacizumab A maintenance therapy with cetuximab only is alone, both for PFS (HR = 1.26; p = 0.061) and still not recommended in routine practice. OS (HR = 0.92) In the CAIRO3 study, patients were randomly Therapy-free intervals assigned to receive either maintenance therapy with capecitabine–bevacizumab or a complete Complete stop after induction therapy without stop of treatment after a 4.5-month induction targeted agents therapy with XELOX–bevacizumab [Koopman The feasibility of a complete stop of chemother- et  al. 2013]. The primary endpoint was PFS2, apy was evaluated in the OPTIMOX2 and in the defined as the time interval from randomization COIN trials [Chibaudel et al. 2009; Adams et al. (i.e. starting maintenance or TFI) to progression 2011] (Table 1 and Figure 3). after reintroduction. Of the 635 patients treated with induction therapy, 558 (87%) were rand- In the OPTIMOX2 trial, patients were rand- omized. The median PFS1 was 8.5 and 4.1 omized to receive either FOLFOX induction months (HR = 0.44; p < 0.001), and the median therapy (3 months) followed by maintenance with PFS2 was 11.8 months and 10.5 months (HR = fluoropyrimidine alone or the same induction 0.81; p = 0.028) in favor of maintenance therapy. therapy followed by a TFI [Chibaudel et al. 2009]. 160 http://tam.sagepub.com B Chibaudel, C Tournigand et al. IT Treatmentsequenceafter IT Trials No. of agents afterIT ChemoTargeted Ox OPTIMOX2 COIN Complete stop afterchemo only FU Ox CAIRO3 SAKK 41/06 FU 00 Complete stop afterchemo+bev Treatment-free interval AIO KRK 0207 bev Ox FU COIN-B Complete stop afterchemo+cetux cetux Ox OPTIMOX1 10 Maint. FU alone OPTIMOX2 FU FU MACRO Ox DREAM FU ACT-1 0 1 Maint. bevafter chemo+bev Maint. single agent SAKK 41/06 bev bev AIO KRK 0207 Ox NORDICVII FU COIN-B Maint. cetuximabafterchemo+cetux MACRO-2 cetux cetux Ox CAIRO3 FU FU AIO KRK 0207 Maint. FU+bev afterchemo+bev bev bev Maint. twoagents Ox DREAM FU ACT-1 Maint. bev+erlotinibafterchemo+bev bev bev erlotinib Figure 3. Maintenance and treatment-free interval (TFI) trials with an oxaliplatin-based induction therapy. Abbreviations: IT, induction therapy; chemo, chemotherapy; ox, oxaliplatin, FU, fluoropyrimidine; bev, bevacizumab; cetux, cetuximab; maint., maintenance. OPTIMOX2 [Chibaudel et al. 2009]; COIN [Adams et al. 2011]; CAIRO3 [Koopman et al. 2013]; SAKK 41/06 [Koeberle et al. 2013]; AIO KRK 0207 [Arnold et al. 2014]; COIN-B [Wasan et al. 2014]; OPTIMOX1 [Tournigand et al. 2006]; DREAM [Chibaudel et al. 2014b]; ACT-1 [Johnsson et al. 2013]; NORDIC VII [Tveit et al. 2012]; MACRO-2 [Alfonso et al. 2014]; MACRO [Diaz-Rubio et al. 2012]. In the COIN trial, patients were randomized to in the intermittent group versus 52% in the main- receive either a continuous oxaliplatin-based tenance arm, and median failure-free survival was chemotherapy until progression or an oxaliplatin- 12.2 and 14.3 months, respectively. based induction therapy (3 months) followed by a TFI [Adams et al. 2011]. Conclusions TFI is inferior to continuous therapy until disease Complete stop after bevacizumab-based progression and to maintenance therapy (what- induction therapy ever the drug) in unselected mCRC patients. A TFI after a bevacizumab-based induction ther- However, a detrimental effect in the median OS of apy was investigated in the CAIRO3, the AIO more than 4 months has never yet been observed. KRK 0207, and the SAKK 41/06 trials (see Some patients could benefit of stopping therapy above) [Koopman et al., 2013; Arnold et al. 2014; using predictive factors for prolonged TFI dura- Koeberle et al. 2013]. tion: pre-TFI chemotherapy duration of at least 6 months without any disease progression (i.e. con- trolled disease) and with normal carcinoembry- Complete stop after cetuximab-based induction onic antigen level during induction therapy and therapy normal baseline platelet count (i.e. below 400,000/ COIN-B study was a randomized phase II trial in mm ) [Perez-Staub et al. 2008; Adams et al. 2011]. which patients with previously untreated mCRC were randomly assigned to receive either 3 months of induction FOLFOX-cetuximab therapy fol- Second-line therapy lowed by TFI or to the same induction treatment After progression on full first-line therapy, the followed by maintenance with cetuximab [Wasan standard practice is to change the chemotherapy et al. 2014]. FOLFOX reintroduction was recom- regimen from 5-FU/oxaliplatin to 5-FU/irinote- mended at progression in both arms. Ten-month can or the reverse sequence [Tournigand et  al. failure-free survival (primary endpoint) was 50% 2004]. http://tam.sagepub.com 161 Therapeutic Advances in Medical Oncology 7(3) Failure of a first-line bevacizumab-based formal hypothesis [Hecht et al. 2013]. A total of therapy 182 patients with KRAS wild-type mCRC were After failure of first-line therapy, the addition of randomized. Neither PFS (primary endpoint, an antiangiogenic agent to chemotherapy HR = 1.01) nor OS (HR = 1.06) seemed to be improved patient outcomes either in CRC different between the two arms. Both antiangio- patients previously treated with bevacizumab genics and anti-EGFR MoAbs in combination [Van Cutsem et  al. 2012; Bennouna et  al. 2013] with chemotherapy are reasonable second-line or in bevacizumab-naïve patients [Giantonio et al. therapeutic options in mCRC patients with RAS 2007; Van Cutsem et  al. 2012]. The TML phase wild-type tumors. Further phase III studies III study has shown that continuing bevacizumab comparing chemotherapy with either anti- beyond first progression and switching backbone EGFR MoAbs or antiangiogenics are needed in chemotherapy regimen improves PFS and OS order to define the best treatment sequence [Bennouna et al. 2013]. This treatment effect was after first-line in patients with wild-type RAS observed whatever KRAS mutational status. In mCRC. the VELOUR phase III study, patients were treated with FOLFIRI with either aflibercept or placebo [Van Cutsem et al. 2012]. All investigated Failure of first-line anti-EGFR MoAb-based patient outcomes (RR, PFS, and OS) were therapy improved over chemotherapy alone, whatever the After failure of first-line therapy containing an prior use of bevacizumab during first-line therapy. EGFR inhibitor agent, second-line chemotherapy This study led to the approval of ziv-aflibercept in should be associated with an antiangiogenic combination with FOLFIRI as second-line ther- agent, either FOLFOX-bevacizumab in the case apy. The RAISE phase III study compared ramu- of prior first-line irinotecan-based regimen cirumab plus FOLFIRI to placebo plus FOLFIRI [Giantonio et  al. 2007] or FOLFIRI-aflibercept as a second-line treatment in patients with mCRC in case of prior first-line oxaliplatin-based regi- after treatment with bevacizumab, oxaliplatin, men [Van Cutsem et al. 2012]. and fluoropyrimidine in the first-line setting. Ramucirumab is a VEGF Receptor 2 antagonist that specifically binds VEGF Receptor 2 and Subsequent lines of therapy blocks binding of VEGF receptor ligands Anti-EGFR MoAbs (cetuximab, panitumumab) VEGF-A, VEGF-C, and VEGF-D. The study increase survival over best supportive care after showed a statistically significant improvement in failure of standard chemotherapy [Jonker et  al. OS (primary endpoint) and PFS. The most com- 2007; Van Cutsem et al. 2007]. A synergy between mon severe toxicities increased when adding these drugs and irinotecan has been shown even ramucirumab to FOLFIRI were neutropenia, in patients refractory to irinotecan [Cunningham fatigue, hypertension, and diarrhea [Tabernero et al. 2004]. et al, 2015]. Regorafenib, a multikinase inhibitor was The addition of panitumumab to FOLFIRI was approved in US (FDA) and Europe [European superior to FOLFIRI alone in patients with Medicines Agency (EMA)] for patients with KRAS wild-type mCRC after failure of an oxali- mCRC refractory to all standard therapies with platin-based therapy in terms of PFS (primary the Eastern Cooperative Oncology Group endpoint, HR = 0.82; p = 0.023) and RR (36% (ECOG) performance status (PS) 0 or 1, based versus 10%; p < 0.001). The lack of OS superior- on the results of the CORRECT phase III study ity (HR = 0.92; p = 0.366) could be explained by [Grothey et  al. 2013]. An early stop in recruit- the 34% of patients who received the MoAb ment was decided after the results of a second EGFR inhibitor after progression in the FOLFIRI interim analysis, showing that OS (primary end- arm [Sobrero et al. 2012]. point) and PFS were improved with regorafenib versus placebo. Hazard ratios for death and pro- The SPIRITT randomized phase II study (study gression were 0.77 and 0.49, respectively. The 20060141) investigated the safety and efficacy main adverse events were asthenia (63%), hand- of FOLFIRI with either panitumumab or beva- and-foot syndrome (47%), and stomatitis (27%). cizumab as second-line therapy in patients pre- Heath-related quality-of-life was not improved. viously treated with an oxaliplatin-based There is no predictive biomarker for regorafenib first-line therapy with bevacizumab, without efficacy. 162 http://tam.sagepub.com B Chibaudel, C Tournigand et al. TAS-102 is a new oral antitumor agent combin- The Austrian PASSION study is a randomized phase ing trifluridine (FTD, active component) and tip- II study evaluating first-line XELIRI–bevacizumab fol- iracil hydrochloride (TPI, thymidine lowed by XELOX–bevacizumab or the reverse phosphorylase inhibitor), which prevents the deg- sequence [ClinicalT rials.gov identifier: NCT02119026; radation of FTD [Van Cutsem et al. 2014]. This Scheithauer, 2014]. The primary endpoint is DDC. drug has been evaluated in the RECOURSE The expected sample size is 120 patients with mCRC. phase III study against placebo in patients with heavily pretreated mCRC, in which TAS-102 pro- The GruppoItaliano per lo Studio dei Carcinomi longed OS (primary endpoint) from 5.3 to 7.1 dell’Apparato Digerente (GISCAD) COMETS is months (HR = 0.68) and PFS (HR = 0.48) a randomized phase III study comparing two differ- [Yoshino et  al. 2014]. The survival benefit was ent therapeutic sequences in patients with mCRC observed whatever prior use of regorafenib (17%) after failure of a first-line treatment with FOLFIRI- and was consistent in all prespecified subgroups, bevacizumab [ClinicalTrials.gov identifier: except for patients who received only two lines of NCT01030042l GruppoItaliano per lo studio dei therapy prior to study entry. Hematological (neu- Carcinomi dell’ Apparato Digerente (GISCAD), tropenia, anemia) and gastrointestinal (nausea, 2014]. Patients are randomized to receive either diarrhea) toxicities were the most frequent adverse second-line FOLFOX followed by cetuximab- events. The incidence of febrile neutropenia was irinotecan or the reverse sequence. The primary 3.8% with TAS-102. One toxic related death was endpoint is OS. The recruitment of 350 patients is observed with TAS-102. There was not HRQoL planned to be achieved in the second part of 2014. evaluation, but the time to ECOG PS deteriora- tion was prolonged with the use of TAS-102 (HR = 0.66). Those results are in line with previously Biomarker-driven trials published data from a randomized phase II study The FOCUS4 is a molecularly driven randomized conducted in Japanese patients [Yoshino et  al. study sponsored by Medical Research Council 2012]. A high expression of TK1 could be associ- (MRC) in United Kingdom for patients with ated with a higher sensitivity of tumor cells for mCRC (EudraCT 2012-005111-12) [Pugh, TAS-102. The main differences and similarities 2014]. A biomarker panel analysis [BRAF, KRAS, between regorafenib and TAS-102 are shown in NRAS, Phosphatase and tensin homolog (PTEN), Table 2. With similar efficacy results, those oral Phosphoinositide-3-kinase (PI3KCA), and drugs have two distinct safety profiles. Mismatch Repair (MMR)] will be performed dur- ing the first 16 weeks of induction therapy, then patients with controlled disease will be randomized Ongoing and future strategy trials according to five molecular subtypes: BRAF mutant, PI3KCA subtype (mutation of PI3KCA Multiline strategy gene or loss of PTEN protein), RAS mutant The GERCOR STRATEGIC-1 study [Clinical (KRAS or NRAS tumor gene mutation), ‘all wild- Trials.gov identifier: NCT01910610; Chibaudel type’ subtype (no mutation), and nonclassified et al. 2014a] is an open-label, randomized, multi- subtype. Each molecularly stratified trial aims to center phase III trial designed to determine an compare a novel intervention to placebo or stand- optimally personalized treatment sequence in ard care. The recruitment period is planned to be patients with unresectable RAS wild-type mCRC. 4–5 years followed by 2-year follow up. Two standard treatment strategies are being com- pared: FOLFIRI-cetuximab, followed by an The MODUL trial [Schmoll et al. 2014] is a bio- oxaliplatin-based chemotherapy with bevaci- marker-driven maintenance treatment rand- zumab (arm 1) and OPTIMOX–bevacizumab, omized study. All patients will receive 4 months of followed by an irinotecan-based chemotherapy induction therapy with FOLFOX–bevacizumab. with bevacizumab, and an anti-EGFR monoclo- Subsequently, patients with controlled disease nal antibody with or without irinotecan (arm 2). will be separated into two cohorts for mainte- The primary endpoint is duration of disease con- nance therapy according to BRAF mutational sta- trol (DDC) that is defined as the sum of PFS of tus. In cohort one, BRAF mutant patients will be each active sequence. Main secondary endpoints randomized to receive either fluoropyrimidine are OS and HRQoL. Recruitment started in with cetuximab and vemurafenib (BRAF TKI) or October 2013 and a total of 500 patients is fluoropyrimidine with bevacizumab. In cohort expected to be randomized. two, BRAF wild-type patients will be randomized http://tam.sagepub.com 163 Therapeutic Advances in Medical Oncology 7(3) Table 2. Differences and similarities between regorafenib and TAS-102 trials. Regorafenib TAS-102 Drug Pharmaceutical Bayer Taiho Mechanism of action Multi-TKI Antimetabolic Route Oral Oral Dose 160 mg daily, 3 weeks of each 35 mg/m² twice a day on days 1–5 4-week cycle and 8–12 every 4 weeks Study CORRECT RECOURSE Reference [Grothey et al. 2013] [Yoshino et al. 2014] Trial phase III III Primary objective (targeted HR) OS (0.70) OS (0.75) Randomization ratio 2:1 2:1 Comparator Placebo Placebo No of patients (investigational / 505 / 255 534 / 266 placebo) Recruitment Early stop for positive results Full Prior antiangiogenic agent 100% 100% Efficacy results OS, HR (absolute median 0.77 (+1.4) 0.68 (+1.8) difference) PFS, HR (absolute median 0.49 (+0.2) 0.48 (+0.3) difference) DCR, % (absolute difference) 41 (+26) 44 (+28) Safety profile Neutropenia, any grade (grade ¾) Not reported 67 (38) Anemia 7 (3) 76 (18) Nausea 14 (<1) 48 (2) Stomatitis 27 (3) 8 (<1) Diarrhea 34 (8) 32 (3) Hand-and-foot syndrome 47 17) 2 (0) Asthenia 63 (10) 35 (4) HRQoL No change Not done Predictive biomarkers None TK1-high expression? FDA/EMA approval Yes Not yet Abbreviations: TKI, tyrosine kinase inhibitor; RECOURSE, Refractory Colorectal Cancer Study; HR, hazard ratio; OS, over- all survival ; PFS, progression-free survival ; DCR, disease control rate; HRQoL, heath-related quality of life; FDA, Food and Drug Administration; EMA, European Medical Agency. to receive either fluoropyrimidine with bevaci- 5-FU with or without panitumumab in patients zumab or the same treatment with MPDL3280A with RAS wild-type MCRC [ClinicalTrials.gov (anti-PDL1 MoAb). The coprimary endpoints identifier: NCT01991873; Trarbach, 2014]. are tumor RR at 2 months and PFS. This study is based on an adaptive design with possibility to Immunomodulatory MGN1703 in Patients with drop treatment comparisons upon sufficient data Advanced Colorectal Carcinoma (IMPALA) is a availability for the efficacy/safety results, and the randomized open-label phase III study that is possibility of adding future promising compounds investigating the role of the immunotherapy into biomarker-driven maintenance phase. MGN 1703 (MOLOGEN AG) as maintenance therapy in patients with mCRC [ClinicalTrials. gov identifier: NCT02077868; Cunningham, Maintenance therapy 2014]. MGN1703 is a DNA-based TLR-9 ago- The AIO-KRK-0212 is a randomized phase II nist developed by MOLOGEN. This trial is study investigating maintenance therapy with designed to improve OS (primary endpoint) and 164 http://tam.sagepub.com B Chibaudel, C Tournigand et al. Antiangiogenic or EGFRi MoAb first in RAS WT MCRC? CALGB 80405 / AIO FIRE3 Antiangiogenic first EGFRiMoAbfirst Oxaliplatin- or irinotecan-based first ? Oxaliplatin- or irinotecan-based first ? GERCOR C97-3 GERCOR C97-3 FU/ox-bev FU/iri-bev FOLFOX-Pmab FOLFIRI-cetux Continuouslyor stop-and-go ? Continuously Continuously Continuously Line #1 AVF2107g PRIME CRYSTAL Continuously Stop-and-Go NO16966 GERCOR OPTIMOX Ox-reintroduction Single or double switch (chemo and/or biologic) ? Double switch (chemo and biologic) afterFU/ox-Pmabfirst-line Rx afterFU/iri-cetuxfirst-line Rx afterFU/ox-bev first-line Rx afterFU/iri-bev first-line Rx Single switch Double switch Single switch Single switch FOLFIRI-aflibercept FU/ox-bevacizumab Line #2 (chemo) (chemo and biologic) (chemo) (biologic) Continuously: VELOUR Continuously: E3200 FU/iri-bev: TML FOLFIRI-Pmab: 181 FU/ox-bev: TML FOLFIRI-Pmab: 181 FU/iri-aflibercept: VELOUR FU/iri-cetux: EPIC FU/iri-cetux: EPIC EGFRi+/- irinotecan Regorafenib Regorafenib FU/ox Line #3 cetux: BOND Continuously Continuously Pmab: 408 CORRECT CORRECT Regorafenib No standard Regorafenib No standard therapy Line #4 Continuously therapy Continuously CORRECT CORRECT Treatment strategy decision Treatment line changes Figure 4. Multiline therapeutic strategies in wild-type RAS metastatic colorectal cancer (mCRC): treatment decisions from first-line to salvage treatment. Abbreviations: chemo, chemotherapy; bev, bevacizumab; ox, oxaliplatin; cetux, cetuximab; iri, irinotecan; Pmab, panitumumab; FU, fluoropyrimidine, Rx, therapy. GERCOR C97-3 [Tournigand et al. 2004]; NO16966 [Saltz et al. 2008]; OPTIMOX1 [Tournigand et al. 2006]; OPTIMOX2 [Chibaudel et al. 2009]; AVF2107g [Hurwitz et al. 2004]; PRIME [Douillard et al. 2010]; CRYSTAL [Van Cutsem et al. 2009]; TML [Bennouna et al. 2013]; 181 [Peeters et al. 2010]; EPIC [Sobrero et al. 2008]; ECOG 3200 [Giantonio et al. 2007]; VELOUR [Van Cutsem et al. 2011]; BOND [Cunningham et al. 2004]; 408 [Van Cutsem et al. 2007]; CORRECT [Grothey et al. 2013]. requires 540 patients from more than 100 Conclusions European centers. Several drugs and combinations are now available for the treatment of patients with advanced CRC, Maintenance chemotherapy with low-dose met- but the optimal sequence of therapy remains ronomic regimen associating capecitabine, unknown (Figure 4). This is a step-by-step treat- celecoxib, and methotrexate will be evaluated in a ment decision level, from first-line with the choice prospective phase II study (HaEmek Medical of both biologic agent (antiangiogenic or EGFR) Center, Israel) in 80 mCRC patients having and chemotherapy regimen (oxaliplatin-based or received FOLFIRI-bevacizumab induction ther- irinotecan-based) to second and subsequent lines. apy [ClinicalTrials.gov identifier: NCT01668680; Starting first-line with bevacizumab and a dou- Loven, 2014]. The primary endpoint is PFS. blet of chemotherapy (either 5-FU/oxaliplatin or 5-FU/irinotecan) optimizes the availability of the The addition of ziv-aflibercept to the OPTIMOX number of lines with approved drugs. Moreover, strategy (oxaliplatin-based induction therapy fol- the use of maintenance therapy during first-line lowed maintenance therapy followed by oxaliplatin and at push therapy-free intervals in selected reintroduction) is being evaluated in the GERCOR patients can be used to limit severe toxicities and VELVET phase II study [ClinicalTrials.gov identi- drug resistance. Finally, reintroduction of oxalipl- fier: NCT01802684; Chibaudel, 2014]. The recruit- atin after progression during first-line is an impor- ment is closed and the results will available in 2015. tant prognostic factor for OS. Strategy trials are needed to better define an optimal treatment Other drugs are currently being investigated as sequence in a given population. maintenance first-line therapy: axitinib (TTD- 11-01) [ClinicalTrials.gov identifier: Molecular testing for KRAS and NRAS tumor NCT01483638; Grávalos and Carrato, 2014] genes (exons 2, 3, and 4) is mandatory but not and simvastatin [ClinicalTrials.gov identifier: sufficient to select appropriate patients for anti- NCT01238094; Kang, 2014]. EGFR MoAbs therapy (Figure 1B). An increase http://tam.sagepub.com 165 Therapeutic Advances in Medical Oncology 7(3) (FP) plus Bevacizumab (Bev), Bev alone, or no of selection level is critical to optimize treatment treatment, following a standard combination of FP, effect. Moreover, a period to acquire that informa- oxaliplatin (Ox), and Bev as first-line treatment for tion should also be shortened in order to give the patients with metastatic colorectal cancer (mCRC): best treatment from the diagnosis of advanced A phase III non-inferiority trial (AIO KRK 0207). disease. ASCO 2010. J Clin Oncol 28 Bennouna, J., Sastre, J., Arnold, D., Osterlund, P., Funding Greil, R., Van Cutsem, E. et al. (2013) Continuation This research received no specific grant from any of bevacizumab after first progression in metastatic funding agency in the public, commercial, or not- colorectal cancer (ML18147): a randomised phase 3 for-profit sectors. trial. Lancet Oncol 14: 29–37. Conflict of interest statement Chibaudel, B. (2014) OPTIMOX-aflibercept as first- line therapy in patients with unresectable metastatic BC has served as a consultant or in an advisory colorectal cancer (VELVET). http://clinicaltrials.gov/ role for Roche and Sanofi. CT has served as a ct2/show/NCT01802684 (accessed 16 October 2014). consultant or in an advisory role and received honoraria from Roche and Sanofi. FB has served Chibaudel, B., Maindrault-Goebel, F., Lledo, G., as a consultant or in an advisory role for Roche, Mineur, L., Andre, T., Bennamoun, M. et al. (2009) Nestlé, and Merck Serono, has received honoraria Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR from Roche, Nestlé, Bristol-Myers Squibb, and OPTIMOX2 Study. J Clin Oncol 27: 5727–5733. Merck Serono, and has received research funding from Roche. TA has served as a consultant or in Chibaudel, B., Tournigand, C., Bonnetain, F., Hug an advisory role for Amgen, Merck Serono, and de Larauze, M., de Gramont, A., Laurent-Puig, P. Roche, and has received honoraria from Amgen, et al. (2014a) STRATEGIC1-multi-line therapy trial Merck Serono, and Roche. AdG has served as a in unresectable wild-type RAS metastatic colorectal cancer: A GERCOR randomized open-label phase III consultant or in an advisory role for Roche, study. ASCO 2014, Abstract TPS3648. Sanofi, and PharmaEngine and received hono- raria from Roche. MB and HR have no conflicts Chibaudel, B., Tournigand, C., Bonnetain, F., of interest to declare. Maindrault-Goebel, F., Lledo, G., Andre, T. et al. (2013) Platinum-sensitivity in metastatic colorectal cancer: towards a definition. Eur J Cancer 49: 3813–3820. Chibaudel, B., Tournigand, C., Samson, B., References Scheithauer, W., Mesange, P., Lledo, G. et al. Adams, R., Meade, A., Seymour, M., Wilson, R., (2014b) Bevacizumab-erlotinib as maintenance Madi, A., Fisher, D. et al. (2011) Intermittent therapy in metastatic colorectal cancer. Final results of versus continuous oxaliplatin and fluoropyrimidine the GERCOR DREAM study. ESMO 2014, Abstract combination chemotherapy for first-line treatment of 497O. 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Therapeutic strategy in unresectable metastatic colorectal cancer: an updated review:

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572343 TAM0010.1177/1758834015572343Therapeutic Advances in Medical OncologyB Chibaudel, C Tournigand research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Therapeutic strategy in unresectable 2015, Vol. 7(3) 153 –169 DOI: 10.1177/ metastatic colorectal cancer: an updated © The Author(s), 2015. Reprints and permissions: review http://www.sagepub.co.uk/ journalsPermissions.nav Benoist Chibaudel, Christophe Tournigand, Franck Bonnetain, Hubert Richa, Magdalena Benetkiewicz, Thierry André and Aimery de Gramont Abstract: Systemic therapy is the standard care for patients with unresectable advanced colorectal cancer (CRC), but salvage surgery of metastatic disease should be considered in the case of adequate tumor shrinkage. Several drugs and combinations are now available for use in treating patients with advanced CRC, but the optimal sequence of therapy remains unknown. Moreover, the administration of antitumor therapy can be modulated by periods Correspondence to: of maintenance or treatment breaks rather than delivered as full therapy until disease Benoist Chibaudel, MD Department of Medical progression or unacceptable toxicity, followed by reintroduction of prior full therapy when Oncology, Institut required, before switching to other drugs. Consequently, randomized strategy trials are Hospitalier Franco- Britannique, 4, rue Kléber, needed to define the optimal treatment sequences. Molecular testing for Kirsten rat sarcoma 92300, Levallois-Perret, viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) France benoist.chibaudel@ihfb. is mandatory but not sufficient to select appropriate patients for epidermal growth factor org receptor (EGFR) monoclonal antibody (MoAb) therapy. Christophe Tournigand, MD Hôpitaux de Paris, Créteil, France Franck Bonnetain, MD Keywords: chemotherapy, colorectal cancer, maintenance, molecular targeted agents, Methodology and strategy, treatment biostatistics Unit, Hôpital Besançon, Besançon, France Hubert Richa, MD Department of Surgery, Institut Hospitalier Franco-Britannique, Levallois-Perret, France Introduction oncologists, gastroenterologists, and radiologists. Magdalena Benetkiewicz, The theoretical definition of potentially resecta- PhD Colorectal cancer ble tumors and patient classification has been GERCOR, Groupe Coopérateur Colorectal cancer (CRC) is the third most com- proposed, but mainly depends on the experience Multidisciplinaire en mon cancer in men and the second most common of each individual surgeon [Adams et al. 2013]. In Oncologie, Paris, France and Fondation ARCAD, cancer in women worldwide but with a geograph- the case of initially unresectable disease, systemic Aide et Recherche en ical variation in incidence and mortality. The therapy is the standard care, but the evaluation Cancérologie Digestive, Paris, France highest mortality rates present in both sexes in for conversion to resectable disease should be Thierry André, MD Central and Eastern Europe [Globocan, 2012]. considered at each tumor assessment. Department of Medical Metastatic disease can occur at the same time as Oncology, Hôpital Saint- Antoine, Assistance the diagnosis of primary tumor (synchronous Publique – Hôpitaux de metastatic disease) or subsequently (metachro- Tumor biology Paris, Paris, France and INSERM U938, Hôpital nous metastatic disease) after surgery of primary Half of the patients with advanced CRC harbor a Saint-Antoine, Paris, tumor followed or not by adjuvant chemotherapy. Kirsten rat sarcoma viral oncogene homolog France The prognosis of patients with metachronous dis- (KRAS) or neuroblastoma N-Ras (NRAS) tumor Aimery de Gramont, MD Department of ease is usually more favorable. gene mutation, which is a negative predictive bio- Medical Oncology, marker for anti-epidermal growth factor receptor Institut Hospitalier Franco-Britannique, Resectability of the metastatic disease should be (EGFR) monoclonal antibodies (MoAbs) therapy Levallois-Perret, assessed at the time of first diagnosis of involve- in these patients [Lièvre et  al. 2006]. Thus, only France and GERCOR, Groupe Coopérateur ment of one or several metastatic sites in a multi- patients with RAS wild-type metastatic CRC Multidisciplinaire en disciplinary approach with surgeons, medical (mCRC) are eligible for MoAbs EGFR inhibitors Oncologie, Paris, France http://tam.sagepub.com 153 Therapeutic Advances in Medical Oncology 7(3) RAS/RAF wild-type KRAS exon 2 (40%) (40%) KRAS exon 3-4 BRAF exon 15 NRAS exon 2-3-4 (10%) (10%) Major effect of EGFRi (21%) Uncertain or minimal effect of EGFRi (11%) RAS mutant (50%) Mutant « like» (17.5%) Figure 1. Colon cancer biology: focus on epidermal growth factor (EGF) pathway and sensitivity to epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs). (A) Frequency of KRAS, NRAS, and BRAF tumor genes mutations in patients with advanced colorectal cancer (CRC). (B) Role of tumor biology for the estimated sensitivity to EGFR MoAbs in metastatic CRC. therapy. When adding patients with serine/threo- was associated with a near-doubling median sur- nine-protein kinase B-Raf (BRAF) mutant vival, which surpassed 2 years with the addition of tumors (10%), the RAS/RAF mutant population molecular-targeted agents. Vascular endothelial represents 60% of previously untreated mCRC growth factor (VEGF) inhibition with MoAbs patients (Figure 1A). increased survival in combination with chemo- therapy in first- or second-line treatment of patients with mCRC. Anti-EGFR MoAbs (i.e. Drugs cetuximab, panitumumab) also improved patient Until the 2000s, 5-fluorouracil (5-FU) was the outcomes, but only in the absence of RAS tumor only approved drug for the treatment of advanced gene mutations. More recently, regorafenib, an CRC, which administration was producing orally active inhibitor of angiogenic, stromal and median overall survival (OS) of less than 1 year. oncogenic kinases, improved survival in heavily Other orally active 5-FU prodrugs (capecitabine, pretreated CRC patients. But the optimal strategy tegafur-uracil, S1) are also available. Patient out- or the best way to combine and sequence all of comes were improved with the use of irinotecan, these drugs available in routine practice has not an inhibitor of topoisomerase I, and oxaliplatin, yet been established. which were approved by the United States (US) Food and Drug Administration (FDA) in 1998 In the case of initially unresectable metastatic and 2002, respectively. The combination of fluo- disease, the association of chemotherapy (single- ropyrimidine with either irinotecan or oxaliplatin agent to three-drug regimen) and a molecular 154 http://tam.sagepub.com B Chibaudel, C Tournigand et al. targeted agent, either antiangiogenic (i.e. bevaci- irinotecan/oxaliplatin), followed by maintenance zumab) or EGFR inhibitor monoclonal antibody therapy with fluoropyrimidine-bevacizumab (cetuximab, panitumumab), is the standard prac- [Loupakis et al. 2014]. The addition of oxaliplatin tice for first-line therapy. Of note, the combina- to FOLFIRI-bevacizumab significantly increased tion of chemotherapy with both the EGFR and PFS (primary endpoint) from 9.7 to 12.1 months VEGF MoAbs inhibitors led to adverse outcomes (HR = 0.75; p = 0.003) and RR from 53% to in two large randomized phase III trials (PACCE, 65% (p = 0.006), but neither R0 salvage surgery CAIRO2) [Hecht et al. 2009; Tol et al. 2009]. rate (12% versus 15%, p = 0.33) nor OS were improved (HR = 0.79; p = 0.054). First-line therapy Fluoropyrimidine-bevacizumab in elderly patients. The international Australasian Gastro- Chemotherapy with antiangiogenic drugs intestinal Trials Group (AGITG) MAX study In the first-line setting, bevacizumab can be com- [Tebbutt et  al. 2010] randomized 471 patients bined with an oxaliplatin-based (NO16966) with unresectable mCRC considered suitable for [Saltz et  al. 2008], an irinotecan-based initial monotherapy. Patients received low-inten- (AVF2107g) [Hurwitz and Kabbinavar, 2005] sity chemotherapy including capecitabine alone, chemotherapy doublet, chemotherapy triplet capecitabine plus bevacizumab, or capecitabine- (GONO TRIBE) [Loupakis et al. 2014], or even mitomycin C plus bevacizumab. The median age with fluoropyrimidine monochemotherapy of patients was 68 years. After a median follow up (MAX, AVF2192, AVEX) [Tebbutt et  al. 2010; of 31 months, median PFS (primary endpoint) Kabbinavar et al. 2005; Cunningham et al. 2013] was improved from 5.7 months in the capecitabine group to 8.5 months in the capecitabine–bevaci- Irinotecan-based chemotherapy with bevaci- zumab group (HR = 0.63, p < 0.001). Median zumab. In the AVF2107g study, the addition of survival was not statistically different between bevacizumab to an irinotecan-based chemother- these patients (18.9 months in both groups). The apy resulted in statistically significant improve- triplet combination arm was not superior to the ment in OS (primary endpoint) among 813 capecitabine–bevacizumab doublet arm neither patients with previously untreated mCRC [haz- for PFS nor OS. The MAX study results were ard ratio (HR) = 0.66; p < 0.001] [Hurwitz consistent with an earlier phase II study OS et al. 2004]. Secondary endpoints of progression- (AVF2192) performed in patients over the age of free survival (PFS; HR = 0.54) and response 65 years and considered unfit for first-line irinote- PFS rate (RR) were also improved. can [Kabbinavar et al. 2005]. Oxaliplatin-based chemotherapy with bevaci- AVEX. In the AVEX randomized phase III trial, zumab. The NO16966 study included 1401 280 patients with previously untreated, unre- patients with previously untreated mCRC with a sectable mCRC, and not eligible to oxaliplatin- median age of 60 years [Saltz et  al. 2008]. The based or irinotecan-based chemotherapy addition of bevacizumab to either FOLFOX regimens were randomly assigned to receive the (leucovorin/5-FU/oxaliplatin regimen) or XELOX bevacizumab–capecitabine combination or (capecitabine plus oxaliplatin regimen) led to a capecitabine only [Cunningham et  al. 2013]. 17% improvement of PFS (primary endpoint, The median age of patients was 76 years. PFS HR = 0.83; p = 0.0023). This benefit was higher (primary endpoint) was significantly longer with when censoring patients at the time of drug dis- bevacizumab and capecitabine than with continuation (‘on-treatment PFS’, HR = 0.63). capecitabine alone (9.1 versus 5.1 months, Unlike other trials, RR was similar with or without HR = 0.53; p < 0.0001). Thus, the combination bevacizumab. of bevacizumab and fluoropyrimidine can be considered as the treatment of choice in elderly Triplet chemotherapy (irinotecan- and oxaliplatin- patients with mCRC. based) with bevacizumab. In the GONO TRIBE study, 508 patients with unresectable mCRC Chemotherapy with anti-EGFR MoAbs. Anti- were randomized to receive 6 months of bevaci- EGFR MoAbs can be combined with a doublet of zumab-based induction therapy with either FOL- chemotherapy that is either FOLFOX (PRIME) FIRI (regimen of leucovorin/5-FU/irinotecan) or [Douillard et  al. 2010, 2014a] or FOLFIRI FOLFOXIRI (regimen of leucovorin/5-FU/ (CRYSTAL) [Van Cutsem et al. 2009, 2011]. http://tam.sagepub.com 155 Therapeutic Advances in Medical Oncology 7(3) Anti-EGFR MoAbs with an oxaliplatin-based che- German or Austrian centers [Heinemann et  al. motherapy. The addition of panitumumab to 2014]. The RR (primary endpoint) and PFS were FOLFOX has been evaluated in the PRIME similar in the two treatment arms. Unexpectedly, study [Douillard et al. 2010, 2014a]. The primary a prolongation of OS (secondary endpoint), was endpoint was PFS. In the ‘all RAS wild-type’ pop- observed in favor of the cetuximab arm from 25.0 ulation (N = 512), which represented 43% of the to 28.7 months, corresponding to a HR of 0.77. randomized population (N = 1183), the median In an exploratory analysis of RAS wild-type PFS and OS were significantly higher (HR = patients excluding 42% of the primary population PFS 0.70; p = 0.004 and HR = 0.78; p = 0.04) in (N = 342), there was still no difference in PFS OS the combination arm [Douillard et al. 2013]. (HR = 0.97; p = 0.770), but the benefit in OS was amplified with an absolute difference in The addition of cetuximab to an oxaliplatin-based median OS of 8.1 months (from 25.0 to 33.1 chemotherapy was evaluated in two randomized months, HR = 0.70; p = 0.006). This unexpected phase III studies [Maughan et al. 2011; Tveit et al. discrepancy between an OS advantage without 2012]. In both studies, the addition of cetuximab any benefit during treatment period could be led to a detrimental effect on survival, whatever partly explained by a high number of active cen- KRAS mutational status. Of note, the chemother- ters and the absence of predefined post-protocol apy regimen used was either FOLFOX or XELOX treatment, leading to significant heterogeneity of in the COIN study [Maughan et  al. 2011], and post-progression therapy. Graphically, the OS FLOX (leucovorin/5-FU bolus/oxaliplatin regi- Kaplan–Meier curves appear similar in 25% of men) in the NORDICVII study [Tveit et al. 2012]. patients, widely different in favor of cetuximab in 55% of patients, and slightly different in 20% in Anti-EGFR MoAbs with an irinotecan-based chemo- favor of cetuximab (Figure 2A). therapy. FOLFIRI in combination with cetuximab is a standard first-line regimen for patients with First-line oxaliplatin- or irinotecan-based ther- RAS wild-type tumors, based on a retrospective apy. The CALGB/SWOG 80405 study random- analysis of the prospective CRYSTAL study limited ized patients with mCRC to receive chemotherapy to patients with KRAS exon 2 wild-type tumors and with cetuximab, or bevacizumab, or both agents including 89% of the overall population [Van Cut- [Lenz et  al. 2014]. The chemotherapy regimen sem et al. 2011]. This combination yielded positive (FOLFIRI or mFOLFOX6) was selected by phy- results in terms of RR (overall response (OR) = sician. The main changes during the study 2.07; p < 0.001), PFS (HR = 0.70; p = 0.001), and included discontinuation of the study arm com- OS (HR = 0.80; p = 0.009) in favor of cetuximab bining both targeted-MoAbs agents after the containing arm [Van Cutsem et al. 2009, 2011]. results of the PACCE and CAIRO2 trials [Hecht et al. 2009; Tol et al. 2009], and the limitation of Conclusions. Overall, if the preferred targeted eligibility to patients with KRAS exon 2 wild-type agent is an anti-EGFR MoAb in first-line treat- tumors. Of 1137 patients with KRAS exon 2 ment of patients with RAS wild-type mCRC, two wild-type tumors, 526 (46.3%) were analyzed in combinations can be recommended: either an expanded RAS wild-type population (KRAS FOLFOX–panitumumab or FOLFIRI–cetux- and NRAS exons 2, 3, and 4). No significant dif- imab until progression or limiting toxicity. The ference was observed between the cetuximab combination of oral fluoropyrimidine (capecitabine (N = 270) and the bevacizumab arms (N = 256) or UFT) to oxaliplatin and cetuximab should defi- in combination with chemotherapy, both for OS nitely not be used [Maughan et  al. 2011; Douil- (32.0 versus 31.2 months, HR 0.90; p = 0.40) and lard et al. 2014b]. PFS (11.3 versus 11.4 months, HR = 1.10; p = 0.310). However, there was higher RR achieved in the cetuximab arm in the expanded Dilemma for treatment-naïve mCRC patients: RAS population than in the bevacizumab arm choice between antiangiogenics and anti-EGFR (68.6% versus 53.6%, p < 0.01). Graphically, the agents, two options OS Kaplan–Meier curves appear similar in 45% First-line irinotecan-based therapy. In the AIO of patients, widely different in favor of cetuximab FIRE-3 randomized study, 592 patients with in 30% of patients, and slightly different in 25% KRAS exon 2 wild-type mCRC were treated with of patients (10% in favor of cetuximab and 15% FOLFIRI in combination with either cetuximab in favor of bevacizumab) (Figure 2B). Subgroup (N = 297) or bevacizumab (N = 295) in 150 analysis of patients treated with FOLFIRI did not 156 http://tam.sagepub.com B Chibaudel, C Tournigand et al. Figure 2. Proportion of patients (%) with graphical overall survival (OS) superiority (green), uncertain difference (orange) and absence of superiority (red) of cetuximab over bevacizumab in the AIO FIRE-3 study (A), in the CALGB/SWOG 80405 study (B), and estimation (mean) from both (C). http://tam.sagepub.com 157 Therapeutic Advances in Medical Oncology 7(3) confirm the results of the AIO FIRE-3 study. Nei- therapy for improving survival [de Gramont et al. ther PFS (HR = 1.10) nor OS (HR = 1.10) was 2007]. The sensitivity to oxaliplatin reintroduc- different between the cetuximab and the bevaci- tion increases with the duration of oxaliplatin-free zumab arms when combined with FOLFIRI. interval [Chibaudel et al. 2013]. Based on a graphical analysis of both CALGB/ Maintenance with antiangiogenic agent only. Main- SWOG 80405 and AIO FIRE-3 studies, the supe- tenance with bevacizumab alone after a bevaci- riority of the MoAbs EGFR inhibitors over beva- zumab-based induction therapy is equivalent to cizumab can be considered as probably maintenance with bevacizumab-fluoropyrimidine unquestionable in 20% of all patients with previ- (AIO KRK 0207) [Hegewisch-Becker et al. 2014] ously untreated mCRC (40% of actual definition or continuous therapy (TTD MACRO) [Diaz- of ‘all RAS wild-type’ patients), and roughly 70% Rubio et al. 2012], but is superior to a complete may not have any benefit of adding anti-EGFR stop of therapy (AIO KRK 0207, SAKK 41/06) MoAbs to chemotherapy. An uncertain or limited [Hegewisch-Becker et  al. 2014; Koeberle et  al. effect of anti-EGFR therapy is observed in further 2013]. 10% of patients (Figures 1B and 2C). MACRO: maintenance bevacizumab as efficient as continuous therapy. In the TTD MACRO trial, Maintenance therapy the bevacizumab maintenance therapy was initi- The aim of maintenance therapy (Table 1 and ated after an induction therapy with XELOX–bev- Figure 3) is to decrease the frequency and severity acizumab, and compared with the continuation of of adverse events induced by antitumor therapy, this regimen until progression or severe toxicity to improve health-related quality of life (HRQoL) [Diaz-Rubio et  al. 2012]. The primary endpoint while maintaining as long as possible the effects was PFS. This trial could not formally conclude to achieved with induction therapy, leading to lower a statistical noninferiority of the maintenance arm treatments costs and decreased rates of drug over the continuous arm, but the absolute differ- resistance by stopping one or more drugs before ence in median PFS was only 0.7 months (9.7 disease progression. versus 10.4 months) and the HR for the observed PFS difference between the two arms was 1.10 [95% Several modalities have been evaluated in pro- confidence interval (CI) 0.89–1.35]. Of note, the spective trials, using chemotherapy alone (e.g. HR for OS was 1.05 (95% CI 0.85–1.29). fluoropyrimidine), molecular-targeted agents only (e.g. antiangiogenics or EGFR inhibitors or AIO KRK 0207: maintenance bevacizumab as effi- both), or chemotherapy with targeted agents. cient as bevacizumab–fluoropyrimidine. The AIO KRK 0207 study investigated whether a complete In addition to maintenance therapy drugs, the main stop of treatment or maintenance with bevaci- differences between those trials are the induction zumab alone was noninferior to maintenance with therapy used (chemotherapy regimen, duration) fluoropyrimidine plus bevacizumab following and the post-progression strategy (reintroduction 4-month oxaliplatin-based induction therapy in of induction therapy, switch to second line). 852 patients with previously untreated mCRC [Hegewisch-Becker et al. 2014]. The primary end- point was time to failure of strategy (TFS), defined Single-agent maintenance as the time from randomization (starting mainte- Maintenance with fluoropyrimidine alone: the nance) to progression after oxaliplatin reintroduc- oxaliplatin stop-and-go strategy. The oxaliplatin tion. The median age of patients was 65 years. The stop-and-go strategy was validated in the OPTI- trial found bevacizumab maintenance until pro- MOX1 and OPTIMOX2 studies [Tournigand gression with or without fluoropyrimidine supe- et  al. 2006; Chibaudel et  al. 2009]. The optimal rior to stopping therapy in terms of PFS and TFS duration of induction therapy is 3 months (6 fort- (maintenance fluoropyrimidine plus bevacizumab, nightly cycles), corresponding to a cumulative HR = 2.05, HR = 1.27; maintenance with PFS TFS dose of oxaliplatin below or equal to 600 mg/m² bevacizumab alone, HR = 1.53, HR not PFS TFS which is a way to reach the maximal tumor reported). The results in both maintenance arms response without severe sensory neuropathy. The were similar, despite a trend for PFS superiority in oxaliplatin stop-and-go strategy has also shown the fluoropyrimidine plus bevacizumab arm the importance of reintroduction of induction (HR = 1.26, HR = 1.03). Finally, the OS PFS TFS 158 http://tam.sagepub.com B Chibaudel, C Tournigand et al. Table 1. PFS and OS in maintenance and TFI trials. Post-IT Strategy Trials Phase N IT mPFS PFS mOS OS Trial result strategy duration (months) Complete TFI after chemo COIN [Adams et al. III 815 3 - - - 14.4 TFI < stop alone 2011] continuous OPTIMOX2 IIR 104 3 - 6.6 - 19.5 TFI < FU [Chibaudel et al. 2009] TFI after CAIRO3 [Koopman III 279 4.5 4.1 - 18.2 - TFI < bev/FU chemo-bev et al. 2013] AIO KRK 0207 III 158 6 3.6 - 23.3 - TFI < bev = [Arnold et al. 2014] bev/FU SAKK 41/06 III 123 4-6 3.1* 8.5 - 22.8 TFI < bev [Koeberle et al. 2013] TFI after COIN-B [Wasan IIR 64 3 3.1 - - 16.8 TFI < cetux chemo-cetux** et al. 2014] Maint. 1 FU maint. after OPTIMOX1 III 309 3 - 8.7 - 21.2 FU = agent chemo alone [Tournigand et al. continuous 2006] OPTIMOX2 IIR 98 3 - 8.6 - 23.8 FU > TFI [Chibaudel et al. 2009] Bev maint. after TTD MACRO [Diaz- III 241 4.5 - 9.7 - 20.0 bev = chemo-bev Rubioet al. 2012] continuous AIO KRK 0207 III 156 6 4.6 - 22.6 - Bev > TFI [Arnold et al. 2014] SAKK 41/06 III 124 4-6 4.5* 9.5 - 24.9 Bev > TFI [Koeberle et al. 2013] DREAM [Chibaudel III 228 3-6 4.9 9.3 22.1 27.0 Bev < bev/ et al. 2014b] erlo ACT-1 [Johnsson III 79 4.5 4.2 - 22.8 - bev = bev/ et al. 2013] erlo Cetux maint. NORDIC VII [Tveit III 109 4 - 7.5 - 21.4 cetux = after chemo- et al. 2012] IIR 129 4 - 8.9 - 23.6 continuous cetux** MACRO-2 [Alfonso cetux < et al. 2014] continuous COIN-B [Wasan IIR 66 3 5.8 - - 22.2 cetux > TFI et al. 2014] Maint. 2 Bev/FU maint CAIRO3 [Koopman III 279 4.5 8.5 - 21.7 - bev/FU > TFI agents after chemo- et al. 2013] III 158 6 6.2 - 23.4 - bev/FU = bev AIO KRK 0207 bev [Arnold et al. 2014] Bev/ DREAM [Chibaudel III 224 3-6 5.9 10.0 24.9 30.0 bev/erlo > erlotinibmaint. et al. 2014b] III 80 4.5 5.7 - 21.5 - bev after chemo- ACT-1 [Johnsson bev/erlo = bev et al. 2013] bev *TTP; **KRAS wild-type population. Abbreviations: TTP, time to progression; PFS, progression-free survival; OS, overall survival; TFI, treatment-free interval; IT, induction therapy; m, median; chemo, chemotherapy; bev, bevacizumab; cetux, cetuximab; FU, fluoropyrimidine; erlo, erlotinib; maint., maintenance. from maintenance was similar in all three arms, reintroduction in the maintenance arm with fluo- ranging from 22.6 to 23.4 months (p = 0.870). Of ropyrimidine plus bevacizumab, compared with note, only 24% of patients received an oxaliplatin 47% of patients in the other arms. http://tam.sagepub.com 159 Therapeutic Advances in Medical Oncology 7(3) SAKK 41/06: maintenance bevacizumab better than OS did not differ significantly between the two treatment-free interval. The SAKK 41/06 phase III arms (HR = 0.87; p = 0.156). Of note, the oxali- trial investigated a complete stop of treatment rather platin reintroduction rate was 47% after mainte- than maintaining bevacizumab until progression fol- nance and 76% after TFI. lowing 4–6 months bevacizumab-based induction therapy [Koeberle et al. 2013]. The primary objective Maintenance with antiangiogenic agent and EGF was to demonstrate a noninferiority of treatment-free receptor agent. Of the 701 patients registered in interval (TFI) over maintenance in terms of time to the GERCOR DREAM phase III trial across three progression (TTP). The median TTP from random- countries (France, Canada, Austria), 452 were ization (i.e. starting maintenance or TFI) was 4.5 and randomized to receive a maintenance therapy with 3.2 months in the maintenance and TFI arms, bevacizumab (7.5 mg/kg, every 3 weeks) or bevaci- respectively (HR = 0.74). The noninferiority of TFI zumab (same dose) and erlotinib (150 mg/day in terms of TTP could not be statistically demon- continuously), an EGFR tyrosine kinase inhibitor strated. The median OS from starting induction ther- [Chibaudel et al. 2014b]. After a median follow up apy was 25.1 and 22.8 months in the maintenance of 50 months, the combination therapy led to an and TFI arms, respectively (HR = 0.83), without any improvement of maintenance PFS (primary end- statistical difference between the arms. point), maintenance OS, and RR. The mainte- nance PFS and OS were prolonged to 1 and 3 Maintenance with EGF receptor only. Maintenance months, respectively, for a maintenance treatment cetuximab alone after a cetuximab-based induc- duration lasting less than 4 months. This effect was tion therapy is equivalent to continuing chemo- observed whatever the KRAS mutational status therapy until progression or limiting toxicity and the subsequent therapy used. (NORDICVII, MACRO-2) [Tveit et  al. 2012; Alfonso et  al. 2014], but might be superior to a This activity was previously suggested in the neg- complete stop of therapy (COIN-B) [Wasan et al. ative ACT-1 study [Johnsson et  al. 2013] that 2014] Further randomized phase III studies are reported similar HR for maintenance PFS or OS. needed to evaluate the role of EGFR inhibitors The trial, however, was underpowered to demon- MoAbs as maintenance therapy. strate any statically significant benefit. Conclusions. Bevacizumab with or without low- Double agents maintenance dose capecitabine is the standard maintenance Maintenance with antiangiogenic agent and fluoro- therapy. However, the association of bevacizumab pyrimidine. In the AIO KRK 0207 study, mainte- with a short period of erlotinib can be considered nance therapy with bevacizumab and capecitabine as a new treatment option after a bevacizumab- prolonged PFS (HR = 2.05; p < 0.0001) but not based induction first-line therapy in patients with OS (HR = 0.94) over a complete stop of therapy unresectable mCRC. [Hegewisch-Becker et al. 2014]. However, there is no evidence of survival benefit over bevacizumab A maintenance therapy with cetuximab only is alone, both for PFS (HR = 1.26; p = 0.061) and still not recommended in routine practice. OS (HR = 0.92) In the CAIRO3 study, patients were randomly Therapy-free intervals assigned to receive either maintenance therapy with capecitabine–bevacizumab or a complete Complete stop after induction therapy without stop of treatment after a 4.5-month induction targeted agents therapy with XELOX–bevacizumab [Koopman The feasibility of a complete stop of chemother- et  al. 2013]. The primary endpoint was PFS2, apy was evaluated in the OPTIMOX2 and in the defined as the time interval from randomization COIN trials [Chibaudel et al. 2009; Adams et al. (i.e. starting maintenance or TFI) to progression 2011] (Table 1 and Figure 3). after reintroduction. Of the 635 patients treated with induction therapy, 558 (87%) were rand- In the OPTIMOX2 trial, patients were rand- omized. The median PFS1 was 8.5 and 4.1 omized to receive either FOLFOX induction months (HR = 0.44; p < 0.001), and the median therapy (3 months) followed by maintenance with PFS2 was 11.8 months and 10.5 months (HR = fluoropyrimidine alone or the same induction 0.81; p = 0.028) in favor of maintenance therapy. therapy followed by a TFI [Chibaudel et al. 2009]. 160 http://tam.sagepub.com B Chibaudel, C Tournigand et al. IT Treatmentsequenceafter IT Trials No. of agents afterIT ChemoTargeted Ox OPTIMOX2 COIN Complete stop afterchemo only FU Ox CAIRO3 SAKK 41/06 FU 00 Complete stop afterchemo+bev Treatment-free interval AIO KRK 0207 bev Ox FU COIN-B Complete stop afterchemo+cetux cetux Ox OPTIMOX1 10 Maint. FU alone OPTIMOX2 FU FU MACRO Ox DREAM FU ACT-1 0 1 Maint. bevafter chemo+bev Maint. single agent SAKK 41/06 bev bev AIO KRK 0207 Ox NORDICVII FU COIN-B Maint. cetuximabafterchemo+cetux MACRO-2 cetux cetux Ox CAIRO3 FU FU AIO KRK 0207 Maint. FU+bev afterchemo+bev bev bev Maint. twoagents Ox DREAM FU ACT-1 Maint. bev+erlotinibafterchemo+bev bev bev erlotinib Figure 3. Maintenance and treatment-free interval (TFI) trials with an oxaliplatin-based induction therapy. Abbreviations: IT, induction therapy; chemo, chemotherapy; ox, oxaliplatin, FU, fluoropyrimidine; bev, bevacizumab; cetux, cetuximab; maint., maintenance. OPTIMOX2 [Chibaudel et al. 2009]; COIN [Adams et al. 2011]; CAIRO3 [Koopman et al. 2013]; SAKK 41/06 [Koeberle et al. 2013]; AIO KRK 0207 [Arnold et al. 2014]; COIN-B [Wasan et al. 2014]; OPTIMOX1 [Tournigand et al. 2006]; DREAM [Chibaudel et al. 2014b]; ACT-1 [Johnsson et al. 2013]; NORDIC VII [Tveit et al. 2012]; MACRO-2 [Alfonso et al. 2014]; MACRO [Diaz-Rubio et al. 2012]. In the COIN trial, patients were randomized to in the intermittent group versus 52% in the main- receive either a continuous oxaliplatin-based tenance arm, and median failure-free survival was chemotherapy until progression or an oxaliplatin- 12.2 and 14.3 months, respectively. based induction therapy (3 months) followed by a TFI [Adams et al. 2011]. Conclusions TFI is inferior to continuous therapy until disease Complete stop after bevacizumab-based progression and to maintenance therapy (what- induction therapy ever the drug) in unselected mCRC patients. A TFI after a bevacizumab-based induction ther- However, a detrimental effect in the median OS of apy was investigated in the CAIRO3, the AIO more than 4 months has never yet been observed. KRK 0207, and the SAKK 41/06 trials (see Some patients could benefit of stopping therapy above) [Koopman et al., 2013; Arnold et al. 2014; using predictive factors for prolonged TFI dura- Koeberle et al. 2013]. tion: pre-TFI chemotherapy duration of at least 6 months without any disease progression (i.e. con- trolled disease) and with normal carcinoembry- Complete stop after cetuximab-based induction onic antigen level during induction therapy and therapy normal baseline platelet count (i.e. below 400,000/ COIN-B study was a randomized phase II trial in mm ) [Perez-Staub et al. 2008; Adams et al. 2011]. which patients with previously untreated mCRC were randomly assigned to receive either 3 months of induction FOLFOX-cetuximab therapy fol- Second-line therapy lowed by TFI or to the same induction treatment After progression on full first-line therapy, the followed by maintenance with cetuximab [Wasan standard practice is to change the chemotherapy et al. 2014]. FOLFOX reintroduction was recom- regimen from 5-FU/oxaliplatin to 5-FU/irinote- mended at progression in both arms. Ten-month can or the reverse sequence [Tournigand et  al. failure-free survival (primary endpoint) was 50% 2004]. http://tam.sagepub.com 161 Therapeutic Advances in Medical Oncology 7(3) Failure of a first-line bevacizumab-based formal hypothesis [Hecht et al. 2013]. A total of therapy 182 patients with KRAS wild-type mCRC were After failure of first-line therapy, the addition of randomized. Neither PFS (primary endpoint, an antiangiogenic agent to chemotherapy HR = 1.01) nor OS (HR = 1.06) seemed to be improved patient outcomes either in CRC different between the two arms. Both antiangio- patients previously treated with bevacizumab genics and anti-EGFR MoAbs in combination [Van Cutsem et  al. 2012; Bennouna et  al. 2013] with chemotherapy are reasonable second-line or in bevacizumab-naïve patients [Giantonio et al. therapeutic options in mCRC patients with RAS 2007; Van Cutsem et  al. 2012]. The TML phase wild-type tumors. Further phase III studies III study has shown that continuing bevacizumab comparing chemotherapy with either anti- beyond first progression and switching backbone EGFR MoAbs or antiangiogenics are needed in chemotherapy regimen improves PFS and OS order to define the best treatment sequence [Bennouna et al. 2013]. This treatment effect was after first-line in patients with wild-type RAS observed whatever KRAS mutational status. In mCRC. the VELOUR phase III study, patients were treated with FOLFIRI with either aflibercept or placebo [Van Cutsem et al. 2012]. All investigated Failure of first-line anti-EGFR MoAb-based patient outcomes (RR, PFS, and OS) were therapy improved over chemotherapy alone, whatever the After failure of first-line therapy containing an prior use of bevacizumab during first-line therapy. EGFR inhibitor agent, second-line chemotherapy This study led to the approval of ziv-aflibercept in should be associated with an antiangiogenic combination with FOLFIRI as second-line ther- agent, either FOLFOX-bevacizumab in the case apy. The RAISE phase III study compared ramu- of prior first-line irinotecan-based regimen cirumab plus FOLFIRI to placebo plus FOLFIRI [Giantonio et  al. 2007] or FOLFIRI-aflibercept as a second-line treatment in patients with mCRC in case of prior first-line oxaliplatin-based regi- after treatment with bevacizumab, oxaliplatin, men [Van Cutsem et al. 2012]. and fluoropyrimidine in the first-line setting. Ramucirumab is a VEGF Receptor 2 antagonist that specifically binds VEGF Receptor 2 and Subsequent lines of therapy blocks binding of VEGF receptor ligands Anti-EGFR MoAbs (cetuximab, panitumumab) VEGF-A, VEGF-C, and VEGF-D. The study increase survival over best supportive care after showed a statistically significant improvement in failure of standard chemotherapy [Jonker et  al. OS (primary endpoint) and PFS. The most com- 2007; Van Cutsem et al. 2007]. A synergy between mon severe toxicities increased when adding these drugs and irinotecan has been shown even ramucirumab to FOLFIRI were neutropenia, in patients refractory to irinotecan [Cunningham fatigue, hypertension, and diarrhea [Tabernero et al. 2004]. et al, 2015]. Regorafenib, a multikinase inhibitor was The addition of panitumumab to FOLFIRI was approved in US (FDA) and Europe [European superior to FOLFIRI alone in patients with Medicines Agency (EMA)] for patients with KRAS wild-type mCRC after failure of an oxali- mCRC refractory to all standard therapies with platin-based therapy in terms of PFS (primary the Eastern Cooperative Oncology Group endpoint, HR = 0.82; p = 0.023) and RR (36% (ECOG) performance status (PS) 0 or 1, based versus 10%; p < 0.001). The lack of OS superior- on the results of the CORRECT phase III study ity (HR = 0.92; p = 0.366) could be explained by [Grothey et  al. 2013]. An early stop in recruit- the 34% of patients who received the MoAb ment was decided after the results of a second EGFR inhibitor after progression in the FOLFIRI interim analysis, showing that OS (primary end- arm [Sobrero et al. 2012]. point) and PFS were improved with regorafenib versus placebo. Hazard ratios for death and pro- The SPIRITT randomized phase II study (study gression were 0.77 and 0.49, respectively. The 20060141) investigated the safety and efficacy main adverse events were asthenia (63%), hand- of FOLFIRI with either panitumumab or beva- and-foot syndrome (47%), and stomatitis (27%). cizumab as second-line therapy in patients pre- Heath-related quality-of-life was not improved. viously treated with an oxaliplatin-based There is no predictive biomarker for regorafenib first-line therapy with bevacizumab, without efficacy. 162 http://tam.sagepub.com B Chibaudel, C Tournigand et al. TAS-102 is a new oral antitumor agent combin- The Austrian PASSION study is a randomized phase ing trifluridine (FTD, active component) and tip- II study evaluating first-line XELIRI–bevacizumab fol- iracil hydrochloride (TPI, thymidine lowed by XELOX–bevacizumab or the reverse phosphorylase inhibitor), which prevents the deg- sequence [ClinicalT rials.gov identifier: NCT02119026; radation of FTD [Van Cutsem et al. 2014]. This Scheithauer, 2014]. The primary endpoint is DDC. drug has been evaluated in the RECOURSE The expected sample size is 120 patients with mCRC. phase III study against placebo in patients with heavily pretreated mCRC, in which TAS-102 pro- The GruppoItaliano per lo Studio dei Carcinomi longed OS (primary endpoint) from 5.3 to 7.1 dell’Apparato Digerente (GISCAD) COMETS is months (HR = 0.68) and PFS (HR = 0.48) a randomized phase III study comparing two differ- [Yoshino et  al. 2014]. The survival benefit was ent therapeutic sequences in patients with mCRC observed whatever prior use of regorafenib (17%) after failure of a first-line treatment with FOLFIRI- and was consistent in all prespecified subgroups, bevacizumab [ClinicalTrials.gov identifier: except for patients who received only two lines of NCT01030042l GruppoItaliano per lo studio dei therapy prior to study entry. Hematological (neu- Carcinomi dell’ Apparato Digerente (GISCAD), tropenia, anemia) and gastrointestinal (nausea, 2014]. Patients are randomized to receive either diarrhea) toxicities were the most frequent adverse second-line FOLFOX followed by cetuximab- events. The incidence of febrile neutropenia was irinotecan or the reverse sequence. The primary 3.8% with TAS-102. One toxic related death was endpoint is OS. The recruitment of 350 patients is observed with TAS-102. There was not HRQoL planned to be achieved in the second part of 2014. evaluation, but the time to ECOG PS deteriora- tion was prolonged with the use of TAS-102 (HR = 0.66). Those results are in line with previously Biomarker-driven trials published data from a randomized phase II study The FOCUS4 is a molecularly driven randomized conducted in Japanese patients [Yoshino et  al. study sponsored by Medical Research Council 2012]. A high expression of TK1 could be associ- (MRC) in United Kingdom for patients with ated with a higher sensitivity of tumor cells for mCRC (EudraCT 2012-005111-12) [Pugh, TAS-102. The main differences and similarities 2014]. A biomarker panel analysis [BRAF, KRAS, between regorafenib and TAS-102 are shown in NRAS, Phosphatase and tensin homolog (PTEN), Table 2. With similar efficacy results, those oral Phosphoinositide-3-kinase (PI3KCA), and drugs have two distinct safety profiles. Mismatch Repair (MMR)] will be performed dur- ing the first 16 weeks of induction therapy, then patients with controlled disease will be randomized Ongoing and future strategy trials according to five molecular subtypes: BRAF mutant, PI3KCA subtype (mutation of PI3KCA Multiline strategy gene or loss of PTEN protein), RAS mutant The GERCOR STRATEGIC-1 study [Clinical (KRAS or NRAS tumor gene mutation), ‘all wild- Trials.gov identifier: NCT01910610; Chibaudel type’ subtype (no mutation), and nonclassified et al. 2014a] is an open-label, randomized, multi- subtype. Each molecularly stratified trial aims to center phase III trial designed to determine an compare a novel intervention to placebo or stand- optimally personalized treatment sequence in ard care. The recruitment period is planned to be patients with unresectable RAS wild-type mCRC. 4–5 years followed by 2-year follow up. Two standard treatment strategies are being com- pared: FOLFIRI-cetuximab, followed by an The MODUL trial [Schmoll et al. 2014] is a bio- oxaliplatin-based chemotherapy with bevaci- marker-driven maintenance treatment rand- zumab (arm 1) and OPTIMOX–bevacizumab, omized study. All patients will receive 4 months of followed by an irinotecan-based chemotherapy induction therapy with FOLFOX–bevacizumab. with bevacizumab, and an anti-EGFR monoclo- Subsequently, patients with controlled disease nal antibody with or without irinotecan (arm 2). will be separated into two cohorts for mainte- The primary endpoint is duration of disease con- nance therapy according to BRAF mutational sta- trol (DDC) that is defined as the sum of PFS of tus. In cohort one, BRAF mutant patients will be each active sequence. Main secondary endpoints randomized to receive either fluoropyrimidine are OS and HRQoL. Recruitment started in with cetuximab and vemurafenib (BRAF TKI) or October 2013 and a total of 500 patients is fluoropyrimidine with bevacizumab. In cohort expected to be randomized. two, BRAF wild-type patients will be randomized http://tam.sagepub.com 163 Therapeutic Advances in Medical Oncology 7(3) Table 2. Differences and similarities between regorafenib and TAS-102 trials. Regorafenib TAS-102 Drug Pharmaceutical Bayer Taiho Mechanism of action Multi-TKI Antimetabolic Route Oral Oral Dose 160 mg daily, 3 weeks of each 35 mg/m² twice a day on days 1–5 4-week cycle and 8–12 every 4 weeks Study CORRECT RECOURSE Reference [Grothey et al. 2013] [Yoshino et al. 2014] Trial phase III III Primary objective (targeted HR) OS (0.70) OS (0.75) Randomization ratio 2:1 2:1 Comparator Placebo Placebo No of patients (investigational / 505 / 255 534 / 266 placebo) Recruitment Early stop for positive results Full Prior antiangiogenic agent 100% 100% Efficacy results OS, HR (absolute median 0.77 (+1.4) 0.68 (+1.8) difference) PFS, HR (absolute median 0.49 (+0.2) 0.48 (+0.3) difference) DCR, % (absolute difference) 41 (+26) 44 (+28) Safety profile Neutropenia, any grade (grade ¾) Not reported 67 (38) Anemia 7 (3) 76 (18) Nausea 14 (<1) 48 (2) Stomatitis 27 (3) 8 (<1) Diarrhea 34 (8) 32 (3) Hand-and-foot syndrome 47 17) 2 (0) Asthenia 63 (10) 35 (4) HRQoL No change Not done Predictive biomarkers None TK1-high expression? FDA/EMA approval Yes Not yet Abbreviations: TKI, tyrosine kinase inhibitor; RECOURSE, Refractory Colorectal Cancer Study; HR, hazard ratio; OS, over- all survival ; PFS, progression-free survival ; DCR, disease control rate; HRQoL, heath-related quality of life; FDA, Food and Drug Administration; EMA, European Medical Agency. to receive either fluoropyrimidine with bevaci- 5-FU with or without panitumumab in patients zumab or the same treatment with MPDL3280A with RAS wild-type MCRC [ClinicalTrials.gov (anti-PDL1 MoAb). The coprimary endpoints identifier: NCT01991873; Trarbach, 2014]. are tumor RR at 2 months and PFS. This study is based on an adaptive design with possibility to Immunomodulatory MGN1703 in Patients with drop treatment comparisons upon sufficient data Advanced Colorectal Carcinoma (IMPALA) is a availability for the efficacy/safety results, and the randomized open-label phase III study that is possibility of adding future promising compounds investigating the role of the immunotherapy into biomarker-driven maintenance phase. MGN 1703 (MOLOGEN AG) as maintenance therapy in patients with mCRC [ClinicalTrials. gov identifier: NCT02077868; Cunningham, Maintenance therapy 2014]. MGN1703 is a DNA-based TLR-9 ago- The AIO-KRK-0212 is a randomized phase II nist developed by MOLOGEN. This trial is study investigating maintenance therapy with designed to improve OS (primary endpoint) and 164 http://tam.sagepub.com B Chibaudel, C Tournigand et al. Antiangiogenic or EGFRi MoAb first in RAS WT MCRC? CALGB 80405 / AIO FIRE3 Antiangiogenic first EGFRiMoAbfirst Oxaliplatin- or irinotecan-based first ? Oxaliplatin- or irinotecan-based first ? GERCOR C97-3 GERCOR C97-3 FU/ox-bev FU/iri-bev FOLFOX-Pmab FOLFIRI-cetux Continuouslyor stop-and-go ? Continuously Continuously Continuously Line #1 AVF2107g PRIME CRYSTAL Continuously Stop-and-Go NO16966 GERCOR OPTIMOX Ox-reintroduction Single or double switch (chemo and/or biologic) ? Double switch (chemo and biologic) afterFU/ox-Pmabfirst-line Rx afterFU/iri-cetuxfirst-line Rx afterFU/ox-bev first-line Rx afterFU/iri-bev first-line Rx Single switch Double switch Single switch Single switch FOLFIRI-aflibercept FU/ox-bevacizumab Line #2 (chemo) (chemo and biologic) (chemo) (biologic) Continuously: VELOUR Continuously: E3200 FU/iri-bev: TML FOLFIRI-Pmab: 181 FU/ox-bev: TML FOLFIRI-Pmab: 181 FU/iri-aflibercept: VELOUR FU/iri-cetux: EPIC FU/iri-cetux: EPIC EGFRi+/- irinotecan Regorafenib Regorafenib FU/ox Line #3 cetux: BOND Continuously Continuously Pmab: 408 CORRECT CORRECT Regorafenib No standard Regorafenib No standard therapy Line #4 Continuously therapy Continuously CORRECT CORRECT Treatment strategy decision Treatment line changes Figure 4. Multiline therapeutic strategies in wild-type RAS metastatic colorectal cancer (mCRC): treatment decisions from first-line to salvage treatment. Abbreviations: chemo, chemotherapy; bev, bevacizumab; ox, oxaliplatin; cetux, cetuximab; iri, irinotecan; Pmab, panitumumab; FU, fluoropyrimidine, Rx, therapy. GERCOR C97-3 [Tournigand et al. 2004]; NO16966 [Saltz et al. 2008]; OPTIMOX1 [Tournigand et al. 2006]; OPTIMOX2 [Chibaudel et al. 2009]; AVF2107g [Hurwitz et al. 2004]; PRIME [Douillard et al. 2010]; CRYSTAL [Van Cutsem et al. 2009]; TML [Bennouna et al. 2013]; 181 [Peeters et al. 2010]; EPIC [Sobrero et al. 2008]; ECOG 3200 [Giantonio et al. 2007]; VELOUR [Van Cutsem et al. 2011]; BOND [Cunningham et al. 2004]; 408 [Van Cutsem et al. 2007]; CORRECT [Grothey et al. 2013]. requires 540 patients from more than 100 Conclusions European centers. Several drugs and combinations are now available for the treatment of patients with advanced CRC, Maintenance chemotherapy with low-dose met- but the optimal sequence of therapy remains ronomic regimen associating capecitabine, unknown (Figure 4). This is a step-by-step treat- celecoxib, and methotrexate will be evaluated in a ment decision level, from first-line with the choice prospective phase II study (HaEmek Medical of both biologic agent (antiangiogenic or EGFR) Center, Israel) in 80 mCRC patients having and chemotherapy regimen (oxaliplatin-based or received FOLFIRI-bevacizumab induction ther- irinotecan-based) to second and subsequent lines. apy [ClinicalTrials.gov identifier: NCT01668680; Starting first-line with bevacizumab and a dou- Loven, 2014]. The primary endpoint is PFS. blet of chemotherapy (either 5-FU/oxaliplatin or 5-FU/irinotecan) optimizes the availability of the The addition of ziv-aflibercept to the OPTIMOX number of lines with approved drugs. Moreover, strategy (oxaliplatin-based induction therapy fol- the use of maintenance therapy during first-line lowed maintenance therapy followed by oxaliplatin and at push therapy-free intervals in selected reintroduction) is being evaluated in the GERCOR patients can be used to limit severe toxicities and VELVET phase II study [ClinicalTrials.gov identi- drug resistance. Finally, reintroduction of oxalipl- fier: NCT01802684; Chibaudel, 2014]. The recruit- atin after progression during first-line is an impor- ment is closed and the results will available in 2015. tant prognostic factor for OS. Strategy trials are needed to better define an optimal treatment Other drugs are currently being investigated as sequence in a given population. maintenance first-line therapy: axitinib (TTD- 11-01) [ClinicalTrials.gov identifier: Molecular testing for KRAS and NRAS tumor NCT01483638; Grávalos and Carrato, 2014] genes (exons 2, 3, and 4) is mandatory but not and simvastatin [ClinicalTrials.gov identifier: sufficient to select appropriate patients for anti- NCT01238094; Kang, 2014]. EGFR MoAbs therapy (Figure 1B). An increase http://tam.sagepub.com 165 Therapeutic Advances in Medical Oncology 7(3) (FP) plus Bevacizumab (Bev), Bev alone, or no of selection level is critical to optimize treatment treatment, following a standard combination of FP, effect. Moreover, a period to acquire that informa- oxaliplatin (Ox), and Bev as first-line treatment for tion should also be shortened in order to give the patients with metastatic colorectal cancer (mCRC): best treatment from the diagnosis of advanced A phase III non-inferiority trial (AIO KRK 0207). disease. ASCO 2010. J Clin Oncol 28 Bennouna, J., Sastre, J., Arnold, D., Osterlund, P., Funding Greil, R., Van Cutsem, E. et al. (2013) Continuation This research received no specific grant from any of bevacizumab after first progression in metastatic funding agency in the public, commercial, or not- colorectal cancer (ML18147): a randomised phase 3 for-profit sectors. trial. Lancet Oncol 14: 29–37. Conflict of interest statement Chibaudel, B. (2014) OPTIMOX-aflibercept as first- line therapy in patients with unresectable metastatic BC has served as a consultant or in an advisory colorectal cancer (VELVET). http://clinicaltrials.gov/ role for Roche and Sanofi. CT has served as a ct2/show/NCT01802684 (accessed 16 October 2014). consultant or in an advisory role and received honoraria from Roche and Sanofi. FB has served Chibaudel, B., Maindrault-Goebel, F., Lledo, G., as a consultant or in an advisory role for Roche, Mineur, L., Andre, T., Bennamoun, M. et al. (2009) Nestlé, and Merck Serono, has received honoraria Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR from Roche, Nestlé, Bristol-Myers Squibb, and OPTIMOX2 Study. J Clin Oncol 27: 5727–5733. Merck Serono, and has received research funding from Roche. TA has served as a consultant or in Chibaudel, B., Tournigand, C., Bonnetain, F., Hug an advisory role for Amgen, Merck Serono, and de Larauze, M., de Gramont, A., Laurent-Puig, P. Roche, and has received honoraria from Amgen, et al. (2014a) STRATEGIC1-multi-line therapy trial Merck Serono, and Roche. 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Journal

Therapeutic Advances in Medical OncologySAGE

Published: Feb 19, 2015

Keywords: chemotherapy; colorectal cancer; maintenance; molecular targeted agents; strategy; treatment

References