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Liposomal irinotecan in gemcitabine-refractory metastatic pancreatic cancer: efficacy, safety and place in therapy:

Liposomal irinotecan in gemcitabine-refractory metastatic pancreatic cancer: efficacy, safety and... 688816 TAM0010.1177/1758834016688816Therapeutic Advances in Medical OncologyE. Kipps et al. research-article2017 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Liposomal irinotecan in gemcitabine- 2017, Vol. 9(3) 159 –170 DOI: 10.1177/ refractory metastatic pancreatic cancer: © The Author(s), 2017. Reprints and permissions: efficacy, safety and place in therapy http://www.sagepub.co.uk/ journalsPermissions.nav Emma Kipps, Kate Young and Naureen Starling Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy. As a direct result, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of liposomal irinotecan in this setting. However, first-line treatment options for this disease now include the combination regimen, FOLFIRINOX, in patients with good performance status, and the role of second-line combination treatment with liposomal irinotecan in this setting is unclear. Recent advances have changed the therapeutic landscape, as clinicians are now able to choose a sequential approach to treatment tailored to the individual patient characteristics. This article reviews current treatment options for metastatic PDAC and focuses on the efficacy, safety and place in therapy of liposomal irinotecan. Keywords: chemotherapy, liposomal irinotecan, metastatic pancreatic cancer, MM-398, nal-Iri, NAPOLI-1, pancreatic cancer, PDAC, PEP02, treatment Correspondence to: Introduction to pancreatic cancer [Cancer Research UK]. This poor survival is Naureen Starling Despite decades of research, pancreatic ductal multifactorial, attributed to the systemic and Royal Marsden NHS Foundation Trust adenocarcinoma (PDAC) remains one of the aggressive nature of PDAC, its complex muta- Ringgold standard most lethal malignancies. Although it is a rela- tional landscape [Waddell et  al. 2015], desmo- institution - Department of Gastrointestinal Oncology, tively uncommon cancer, due to its high mortality plastic stroma [Kleeff et al. 2007] and the current London, UK. rate it represents a significant global health bur- lack of effective therapies. naureen.starling@rmh. nhs.uk den. Worldwide in 2012 there were 338,000 new Emma Kipps cases of pancreatic cancer and 331,000 associated Surgery is the one curative treatment for PDAC Kate Young deaths [Ferlay et al. 2015]. The striking similarity but only a minority of patients present with Royal Marsden NHS Foundation Trust between incidence and deaths highlights the dis- potentially operable disease (10–20%) [Willett Ringgold standard mal prognosis of this disease. Further, by 2030 it et  al. 2005; Gandy et  al. 2016]. Further, as the institution - Department of Gastrointestinal Oncology, has been predicted that pancreatic cancer will disease is characterized by early micrometastatic London, UK surpass breast, prostate and colorectal cancer to spread [Sohal et al. 2014] long-term survival fol- become the second leading cause of cancer related lowing surgery is poor with 80% of patients expe- deaths in the United States [Rahib et al. 2014]. riencing a local or distant recurrence within 2 years [Geer et al. 1993]. More than 95% of those diagnosed with pancre- atic cancer will succumb to it and across Europe The majority of patients present with locally the 5-year overall survival (OS) ranges from 2–9% advanced inoperable (40%) or metastatic disease journals.sagepub.com/home/tam 159 Therapeutic Advances in Medical Oncology 9(3) (40–45%) where the outlook is even bleaker, with surprising considering the significant inter- a median OS of 6–11 months and 2–6 months tumoural heterogeneity seen in PDAC. In addi- respectively [Willett et  al. 2005; Sclafani et  al. tion to common alterations in KRAS, TP53, 2015; Cancer Research UK]. SMAD4 and CDKN2A [Bryant et  al. 2014], there are also a multitude of infrequently mutated genes in pancreatic cancer [Waddell et  al. 2015] Current treatment for advanced disease and the majority of the trials to date have been in unselected populations. First-line treatment Chemotherapy remains the cornerstone of treat- The one targeted agent to have demonstrated a ment for advanced PDAC. Following the Burris survival benefit in a phase III study is erlotinib in and colleagues study in 1997, single-agent gem- combination with gemcitabine versus gemcitabine citabine became the gold standard first-line treat- alone (HR 0.82, 95% CI 0.69–0.99, p = 0.038). ment for patients with advanced disease [Burris However, in the results published in 2007 the et  al. 1997]. This study demonstrated a modest numerical increase in median OS was only 12 improvement in survival of 1.24 months (5.65 days [Moore et al. 2007] with a higher incidence versus 4.41 months, p = 0.0025) with gemcitabine of adverse events, including rash, interstitial lung versus 5-fluoropyrimidine (5-FU) but became a disease and diarrhoea. The group of patients who standard treatment due to the associated incre- developed a rash of grade ⩾2 did have a more ment in clinical benefit rate from 4.2% with 5-FU clinically meaningful benefit (median OS 10.5 to 23.8% with gemcitabine. months with grade ⩾2 rash versus 5.8 months with grade 1 rash versus 5.3 months for those who Despite a myriad of trials investigating the use of did not develop a rash) but this combination is more intensive combination regimens, often with rarely used in clinical practice despite being US a gemcitabine backbone, no chemotherapy regi- FDA and EMA-approved. men was found to be superior to single-agent gemcitabine until more recently. In light of non- The first combination chemotherapy regimen to statistically significant trends in improved survival demonstrate a statistically significant survival seen with gemcitabine combinations in a number benefit versus gemcitabine in a phase III study was of large phase III studies Sultana and colleagues the ACCORD-11 study in 2011. This study dem- conducted a meta-analysis of 51 trials, including onstrated that the triplet FOLFIRINOX (5-FU, almost 10,000 patients. This demonstrated a sur- irinotecan and oxaliplatin) improved progression- vival benefit with gemcitabine combination free survival (PFS), OS and response rate (RR) chemotherapy versus gemcitabine alone [hazard when compared with single-agent gemcitabine ratio (HR) = 0.91, 95% confidence interval (CI) (OS 11.1 versus 6.8 months, HR 0.57, p < 0.001, 0.85–0.97] [Sultana et al. 2007]. The same group PFS 6.4 versus 3.3 months, HR 0.47, p < 0.001, also assessed different gemcitabine combina- RR 31.6% versus 9.4%, p < 0.001) [Conroy et al. tions and found a trend favouring gemcitabine 2011]. Unsurprisingly this increased efficacy plus capecitabine or a platinum [Sultana et  al. came at the cost of increased toxicity and this is a 2008]. Based on such analyses the National regimen for patients with excellent performance Comprehensive Cancer Network (NCCN) guide- status (PS). However, despite this increased tox- lines and recent American Society of Clinical icity the FOLFIRINOX patients had a signifi- Oncology (ASCO) guidelines include these gem- cantly longer time to deterioration in quality of citabine combinations in their recommendations life than the gemcitabine patients [Gourgou- [Sohal et al. 2016]. Bourgade et  al. 2013]. Furthermore, since the adoption of this regimen into the clinic various With the elucidation of the molecular nature of institutional series have been published suggest- pancreatic cancer, a wide variety of targeted ing modifications to the regimen to increase its agents have also been investigated, again often tolerability without reducing efficacy [Mahaseth with a gemcitabine backbone. The targets studied et al. 2013; Mantripragada et al. 2016]. have included EGFR, KRAS signalling, MEK, mTOR, HER2, VEGF and the Hedgehog path- Following ACCORD-11 the MPACT study of way, all with disappointing clinical results, despite the addition of nab-paclitaxel to gemcitabine sometimes promising preclinical and early phase reported a median OS of 8.5 months in the com- studies [Sclafani et al. 2015]. This is not entirely bination arm versus 6.7 months in the gemcitabine 160 journals.sagepub.com/home/tam E Kipps, K Young et al. alone arm (HR 0.72, p < 0.0001). Again PFS log-rank p = 0.01) with similar toxicity other than and RR were also improved (PFS 5.5 versus peripheral neuropathy which was, as would be 3.7 months, HR 0.69, p < 0.0001, RR 23% expected, higher in the oxaliplatin arm (grade 1/2 versus 7%, p < 0.001) [von Hoff et  al. 2013]. neurotoxicity: 38.3% versus 7.1%, p < 0.001) Again toxicity including sensory neuropathy was [Oettle et al. 2014]. However, the results from the increased in the combination arm, although qual- randomized phase III PANCREOX study were ity of life was not assessed, and this is a regimen not aligned with CONO-003, with patients receiv- for good PS patients. ing FOLFOX having an inferior OS than those receiving FF (6.1 versus 9.9 months, HR 1.78, p = The lack of direct comparisons of these regimens 0.02). It has been suggested that this disparity is leaves some uncertainty as to the best first-line due to a higher level of treatment discontinuation treatment for advanced PDAC and as yet there in the FOLFOX arm than the FF arm (20.4% ver- are no established biomarkers for selecting patients sus 1.9% respectively) and an imbalance in the for a particular therapy. For patients with a PS of post-discontinuation treatments received in each 2, single-agent gemcitabine remains a reasonable arm (6.8% in the FOLFOX arm and 25% in the option. For those patients who are fitter, PS 0–1, FF arm) [Gill et al. 2014]. either FOLFIRINOX or gemcitabine-nab-pacli- taxel are preferred and the decision depends on a The most recent phase III study is the NAPOLI-1 combination of factors including patient comor- trial of nanoliposomal irinotecan, which is dis- bidities, toxicity profile, consideration of central cussed in much greater detail below, and provides venous access and patient preference and reim- another second-line regimen for consideration bursement. Clinical trials in the first-line setting [Wang-Gillam et al. 2016]. are also recommended and there are currently numerous ongoing trials globally of targeted drugs Additional regimens have been investigated in with a chemotherapy backbone and increasing the second or subsequent line setting in a num- studies of immune-directed approaches. ber of small phase II studies and case series, including capecitabine and oxaliplatin (CAPOX), taxanes, 5-FU and irinotecan (FOLFIRI) as well Second and subsequent line treatment as FOLFIRINOX and gemcitabine plus nab- Historically there has been very little use of sec- paclitaxel. These studies have reported mixed ond-line chemotherapy for PDAC. However, results and such regimens require further assess- with improvements in first-line therapy for ment in larger studies [Oettle et al. 2000; Xiong advanced disease, this is now changing. et  al. 2008; Yoo et  al. 2009; Hosein et  al. 2013; Unfortunately, there is no good quality evidence Lee et al. 2013]. to support a particular regimen following first- line treatment with FOLFIRINOX or gemcit- Extrapolating from the data available it is not abine and nab-paclitaxel as the few trials of unreasonable to consider that second-line chemo- second-line treatment conducted were following therapy may provide a clinical benefit. A systemic progression on gemcitabine monotherapy. analysis of 34 second-line studies, including over 1500 patients who had progressed on gemcit- The randomized phase III CONKO-01 study abine, reported a median OS of 2.8 months for sought to establish if the combination of oxalipl- patients who received BSC and 6 months for atin, folinic acid and 5-FU (OFF) was superior to patients who received second-line treatment best supportive care (BSC). Despite terminating [Rahma et  al. 2013]. The choice of second-line early due to recruitment difficulties (n = 46 regimen then depends upon the first-line regimen patients) this study demonstrated a survival bene- used, the patients’ PS, residual toxicities and fit of 2.52 months with chemotherapy (mOS 4.82 comorbidities and in this very palliative setting it OFF versus 2.30 BSC, HR 0.45, CI: 0.24–0.83, must be remembered that toxicities and quality of p = 0.008) [Pelzer et  al. 2011]. CONKO-003, life are of paramount importance. There are even another phase III study, then evaluated whether less data to support third or subsequent line treat- oxaliplatin was required, randomizing 168 patients ment and here clinical trial entry is strongly to OFF or 5-FU and folinic acid (FF). Both encouraged for fit patients. median OS and PFS favoured the addition of oxaliplatin (mOS 5.9 months OFF versus 3.3 Overall therefore, despite the small improvements months FF, HR 0.66, 95% CI 0.48–0.91, in the treatment options for pancreatic cancer in journals.sagepub.com/home/tam 161 Therapeutic Advances in Medical Oncology 9(3) the last decade described above, prognosis 2006]. Unlike previous liposomal irinotecan remains poor and there is an urgent need to preparations [Messerer et  al. 2004], a reduced develop novel therapies, consider new combina- toxicity profile was reported, as well as increased tions and appropriately select those patients who tumour efficacy when compared with irinotecan may benefit. in animal models [Drummond et  al. 2006]. The nanoparticle consists of a lipid bilayer scaffold, which encapsulates the drug complex and facili- Introduction to irinotecan tates in vivo drug retention. A transmembrane Camptothecin is a naturally occurring cytotoxic gradient of triethylammonium cations was used alkaloid that targets topoisomerase I, a nuclear to drive the irinotecan into the liposome where enzyme that reduces the torsional stress of super- upon sucrose octasulphate, a highly charged coiled DNA during the replication, recombina- anion, trapped the irinotecan within the liposome tion, transcription, and repair of DNA (see Figure 1). [Garcia-Carbonero et  al. 2002]. Irinotecan is a synthetic derivative of camptothecin, with func- tional groups to enhance solubility and was first Pharmacokinetics, pharmacodynamics and approved by the US FDA in 1996 [Hsiang et al. pharmacogenetics 1985]. As a prodrug, it is converted in to the Preclinical in vivo pharmacokinetic studies have active metabolite SN38, predominantly in the shown liposomal encapsulation of irinotecan was liver, by carboxylesterases. SN-38 is subsequently associated with significantly longer circulation conjugated, with significant pharmacogenetic times (t = 10.7 h) compared with unencapsu- variability, into inactive, nontoxic SN38- lated irinotecan (t = 0.27 h) [Drummond et al. glucuronide (SN-38G). Both irinotecan and 2006]. At 24 h, 23.3% of injected liposomal SN-38 have a labile α-hydroxy-δ-lactone ring that irinotecan still remained, with no detectable con- undergoes pH-dependent reversible hydrolysis version to SN-38 or the carboxylate form. [Swami et  al. 2013]. In acidic conditions, the Conversely, only 2% of the injected dose of unen- more active, potent lactone form predominates, capsulated irinotecan remained at 30 min, 35% of while in more basic conditions, the inactive, less which had been converted to SN-38 and subse- toxic carboxylate form is favoured. These proper- quently conjugated to the in the inactive carboxy- ties contribute to the marked heterogeneity of the late form. A similar pharmacokinetic profile was main dose-limiting toxicities observed in patients, reported in patients by Chang and colleagues that of neutropaenia and late onset diarrhoea. [Chang et  al. 2015]. In this phase I trial, treat- The direct effect of SN-38 on intestinal epithe- ment with liposomal irinotecan at 120 mg/m was lium is thought to be responsible for irinotecan- characterized by slow clearance (mean = 0.0591 induced diarrhoea [Hecht, 1998], which can be l/m /h), small volume of distribution (mean = 1.8 severe, resulting in dose reductions or omissions l/m ≅ plasma volume) and prolonged terminal leading to ineffective treatment administration. half-life of total irinotecan in circulation (mean = 29.5 h) when compared with published pharma- There is therefore a rationale for the development cokinetic data for unencapsulated irinotecan of formulations that can improve the distribution [Chabot, 1997; Chang et  al. 2015]. The plasma and protect the premature metabolism of irinote- concentration profile of liposomal irinotecan can to achieve maximum efficacy while minimizing matched that of the total irinotecan, suggesting toxicity. Liposomal constructs have been engi- the release of irinotecan from the liposome occurs neered to improve the circulation time and intra- slowly over time. tumoural drug concentration of anthracyclines, for example, PEGylated liposomal doxorubicin The mechanism of irinotecan release is not fully [Gabizon, 2001], and nab-paclitaxel [Gradishar, understood. Preclinical models have shown lipo- 2006], but it has been difficult to replicate the somal irinotecan increases tumoural drug reten- technology in other classes of chemotherapy drugs. tion, resulting in local release and conversion into irinotecan and SN-38 [Drummond et  al. 2006]. However, the correlation between the C and max Liposomal irinotecan (MM-398, PEP02, AUC of liposomal irinotecan and the active 0-∞ nal-Iri) metabolite SN-38, reported by Chang and col- In 2006, a novel liposomal construct containing leagues, was weak [Chang et al. 2015]. This vari- irinotecan was developed [Drummond et  al. ability may be attributable to the small sample 162 journals.sagepub.com/home/tam E Kipps, K Young et al. Figure 1. A schematic of encapsulation of irinotecan inside the liposome. Irinotecan is exchanged with triethylammonium cations across the bilipid layer. size or the pharmacogenetic variability of irinote- 5 of whom were able to escalate to the standard can metabolism. dose, 2 of whom needed a further dose reduction and 1 discontinued secondary to grade 3 vomiting Patients with a genetic polymorphism in the gene [Wang-Gillam et al. 2016]. encoding uridine diphosphate glucuronosyltrans- ferase (UGT) 1A1, have a lower than normal Although early phase studies have demonstrated capacity to metabolize SN-38, the active metabo- the different pharmacokinetic and toxicity pro- lite of irinotecan. UGT conjugates SN-38 into files of patients homozygous and heterozygous for the inactive SN-38 glucuronide (SN-38G). The the UGT1A1*28 allele, the available data are not presence of the UGT1A1*28 allele, present in conclusive for defining a precise genotype-based approximately 17% of Whites [Lampe et  al. dosage [Toffoli et  al. 2006; Biason et  al. 2008; 1999], has been shown to cause a 70% reduction Palomaki et al. 2009]. There are therefore no cur- in expression of UGT, leading to an increased rent guidelines on how UGT1A1 testing could be exposure of patients to the cytotoxic metabolite, used to effect treatment with clinical practice. SN-38. Patients homozygous for the UGT1A1*28 allele are 3.5 times more likely to suffer from grade 3/4 toxicities [Palomaki et  al. 2009] and Clinical Efficacy may benefit from a dose reduction of up to 40% Preclinical in vivo efficacy data have shown the [Innocenti et al. 2014]. enhanced anti-tumour effect of liposomal irinote- can compared with equivalent dose of free irinote- In a phase I trial, a woman with heterozygosity of can in human pancreatic cancer cell line xenograft UGT1A1*6/*28 died from grade 4 diarrhoea and mouse models [Hann et  al. 2007]. Chang and was found to have C and AUC of SN-38 colleagues reported the results of a phase I dose- max 0-∞ that were 3-times higher than in other patients escalation study of liposomal irinotecan, in 11 treated at the same dose [Chang et  al. 2015]. patients with treatment refractory advanced solid Moreover, in a recent phase III study, the dose of tumours [Chang et al. 2015]. Liposomal irinote- liposomal irinotecan was reduced by 25% in 14 can was delivered as a 90-min intravenous infu- patients homozygous for the UGT1A1*28 allele, sion every 21 days. Overall, two patients, journals.sagepub.com/home/tam 163 Therapeutic Advances in Medical Oncology 9(3) including one patient with pancreatic cancer who In NAPOLI-1, OS was the primary endpoint and was treated with the higher dose of 180 mg/m , patients were stratified by baseline albumin level, achieved a partial response to treatment. The dis- PS and ethnicity. Although all patients had previ- ease control rate was 45% for the intention-to- ously been treated with gemcitabine, 12% of treat population. patients had received this in the neoadjuvant, adjuvant or locally advanced setting. Interestingly, The favourable pharmacokinetics described in over half the patients enrolled had previously this study, led to a nonrandomized phase II trial been treated with fluorouracil or irinotecan-based that sought to establish the efficacy and toxicity of regimes; 56% and 15%, respectively. single-agent liposomal irinotecan, at 120 mg/m 3-weekly, in patients with metastatic pancreatic Median OS was 6.1 months in the combination cancer after progression following first-line gem- arm and 4.2 months in those assigned 5-FU/LV citabine-based chemotherapy [Ko et al. 2013]. A control (HR 0.67, 95% CI 0.49–0.92; p = total of 40 patients were enrolled, 60% of whom 0.012). In patients who were allocated liposomal had a Karnofsky score of 90–100. The protocol irinotecan monotherapy, median OS was 4.9 was amended during the second stage of the study months, which was not significantly different to to permit a starting dose of 100 mg/m . However, the control arm, (HR 0.99, 95% CI 0.77–1.28; 27 of the 40 patients remained on 120 mg/m for p = 0.94) (see Table 1). Interestingly, quality of the duration of their treatment. The mean and life scores and clinical benefit response did not median number of cycles received was, 5.88 and differ significantly between treatment groups. 2.5, respectively. Half of the patients achieved The authors acknowledge that using a different disease control defined as objective response 5-FU/LV regimen in the combination arm to the (7.5% of patients) or stable disease for more than control arm is not standard design but argue it two cycles (42.5% of patients). The median PFS was unlikely to have created bias in favour of the and OS were, 2.4 and 5.2 months, respectively. investigational arm which delivered lower dose intensities of 5-FU. This phase II study provided evidence of antitu- mour activity and led to the pivotal NAPOLI-1 In a pre-planned analysis of each subgroup, OS trial of liposomal irinotecan in advanced pancre- was increased in patients with poorer prognostic atic cancer [Wang-Gillam et  al. 2016]. Wang- features who were treated in the combination arm Gillam and colleagues published the results from compared with those treated with 5-FU/LV; this global, randomized, open-label, phase III lower PS (Karnofsky score 70–80), albumin study in which 417 patients previously treated <40 g/l, Ca19-9 ⩾40 U/ml, liver metastases, with gemcitabine-based chemotherapy, were stage IV at diagnosis and patients whose time assigned to receive either, liposomal irinotecan from diagnosis to enrolment was less than the monotherapy (120 mg/m ) every 3 weeks or median. However, it should be noted that patients folinic acid and fluorouracil (2000 mg/m over with a Karnofsky score <70% or an albumin 24 h every week for the first 4 weeks of every <30 g/l were not included in the study. 6-week cycle, based on the CONKO-003 trial [Oettle et  al. 2014]. A third arm, consisting of 2-weekly combination treatment of liposomal Safety irinotecan (80 mg/m ) with folinic acid and fluo- The dose-limiting toxicities for liposomal irinote- rouracil (2400 mg/m infusion over 46 h) was can are myelosuppression and diarrhoea. The two added later in a protocol amendment. The patients treated with 180 mg/m of liposomal rationale for protocol amendment was based on irinotecan suffered from grade 4 toxicities. One preliminary data from the PEPCOL study; a patient had grade 4 neutropaenia, while the sec- randomized phase II trial which showed liposo- ond patient developed grade 4 febrile neutropae- mal irinotecan in combination with 5-fluoroura- nia, grade 4 thrombocytopaenia with a bleeding cil/leucovorin (5-FU/LV) to have activity and an event and grade 4 diarrhoea. The dose escalation acceptable safety profile in patients with colorec- was therefore stopped and 120 mg/m was deter- tal cancer [Chibaudel et  al. 2016]. In vitro data mined to be the maximum tolerated dose [Chang suggest liposomal irinotecan may improve vas- et  al. 2015] (see Table 2). At a dose of 120 mg/ cular function thereby increasing the delivery m , the phase II trial found the majority of patients and accumulation of a second drug when used in experienced at least one grade 3/4 event. The combination [Baker et al. 2008]. three deaths that occurred within 30 days of study 164 journals.sagepub.com/home/tam E Kipps, K Young et al. Table 1. Summary table of main efficacy results from the three arms of NAPOLI-1 trial [Wang-Gillam et al. 2016]. Liposomal irinotecan + Liposomal irinotecan 5-FU/LV 5-FU/LV Median OS 6.1 months [CI 4.8–8.9] 4.9 months [CI 4.2–5.6] 4.2 months [CI 3.3–5.3] Median PFS 3.1 months [CI 2.7–4.2] 2.7 months [CI 2.1–2.9] 1.5 months [1.4–1.8] ORR 16% of patients 6% of patients 1% of patients 36% of patients 31% of patients 12% of patients Reduction in Ca19-9 ⩾50% from abnormal baseline CI, 95% confidence interval; Ca19-9, carbohydrate antigen 19-9; 5-FU, 5-fluorouracil; LV, leucovorin; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. Table 2. Summary table of trials investigating liposomal irinotecan in advanced pancreatic cancer. Phase I Phase II Phase III Chang [Chang Ko [Ko et al. Wang-Gillam [Wang-Gillam et al. 2016] et al. 2015] 2013] 3-weekly 120 3-weekly 120 3-weekly 120 2-weekly 80 mg/m 2 2 2 mg/m liposomal mg/m liposomal mg/m liposomal liposomal irinotecan irinotecan irinotecan irinotecan +5-FU/LV Patients (n) 6 40 151 149 % All grades (% grade 3 /4) Diarrhoea 100 (33.3) 75 (15) 70 (21) 59 (13) Vomiting 83.3 (66.7) 57.5 (0) 54 (14) 52 (11) Nausea 66.7 (33.7) 60 (10) 61 (5) 51 (8) Fatigue 50 (16.7) 62.5 (20) 37 (6) 40 (14) Anorexia 16.7 (0) 57.5 (10) 49 (19) 44 (4) Neutropaenia 33.3 (16.7) 40 (30) 25 (15) 39 (27) Anaemia 16.7 (0) 32.5 (15) 33 (11) 38 (9) Hypernatraemia NA 15 (15) NA NA Hypokalaemia NA NA 22 (12) 12 (3) 5-FU, 5-fluorouracil; LV, leucovorin; NA, not applicable. treatment were attributed to infection in the set- as well as more grade 4 treatment-related adverse ting of neutropaenia [Ko et  al. 2013]. Overall, events, 16% versus 10%, respectively. Moreover, one-third of patients treated with liposomal 4 of the 5 treatment-associated toxicities which 2) irinotecan, either as monotherapy (120 mg/m or resulted in death, occurred in patients being in combination (80 mg/m ) with 5-FU/LV, were treated with single-agent liposomal irinotecan. reported by Wang-Gillam and colleagues to suffer from adverse events necessitating a treatment Liposomal irinotecan, at the lower dose of (80 dose reduction, compared with only 4% of mg/m ), in combination with 5-FU/LV appears to patients treated with 5-FU/LV [Wang-Gillam be associated with a more tolerable toxicity profile et  al. 2016]. In a predefined subgroup analysis as well as improved efficacy compared with lipo- 2) recently reported, the safety profile of the combi- somal irinotecan monotherapy (120 mg/m . nation arm was generally similar across patient However, in the context of second-line treatment subgroups, apart from an increased risk of grade for metastatic pancreatic cancer, all toxicity grades ⩾3 neutropaenia and reduced neutrophil counts need to be considered and it is worth highlighting in Asian patients [Chen et al. 2016]. Single-agent that over half of patients who received liposomal liposomal irinotecan was associated with more irinotecan, as monotherapy or in combination, diarrhoea (any grade) than the combination arm reported diarrhoea, vomiting or nausea. journals.sagepub.com/home/tam 165 Therapeutic Advances in Medical Oncology 9(3) Table 3. Trials of unencapsulated irinotecan as a single agent or in combination with 5-FU in pretreated patients with advanced pancreatic cancer. Author N Treatment (cycle) Treatment Regimen Median PFS Median OS (months) (months) Yi [Yi et al., 2009] 33 Irinotecan (2W) 150mg/m 2 6.6 Takahara [Takahara 56 Irinotecan 100 mg/m D1, 8, 15, 2.9 5.3 et al., 2013] (4W) Yoo [Yoo et al., 31 Irinotecan +5FU/LV Irinotecan: 70mg /m D1+3; 1.9 3.8 2 2 2009] (2W) LV: 400mg/m D1; 5-FU: 2000 mg/m D1+2 2 2 Zaniboni [Zaniboni 50 Irinotecan +5FU/LV Irinotecan: 180mg /m D1; LV: 200mg/m 3.2 5 et al., 2012] (2W) D1+D2; 5-FU: 400 mg/m bolus D1+2 and 600 mg/m CI D1+2 Neuzillet [Neuzillet 63 FOLFIRI-1 regimen, 55 patients: Irinotecan: 3.0 6.6 Irinotecan +5FU/LV 2 2 et al., 2012] 180mg /m D1; LV:400mg/ m D1; 5-FU: 400 (2W) 2 2 mg/m bolus D1 and 2400 mg/m CI D1+2 FOLFIRI-3 regimen: 8 patients Irinotecan: 100mg /m D1+3; LV: 400mg/ m D1; 5-FU: 2400 mg/m CI D1+2 N, number of patients; PFS, progression-free survival; OS, overall survival, D, Day; W, Week; LV, leucovorin; 5-FU, fluorouracil; CI, continuous infusion. Place in therapy a single agent or in combination. The efficacy of Single-agent liposomal irinotecan does not have unencapsulated irinotecan as a single agent, fol- a role in the treatment of metastatic pancreatic lowing failure of gemcitabine-based chemother- cancer in patients who have progressed on gem- apy, was studied in a phase II of 33 patients citabine-based treatment. Liposomal irinotecan treated with 150 mg/m irinotecan every 2 weeks. monotherapy at 120 mg/m performs similarly to They reported a PFS and OS of 2.0 months (95% single-agent 5-FU/LV, but has a less favourable CI, 0.7–3.3) and 6.6 months (95% CI, 5.8–7.4), toxicity profile. First-line treatment with gemcit- respectively [Yi et al. 2009] (see Table 3). A simi- abine-based chemotherapy has been standard of lar PFS of 2.7 months (95% CI, 2.1–2.9) was care for patients with metastatic pancreatic can- found in patients treated with liposomal irinote- cer for over 10 years and in October 2015 the can in the NAPOLI-1 trial, although the OS was results of NAPOLI-1 led to US FDA and EMA less, at 4.9 months (95% CI, 4.2–5.6). Toxicities approval of liposomal irinotecan in combination following different irinotecan preparations were with 5-FU/LV for the treatment of patients with directly compared in a randomized phase II trial metastatic pancreatic cancer following disease of patients with locally advanced or metastatic progression on gemcitabine-based therapy. This gastric or gastro-oesophageal junction adenocar- is the first treatment regime to be approved cinoma. Grade 3/4 neutropaenia and diarrhoea for use in the second-line setting for pancreatic was reported in 11.4% and 27.3% of patients cancer. However, as previously discussed, treated with 120 mg/m of liposomal irinotecan. FOLFIRINOX has more recently emerged as an While 15.9% and 18.2% of patients suffered alternative to gemcitabine in the first-line set- from grade 3/4 neutropaenia and diarrhoea, ting, in patients with a good PS after demon- respectively, following 300 mg/m of unencapsu- strating superior survival outcome. It is therefore lated irinotecan [Roy et al. 2013]. unclear how combination liposomal irinotecan and 5-FU/LV will be used in clinical practice The combination of unencapsulated irinotecan relative to first-line FOLFIRINOX. with 5-FU/LV has also previously been explored. In a randomized phase II trial comparing modi- Despite a clear preclinical rationale for liposomal fied FOLFOX (5-FU/LV and oxaliplatin) with preparations, the clinical efficacy and toxicity of FOLFIRI (5-FU/LV and irinotecan), the median liposomal irinotecan has not been directly com- OS of patients in the FOLFIRI arm was disap- pared with unencapsulated irinotecan in the treat- pointing at 3.8 months [Yoo et  al. 2009]. The ment of patients with pancreatic cancer either as two nonrandomized studies [Neuzillet et  al. 166 journals.sagepub.com/home/tam E Kipps, K Young et al. 2012; Zaniboni et  al. 2012] with small sample with 5-FU/LV and to compare the efficacy of sizes reported a more favourable median OS of 5 combination treatment with single-agent 5-FU/ and 6.6 months, respectively, following treat- LV [ClinicalTrials.gov identifier: NCT02697058]. ment with encapsulated irinotecan in combina- tion with 5-FU/LV using the schedules shown in Patients are also currently being recruited to Table 3. In one of these studies, Zaniboni and study the pharmacokinetic and pharmacody- colleagues reported combination treatment namic profile of BBI608 (a first-in-class cancer resulted in grade 3/4 neutropaenia and diarrhoea stem cell inhibitor), when administered in combi- in 20% and 12% of patients, respectively nation with standard chemotherapies including [Zaniboni et  al. 2012]. Interestingly, a similar combination liposomal irinotecan and 5-FU/LV incidence of grade 3/4 neutropaenia and diar- in patients with metastatic pancreatic cancer rhoea was reported in patients receiving combi- [ClinicalTrials.gov identifier: NCT02231723]. nation liposomal irinotecan and 5-FU/LV within the NAPOLI-1 trial (Table 2). There is a clear need for well-designed, rand- omized clinical trials in the second-line setting Patients with metastatic pancreatic cancer, who after FOLFIRNOX failure. The role of liposomal are well for second-line treatment, may have a irinotecan and 5-FU/LV in this setting is unclear. favourable biology and a longer survival inde- A pre-planned subgroup analysis in NAPOLI-1, pendent of choice of therapy. Although combina- showed no survival benefit of combination ther- tion treatment of liposomal irinotecan and 5FU/ apy over control, in the 12 patients who had LV met criteria for a statistically significant previously been treated with irinotecan; HR increase in OS compared with the control, the 1.25 (0.49–3.19). However, the results from overall clinical benefit to the individual patient NAPOLI-1 alter the therapeutic landscape for must be considered. A 2-weekly regime, associ- metastatic pancreatic cancer by enabling clini- ated with grade 3/4 neutropaenia in 27% of cians and patients to choose a sequential approach patients and any grade diarrhoea, nausea and to treatment. For patients in whom first-line vomiting in over 50% of patients, is not insignifi- FOLFIRINOX is not the preferred option, gem- cant in the palliative setting. Although, it must be citabine-based chemotherapy followed by liposo- noted that the quality of life of patients on combi- mal irinotecan and 5-FU/LV is a reasonable nation treatment was not reported to be appreci- treatment paradigm for a subset of patients. ably different from those allocated 5-FU/LV. Funding Despite preclinical studies suggesting otherwise, This research received no specific grant from any the toxicity profile of liposomal irinotecan does funding agency in the public, commercial, or not- not seem to be significantly better than standard for-profit sectors. unencapsulated irinotecan in vivo. It would be interesting to compare the efficacy and toxicity Conflict of interest statement profile of the two irinotecan preparations in The authors declare that there is no conflict of FOLFIRINOX, which is likely to remain the interest. treatment of choice in first-line metastatic pan- creatic cancer for patients with a good PS. 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Liposomal irinotecan in gemcitabine-refractory metastatic pancreatic cancer: efficacy, safety and place in therapy:

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688816 TAM0010.1177/1758834016688816Therapeutic Advances in Medical OncologyE. Kipps et al. research-article2017 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Liposomal irinotecan in gemcitabine- 2017, Vol. 9(3) 159 –170 DOI: 10.1177/ refractory metastatic pancreatic cancer: © The Author(s), 2017. Reprints and permissions: efficacy, safety and place in therapy http://www.sagepub.co.uk/ journalsPermissions.nav Emma Kipps, Kate Young and Naureen Starling Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy. As a direct result, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of liposomal irinotecan in this setting. However, first-line treatment options for this disease now include the combination regimen, FOLFIRINOX, in patients with good performance status, and the role of second-line combination treatment with liposomal irinotecan in this setting is unclear. Recent advances have changed the therapeutic landscape, as clinicians are now able to choose a sequential approach to treatment tailored to the individual patient characteristics. This article reviews current treatment options for metastatic PDAC and focuses on the efficacy, safety and place in therapy of liposomal irinotecan. Keywords: chemotherapy, liposomal irinotecan, metastatic pancreatic cancer, MM-398, nal-Iri, NAPOLI-1, pancreatic cancer, PDAC, PEP02, treatment Correspondence to: Introduction to pancreatic cancer [Cancer Research UK]. This poor survival is Naureen Starling Despite decades of research, pancreatic ductal multifactorial, attributed to the systemic and Royal Marsden NHS Foundation Trust adenocarcinoma (PDAC) remains one of the aggressive nature of PDAC, its complex muta- Ringgold standard most lethal malignancies. Although it is a rela- tional landscape [Waddell et  al. 2015], desmo- institution - Department of Gastrointestinal Oncology, tively uncommon cancer, due to its high mortality plastic stroma [Kleeff et al. 2007] and the current London, UK. rate it represents a significant global health bur- lack of effective therapies. naureen.starling@rmh. nhs.uk den. Worldwide in 2012 there were 338,000 new Emma Kipps cases of pancreatic cancer and 331,000 associated Surgery is the one curative treatment for PDAC Kate Young deaths [Ferlay et al. 2015]. The striking similarity but only a minority of patients present with Royal Marsden NHS Foundation Trust between incidence and deaths highlights the dis- potentially operable disease (10–20%) [Willett Ringgold standard mal prognosis of this disease. Further, by 2030 it et  al. 2005; Gandy et  al. 2016]. Further, as the institution - Department of Gastrointestinal Oncology, has been predicted that pancreatic cancer will disease is characterized by early micrometastatic London, UK surpass breast, prostate and colorectal cancer to spread [Sohal et al. 2014] long-term survival fol- become the second leading cause of cancer related lowing surgery is poor with 80% of patients expe- deaths in the United States [Rahib et al. 2014]. riencing a local or distant recurrence within 2 years [Geer et al. 1993]. More than 95% of those diagnosed with pancre- atic cancer will succumb to it and across Europe The majority of patients present with locally the 5-year overall survival (OS) ranges from 2–9% advanced inoperable (40%) or metastatic disease journals.sagepub.com/home/tam 159 Therapeutic Advances in Medical Oncology 9(3) (40–45%) where the outlook is even bleaker, with surprising considering the significant inter- a median OS of 6–11 months and 2–6 months tumoural heterogeneity seen in PDAC. In addi- respectively [Willett et  al. 2005; Sclafani et  al. tion to common alterations in KRAS, TP53, 2015; Cancer Research UK]. SMAD4 and CDKN2A [Bryant et  al. 2014], there are also a multitude of infrequently mutated genes in pancreatic cancer [Waddell et  al. 2015] Current treatment for advanced disease and the majority of the trials to date have been in unselected populations. First-line treatment Chemotherapy remains the cornerstone of treat- The one targeted agent to have demonstrated a ment for advanced PDAC. Following the Burris survival benefit in a phase III study is erlotinib in and colleagues study in 1997, single-agent gem- combination with gemcitabine versus gemcitabine citabine became the gold standard first-line treat- alone (HR 0.82, 95% CI 0.69–0.99, p = 0.038). ment for patients with advanced disease [Burris However, in the results published in 2007 the et  al. 1997]. This study demonstrated a modest numerical increase in median OS was only 12 improvement in survival of 1.24 months (5.65 days [Moore et al. 2007] with a higher incidence versus 4.41 months, p = 0.0025) with gemcitabine of adverse events, including rash, interstitial lung versus 5-fluoropyrimidine (5-FU) but became a disease and diarrhoea. The group of patients who standard treatment due to the associated incre- developed a rash of grade ⩾2 did have a more ment in clinical benefit rate from 4.2% with 5-FU clinically meaningful benefit (median OS 10.5 to 23.8% with gemcitabine. months with grade ⩾2 rash versus 5.8 months with grade 1 rash versus 5.3 months for those who Despite a myriad of trials investigating the use of did not develop a rash) but this combination is more intensive combination regimens, often with rarely used in clinical practice despite being US a gemcitabine backbone, no chemotherapy regi- FDA and EMA-approved. men was found to be superior to single-agent gemcitabine until more recently. In light of non- The first combination chemotherapy regimen to statistically significant trends in improved survival demonstrate a statistically significant survival seen with gemcitabine combinations in a number benefit versus gemcitabine in a phase III study was of large phase III studies Sultana and colleagues the ACCORD-11 study in 2011. This study dem- conducted a meta-analysis of 51 trials, including onstrated that the triplet FOLFIRINOX (5-FU, almost 10,000 patients. This demonstrated a sur- irinotecan and oxaliplatin) improved progression- vival benefit with gemcitabine combination free survival (PFS), OS and response rate (RR) chemotherapy versus gemcitabine alone [hazard when compared with single-agent gemcitabine ratio (HR) = 0.91, 95% confidence interval (CI) (OS 11.1 versus 6.8 months, HR 0.57, p < 0.001, 0.85–0.97] [Sultana et al. 2007]. The same group PFS 6.4 versus 3.3 months, HR 0.47, p < 0.001, also assessed different gemcitabine combina- RR 31.6% versus 9.4%, p < 0.001) [Conroy et al. tions and found a trend favouring gemcitabine 2011]. Unsurprisingly this increased efficacy plus capecitabine or a platinum [Sultana et  al. came at the cost of increased toxicity and this is a 2008]. Based on such analyses the National regimen for patients with excellent performance Comprehensive Cancer Network (NCCN) guide- status (PS). However, despite this increased tox- lines and recent American Society of Clinical icity the FOLFIRINOX patients had a signifi- Oncology (ASCO) guidelines include these gem- cantly longer time to deterioration in quality of citabine combinations in their recommendations life than the gemcitabine patients [Gourgou- [Sohal et al. 2016]. Bourgade et  al. 2013]. Furthermore, since the adoption of this regimen into the clinic various With the elucidation of the molecular nature of institutional series have been published suggest- pancreatic cancer, a wide variety of targeted ing modifications to the regimen to increase its agents have also been investigated, again often tolerability without reducing efficacy [Mahaseth with a gemcitabine backbone. The targets studied et al. 2013; Mantripragada et al. 2016]. have included EGFR, KRAS signalling, MEK, mTOR, HER2, VEGF and the Hedgehog path- Following ACCORD-11 the MPACT study of way, all with disappointing clinical results, despite the addition of nab-paclitaxel to gemcitabine sometimes promising preclinical and early phase reported a median OS of 8.5 months in the com- studies [Sclafani et al. 2015]. This is not entirely bination arm versus 6.7 months in the gemcitabine 160 journals.sagepub.com/home/tam E Kipps, K Young et al. alone arm (HR 0.72, p < 0.0001). Again PFS log-rank p = 0.01) with similar toxicity other than and RR were also improved (PFS 5.5 versus peripheral neuropathy which was, as would be 3.7 months, HR 0.69, p < 0.0001, RR 23% expected, higher in the oxaliplatin arm (grade 1/2 versus 7%, p < 0.001) [von Hoff et  al. 2013]. neurotoxicity: 38.3% versus 7.1%, p < 0.001) Again toxicity including sensory neuropathy was [Oettle et al. 2014]. However, the results from the increased in the combination arm, although qual- randomized phase III PANCREOX study were ity of life was not assessed, and this is a regimen not aligned with CONO-003, with patients receiv- for good PS patients. ing FOLFOX having an inferior OS than those receiving FF (6.1 versus 9.9 months, HR 1.78, p = The lack of direct comparisons of these regimens 0.02). It has been suggested that this disparity is leaves some uncertainty as to the best first-line due to a higher level of treatment discontinuation treatment for advanced PDAC and as yet there in the FOLFOX arm than the FF arm (20.4% ver- are no established biomarkers for selecting patients sus 1.9% respectively) and an imbalance in the for a particular therapy. For patients with a PS of post-discontinuation treatments received in each 2, single-agent gemcitabine remains a reasonable arm (6.8% in the FOLFOX arm and 25% in the option. For those patients who are fitter, PS 0–1, FF arm) [Gill et al. 2014]. either FOLFIRINOX or gemcitabine-nab-pacli- taxel are preferred and the decision depends on a The most recent phase III study is the NAPOLI-1 combination of factors including patient comor- trial of nanoliposomal irinotecan, which is dis- bidities, toxicity profile, consideration of central cussed in much greater detail below, and provides venous access and patient preference and reim- another second-line regimen for consideration bursement. Clinical trials in the first-line setting [Wang-Gillam et al. 2016]. are also recommended and there are currently numerous ongoing trials globally of targeted drugs Additional regimens have been investigated in with a chemotherapy backbone and increasing the second or subsequent line setting in a num- studies of immune-directed approaches. ber of small phase II studies and case series, including capecitabine and oxaliplatin (CAPOX), taxanes, 5-FU and irinotecan (FOLFIRI) as well Second and subsequent line treatment as FOLFIRINOX and gemcitabine plus nab- Historically there has been very little use of sec- paclitaxel. These studies have reported mixed ond-line chemotherapy for PDAC. However, results and such regimens require further assess- with improvements in first-line therapy for ment in larger studies [Oettle et al. 2000; Xiong advanced disease, this is now changing. et  al. 2008; Yoo et  al. 2009; Hosein et  al. 2013; Unfortunately, there is no good quality evidence Lee et al. 2013]. to support a particular regimen following first- line treatment with FOLFIRINOX or gemcit- Extrapolating from the data available it is not abine and nab-paclitaxel as the few trials of unreasonable to consider that second-line chemo- second-line treatment conducted were following therapy may provide a clinical benefit. A systemic progression on gemcitabine monotherapy. analysis of 34 second-line studies, including over 1500 patients who had progressed on gemcit- The randomized phase III CONKO-01 study abine, reported a median OS of 2.8 months for sought to establish if the combination of oxalipl- patients who received BSC and 6 months for atin, folinic acid and 5-FU (OFF) was superior to patients who received second-line treatment best supportive care (BSC). Despite terminating [Rahma et  al. 2013]. The choice of second-line early due to recruitment difficulties (n = 46 regimen then depends upon the first-line regimen patients) this study demonstrated a survival bene- used, the patients’ PS, residual toxicities and fit of 2.52 months with chemotherapy (mOS 4.82 comorbidities and in this very palliative setting it OFF versus 2.30 BSC, HR 0.45, CI: 0.24–0.83, must be remembered that toxicities and quality of p = 0.008) [Pelzer et  al. 2011]. CONKO-003, life are of paramount importance. There are even another phase III study, then evaluated whether less data to support third or subsequent line treat- oxaliplatin was required, randomizing 168 patients ment and here clinical trial entry is strongly to OFF or 5-FU and folinic acid (FF). Both encouraged for fit patients. median OS and PFS favoured the addition of oxaliplatin (mOS 5.9 months OFF versus 3.3 Overall therefore, despite the small improvements months FF, HR 0.66, 95% CI 0.48–0.91, in the treatment options for pancreatic cancer in journals.sagepub.com/home/tam 161 Therapeutic Advances in Medical Oncology 9(3) the last decade described above, prognosis 2006]. Unlike previous liposomal irinotecan remains poor and there is an urgent need to preparations [Messerer et  al. 2004], a reduced develop novel therapies, consider new combina- toxicity profile was reported, as well as increased tions and appropriately select those patients who tumour efficacy when compared with irinotecan may benefit. in animal models [Drummond et  al. 2006]. The nanoparticle consists of a lipid bilayer scaffold, which encapsulates the drug complex and facili- Introduction to irinotecan tates in vivo drug retention. A transmembrane Camptothecin is a naturally occurring cytotoxic gradient of triethylammonium cations was used alkaloid that targets topoisomerase I, a nuclear to drive the irinotecan into the liposome where enzyme that reduces the torsional stress of super- upon sucrose octasulphate, a highly charged coiled DNA during the replication, recombina- anion, trapped the irinotecan within the liposome tion, transcription, and repair of DNA (see Figure 1). [Garcia-Carbonero et  al. 2002]. Irinotecan is a synthetic derivative of camptothecin, with func- tional groups to enhance solubility and was first Pharmacokinetics, pharmacodynamics and approved by the US FDA in 1996 [Hsiang et al. pharmacogenetics 1985]. As a prodrug, it is converted in to the Preclinical in vivo pharmacokinetic studies have active metabolite SN38, predominantly in the shown liposomal encapsulation of irinotecan was liver, by carboxylesterases. SN-38 is subsequently associated with significantly longer circulation conjugated, with significant pharmacogenetic times (t = 10.7 h) compared with unencapsu- variability, into inactive, nontoxic SN38- lated irinotecan (t = 0.27 h) [Drummond et al. glucuronide (SN-38G). Both irinotecan and 2006]. At 24 h, 23.3% of injected liposomal SN-38 have a labile α-hydroxy-δ-lactone ring that irinotecan still remained, with no detectable con- undergoes pH-dependent reversible hydrolysis version to SN-38 or the carboxylate form. [Swami et  al. 2013]. In acidic conditions, the Conversely, only 2% of the injected dose of unen- more active, potent lactone form predominates, capsulated irinotecan remained at 30 min, 35% of while in more basic conditions, the inactive, less which had been converted to SN-38 and subse- toxic carboxylate form is favoured. These proper- quently conjugated to the in the inactive carboxy- ties contribute to the marked heterogeneity of the late form. A similar pharmacokinetic profile was main dose-limiting toxicities observed in patients, reported in patients by Chang and colleagues that of neutropaenia and late onset diarrhoea. [Chang et  al. 2015]. In this phase I trial, treat- The direct effect of SN-38 on intestinal epithe- ment with liposomal irinotecan at 120 mg/m was lium is thought to be responsible for irinotecan- characterized by slow clearance (mean = 0.0591 induced diarrhoea [Hecht, 1998], which can be l/m /h), small volume of distribution (mean = 1.8 severe, resulting in dose reductions or omissions l/m ≅ plasma volume) and prolonged terminal leading to ineffective treatment administration. half-life of total irinotecan in circulation (mean = 29.5 h) when compared with published pharma- There is therefore a rationale for the development cokinetic data for unencapsulated irinotecan of formulations that can improve the distribution [Chabot, 1997; Chang et  al. 2015]. The plasma and protect the premature metabolism of irinote- concentration profile of liposomal irinotecan can to achieve maximum efficacy while minimizing matched that of the total irinotecan, suggesting toxicity. Liposomal constructs have been engi- the release of irinotecan from the liposome occurs neered to improve the circulation time and intra- slowly over time. tumoural drug concentration of anthracyclines, for example, PEGylated liposomal doxorubicin The mechanism of irinotecan release is not fully [Gabizon, 2001], and nab-paclitaxel [Gradishar, understood. Preclinical models have shown lipo- 2006], but it has been difficult to replicate the somal irinotecan increases tumoural drug reten- technology in other classes of chemotherapy drugs. tion, resulting in local release and conversion into irinotecan and SN-38 [Drummond et  al. 2006]. However, the correlation between the C and max Liposomal irinotecan (MM-398, PEP02, AUC of liposomal irinotecan and the active 0-∞ nal-Iri) metabolite SN-38, reported by Chang and col- In 2006, a novel liposomal construct containing leagues, was weak [Chang et al. 2015]. This vari- irinotecan was developed [Drummond et  al. ability may be attributable to the small sample 162 journals.sagepub.com/home/tam E Kipps, K Young et al. Figure 1. A schematic of encapsulation of irinotecan inside the liposome. Irinotecan is exchanged with triethylammonium cations across the bilipid layer. size or the pharmacogenetic variability of irinote- 5 of whom were able to escalate to the standard can metabolism. dose, 2 of whom needed a further dose reduction and 1 discontinued secondary to grade 3 vomiting Patients with a genetic polymorphism in the gene [Wang-Gillam et al. 2016]. encoding uridine diphosphate glucuronosyltrans- ferase (UGT) 1A1, have a lower than normal Although early phase studies have demonstrated capacity to metabolize SN-38, the active metabo- the different pharmacokinetic and toxicity pro- lite of irinotecan. UGT conjugates SN-38 into files of patients homozygous and heterozygous for the inactive SN-38 glucuronide (SN-38G). The the UGT1A1*28 allele, the available data are not presence of the UGT1A1*28 allele, present in conclusive for defining a precise genotype-based approximately 17% of Whites [Lampe et  al. dosage [Toffoli et  al. 2006; Biason et  al. 2008; 1999], has been shown to cause a 70% reduction Palomaki et al. 2009]. There are therefore no cur- in expression of UGT, leading to an increased rent guidelines on how UGT1A1 testing could be exposure of patients to the cytotoxic metabolite, used to effect treatment with clinical practice. SN-38. Patients homozygous for the UGT1A1*28 allele are 3.5 times more likely to suffer from grade 3/4 toxicities [Palomaki et  al. 2009] and Clinical Efficacy may benefit from a dose reduction of up to 40% Preclinical in vivo efficacy data have shown the [Innocenti et al. 2014]. enhanced anti-tumour effect of liposomal irinote- can compared with equivalent dose of free irinote- In a phase I trial, a woman with heterozygosity of can in human pancreatic cancer cell line xenograft UGT1A1*6/*28 died from grade 4 diarrhoea and mouse models [Hann et  al. 2007]. Chang and was found to have C and AUC of SN-38 colleagues reported the results of a phase I dose- max 0-∞ that were 3-times higher than in other patients escalation study of liposomal irinotecan, in 11 treated at the same dose [Chang et  al. 2015]. patients with treatment refractory advanced solid Moreover, in a recent phase III study, the dose of tumours [Chang et al. 2015]. Liposomal irinote- liposomal irinotecan was reduced by 25% in 14 can was delivered as a 90-min intravenous infu- patients homozygous for the UGT1A1*28 allele, sion every 21 days. Overall, two patients, journals.sagepub.com/home/tam 163 Therapeutic Advances in Medical Oncology 9(3) including one patient with pancreatic cancer who In NAPOLI-1, OS was the primary endpoint and was treated with the higher dose of 180 mg/m , patients were stratified by baseline albumin level, achieved a partial response to treatment. The dis- PS and ethnicity. Although all patients had previ- ease control rate was 45% for the intention-to- ously been treated with gemcitabine, 12% of treat population. patients had received this in the neoadjuvant, adjuvant or locally advanced setting. Interestingly, The favourable pharmacokinetics described in over half the patients enrolled had previously this study, led to a nonrandomized phase II trial been treated with fluorouracil or irinotecan-based that sought to establish the efficacy and toxicity of regimes; 56% and 15%, respectively. single-agent liposomal irinotecan, at 120 mg/m 3-weekly, in patients with metastatic pancreatic Median OS was 6.1 months in the combination cancer after progression following first-line gem- arm and 4.2 months in those assigned 5-FU/LV citabine-based chemotherapy [Ko et al. 2013]. A control (HR 0.67, 95% CI 0.49–0.92; p = total of 40 patients were enrolled, 60% of whom 0.012). In patients who were allocated liposomal had a Karnofsky score of 90–100. The protocol irinotecan monotherapy, median OS was 4.9 was amended during the second stage of the study months, which was not significantly different to to permit a starting dose of 100 mg/m . However, the control arm, (HR 0.99, 95% CI 0.77–1.28; 27 of the 40 patients remained on 120 mg/m for p = 0.94) (see Table 1). Interestingly, quality of the duration of their treatment. The mean and life scores and clinical benefit response did not median number of cycles received was, 5.88 and differ significantly between treatment groups. 2.5, respectively. Half of the patients achieved The authors acknowledge that using a different disease control defined as objective response 5-FU/LV regimen in the combination arm to the (7.5% of patients) or stable disease for more than control arm is not standard design but argue it two cycles (42.5% of patients). The median PFS was unlikely to have created bias in favour of the and OS were, 2.4 and 5.2 months, respectively. investigational arm which delivered lower dose intensities of 5-FU. This phase II study provided evidence of antitu- mour activity and led to the pivotal NAPOLI-1 In a pre-planned analysis of each subgroup, OS trial of liposomal irinotecan in advanced pancre- was increased in patients with poorer prognostic atic cancer [Wang-Gillam et  al. 2016]. Wang- features who were treated in the combination arm Gillam and colleagues published the results from compared with those treated with 5-FU/LV; this global, randomized, open-label, phase III lower PS (Karnofsky score 70–80), albumin study in which 417 patients previously treated <40 g/l, Ca19-9 ⩾40 U/ml, liver metastases, with gemcitabine-based chemotherapy, were stage IV at diagnosis and patients whose time assigned to receive either, liposomal irinotecan from diagnosis to enrolment was less than the monotherapy (120 mg/m ) every 3 weeks or median. However, it should be noted that patients folinic acid and fluorouracil (2000 mg/m over with a Karnofsky score <70% or an albumin 24 h every week for the first 4 weeks of every <30 g/l were not included in the study. 6-week cycle, based on the CONKO-003 trial [Oettle et  al. 2014]. A third arm, consisting of 2-weekly combination treatment of liposomal Safety irinotecan (80 mg/m ) with folinic acid and fluo- The dose-limiting toxicities for liposomal irinote- rouracil (2400 mg/m infusion over 46 h) was can are myelosuppression and diarrhoea. The two added later in a protocol amendment. The patients treated with 180 mg/m of liposomal rationale for protocol amendment was based on irinotecan suffered from grade 4 toxicities. One preliminary data from the PEPCOL study; a patient had grade 4 neutropaenia, while the sec- randomized phase II trial which showed liposo- ond patient developed grade 4 febrile neutropae- mal irinotecan in combination with 5-fluoroura- nia, grade 4 thrombocytopaenia with a bleeding cil/leucovorin (5-FU/LV) to have activity and an event and grade 4 diarrhoea. The dose escalation acceptable safety profile in patients with colorec- was therefore stopped and 120 mg/m was deter- tal cancer [Chibaudel et  al. 2016]. In vitro data mined to be the maximum tolerated dose [Chang suggest liposomal irinotecan may improve vas- et  al. 2015] (see Table 2). At a dose of 120 mg/ cular function thereby increasing the delivery m , the phase II trial found the majority of patients and accumulation of a second drug when used in experienced at least one grade 3/4 event. The combination [Baker et al. 2008]. three deaths that occurred within 30 days of study 164 journals.sagepub.com/home/tam E Kipps, K Young et al. Table 1. Summary table of main efficacy results from the three arms of NAPOLI-1 trial [Wang-Gillam et al. 2016]. Liposomal irinotecan + Liposomal irinotecan 5-FU/LV 5-FU/LV Median OS 6.1 months [CI 4.8–8.9] 4.9 months [CI 4.2–5.6] 4.2 months [CI 3.3–5.3] Median PFS 3.1 months [CI 2.7–4.2] 2.7 months [CI 2.1–2.9] 1.5 months [1.4–1.8] ORR 16% of patients 6% of patients 1% of patients 36% of patients 31% of patients 12% of patients Reduction in Ca19-9 ⩾50% from abnormal baseline CI, 95% confidence interval; Ca19-9, carbohydrate antigen 19-9; 5-FU, 5-fluorouracil; LV, leucovorin; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. Table 2. Summary table of trials investigating liposomal irinotecan in advanced pancreatic cancer. Phase I Phase II Phase III Chang [Chang Ko [Ko et al. Wang-Gillam [Wang-Gillam et al. 2016] et al. 2015] 2013] 3-weekly 120 3-weekly 120 3-weekly 120 2-weekly 80 mg/m 2 2 2 mg/m liposomal mg/m liposomal mg/m liposomal liposomal irinotecan irinotecan irinotecan irinotecan +5-FU/LV Patients (n) 6 40 151 149 % All grades (% grade 3 /4) Diarrhoea 100 (33.3) 75 (15) 70 (21) 59 (13) Vomiting 83.3 (66.7) 57.5 (0) 54 (14) 52 (11) Nausea 66.7 (33.7) 60 (10) 61 (5) 51 (8) Fatigue 50 (16.7) 62.5 (20) 37 (6) 40 (14) Anorexia 16.7 (0) 57.5 (10) 49 (19) 44 (4) Neutropaenia 33.3 (16.7) 40 (30) 25 (15) 39 (27) Anaemia 16.7 (0) 32.5 (15) 33 (11) 38 (9) Hypernatraemia NA 15 (15) NA NA Hypokalaemia NA NA 22 (12) 12 (3) 5-FU, 5-fluorouracil; LV, leucovorin; NA, not applicable. treatment were attributed to infection in the set- as well as more grade 4 treatment-related adverse ting of neutropaenia [Ko et  al. 2013]. Overall, events, 16% versus 10%, respectively. Moreover, one-third of patients treated with liposomal 4 of the 5 treatment-associated toxicities which 2) irinotecan, either as monotherapy (120 mg/m or resulted in death, occurred in patients being in combination (80 mg/m ) with 5-FU/LV, were treated with single-agent liposomal irinotecan. reported by Wang-Gillam and colleagues to suffer from adverse events necessitating a treatment Liposomal irinotecan, at the lower dose of (80 dose reduction, compared with only 4% of mg/m ), in combination with 5-FU/LV appears to patients treated with 5-FU/LV [Wang-Gillam be associated with a more tolerable toxicity profile et  al. 2016]. In a predefined subgroup analysis as well as improved efficacy compared with lipo- 2) recently reported, the safety profile of the combi- somal irinotecan monotherapy (120 mg/m . nation arm was generally similar across patient However, in the context of second-line treatment subgroups, apart from an increased risk of grade for metastatic pancreatic cancer, all toxicity grades ⩾3 neutropaenia and reduced neutrophil counts need to be considered and it is worth highlighting in Asian patients [Chen et al. 2016]. Single-agent that over half of patients who received liposomal liposomal irinotecan was associated with more irinotecan, as monotherapy or in combination, diarrhoea (any grade) than the combination arm reported diarrhoea, vomiting or nausea. journals.sagepub.com/home/tam 165 Therapeutic Advances in Medical Oncology 9(3) Table 3. Trials of unencapsulated irinotecan as a single agent or in combination with 5-FU in pretreated patients with advanced pancreatic cancer. Author N Treatment (cycle) Treatment Regimen Median PFS Median OS (months) (months) Yi [Yi et al., 2009] 33 Irinotecan (2W) 150mg/m 2 6.6 Takahara [Takahara 56 Irinotecan 100 mg/m D1, 8, 15, 2.9 5.3 et al., 2013] (4W) Yoo [Yoo et al., 31 Irinotecan +5FU/LV Irinotecan: 70mg /m D1+3; 1.9 3.8 2 2 2009] (2W) LV: 400mg/m D1; 5-FU: 2000 mg/m D1+2 2 2 Zaniboni [Zaniboni 50 Irinotecan +5FU/LV Irinotecan: 180mg /m D1; LV: 200mg/m 3.2 5 et al., 2012] (2W) D1+D2; 5-FU: 400 mg/m bolus D1+2 and 600 mg/m CI D1+2 Neuzillet [Neuzillet 63 FOLFIRI-1 regimen, 55 patients: Irinotecan: 3.0 6.6 Irinotecan +5FU/LV 2 2 et al., 2012] 180mg /m D1; LV:400mg/ m D1; 5-FU: 400 (2W) 2 2 mg/m bolus D1 and 2400 mg/m CI D1+2 FOLFIRI-3 regimen: 8 patients Irinotecan: 100mg /m D1+3; LV: 400mg/ m D1; 5-FU: 2400 mg/m CI D1+2 N, number of patients; PFS, progression-free survival; OS, overall survival, D, Day; W, Week; LV, leucovorin; 5-FU, fluorouracil; CI, continuous infusion. Place in therapy a single agent or in combination. The efficacy of Single-agent liposomal irinotecan does not have unencapsulated irinotecan as a single agent, fol- a role in the treatment of metastatic pancreatic lowing failure of gemcitabine-based chemother- cancer in patients who have progressed on gem- apy, was studied in a phase II of 33 patients citabine-based treatment. Liposomal irinotecan treated with 150 mg/m irinotecan every 2 weeks. monotherapy at 120 mg/m performs similarly to They reported a PFS and OS of 2.0 months (95% single-agent 5-FU/LV, but has a less favourable CI, 0.7–3.3) and 6.6 months (95% CI, 5.8–7.4), toxicity profile. First-line treatment with gemcit- respectively [Yi et al. 2009] (see Table 3). A simi- abine-based chemotherapy has been standard of lar PFS of 2.7 months (95% CI, 2.1–2.9) was care for patients with metastatic pancreatic can- found in patients treated with liposomal irinote- cer for over 10 years and in October 2015 the can in the NAPOLI-1 trial, although the OS was results of NAPOLI-1 led to US FDA and EMA less, at 4.9 months (95% CI, 4.2–5.6). Toxicities approval of liposomal irinotecan in combination following different irinotecan preparations were with 5-FU/LV for the treatment of patients with directly compared in a randomized phase II trial metastatic pancreatic cancer following disease of patients with locally advanced or metastatic progression on gemcitabine-based therapy. This gastric or gastro-oesophageal junction adenocar- is the first treatment regime to be approved cinoma. Grade 3/4 neutropaenia and diarrhoea for use in the second-line setting for pancreatic was reported in 11.4% and 27.3% of patients cancer. However, as previously discussed, treated with 120 mg/m of liposomal irinotecan. FOLFIRINOX has more recently emerged as an While 15.9% and 18.2% of patients suffered alternative to gemcitabine in the first-line set- from grade 3/4 neutropaenia and diarrhoea, ting, in patients with a good PS after demon- respectively, following 300 mg/m of unencapsu- strating superior survival outcome. It is therefore lated irinotecan [Roy et al. 2013]. unclear how combination liposomal irinotecan and 5-FU/LV will be used in clinical practice The combination of unencapsulated irinotecan relative to first-line FOLFIRINOX. with 5-FU/LV has also previously been explored. In a randomized phase II trial comparing modi- Despite a clear preclinical rationale for liposomal fied FOLFOX (5-FU/LV and oxaliplatin) with preparations, the clinical efficacy and toxicity of FOLFIRI (5-FU/LV and irinotecan), the median liposomal irinotecan has not been directly com- OS of patients in the FOLFIRI arm was disap- pared with unencapsulated irinotecan in the treat- pointing at 3.8 months [Yoo et  al. 2009]. The ment of patients with pancreatic cancer either as two nonrandomized studies [Neuzillet et  al. 166 journals.sagepub.com/home/tam E Kipps, K Young et al. 2012; Zaniboni et  al. 2012] with small sample with 5-FU/LV and to compare the efficacy of sizes reported a more favourable median OS of 5 combination treatment with single-agent 5-FU/ and 6.6 months, respectively, following treat- LV [ClinicalTrials.gov identifier: NCT02697058]. ment with encapsulated irinotecan in combina- tion with 5-FU/LV using the schedules shown in Patients are also currently being recruited to Table 3. In one of these studies, Zaniboni and study the pharmacokinetic and pharmacody- colleagues reported combination treatment namic profile of BBI608 (a first-in-class cancer resulted in grade 3/4 neutropaenia and diarrhoea stem cell inhibitor), when administered in combi- in 20% and 12% of patients, respectively nation with standard chemotherapies including [Zaniboni et  al. 2012]. Interestingly, a similar combination liposomal irinotecan and 5-FU/LV incidence of grade 3/4 neutropaenia and diar- in patients with metastatic pancreatic cancer rhoea was reported in patients receiving combi- [ClinicalTrials.gov identifier: NCT02231723]. nation liposomal irinotecan and 5-FU/LV within the NAPOLI-1 trial (Table 2). There is a clear need for well-designed, rand- omized clinical trials in the second-line setting Patients with metastatic pancreatic cancer, who after FOLFIRNOX failure. The role of liposomal are well for second-line treatment, may have a irinotecan and 5-FU/LV in this setting is unclear. favourable biology and a longer survival inde- A pre-planned subgroup analysis in NAPOLI-1, pendent of choice of therapy. Although combina- showed no survival benefit of combination ther- tion treatment of liposomal irinotecan and 5FU/ apy over control, in the 12 patients who had LV met criteria for a statistically significant previously been treated with irinotecan; HR increase in OS compared with the control, the 1.25 (0.49–3.19). However, the results from overall clinical benefit to the individual patient NAPOLI-1 alter the therapeutic landscape for must be considered. A 2-weekly regime, associ- metastatic pancreatic cancer by enabling clini- ated with grade 3/4 neutropaenia in 27% of cians and patients to choose a sequential approach patients and any grade diarrhoea, nausea and to treatment. For patients in whom first-line vomiting in over 50% of patients, is not insignifi- FOLFIRINOX is not the preferred option, gem- cant in the palliative setting. Although, it must be citabine-based chemotherapy followed by liposo- noted that the quality of life of patients on combi- mal irinotecan and 5-FU/LV is a reasonable nation treatment was not reported to be appreci- treatment paradigm for a subset of patients. ably different from those allocated 5-FU/LV. Funding Despite preclinical studies suggesting otherwise, This research received no specific grant from any the toxicity profile of liposomal irinotecan does funding agency in the public, commercial, or not- not seem to be significantly better than standard for-profit sectors. unencapsulated irinotecan in vivo. It would be interesting to compare the efficacy and toxicity Conflict of interest statement profile of the two irinotecan preparations in The authors declare that there is no conflict of FOLFIRINOX, which is likely to remain the interest. treatment of choice in first-line metastatic pan- creatic cancer for patients with a good PS. 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Journal

Therapeutic Advances in Medical OncologySAGE

Published: Mar 1, 2017

Keywords: chemotherapy; liposomal irinotecan; metastatic pancreatic cancer; MM-398; nal-Iri; NAPOLI-1; pancreatic cancer; PDAC; PEP02; treatment

References