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Moving beyond vascular endothelial growth factor-targeted therapy in renal cell cancer: latest evidence and therapeutic implications:

Moving beyond vascular endothelial growth factor-targeted therapy in renal cell cancer: latest... 687261 TAM0010.1177/1758834016687261Therapeutic Advances in Medical OncologyC-K Tsao, B Liaw research-article2017 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Moving beyond vascular endothelial growth 2017, Vol. 9(4) 287 –298 DOI: 10.1177/ factor-targeted therapy in renal cell cancer: © The Author(s), 2017. Reprints and permissions: latest evidence and therapeutic implications http://www.sagepub.co.uk/ journalsPermissions.nav Che-Kai Tsao, Bobby Liaw, Catherine He, Matthew D. Galsky, John Sfakianos and William K. Oh Abstract: Renal cell cancer (RCC) continues to be among the most lethal malignancies in the USA. Introduction of anti-vascular epidermal growth factor receptor tyrosine kinase inhibitors over a decade ago resulted in improvement in disease outcomes, but further development of new therapies largely stagnated for many years. More recently, a better understanding of disease biology and treatment-resistance patterns has led to a second renaissance in drug development, with the anti-programmed cell death protein 1 immune checkpoint inhibitor, nivolumab, paving the way for additional therapies entering clinical trial testing in the treatment of RCC. Keywords: clear cell, immunotherapy, renal cell carcinoma, targeted therapies, vascular epidermal growth factor Correspondence to: Introduction clinical trial testing for the treatment of RCC. Che-Kai Tsao, MD Metastatic renal cell cancer (RCC) continues to be Here, we will focus on emerging therapies for clear Division of Hematology and Medical Oncology, among the most lethal malignancies in the USA, cell (cc) RCC beyond VEGF-R inhibition. Icahn School of Medicine with an estimated 14,080 deaths alone in 2015. at Mount Sinai, The Tisch Cancer Institute, 1 Gustave Nephrectomy remains the mainstay of treatment L Levy Place, New York, for localized disease, but a subset of these patients Treatment of metastatic ccRCC: historical NY 10029, USA 2 che-kai.tsao@mssm.edu eventually develops metastatic disease. Prognosis challenges Bobby Liaw, MD to date remains poor, as RCC is predominantly Catherine He, MD resistant to cytotoxic chemotherapy. While Failure of cytotoxic chemotherapy Matthew D. Galsky, MD Division of Hematology cytokine immunostimulatory therapy can lead to While chemotherapy is widely considered a stand- and Medical Oncology, The disease control for some, significant toxicities have ard treatment for patients with predominantly Tisch Cancer Institute, Icahn School of Medicine largely limited their use. The introduction of anti- sarcomatoid and collecting duct RCC variants, its at Mount Sinai, New York, vascular epidermal growth factor receptor role in treating ccRCC is poorly defined. Several NY, USA John Sfakianos, MD (VEGF-R) tyrosine kinase inhibitors (TKIs) has regimens have demonstrated only modest activity Department of Urology, resulted in improvement in disease outcomes, in early phase clinical trials, and there are almost Icahn School of Medicine at Mount Sinai, New York, including overall survival (OS). However, for many no phase III clinical trials evaluating the utility of NY, USA years, development of treatment beyond VEGF- cytotoxic chemotherapy in metastatic RCC. William K. Oh, MD targeted therapies has largely stagnated. More Division of Hematology and Medical Oncology, The recently, however, a better understanding of dis- The mechanisms of resistance to chemotherapy Tisch Cancer Institute, ease biology and treatment-resistance patterns is in RCC remain undefined. Reduction of intra- Icahn School of Medicine at Mount Sinai, New York, leading to a second renaissance in drug develop- cellular drug accumulation via overexpression of NY, USA ment, with the anti- programmed cell death pro- transporter efflux pump permeability glycopro- tein 1 (PD-1) immune checkpoint inhibitor tein was not seen to be an important mediator in nivolumab and multitargeted TKI cabozantinib in vitro studies. Another hypothesis is that paving the way for additional therapies entering molecular drug target  alterations may confer journals.sagepub.com/home/tam 287 Therapeutic Advances in Medical Oncology 9(4) chemotherapy resistance in RCC. Acquired Immunostimulatory therapy: cytokine mutation in the Von Hippel–Lindau (VHL) gene immunotherapy is commonly seen in ccRCC, and its inactivation The lack of sensitivity to cytotoxic chemotherapy leads to the intracellular accumulation of for most patients with mRCC prompted research hypoxia-inducible factor (HIF), a microtubule- efforts for novel approaches. Spontaneous tumor dependent transcription factor of genes involved regressions in mRCC after cytoreductive nephrec- in angiogenesis and tumor cell proliferation and tomy, with the observation that immune cells survival. Antimicrotubule chemotherapies are often infiltrate the tumor tissue, suggested that 6,7 ineffective in RCC, but no mutations have adaptive immunity might play an important role 15,16 been identified in tubulin drug-binding sites for in this malignancy. This hypothesis led to taxanes to account for this resistance. One immunostimulatory trials with interleukin-2 (IL- hypothesis is that RCC has altered expression of 2) and interferon alpha (IFN-α). tubulin isotypes, resulting in changes in microtu- bule dynamics as well as drug binding. VHL has been associated with regulation of microtubule IL-2 dynamics, suggesting that the loss of VHL may In phase II clinical trials, high-dose recombinant affect taxane resistance. Microtubule inhibitors IL-2 achieved 7% complete responses (CR) and have been shown to be potent inhibitors of HIF-1 8% partial responses (PR) in 25 patients with 17,18 expression and activity, thus HIF inhibition mRCC. Long-term durability of the treat- downstream of microtubule perturbation is a key ment response in this small subset of responding determinant in the clinical response to antitubu- patients was likely due to the ability of IL-2 to lin therapy. RCC is the lone tumor type where modulate T-cell proliferation and differentiation. microtubule-targeting drugs fail to suppress Patients that achieved CR had a median duration HIF-1, independently of VHL functional sta- of response exceeding 80 months, and those that 11 19 tus. These data suggest that the HIF-signaling achieved PR, 20 months. Though these figures axis has been uncoupled from microtubule con- remain unrivaled by current-generation VEGF- trol in RCC, and thus deregulation of the micro- targeted therapy, the general adoption of high- tubule/HIF axis in RCC may contribute to taxane dose IL-2 has been hindered by its low response resistance. rate and significant toxicity profile, including a 20,21 4% risk of treatment-related mortality. Intratumoral heterogeneity While some systemic therapies may lead to tumor IFN-α shrinkage and alleviation of symptoms in meta- The ability of IFN-α to regulate anti-angiogenesis static (m) RCC, resistance ensues when the dis- and immune functions translates to a response ease resorts to alternative pathways to drive rate of approximately 12% when used as mono- angiogenesis and cell proliferation, either through therapy in mRCC, and confers a modest survival adaptation of individual tumor cells or selection benefit of 3.8 months in the pooled data of four of surviving cells that are already using alternative clinical trials over the control arm, although cases pathways. Ideally, one can characterize tumors of long-term durable responses have been 22,23 individually based on DNA sequencing and other reported. Combining IFN-α with other agents means, leading to selection of the specific path- has typically yielded additional modest clinical ways that drive cell proliferation, an approach benefits. Most notably, the AVOREN and also known as ‘personalized medicine’. However, CALGB 90206 trials randomized treatment-naïve this methodology has largely been limited by mRCC patients to receive IFN-α with or without 25,26 extensive intratumoral heterogeneity; varying bevacizumab. While both phase III studies gene expression signatures can be detected even found a consistent improvement in progression- within the same tumor specimen in samples of free survival (PFS) (AVOREN: 10.2 months ver- 12,13 those with RCC. This largely limits the utility sus 5.4 months, hazard ratio [HR] = 0.63; of prognostic impact of biomarkers and, in addi- CALGB 90206: 8.5 months versus 5.2 months, tion, spatial variation in genetic and phenotypic HR = 0.71) and overall response rates (ORR) properties poses a significant obstacle for optimal (AVOREN: 31% versus 13%; CALGB 90206: 14 8,9 personalized treatment. 25.5% versus 13.1%), neither met significance 288 journals.sagepub.com/home/tam C-K Tsao, B Liaw et al. for OS benefit (AVOREN: 23.3 months versus noninferior to sunitinib for the primary endpoint 21.3 months, HR = 0.86; CALGB 90206: 18.3 of PFS (8.4 months versus 9.5 months, HR = months versus 17.4 months, HR = 0.86). 1.05, 95% CI: 0.71–1.16) and secondary end- point of OS (28.3 months versus 29.1 months, 33,34 HR = 0.92, 95% CI: 0.79–1.01). However, VEGF and mechanistic target of rapamycin health-related quality of life measures and patient inhibitors: a paradigm shift for mRCC preference favored pazopanib in two different therapy randomized studies. Deeper insight into the somatic genetics of heredi- tary ccRCC led to the identification of the VHL Axitinib and sorafenib both demonstrate PFS tumor suppressor gene. Its interaction with HIF benefit as second-line agents, though axitinib plays a key role not only in inherited disease, but outperformed sorafenib (AXIS: 8.3 months ver- also in sporadic forms of RCC. Inactivation or sus 5.7 months, HR = 0.66, 95% CI: 0.55– loss of the VHL gene product prevents ubiquitin- 0.78), whereas sorafenib was only compared mediated degradation of HIF-1a/2a leading to with placebo (5.5 months versus 2.8 months, upregulation and constitutive expression of pro- HR = 0.44, 95% CI: 0.35–0.55) in randomized 36–38 angiogenesis agents, including VEGF, erythropoi- trials. It is noteworthy that the PFS benefit etin, platelet-derived growth factor (PDGF), of axitinib in AXIS is less prominent in patients transforming growth factor-beta, and carbonic previously treated with first-line VEGF-TKI anhydrase IX. These angiogenic signals confer the compared with those treated with first-line ability to proliferate under hypoxic conditions, cytokine therapy. driving oncogenesis, and accounts for the hyper- vascular nature of VHL-associated neoplasms. This was the basis for exploring anti-angiogenic VEGF-R monoclonal antibody therapy targeting VEGF. Multiple VEGF path- Bevacizumab is a monoclonal antibody that binds way inhibitors have been subsequently developed the ligand, VEGF, preventing its interaction with and approved for mRCC. As a therapeutic class, VEGF-R and its downstream effects. Two large VEGF pathway inhibitors have consistently out- phase III trials (AVOREN and CALGB 90206) performed IFN or placebo in randomized phase randomized treatment-naïve mRCC patients to III trials, and have become accepted as the pre- receive bevacizumab plus IFN-α or placebo plus ferred first-line therapy for mRCC. IFN-α. A consistent PFS benefit was associated with bevacizumab in both AVOREN (10.2 months versus 5.4 months, HR = 0.63, 95% CI: VEGF-R TKIs 0.52–0.75) and CALGB 90206 (8.5 months ver- Multiple VEGF-R TKIs have demonstrated effi- sus 5.2 months, HR = 0.71, 95% CI: 0.61–0.83), cacy in RCC (Table 1), with sunitinib and pazo- as well as ORR improvement (AVOREN: 31% panib both approved for first-line treatment in versus 13%; CALGB 90206: 25.5% versus 39,40 those with metastatic disease. Sunitinib showed 13.1%). Neither trial met significance for OS improved PFS (11 months versus 5 months, HR benefit, though a trend towards better survival 41,42 = 0.42, 95% confidence interval [CI]: 0.32– was observed in both studies. Combining 0.54), ORR (47% versus 12%), and trend for bevacizumab with sorafenib or temosirolimus has superior OS (26.4 months versus 21.8 months, not been shown to improve PFS compared with HR = 0.82, 95% CI: 0.67–1.01) compared with bevacizumab alone, and no trials to date have IFN-α in treatment-naïve mRCC. Pazopanib compared bevacizumab plus IFN-α with bevaci- similarly demonstrated a first-line PFS benefit zumab monotherapy. (9.2 months versus 4.2 months, HR = 0.46, 95% CI: 0.34–0.62) and ORR improvement (30% ver- sus 3%) compared with placebo, though no OS Mechanistic target of rapamycin inhibitors improvement was seen (22.9 months versus 20.5 In addition to VEGF pathway inhibition, months, HR = 0.91, 95% CI: 0.71–1.16), likely upstream target mechanistic target of rapamycin 31,32 due to the high crossover rate. Head-to-head (mTOR) was identified as another therapeutic comparison of these TKIs in the phase III target for mRCC. mTOR has the potential to COMPARZ trial showed that pazopanib was inhibit tumor growth via regulating cell growth, journals.sagepub.com/home/tam 289 Therapeutic Advances in Medical Oncology 9(4) Table 1. Phase III trials in metastatic renal cell carcinoma. Study Treatment arms n ORR mPFS mOS (%) (months) (months) 4,6 First-line AVOREN Bevacizumab + IFN-α 649 31 versus 13 10.4 versus 5.5 23.3 versus 21.3 therapy versus IFN-α 5,7 CALGB 90206 732 25.5 versus 13.1 8.5 versus 5.2 18.3 versus 17.4 Motzer et al. Sunitinib versus IFN-α 750 47 versus 12 11 versus 5 26.4 versus 21.8 9,10 Global ARCC Temsirolimus versus 626 8.6 versus 4.8 5.5 versus 3.1 10.9 versus 7.3 IFN-α Motzer et al. Everolimus versus 416 1 versus 0 4.9 versus 1.9 14.8 versus 14.4 27,28 2008 placebo 11,12 VEG105192 Pazopanib versus 233 30 versus 3 11.1 versus 2.8 22.9 versus 20.5 placebo Hutson et al. Axitinib versus 288 32 versus 15 10.1 versus 6.5 N/A 2013 sorafenib 13,14 COMPARZ Pazopanib versus 1110 31 versus 25 8.4 versus 9.5 28.4 versus 29.3 sunitinib 18,30 Second-line TARGET Sorafenib versus 903 10 versus 2 5.5 versus 2.8 17.8 versus 15.2 therapy placebo 16,17 AXIS Axitinib versus 723 23 versus 12 8.3 versus 5.7 20.1 versus 19.2 sorafenib INTORSECT Temsirolimus versus 512 8 versus 8 4.3 versus 3.9 12.3 versus 16.6 sorafenib METEOR Cabozantinib versus 658 21 versus 5 7.4 versus 3.8 NR, HR 0.67 everolimus CheckMate 025 Nivolumab versus 821 25 versus 5 4.6 versus 4.4 25.0 versus 19.6 everolimus Bold: denotes statistically significant. HR, hazard ratio; IFN-α, interferon alfa; mOS, median overall survival; mPFS, median progression-free survival; N/A, not applicable; NR, not reached; ORR, overall response rate. cell-cycle progression, angiogenesis, and response everolimus is generally better tolerated, axitinib is to hypoxic stress through the HIF-1a pathway. associated with a higher response rate albeit simi- However, recent data suggest a more modest role lar PFS benefit. With more promising therapies for mTOR inhibitors in the management of becoming available in the armamentarium of mRCC. While temsirolimus originally demon- RCC treatment, both therapies have been rele- strated a significant OS benefit over IFN-α (10.9 gated to later lines of therapy. months versus 7.3 months, HR = 0.73, 95% CI: 0.58–0.92) in the first-line setting for poor-risk mRCC, as a second-line therapy it was associated A new era in immunotherapy in mRCC: anti- with a worse OS when compared with sorafenib PD1/programmed death ligand-1 checkpoint (12.3 months versus 16.6 months, HR = 1.31, inhibitors 45,46 95% CI: 1.05–1.63). Similarly, everolimus The interaction between PD-1 (present on T failed to show noninferiority for PFS against suni- cells), and one of its ligands (PD-L1) (present on tinib (7.4 months versus 10.7 months, HR = 1.4, antigen-presenting cells and tumor cells) consti- 95% CI: 1.2–1.8) as first-line therapy. For tutes an immune checkpoint through which years, treatment after progression on first-line tumors can induce T-cell tolerance and avoid VEGF-R TKI remained controversial; while immune destruction. A retrospective analysis of 290 journals.sagepub.com/home/tam C-K Tsao, B Liaw et al. 306 patients who underwent nephrectomy for VEGF-R TKI on 25 November 2015. Other ccRCC at the Mayo Clinic from 1990 to 1994 anti-PD-1 antibodies (MK-3745) and anti-PD- revealed that patients whose tissue demonstrated L1 (MPDL3280A) inhibitors are currently in expression of PD-L1 (B7-H1) had significantly clinical trial testing, as are combinations with worse 5-year cancer-specific survival (41.9%) other modalities (cytokine therapy, VEGF-R when compared with those whose tumors did not inhibitors, and other immune checkpoint inhibi- express PD-L1 (82.9%), suggesting that blocking tors) (Table 2). the interaction of PD-L1 with PD-1 might reverse tumor-induced immune tolerance and serve as an attractive approach for RCC therapy. Similar to Promising novel therapies: the next steps results seen in murine models, initial phase I For years, development of treatment beyond studies of MDX-1106/BMS-936558/ONO-4538 VEGF-targeted therapies had been largely (nivolumab) (Bristol-Myers Squibb, New York, unsuccessful. More recently, better understand- USA) demonstrated that antibody-mediated ing of disease biology and treatment-resistance blockade of PD-1 induced durable tumor regres- patterns has led to the introduction of effective sion and prolonged stabilization of disease in therapies adding to inhibitors of VEGF-R sign- patients with various advanced cancers, including aling (Figure 1). Here, we will focus on those mRCC. A subsequent phase II study evaluated emerging therapies for ccRCC beyond VEGF-R 168 patients with mRCC who had received 1–3 inhibition. prior anti-angiogenic therapies, randomized to receive nivolumab at doses of 0.3 mg/kg (n = 60), 2.0 mg/kg (n = 54), or 10.0 mg/kg (n = 54) every Targeted TKIs 3 weeks until disease progression or unacceptable toxicity. A manageable safety profile was seen MET/AXL inhibition across all three doses, with notable antitumor The MET pathway plays a crucial role in the acti- activity seen, supporting phase III testing. vation of key oncogenic signaling pathways (RAS, PI2K, STAT3) and angiogenesis, while the AXL CheckMate 025 is a randomized, open-label, pathway is involved in epithelial-mesenchymal phase III study that compared nivolumab with transition and cancer metastasis. Cabozantinib everolimus in patients with mRCC who had (formerly known as XL-184) inhibits MET and received one or two prior anti-angiogenic thera- AXL in addition to VEGF-R, as their upregu- pies. A total of 821 patients with metastatic lated gene expression by VHL inactivation has ccRCC were randomly assigned in a 1:1 ratio to been implicated as a resistance pathway to anti- receive 3 mg/kg of nivolumab intravenously every angiogenic therapy. An initial phase I study 2 weeks or a 10 mg everolimus tablet once daily. demonstrated promising antitumor activity and At the first interim analysis, median OS was 25.0 safety with cabozantinib in patients with mRCC months (95% CI, 21.8–not reached) with resistant to VEGF-R and mTOR inhibitors. nivolumab and 19.6 months (95% CI: 17.6–23.1) This paved the way for a landmark phase III study with everolimus, with a HR for death of 0.73 METEOR, in which 658 mRCC patients who (95% CI: 0.57–0.93; p = 0.002), meeting the had received at least one VEGF-R-targeting TKI prespecified criterion for superiority (p ⩽ 0.0148). were randomized to receive either second-line The ORR (25% versus 5%) favored nivolumab, cabozantinib or everolimus. A significant PFS despite similar median PFS (4.6 months versus benefit was seen with cabozantinib compared 4.4 months). Grade 3/4 treatment-related adverse with everolimus (7.4 months versus 3.8 months, events occurred in 19% (most common: fatigue HR = 0.58, 95% CI: 0.45–0.75), with benefit 2%) of patients receiving nivolumab and in 37% consistently observed regardless of number of (most common: anemia 8%) of the patients prior lines of VEGF-R inhibitors, and across all receiving everolimus. These remarkable results Memorial Sloan-Kettering Cancer Center risk demonstrated for the first time that a treatment subgroups. A subsequent analysis showed median for mRCC could provide definitive OS benefit OS favored caboazantib (21.4 months versus 16.5 after progression on first-line anti-angiogenic months, HR = 0.67, 95% CI: 0.53–0.83; p = therapy, establishing nivolumab as the new stand- 0.0003). These promising results provided ard of care in this setting. The US Food and Drug proof of principle that co-inhibition of the MET/ Administration approved nivolumab for the treat- AXL pathways is effective and clinically meaning- ment of metastatic ccRCC after progression on ful, and cabozantinib has now received regulatory journals.sagepub.com/home/tam 291 Therapeutic Advances in Medical Oncology 9(4) Table 2. Ongoing clinical trials for renal cell carcinoma. Study name NCT number Investigational agent Primary Phase Enrollment Expected date of endpoint completion METEOR 01865747 Cabozantinib Safety/efficacy III 650 August 2016 CheckMate 02231749 Ipilimumab + nivolumab Efficacy III 1070 April 2019 214 versus sunitinib ADAPT 01582672 AGS-003 + sunitinib versus Efficacy III 450 April 2017 sunitinib IMA901 01265901 IMA901 + sunitinib versus Efficacy III 330 Results pending sunitinib AMG 386 00853372 AMG 386 + sunitinib Safety/efficacy II 85 March 2016 Dalantercept 01642082 Dalantercept + axitinib Safety/efficacy II 174 December 2018 BKM120 01283048 BKM120 + avastin Safety/efficacy I 32 December 2016 AGS-16C3F 02639182 AGS-16C3F versus axitinib Safety/efficacy II 134 January 2018 CRLX101 02187302 CRLX101 versus standard Safety/efficacy II 110 February 2016 of care approval for the treatment of mRCC after pro- common treatment-emergent adverse events were gression on VEGF-R TKI therapy in the USA. diarrhea (84%), decreased appetite (51%), and fatigue (47%), with ⩾ grade 3 adverse events of diarrhea (20%), hypertension (14%), and fatigue Multitargeted kinase inhibition (10%). Based on these impressive results, this Lenvatinib is an oral TKI that inhibits multiple combination is now approved for the treatment of targets, including VEGF-R1–3, fibroblast growth mRCC for those who have progressed on first- factor receptors 1–4, PDGF-Rα, RET, and KIT. line VEGF-R TKI therapy. A phase III rand- Using mouse xenograft models of human RCC omized trial of the combination in mRCC is showed that the combination of lenvatinib plus currently being planned. everolimus, rather than either alone, resulted in a synergistic treatment response. In a phase Ib study, lenvatinib in combination with everolimus Immunotherapy showed manageable toxicity and promising activ- ity: 15 of 18 patients in both lower dose and max- CTLA-4 checkpoint inhibition imal tolerated dose cohorts achieved either PR (n CTLA-4 is an inhibitory receptor expressed by = 6) or stable disease (SD) (n = 9). This led to T cells, which upon ligand binding, initiates a phase II study, as patients with progressive cc T-cell proliferation and function, and mainte- mRCC following one prior VEGF-targeted ther- nance of immune tolerance. A phase II study apy were randomized 1:1:1 to lenvatinib (24 mg/ of the anti-CTLA-4 monoclonal antibody ipili- day), everolimus (10 mg/day), or lenvatinib plus mumab was conducted in patients with mRCC. everolimus (18 mg/day and 5 mg/day) in 28-day A total of 5 out of 40 patients who received ipili- cycles. A total of 153 patients were enrolled: mumab 3 mg/kg every 3 weeks achieved PR with lenvatinib plus everolimus prolonged PFS versus durations ranging from 7 months to 21 months; everolimus alone (HR = 0.40; 95% CI: 0.24– the longest responses were among patients who 0.68; p < 0.001). Lenvatinib monotherapy also had no prior treatment with IL-2. Immune- prolonged PFS versus everolimus (HR = 0.61; related adverse effects grade 3/4 or lower were 95% CI: 0.38–0.98; p = 0.048). OS analysis reported in 17 of 40 patients, with the most showed a statistically significant survival benefit common effect being enteritis. There was a favoring the combination compared with everoli- highly significant association between autoim- mus alone (HR = 0.51; 95% CI: 0.30–0.88; p = mune events and tumor regression (response 0.024). For the combination treatment, the most rate = 30% with autoimmune event, 0% without 292 journals.sagepub.com/home/tam C-K Tsao, B Liaw et al. Figure I. Mechanisms of action of current treatments in metastatic renal cell cancer. c-MET, tyrosine- protein kinase Met; mTOR, mechanistic target of rapamycin; PD-1, programmed cell death protein 1; PD-L1 programmed cell death ligand 1; PDGF, platelet-derived growth factor; PDGF-R, platelet-derived growth factor receptor; VEGF, vascular epidermal growth factor; VEGF-R, vascular epidermal growth factor receptor. autoimmune event; p = 0.009). These promis- sunitinib alone for those with de novo mRCC ing data have led to CheckMate 214, a rand- (NCT 02639182). omized phase III study evaluating nivolumab combined with ipilimumab versus sunitinib in previously untreated advanced or mRCC. Multipeptide vaccines IMA901 is a multipeptide vaccine, developed based on the selection of nine human leukocyte Dendritic cell vaccines antigen (HLA)-class I- and one HLA-class AGS-003 is an autologous dendritic cell vaccine, II-binding tumor-associated peptides. A com- prepared from matured and optimized monocyte- parison was performed of RNA and HLA ligands derived dendritic cells, which are co-electropo- derived from normal tissue versus tumor tissue rated with amplified tumor RNA plus synthetic from 32 patients with RCC; immunogenicity was CD40L RNA. AGS-003, was administered in assessed using peripheral blood mononuclear cells combination with sunitinib in a phase II study to derived from healthy donors. A phase II clinical 21 patients with intermediate and poor risk study evaluated disease control rate, OS, and mRCC, and demonstrated a 62% clinical benefit safety of IMA901 intradermal vaccinations admin- rate (9 PRs, 4 SD) and median PFS of 11.2 istered with or without low-dose cyclophospha- 62 2 64 months. Notably, five patients (24%) survived mide 300 mg/m . Disease control rates at 6 more than 5 years, and AGS-003 was well toler- months were 31% in the postcytokine group (n = ated with only mild injection-site reactions. The 40), and OS rates were 87%, 79%, and 68% at 6 magnitude of the increase in CD8(+) CD28(+) months, 12 months, and 18 months, respectively. CD45RA(–) effector/memory T cells (CTLs) Notably, myeloid-derived suppressor cells, apoli- correlated with OS. Given these encouraging poprotein A-I, and chemokine ligand 17 were pre- results, a phase III randomized study ADAPT has dictive for both immune response to IMA901 and been launched, with 450 patients randomized in a OS. A multicenter, open-label, randomized, phase 2:1 fashion to either sunitinib with AGS-003 or III study with OS as the primary endpoint is journals.sagepub.com/home/tam 293 Therapeutic Advances in Medical Oncology 9(4) ongoing in patients with metastatic or locally and ultimately HIF-2 upregulation. Dual advanced RCC when IMA901 is added to first- TORC1 and TORC2 inhibition have been line therapy with sunitinib (NCT01265901). hypothesized to enhance the efficacy associated with TORC1 inhibition in patients with RCC. Other novel targeted therapies in early Several novel dual mTORC1/2 inhibitors have clinical development been studied in preclinical models of human RCC. One example is GDC-0980, a dual PI3K/ Ang/Tie-2 inhibition: trebananib mTORC1/2 inhibitor, which was associated with The Ang/Tie-2 pathway is involved in both high rates of adverse effects. BEZ235, showed basal angiogenesis in response to hypoxia in enhanced efficacy relative to a rapamycin in RCC RCC and in vascular stability in the setting of xenograft models, but development has been 65,66 VEGF blockade. Trebananib (AMG-386) is halted due to a profound side-effect profile. an anti-angiopoietin peptibody that can disrupt BKM120, another PI3K inhibitor, is now being the Ang/Tie-2 axis. A phase II study of sunitinib tested in combination with bevacizumab in plus sequential cohorts of trebananib at either patients with advanced RCC (NCT01283048). 10 mg/kg or 15 mg/kg reported PFS of 13.9 months and 16.0 months, with ORRs at 58% and 59%, suggesting enhanced antitumor activ- Novel drug conjugates ity for the combination. Importantly the toxic- ENPP3 is a protein expressed in greater than ity profiles seen were predominantly attributable 90% of ccRCCs. AGS-16C3F is a fully human to sunitinib. A phase II study evaluating treba- immunoglobulin G 2k monoclonal antibody con- nanib with various anti-VEGF TKIs is currently jugated to the microtubule disrupting agent mon- ongoing. omethyl auristatin F via a plasma-stable linker, which binds to ENPP3. In a phase I study of patients with ccRCC (median prior treatment = ALK-1 inhibition: dalantercept 3), AGS-16C3F was well tolerated at 1.8 mg/kg The role of ALK-1 in angiogenesis is complex and and showed antitumor activity, with a median context dependent, but emerging data suggest that disease control of nore than 23 weeks and durable although VEGF is critical for early endothelial pro- PR in 2 of 10 of those with ccRCC. A phase II liferation and sprouting, it has a major role in the study with AGS-16C3F at 1.8 mg/kg is currently development of mature, functional vascular ongoing (NCT01672775). 68,69 beds. ALK-1 inhibitors under development include dalantercept (ACE-041) and PF-03446962. Another drug conjugate therapy, CRLX101, is a Dalantercept inhibits angiogenesis in several novel camptothecin containing nanoparticle drug preclinical models, and was shown to enhance conjugates that deliver sustained levels of active the efficacy of VEGF-R TKI in RCC xenograft camptothecin into cancer cells while reducing 70,71 models. Dalantercept is currently being studied systemic exposure and toxicity. CRLX101 also in a phase I/II clinical trial in combination with durably inhibits HIF-1a, and in preclinical mod- axitinib in patients with VEGF-R TKI-resistant els is seen to be synergistic with bevacizumab. advanced RCC (NCT01642082). Presented at ASCO 2015, an ongoing phase I/II study has thus far enrolled 22 patients with a median of two prior therapies. The median PFS mTOR complex 1 and 2 and phosphatidylinositol was 9.9 months, with no dose-limiting toxicities 3 kinase observed. ORR was 23%, and 85% experienced Currently approved mTOR inhibitors primarily clinical benefit (PR or SD). A randomized phase inhibit TORC1 and have less activity against II clinical trial in mRCC is currently ongoing TORC2. The translation of HIF-2a, the domi- (NCT01625936). nant oncogene in RCC, is more dependent on the activity of TORC2, and a potential mechanism for acquired resistance to the mTOR complex Future directions (mTORC) 1 inhibitors is loss of negative feed- With better understanding in pathogenesis and back loops that are normally operative when mechanisms of treatment resistance in RCC, mTORC1 is active potentially leading to phos- there is hope that treatment beyond VEGF inhi- phatidylinositol 3 kinase (PI3K), AKT, TORC2, bition will continue to expand. Understanding 294 journals.sagepub.com/home/tam C-K Tsao, B Liaw et al. renal cell carcinoma with taxol or high-dose the relationship between the tumor microenvi- interleukin-2. J Immunother Emphas Tumor ronment, mechanisms of resistance to specific Immunol 1993; 13: 275–281. treatments, and identifying driver/activating mutations of RCC will require real-time, large- 8. Ferguson RE, Taylor C, Stanley A, et al. scale genomic analyses of tumor samples at differ- Resistance to the tubulin-binding agents in ent disease states. Importantly, using the Cancer renal cell carcinoma: no mutations in the class I beta-tubulin gene but changes in tubulin isotype Genome Atlas analyses can be useful to identify protein expression. Clin Cancer Res 2005; 11: novel driver mutations/activated pathways, and 3439–3445. future clinical trials incorporating tissue sampling of a metastatic site before and after disease pro- 9. Hergovich A, Lisztwan J, Barry R, et al. gression will be key to continuing clinical devel- Regulation of microtubule stability by the von opment of RCC therapy going forward. Hippel–Lindau tumour suppressor protein pVHL. Nat Cell Biol 2003; 5: 64–70. 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Moving beyond vascular endothelial growth factor-targeted therapy in renal cell cancer: latest evidence and therapeutic implications:

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687261 TAM0010.1177/1758834016687261Therapeutic Advances in Medical OncologyC-K Tsao, B Liaw research-article2017 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Moving beyond vascular endothelial growth 2017, Vol. 9(4) 287 –298 DOI: 10.1177/ factor-targeted therapy in renal cell cancer: © The Author(s), 2017. Reprints and permissions: latest evidence and therapeutic implications http://www.sagepub.co.uk/ journalsPermissions.nav Che-Kai Tsao, Bobby Liaw, Catherine He, Matthew D. Galsky, John Sfakianos and William K. Oh Abstract: Renal cell cancer (RCC) continues to be among the most lethal malignancies in the USA. Introduction of anti-vascular epidermal growth factor receptor tyrosine kinase inhibitors over a decade ago resulted in improvement in disease outcomes, but further development of new therapies largely stagnated for many years. More recently, a better understanding of disease biology and treatment-resistance patterns has led to a second renaissance in drug development, with the anti-programmed cell death protein 1 immune checkpoint inhibitor, nivolumab, paving the way for additional therapies entering clinical trial testing in the treatment of RCC. Keywords: clear cell, immunotherapy, renal cell carcinoma, targeted therapies, vascular epidermal growth factor Correspondence to: Introduction clinical trial testing for the treatment of RCC. Che-Kai Tsao, MD Metastatic renal cell cancer (RCC) continues to be Here, we will focus on emerging therapies for clear Division of Hematology and Medical Oncology, among the most lethal malignancies in the USA, cell (cc) RCC beyond VEGF-R inhibition. Icahn School of Medicine with an estimated 14,080 deaths alone in 2015. at Mount Sinai, The Tisch Cancer Institute, 1 Gustave Nephrectomy remains the mainstay of treatment L Levy Place, New York, for localized disease, but a subset of these patients Treatment of metastatic ccRCC: historical NY 10029, USA 2 che-kai.tsao@mssm.edu eventually develops metastatic disease. Prognosis challenges Bobby Liaw, MD to date remains poor, as RCC is predominantly Catherine He, MD resistant to cytotoxic chemotherapy. While Failure of cytotoxic chemotherapy Matthew D. Galsky, MD Division of Hematology cytokine immunostimulatory therapy can lead to While chemotherapy is widely considered a stand- and Medical Oncology, The disease control for some, significant toxicities have ard treatment for patients with predominantly Tisch Cancer Institute, Icahn School of Medicine largely limited their use. The introduction of anti- sarcomatoid and collecting duct RCC variants, its at Mount Sinai, New York, vascular epidermal growth factor receptor role in treating ccRCC is poorly defined. Several NY, USA John Sfakianos, MD (VEGF-R) tyrosine kinase inhibitors (TKIs) has regimens have demonstrated only modest activity Department of Urology, resulted in improvement in disease outcomes, in early phase clinical trials, and there are almost Icahn School of Medicine at Mount Sinai, New York, including overall survival (OS). However, for many no phase III clinical trials evaluating the utility of NY, USA years, development of treatment beyond VEGF- cytotoxic chemotherapy in metastatic RCC. William K. Oh, MD targeted therapies has largely stagnated. More Division of Hematology and Medical Oncology, The recently, however, a better understanding of dis- The mechanisms of resistance to chemotherapy Tisch Cancer Institute, ease biology and treatment-resistance patterns is in RCC remain undefined. Reduction of intra- Icahn School of Medicine at Mount Sinai, New York, leading to a second renaissance in drug develop- cellular drug accumulation via overexpression of NY, USA ment, with the anti- programmed cell death pro- transporter efflux pump permeability glycopro- tein 1 (PD-1) immune checkpoint inhibitor tein was not seen to be an important mediator in nivolumab and multitargeted TKI cabozantinib in vitro studies. Another hypothesis is that paving the way for additional therapies entering molecular drug target  alterations may confer journals.sagepub.com/home/tam 287 Therapeutic Advances in Medical Oncology 9(4) chemotherapy resistance in RCC. Acquired Immunostimulatory therapy: cytokine mutation in the Von Hippel–Lindau (VHL) gene immunotherapy is commonly seen in ccRCC, and its inactivation The lack of sensitivity to cytotoxic chemotherapy leads to the intracellular accumulation of for most patients with mRCC prompted research hypoxia-inducible factor (HIF), a microtubule- efforts for novel approaches. Spontaneous tumor dependent transcription factor of genes involved regressions in mRCC after cytoreductive nephrec- in angiogenesis and tumor cell proliferation and tomy, with the observation that immune cells survival. Antimicrotubule chemotherapies are often infiltrate the tumor tissue, suggested that 6,7 ineffective in RCC, but no mutations have adaptive immunity might play an important role 15,16 been identified in tubulin drug-binding sites for in this malignancy. This hypothesis led to taxanes to account for this resistance. One immunostimulatory trials with interleukin-2 (IL- hypothesis is that RCC has altered expression of 2) and interferon alpha (IFN-α). tubulin isotypes, resulting in changes in microtu- bule dynamics as well as drug binding. VHL has been associated with regulation of microtubule IL-2 dynamics, suggesting that the loss of VHL may In phase II clinical trials, high-dose recombinant affect taxane resistance. Microtubule inhibitors IL-2 achieved 7% complete responses (CR) and have been shown to be potent inhibitors of HIF-1 8% partial responses (PR) in 25 patients with 17,18 expression and activity, thus HIF inhibition mRCC. Long-term durability of the treat- downstream of microtubule perturbation is a key ment response in this small subset of responding determinant in the clinical response to antitubu- patients was likely due to the ability of IL-2 to lin therapy. RCC is the lone tumor type where modulate T-cell proliferation and differentiation. microtubule-targeting drugs fail to suppress Patients that achieved CR had a median duration HIF-1, independently of VHL functional sta- of response exceeding 80 months, and those that 11 19 tus. These data suggest that the HIF-signaling achieved PR, 20 months. Though these figures axis has been uncoupled from microtubule con- remain unrivaled by current-generation VEGF- trol in RCC, and thus deregulation of the micro- targeted therapy, the general adoption of high- tubule/HIF axis in RCC may contribute to taxane dose IL-2 has been hindered by its low response resistance. rate and significant toxicity profile, including a 20,21 4% risk of treatment-related mortality. Intratumoral heterogeneity While some systemic therapies may lead to tumor IFN-α shrinkage and alleviation of symptoms in meta- The ability of IFN-α to regulate anti-angiogenesis static (m) RCC, resistance ensues when the dis- and immune functions translates to a response ease resorts to alternative pathways to drive rate of approximately 12% when used as mono- angiogenesis and cell proliferation, either through therapy in mRCC, and confers a modest survival adaptation of individual tumor cells or selection benefit of 3.8 months in the pooled data of four of surviving cells that are already using alternative clinical trials over the control arm, although cases pathways. Ideally, one can characterize tumors of long-term durable responses have been 22,23 individually based on DNA sequencing and other reported. Combining IFN-α with other agents means, leading to selection of the specific path- has typically yielded additional modest clinical ways that drive cell proliferation, an approach benefits. Most notably, the AVOREN and also known as ‘personalized medicine’. However, CALGB 90206 trials randomized treatment-naïve this methodology has largely been limited by mRCC patients to receive IFN-α with or without 25,26 extensive intratumoral heterogeneity; varying bevacizumab. While both phase III studies gene expression signatures can be detected even found a consistent improvement in progression- within the same tumor specimen in samples of free survival (PFS) (AVOREN: 10.2 months ver- 12,13 those with RCC. This largely limits the utility sus 5.4 months, hazard ratio [HR] = 0.63; of prognostic impact of biomarkers and, in addi- CALGB 90206: 8.5 months versus 5.2 months, tion, spatial variation in genetic and phenotypic HR = 0.71) and overall response rates (ORR) properties poses a significant obstacle for optimal (AVOREN: 31% versus 13%; CALGB 90206: 14 8,9 personalized treatment. 25.5% versus 13.1%), neither met significance 288 journals.sagepub.com/home/tam C-K Tsao, B Liaw et al. for OS benefit (AVOREN: 23.3 months versus noninferior to sunitinib for the primary endpoint 21.3 months, HR = 0.86; CALGB 90206: 18.3 of PFS (8.4 months versus 9.5 months, HR = months versus 17.4 months, HR = 0.86). 1.05, 95% CI: 0.71–1.16) and secondary end- point of OS (28.3 months versus 29.1 months, 33,34 HR = 0.92, 95% CI: 0.79–1.01). However, VEGF and mechanistic target of rapamycin health-related quality of life measures and patient inhibitors: a paradigm shift for mRCC preference favored pazopanib in two different therapy randomized studies. Deeper insight into the somatic genetics of heredi- tary ccRCC led to the identification of the VHL Axitinib and sorafenib both demonstrate PFS tumor suppressor gene. Its interaction with HIF benefit as second-line agents, though axitinib plays a key role not only in inherited disease, but outperformed sorafenib (AXIS: 8.3 months ver- also in sporadic forms of RCC. Inactivation or sus 5.7 months, HR = 0.66, 95% CI: 0.55– loss of the VHL gene product prevents ubiquitin- 0.78), whereas sorafenib was only compared mediated degradation of HIF-1a/2a leading to with placebo (5.5 months versus 2.8 months, upregulation and constitutive expression of pro- HR = 0.44, 95% CI: 0.35–0.55) in randomized 36–38 angiogenesis agents, including VEGF, erythropoi- trials. It is noteworthy that the PFS benefit etin, platelet-derived growth factor (PDGF), of axitinib in AXIS is less prominent in patients transforming growth factor-beta, and carbonic previously treated with first-line VEGF-TKI anhydrase IX. These angiogenic signals confer the compared with those treated with first-line ability to proliferate under hypoxic conditions, cytokine therapy. driving oncogenesis, and accounts for the hyper- vascular nature of VHL-associated neoplasms. This was the basis for exploring anti-angiogenic VEGF-R monoclonal antibody therapy targeting VEGF. Multiple VEGF path- Bevacizumab is a monoclonal antibody that binds way inhibitors have been subsequently developed the ligand, VEGF, preventing its interaction with and approved for mRCC. As a therapeutic class, VEGF-R and its downstream effects. Two large VEGF pathway inhibitors have consistently out- phase III trials (AVOREN and CALGB 90206) performed IFN or placebo in randomized phase randomized treatment-naïve mRCC patients to III trials, and have become accepted as the pre- receive bevacizumab plus IFN-α or placebo plus ferred first-line therapy for mRCC. IFN-α. A consistent PFS benefit was associated with bevacizumab in both AVOREN (10.2 months versus 5.4 months, HR = 0.63, 95% CI: VEGF-R TKIs 0.52–0.75) and CALGB 90206 (8.5 months ver- Multiple VEGF-R TKIs have demonstrated effi- sus 5.2 months, HR = 0.71, 95% CI: 0.61–0.83), cacy in RCC (Table 1), with sunitinib and pazo- as well as ORR improvement (AVOREN: 31% panib both approved for first-line treatment in versus 13%; CALGB 90206: 25.5% versus 39,40 those with metastatic disease. Sunitinib showed 13.1%). Neither trial met significance for OS improved PFS (11 months versus 5 months, HR benefit, though a trend towards better survival 41,42 = 0.42, 95% confidence interval [CI]: 0.32– was observed in both studies. Combining 0.54), ORR (47% versus 12%), and trend for bevacizumab with sorafenib or temosirolimus has superior OS (26.4 months versus 21.8 months, not been shown to improve PFS compared with HR = 0.82, 95% CI: 0.67–1.01) compared with bevacizumab alone, and no trials to date have IFN-α in treatment-naïve mRCC. Pazopanib compared bevacizumab plus IFN-α with bevaci- similarly demonstrated a first-line PFS benefit zumab monotherapy. (9.2 months versus 4.2 months, HR = 0.46, 95% CI: 0.34–0.62) and ORR improvement (30% ver- sus 3%) compared with placebo, though no OS Mechanistic target of rapamycin inhibitors improvement was seen (22.9 months versus 20.5 In addition to VEGF pathway inhibition, months, HR = 0.91, 95% CI: 0.71–1.16), likely upstream target mechanistic target of rapamycin 31,32 due to the high crossover rate. Head-to-head (mTOR) was identified as another therapeutic comparison of these TKIs in the phase III target for mRCC. mTOR has the potential to COMPARZ trial showed that pazopanib was inhibit tumor growth via regulating cell growth, journals.sagepub.com/home/tam 289 Therapeutic Advances in Medical Oncology 9(4) Table 1. Phase III trials in metastatic renal cell carcinoma. Study Treatment arms n ORR mPFS mOS (%) (months) (months) 4,6 First-line AVOREN Bevacizumab + IFN-α 649 31 versus 13 10.4 versus 5.5 23.3 versus 21.3 therapy versus IFN-α 5,7 CALGB 90206 732 25.5 versus 13.1 8.5 versus 5.2 18.3 versus 17.4 Motzer et al. Sunitinib versus IFN-α 750 47 versus 12 11 versus 5 26.4 versus 21.8 9,10 Global ARCC Temsirolimus versus 626 8.6 versus 4.8 5.5 versus 3.1 10.9 versus 7.3 IFN-α Motzer et al. Everolimus versus 416 1 versus 0 4.9 versus 1.9 14.8 versus 14.4 27,28 2008 placebo 11,12 VEG105192 Pazopanib versus 233 30 versus 3 11.1 versus 2.8 22.9 versus 20.5 placebo Hutson et al. Axitinib versus 288 32 versus 15 10.1 versus 6.5 N/A 2013 sorafenib 13,14 COMPARZ Pazopanib versus 1110 31 versus 25 8.4 versus 9.5 28.4 versus 29.3 sunitinib 18,30 Second-line TARGET Sorafenib versus 903 10 versus 2 5.5 versus 2.8 17.8 versus 15.2 therapy placebo 16,17 AXIS Axitinib versus 723 23 versus 12 8.3 versus 5.7 20.1 versus 19.2 sorafenib INTORSECT Temsirolimus versus 512 8 versus 8 4.3 versus 3.9 12.3 versus 16.6 sorafenib METEOR Cabozantinib versus 658 21 versus 5 7.4 versus 3.8 NR, HR 0.67 everolimus CheckMate 025 Nivolumab versus 821 25 versus 5 4.6 versus 4.4 25.0 versus 19.6 everolimus Bold: denotes statistically significant. HR, hazard ratio; IFN-α, interferon alfa; mOS, median overall survival; mPFS, median progression-free survival; N/A, not applicable; NR, not reached; ORR, overall response rate. cell-cycle progression, angiogenesis, and response everolimus is generally better tolerated, axitinib is to hypoxic stress through the HIF-1a pathway. associated with a higher response rate albeit simi- However, recent data suggest a more modest role lar PFS benefit. With more promising therapies for mTOR inhibitors in the management of becoming available in the armamentarium of mRCC. While temsirolimus originally demon- RCC treatment, both therapies have been rele- strated a significant OS benefit over IFN-α (10.9 gated to later lines of therapy. months versus 7.3 months, HR = 0.73, 95% CI: 0.58–0.92) in the first-line setting for poor-risk mRCC, as a second-line therapy it was associated A new era in immunotherapy in mRCC: anti- with a worse OS when compared with sorafenib PD1/programmed death ligand-1 checkpoint (12.3 months versus 16.6 months, HR = 1.31, inhibitors 45,46 95% CI: 1.05–1.63). Similarly, everolimus The interaction between PD-1 (present on T failed to show noninferiority for PFS against suni- cells), and one of its ligands (PD-L1) (present on tinib (7.4 months versus 10.7 months, HR = 1.4, antigen-presenting cells and tumor cells) consti- 95% CI: 1.2–1.8) as first-line therapy. For tutes an immune checkpoint through which years, treatment after progression on first-line tumors can induce T-cell tolerance and avoid VEGF-R TKI remained controversial; while immune destruction. A retrospective analysis of 290 journals.sagepub.com/home/tam C-K Tsao, B Liaw et al. 306 patients who underwent nephrectomy for VEGF-R TKI on 25 November 2015. Other ccRCC at the Mayo Clinic from 1990 to 1994 anti-PD-1 antibodies (MK-3745) and anti-PD- revealed that patients whose tissue demonstrated L1 (MPDL3280A) inhibitors are currently in expression of PD-L1 (B7-H1) had significantly clinical trial testing, as are combinations with worse 5-year cancer-specific survival (41.9%) other modalities (cytokine therapy, VEGF-R when compared with those whose tumors did not inhibitors, and other immune checkpoint inhibi- express PD-L1 (82.9%), suggesting that blocking tors) (Table 2). the interaction of PD-L1 with PD-1 might reverse tumor-induced immune tolerance and serve as an attractive approach for RCC therapy. Similar to Promising novel therapies: the next steps results seen in murine models, initial phase I For years, development of treatment beyond studies of MDX-1106/BMS-936558/ONO-4538 VEGF-targeted therapies had been largely (nivolumab) (Bristol-Myers Squibb, New York, unsuccessful. More recently, better understand- USA) demonstrated that antibody-mediated ing of disease biology and treatment-resistance blockade of PD-1 induced durable tumor regres- patterns has led to the introduction of effective sion and prolonged stabilization of disease in therapies adding to inhibitors of VEGF-R sign- patients with various advanced cancers, including aling (Figure 1). Here, we will focus on those mRCC. A subsequent phase II study evaluated emerging therapies for ccRCC beyond VEGF-R 168 patients with mRCC who had received 1–3 inhibition. prior anti-angiogenic therapies, randomized to receive nivolumab at doses of 0.3 mg/kg (n = 60), 2.0 mg/kg (n = 54), or 10.0 mg/kg (n = 54) every Targeted TKIs 3 weeks until disease progression or unacceptable toxicity. A manageable safety profile was seen MET/AXL inhibition across all three doses, with notable antitumor The MET pathway plays a crucial role in the acti- activity seen, supporting phase III testing. vation of key oncogenic signaling pathways (RAS, PI2K, STAT3) and angiogenesis, while the AXL CheckMate 025 is a randomized, open-label, pathway is involved in epithelial-mesenchymal phase III study that compared nivolumab with transition and cancer metastasis. Cabozantinib everolimus in patients with mRCC who had (formerly known as XL-184) inhibits MET and received one or two prior anti-angiogenic thera- AXL in addition to VEGF-R, as their upregu- pies. A total of 821 patients with metastatic lated gene expression by VHL inactivation has ccRCC were randomly assigned in a 1:1 ratio to been implicated as a resistance pathway to anti- receive 3 mg/kg of nivolumab intravenously every angiogenic therapy. An initial phase I study 2 weeks or a 10 mg everolimus tablet once daily. demonstrated promising antitumor activity and At the first interim analysis, median OS was 25.0 safety with cabozantinib in patients with mRCC months (95% CI, 21.8–not reached) with resistant to VEGF-R and mTOR inhibitors. nivolumab and 19.6 months (95% CI: 17.6–23.1) This paved the way for a landmark phase III study with everolimus, with a HR for death of 0.73 METEOR, in which 658 mRCC patients who (95% CI: 0.57–0.93; p = 0.002), meeting the had received at least one VEGF-R-targeting TKI prespecified criterion for superiority (p ⩽ 0.0148). were randomized to receive either second-line The ORR (25% versus 5%) favored nivolumab, cabozantinib or everolimus. A significant PFS despite similar median PFS (4.6 months versus benefit was seen with cabozantinib compared 4.4 months). Grade 3/4 treatment-related adverse with everolimus (7.4 months versus 3.8 months, events occurred in 19% (most common: fatigue HR = 0.58, 95% CI: 0.45–0.75), with benefit 2%) of patients receiving nivolumab and in 37% consistently observed regardless of number of (most common: anemia 8%) of the patients prior lines of VEGF-R inhibitors, and across all receiving everolimus. These remarkable results Memorial Sloan-Kettering Cancer Center risk demonstrated for the first time that a treatment subgroups. A subsequent analysis showed median for mRCC could provide definitive OS benefit OS favored caboazantib (21.4 months versus 16.5 after progression on first-line anti-angiogenic months, HR = 0.67, 95% CI: 0.53–0.83; p = therapy, establishing nivolumab as the new stand- 0.0003). These promising results provided ard of care in this setting. The US Food and Drug proof of principle that co-inhibition of the MET/ Administration approved nivolumab for the treat- AXL pathways is effective and clinically meaning- ment of metastatic ccRCC after progression on ful, and cabozantinib has now received regulatory journals.sagepub.com/home/tam 291 Therapeutic Advances in Medical Oncology 9(4) Table 2. Ongoing clinical trials for renal cell carcinoma. Study name NCT number Investigational agent Primary Phase Enrollment Expected date of endpoint completion METEOR 01865747 Cabozantinib Safety/efficacy III 650 August 2016 CheckMate 02231749 Ipilimumab + nivolumab Efficacy III 1070 April 2019 214 versus sunitinib ADAPT 01582672 AGS-003 + sunitinib versus Efficacy III 450 April 2017 sunitinib IMA901 01265901 IMA901 + sunitinib versus Efficacy III 330 Results pending sunitinib AMG 386 00853372 AMG 386 + sunitinib Safety/efficacy II 85 March 2016 Dalantercept 01642082 Dalantercept + axitinib Safety/efficacy II 174 December 2018 BKM120 01283048 BKM120 + avastin Safety/efficacy I 32 December 2016 AGS-16C3F 02639182 AGS-16C3F versus axitinib Safety/efficacy II 134 January 2018 CRLX101 02187302 CRLX101 versus standard Safety/efficacy II 110 February 2016 of care approval for the treatment of mRCC after pro- common treatment-emergent adverse events were gression on VEGF-R TKI therapy in the USA. diarrhea (84%), decreased appetite (51%), and fatigue (47%), with ⩾ grade 3 adverse events of diarrhea (20%), hypertension (14%), and fatigue Multitargeted kinase inhibition (10%). Based on these impressive results, this Lenvatinib is an oral TKI that inhibits multiple combination is now approved for the treatment of targets, including VEGF-R1–3, fibroblast growth mRCC for those who have progressed on first- factor receptors 1–4, PDGF-Rα, RET, and KIT. line VEGF-R TKI therapy. A phase III rand- Using mouse xenograft models of human RCC omized trial of the combination in mRCC is showed that the combination of lenvatinib plus currently being planned. everolimus, rather than either alone, resulted in a synergistic treatment response. In a phase Ib study, lenvatinib in combination with everolimus Immunotherapy showed manageable toxicity and promising activ- ity: 15 of 18 patients in both lower dose and max- CTLA-4 checkpoint inhibition imal tolerated dose cohorts achieved either PR (n CTLA-4 is an inhibitory receptor expressed by = 6) or stable disease (SD) (n = 9). This led to T cells, which upon ligand binding, initiates a phase II study, as patients with progressive cc T-cell proliferation and function, and mainte- mRCC following one prior VEGF-targeted ther- nance of immune tolerance. A phase II study apy were randomized 1:1:1 to lenvatinib (24 mg/ of the anti-CTLA-4 monoclonal antibody ipili- day), everolimus (10 mg/day), or lenvatinib plus mumab was conducted in patients with mRCC. everolimus (18 mg/day and 5 mg/day) in 28-day A total of 5 out of 40 patients who received ipili- cycles. A total of 153 patients were enrolled: mumab 3 mg/kg every 3 weeks achieved PR with lenvatinib plus everolimus prolonged PFS versus durations ranging from 7 months to 21 months; everolimus alone (HR = 0.40; 95% CI: 0.24– the longest responses were among patients who 0.68; p < 0.001). Lenvatinib monotherapy also had no prior treatment with IL-2. Immune- prolonged PFS versus everolimus (HR = 0.61; related adverse effects grade 3/4 or lower were 95% CI: 0.38–0.98; p = 0.048). OS analysis reported in 17 of 40 patients, with the most showed a statistically significant survival benefit common effect being enteritis. There was a favoring the combination compared with everoli- highly significant association between autoim- mus alone (HR = 0.51; 95% CI: 0.30–0.88; p = mune events and tumor regression (response 0.024). For the combination treatment, the most rate = 30% with autoimmune event, 0% without 292 journals.sagepub.com/home/tam C-K Tsao, B Liaw et al. Figure I. Mechanisms of action of current treatments in metastatic renal cell cancer. c-MET, tyrosine- protein kinase Met; mTOR, mechanistic target of rapamycin; PD-1, programmed cell death protein 1; PD-L1 programmed cell death ligand 1; PDGF, platelet-derived growth factor; PDGF-R, platelet-derived growth factor receptor; VEGF, vascular epidermal growth factor; VEGF-R, vascular epidermal growth factor receptor. autoimmune event; p = 0.009). These promis- sunitinib alone for those with de novo mRCC ing data have led to CheckMate 214, a rand- (NCT 02639182). omized phase III study evaluating nivolumab combined with ipilimumab versus sunitinib in previously untreated advanced or mRCC. Multipeptide vaccines IMA901 is a multipeptide vaccine, developed based on the selection of nine human leukocyte Dendritic cell vaccines antigen (HLA)-class I- and one HLA-class AGS-003 is an autologous dendritic cell vaccine, II-binding tumor-associated peptides. A com- prepared from matured and optimized monocyte- parison was performed of RNA and HLA ligands derived dendritic cells, which are co-electropo- derived from normal tissue versus tumor tissue rated with amplified tumor RNA plus synthetic from 32 patients with RCC; immunogenicity was CD40L RNA. AGS-003, was administered in assessed using peripheral blood mononuclear cells combination with sunitinib in a phase II study to derived from healthy donors. A phase II clinical 21 patients with intermediate and poor risk study evaluated disease control rate, OS, and mRCC, and demonstrated a 62% clinical benefit safety of IMA901 intradermal vaccinations admin- rate (9 PRs, 4 SD) and median PFS of 11.2 istered with or without low-dose cyclophospha- 62 2 64 months. Notably, five patients (24%) survived mide 300 mg/m . Disease control rates at 6 more than 5 years, and AGS-003 was well toler- months were 31% in the postcytokine group (n = ated with only mild injection-site reactions. The 40), and OS rates were 87%, 79%, and 68% at 6 magnitude of the increase in CD8(+) CD28(+) months, 12 months, and 18 months, respectively. CD45RA(–) effector/memory T cells (CTLs) Notably, myeloid-derived suppressor cells, apoli- correlated with OS. Given these encouraging poprotein A-I, and chemokine ligand 17 were pre- results, a phase III randomized study ADAPT has dictive for both immune response to IMA901 and been launched, with 450 patients randomized in a OS. A multicenter, open-label, randomized, phase 2:1 fashion to either sunitinib with AGS-003 or III study with OS as the primary endpoint is journals.sagepub.com/home/tam 293 Therapeutic Advances in Medical Oncology 9(4) ongoing in patients with metastatic or locally and ultimately HIF-2 upregulation. Dual advanced RCC when IMA901 is added to first- TORC1 and TORC2 inhibition have been line therapy with sunitinib (NCT01265901). hypothesized to enhance the efficacy associated with TORC1 inhibition in patients with RCC. Other novel targeted therapies in early Several novel dual mTORC1/2 inhibitors have clinical development been studied in preclinical models of human RCC. One example is GDC-0980, a dual PI3K/ Ang/Tie-2 inhibition: trebananib mTORC1/2 inhibitor, which was associated with The Ang/Tie-2 pathway is involved in both high rates of adverse effects. BEZ235, showed basal angiogenesis in response to hypoxia in enhanced efficacy relative to a rapamycin in RCC RCC and in vascular stability in the setting of xenograft models, but development has been 65,66 VEGF blockade. Trebananib (AMG-386) is halted due to a profound side-effect profile. an anti-angiopoietin peptibody that can disrupt BKM120, another PI3K inhibitor, is now being the Ang/Tie-2 axis. A phase II study of sunitinib tested in combination with bevacizumab in plus sequential cohorts of trebananib at either patients with advanced RCC (NCT01283048). 10 mg/kg or 15 mg/kg reported PFS of 13.9 months and 16.0 months, with ORRs at 58% and 59%, suggesting enhanced antitumor activ- Novel drug conjugates ity for the combination. Importantly the toxic- ENPP3 is a protein expressed in greater than ity profiles seen were predominantly attributable 90% of ccRCCs. AGS-16C3F is a fully human to sunitinib. A phase II study evaluating treba- immunoglobulin G 2k monoclonal antibody con- nanib with various anti-VEGF TKIs is currently jugated to the microtubule disrupting agent mon- ongoing. omethyl auristatin F via a plasma-stable linker, which binds to ENPP3. In a phase I study of patients with ccRCC (median prior treatment = ALK-1 inhibition: dalantercept 3), AGS-16C3F was well tolerated at 1.8 mg/kg The role of ALK-1 in angiogenesis is complex and and showed antitumor activity, with a median context dependent, but emerging data suggest that disease control of nore than 23 weeks and durable although VEGF is critical for early endothelial pro- PR in 2 of 10 of those with ccRCC. A phase II liferation and sprouting, it has a major role in the study with AGS-16C3F at 1.8 mg/kg is currently development of mature, functional vascular ongoing (NCT01672775). 68,69 beds. ALK-1 inhibitors under development include dalantercept (ACE-041) and PF-03446962. Another drug conjugate therapy, CRLX101, is a Dalantercept inhibits angiogenesis in several novel camptothecin containing nanoparticle drug preclinical models, and was shown to enhance conjugates that deliver sustained levels of active the efficacy of VEGF-R TKI in RCC xenograft camptothecin into cancer cells while reducing 70,71 models. Dalantercept is currently being studied systemic exposure and toxicity. CRLX101 also in a phase I/II clinical trial in combination with durably inhibits HIF-1a, and in preclinical mod- axitinib in patients with VEGF-R TKI-resistant els is seen to be synergistic with bevacizumab. advanced RCC (NCT01642082). Presented at ASCO 2015, an ongoing phase I/II study has thus far enrolled 22 patients with a median of two prior therapies. The median PFS mTOR complex 1 and 2 and phosphatidylinositol was 9.9 months, with no dose-limiting toxicities 3 kinase observed. ORR was 23%, and 85% experienced Currently approved mTOR inhibitors primarily clinical benefit (PR or SD). A randomized phase inhibit TORC1 and have less activity against II clinical trial in mRCC is currently ongoing TORC2. The translation of HIF-2a, the domi- (NCT01625936). nant oncogene in RCC, is more dependent on the activity of TORC2, and a potential mechanism for acquired resistance to the mTOR complex Future directions (mTORC) 1 inhibitors is loss of negative feed- With better understanding in pathogenesis and back loops that are normally operative when mechanisms of treatment resistance in RCC, mTORC1 is active potentially leading to phos- there is hope that treatment beyond VEGF inhi- phatidylinositol 3 kinase (PI3K), AKT, TORC2, bition will continue to expand. Understanding 294 journals.sagepub.com/home/tam C-K Tsao, B Liaw et al. renal cell carcinoma with taxol or high-dose the relationship between the tumor microenvi- interleukin-2. 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Journal

Therapeutic Advances in Medical Oncology – SAGE

Published: Feb 14, 2017

Keywords: clear cell; immunotherapy; renal cell carcinoma; targeted therapies; vascular epidermal growth factor

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