Until very recently, the foundation of treatment for metastatic renal cell carcinoma (mRCC) has been therapies that target the vascular endothelial growth factor (VEGF) pathway (CA Cancer J Clin 2017;67:507-524). With the exception of a small percentage of patients who are treated with high-dose interleukin-2, the frontline treatment for most patients with mRCC is a VEGFR inhibitor (most commonly, sunitinib or pazopanib). Unfortunately, almost all patients treated with these agents will ultimately develop resistance to therapy and eventually succumb to their disease.
The advent of immunotherapy in the form of checkpoint inhibitors has altered the landscape of mRCC treatment. In November 2015, the FDA approved the immune checkpoint inhibitor (ICI) nivolumab (anti-PD-1 antibody) for the treatment of patients with mRCC who had received prior treatment with anti-angiogenesis therapy. This approval was based on the phase III Checkmate 025 trial that demonstrated an overall survival (OS) advantage in previously treated patients who received nivolumab versus the mTOR inhibitor everolimus (25.0 vs. 19.6 months; HR 0.73, 98.5% CI 0.57-0.93; p=0.002) (J Clin Oncol 2015;33:1430-1437).
Although this approval opened the door for ICI in mRCC, the use of nivolumab was limited to previously treated patients and frontline treatment options remained the same. Subsequent investigations thus focused on ICIs for treatment-naive mRCC patients as well as the use of ICIs as part of combination therapy. Combination therapy with ICIs includes combining multiple ICIs with varying mechanisms of action as well as combining ICIs with VEGF-directed therapy. The latter combination is especially appealing given preclinical data suggesting that anti-VEGF therapy can potentially generate a more immunogenic environment to enhance the function of ICI therapy (Clin Cancer Res 2009;15:2148-2157, Nat Rev Immunol 2009;9:162-174, Nat Med 1006;2:1096-1103).
JAVELIN Renal 100
The JAVELIN Renal 100 Trial (NCT02493751) was a phase Ib dose-finding and dose-expansion clinical trial investigating the combination of avelumab (PD-L1 antibody) and axitinib (VEGFR inhibitor) in patients with treatment-naive mRCC. Key eligibility criteria included advanced RCC with a clear cell component, resected primary tumor, no prior systemic treatment for RCC, no CNS disease, and ECOG <= 1. In the dose-finding phase, patients were treated for 7 days with axitinib 5 mg BID and then avelumab 10 mg/kg every 2 weeks while remaining on the daily axitinib. In the dose-expansion cohort, 10 patients received the same regimen as the dose-finding phase and the remaining patients were treated with the combination immediately (without the 7-day lead-in axitinib treatment). The study's primary endpoint was dose-limiting toxicities during the first 4 weeks of combined axitinib/aveluamb therapy (Lancet Oncol 2018;19:451-460).
Six patients were enrolled in the dose-finding phase and 49 patients in the dose-expansion phase. Of all 55 patients, 42 (76%) were men, median age 60, 36 (66%) had ECOG 0, and 51 percent had favorable risk mRCC by MSKCC criteria. With a median follow-up of 52.1 weeks, 32 (58%) of the 55 patients had a confirmed objective response: 6/6 (100%) of the dose-finding patients and 26 (53%) of the dose-expansion cohort patients. At the data cutoff date, 29 (53%) of 55 patients were still receiving combination therapy, while two (4%) patients remained on axitinib monotherapy, and one (2%) patient was on avelumab alone.
Adverse events (AE) of combination therapy mirrored the AEs of each individual therapy without significant overlapping toxicities. Ninety-six percent of patients had at least one treatment-related AE of any grade. The only dose-limiting toxicity was one grade 3 proteinuria in the dose-finding cohort. Although 32 (58%) patients had a grade 3 or worse treatment-related AEs, hypertension (29%) was the only such event occurring in more than 7 percent of patients. One patient died from a treatment-related AE (autoimmune myocarditis). Overall, 10 (18%) patients discontinued with axitinib, avelumab, or both due to a treatment-related AE (Lancet Oncol 2018;19:451-460).
The safety and efficacy of axitinib and avelumab in treatment-naive mRCC is encouraging. This combination is being tested versus sunitinib in the ongoing phase III JAVELIN Renal 101 trial (NCT02684006). Importantly, results from a similar phase 1b trial of axitinib and pembrolizumab (PD-1 inhibitor) in previously untreated mRCC were also recently reported and demonstrated an ORR of 73 percent, with a phase III confirmatory trial in progress (Lancet Oncol 2018;19:405-415).
Current ICI Combination Landscape
The encouraging preliminary results of JAVELIN Renal 100 come on the heels of the recently published randomized, phase III, CheckMate 214 trial that compared the combination of ipilimumab (CTLA-4 antibody) and nivolumab in patients with mRCC (N Engl J Med 2018;378:1277-1290). Although this trial accrued all IMDC risk groups, the trial's co-primary endpoints of ORR, PFS, and OS were focused on the intermediate- and poor-risk mRCC patients (n=847). With a median follow-up of 25.2 months, the ipilimumab/nivolumab patient cohort was superior to the sunitinib cohort both in terms of ORR (42% vs. 27%; p<0.001) and OS (NR vs. 26.0 months; p<0.001). The 18-month survival rate was significantly better for the ipilimumab/nivolumab patients (75%) versus the sunitinib cohort (60%). Similarly, the complete response rate was 9 percent for the ipilimumab/nivolumab cohort and 1 percent in the sunitinib treated patients. Based on these results, on April 16, 2018, the FDA approved the combination of ipilimumab and nivolumab for treatment-naive intermediate- and poor-risk mRCC patients (N Engl J Med 2018;378:1277-1290).
Similarly, at ASCO GU in February 2018, the results of IMmotion 151, a randomized phase III trial comparing atezolizumab and bevacizumab versus sunitinib in treatment-naive mRCC was presented (J Clin Oncol 2018;36(suppl 6S; abstr 578)). The co-primary endpoints were PFS in PD-L1 positive (PD-L1 IC IHC >= 1%) patients and OS in the intent-to-treat (ITT) population. A total of 915 patients were accrued and randomized as part of the ITT population, of which 362 met the pre-specified definition of PD-L1 positivity. The median PFS for the PD-L1-positive patients was 11.2 months for the atezolizumab/bevacizumab cohort and 7.7 months for the sunitinib arm (HR 0.74; 95% CI 0.57-0.96; p=0.02). The co-primary endpoint of OS in ITT demonstrated a trend favoring the atezolizumab/bevacizumab arm (HR 0.81; 95% CI 0.63-1.03; p=0.09), although these data were immature at the time of presentation and further follow-up is needed (J Clin Oncol 2018;36(suppl 6S; abstr 578)). In addition to the CheckMate 214 and IMmotion 151 trials, a number of other phase III trials investigating other ICI combinations are currently in progress (see Table).
More Data, More Questions
The results of JAVELIN Renal 100 (axitinib/avelumab) in the context of the results of CheckMate 214 (ipilimumab/nivolumab) and IMmotion 151 (atezolizumab/bevacizumab) trials raise a number of important questions. Are certain patients more likely to respond to ICI + VEGF-directed combinations versus ICI+ICI combinations? Is there an inherent benefit to therapy with different drug classes (ICI+VEGF) as opposed to those from similar drug classes (ICI+ICI)? Is there a subset of patients who might achieve the same response from monotherapy as they would from combination therapy and can thus be spared additional toxicity that accompanies combination therapy?
Similarly, as ICI combination therapy begins to invade the frontline therapeutic arena, the sequencing of treatment in mRCC becomes more complicated. Most patients will be treated with some VEGF-directed therapy following disease progression on ICI combination. Does the selection of upfront combination impact the choice of second-line therapy? Is there an intrinsic benefit to targeted therapy following ICI+ICI versus ICI+VEGF therapy or vice versa? Prospective trials are needed to clarify sequencing therapies as the frontline treatment armamentarium grows. Other areas requiring further clarity include duration of therapy, biomarker-driven treatment, choice of therapy for favorable risk mRCC, adjuvant ICI therapy, etc.
Conclusion
The preliminary results of the JAVELIN Renal 100 demonstrate the safety and efficacy of the combination of axitinib and avelumab in treatment-naive mRCC. These results await confirmation in an ongoing phase III trial and add to the excitement of ICI therapy as frontline options for mRCC patients. During the next few years, the rapid evolution of therapy for frontline mRCC will continue to progress as the results of multiple immunotherapy trials mature (see Table). In the absence of clear differences in efficacy, treatment decisions will likely be driven by a host of other factors including, but not limited to, toxicity, intravenous versus oral treatment, frequency of treatment, duration of therapy, cost, and institutional formulary policies. Although additional studies are required to resolve some of the aforementioned answered questions, ICI therapy in frontline mRCC will revolutionize the treatment of frontline mRCC and improve patient outcomes.
MOSHE C. ORNSTEIN, MD, MA, is Associate Staff, Genitourinary Oncology, Cleveland Clinic Taussig Cancer Institute. BRIAN I. RINI, MD, FACP, is Professor of Medicine, Lerner College of Medicine, and Leader, GU Program, Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute.