There were two practice-changing stories this year in renal cell carcinoma (RCC) that comprise my votes for Top Story of 2020.
The recently presented CheckMate 9ER trial at ESMO 2020 demonstrated positive findings of the combination of cabozantinib and nivolumab in the first-line treatment of advanced RCC.1 In this multinational, randomized, open-label, phase III trial presented by Dr. Choueiri, 651 patients with previously untreated advanced or metastatic RCC a clear cell component across all IMDC risk groups were randomized 1:1 to first-line treatment with intravenous nivolumab at 240 mg every 2 weeks plus oral cabozantinib at 40 mg/d versus standard oral sunitinib at 50 mg/d in 4-week–on, 2-week–off cycles. The study’s primary endpoint was met, with a doubling of the median progression-free survival (PFS) at 16.6 months for the combination versus 8.3 months for sunitinib (P < .0001). For the secondary endpoints, although mature overall survival data were not mature, overall survival (OS) seemed to favor the combination arm nivolumab and cabozantinib whereby, at first analysis, the risk of death was reduced by 40% (P = .0010). The overall response rate of the combination was also higher at 55.7% versus 27.1% (P < .0001), and complete response rates were doubled at 8% versus 4.6% in favor of the combination. The duration of response was longer with cabozantinib and nivolumab as well. The rate of treatment discontinuations due to treatment-related adverse events was 15.3% in the combination arm and 8.8% in the sunitinib arm. Although the overall rate of serious adverse events was similar between the two arms, liver toxicity was more common with nivolumab and cabozantinib whereby increased liver enzymes were reported in 25% versus 6% with sunitinib. The efficacy results were seen irrespective of IMDC risk score and PD-L1 subgroups.
As a result of this groundbreaking trial, it is likely that cabozantinib and nivolumab will be established as a new first-line option in advanced RCC across all risk categories, placing the combination in a space already occupied by axitinib and pembrolizumab (KEYNOTE-426),2 axitinib and avelumab (JAVELIN Renal 101),3 and nivolumab and ipilimumab (CheckMate 214),4 which all demonstrated superiority over sunitinib in the first-line treatment of advanced RCC as well.
The mature OS data are something to pay attention to for the combination of cabozantinib and nivolumab, and notably the dosing of cabozantinib was at 40 mg daily in CheckMate 9ER, whereby more than 50% of patients in the trial did require dose reductions.1 This implies that a lot of patients were actually on the 20 mg daily dose. Despite these points, this trial is sure to stimulate ongoing discussion into what is the optimal first-line IO-based combination in advanced RCC.
A separate study presented by Dr. Monty Pal at ESMO 2020 with very promising findings as well was COSMIC-021, which was a phase Ib trial, investigating cabozantinib and atezolizumab, a different checkpoint inhibitor.5 In this study, two doses of cabozantinib were examined, 40 mg daily and 60 mg daily, and the combination had comparable efficacy to that of cabozantinib and nivolumab. The 60-mg daily dose will be the dose that is taken to the CONTACT-03 phase III trial, which is an investigational trial of cabozantinib and atezolizumab versus cabozantinib in the treatment-refractory setting of mRCC—those treated with one to two lines of prior therapy.6 It is with hope that, with these ongoing studies, the optimal dosing of cabozantinib can be teased out when combined with IO.
My second Top Story of 2020 in RCC, is more of a collection of stories—that being the positive results supporting the routine use of IO in non–clear cell RCC (nccRCC). For the most part, metastatic nccRCC has been largely underrepresented in prospective clinical trials compared with the more common histologic clear cell subtype. However, this group comprises a high unmet need with often a more aggressive course than clear cell RCC. Historically, treatment has comprised a VEGF-TKI, and more recently with IO based on extrapolation of nivolumab and ipilimumab from CheckMate 214. However, several prospective trials have finally reported on the safety and efficacy of IO in advanced nccRCC. The phase IIIb/IV study of nivolumab monotherapy (CheckMate 374) demonstrated a 13.6% confirmed ORR in a total of 44 patients with subtypes including papillary (54.5%), chromophobe (15.9%), pathology unclassified (18.2%), translocation-associated (4.5%), collecting duct (2.3%), and medullary (2.3%), where 65.9% of patients had received no prior systemic treatments in the advanced or metastatic setting.7 Earlier in 2019, interim results of pembrolizumab first-line monotherapy for advanced nccRCC showed an ORR of 24.8% in 165 patients with nccRCC where a median duration of response was not reached.8 The majority of patients had papillary subtype 72% (n = 118), 13% had chromophobe (n = 21), and 16% had unclassified (n = 26), whereas the majority 62% were PD-L1+.
Additionally, RCC with sarcomatoid features (sRCC) represents an aggressive subtype associated with rapid disease progression and mortality, and where systemic treatment options remain poorly defined. Two recent studies reinforced the promising activity of IO-based regimens in sRCC as well. The first, a prespecified subgroup analysis of the phase III IMmotion151 trial, evaluated the efficacy and safety of atezolizumab plus bevacizumab versus sunitinib in 68 and 74 patients, respectively, with sRCC.9 The combination demonstrated a significantly improved median PFS in the group receiving atezolizumab plus bevacizumab overall (8.3 vs 5.3 months; HR, 0.52) and in the subset of patients with PD-L1–positive tumors (8.6 vs 5.6 months; HR, 0.45). More patients receiving atezolizumab plus bevacizumab achieved an objective response (49% vs 14%), including complete responses (10% vs 3%), and reported greater symptom improvements versus sunitinib.
A second study, which was a post hoc analysis of the phase III CheckMate 214 trial, evaluated the efficacy of nivolumab and ipilimumab in 145 patients with advanced RCC having sarcomatoid-positive tumors.10 Here, the combination of nivolumab and ipilimumab was associated with a superior survival benefit over sunitinib (median OS not reached vs 14.2 months; HR for death, 0.45; P = .0004). The median PFS (95% CI) was also significantly longer with the combination over sunitinib: 26.5 months (8.4–not estimable) versus 5.1 months (4.0–6.9), with higher ORR as well (60.8% vs 23.1%; P < .001). Impressively, 18.9% treated with the combination and 3.1% of patients treated with sunitinib achieved complete responses (CRs).
With these promising findings in such a high-risk subgroup, recent guidelines such as the Society for Immunotherapy of Cancer consensus statement have recommended nivolumab and ipilimumab as a first-line treatment option for patients with sRCC based on the sarcomatoid subset analyses of several trials enrolling patients with clear cell RCC. A phase III randomized trial directly comparing nivolumab plus ipilimumab versus sunitinib in those with nccRCC is ongoing (SUNIFORCAST, NCT03075423).11 Although nccRCC and sRCC represent rare and often aggressive subtypes of RCC with limited options, these breakthrough findings this year have provided hope with IO-based therapies in this subgroup of RCC patients in desperate need of better treatments and outcomes.