ASCO 2021: Making Strides in the Treatment of Non-Clear Cell Carcinoma: Are We Ready for Adaptive and Biomarker-Driven Strategies?

( Following three presentations regarding novel treatment approaches for patients with advanced non-clear cell renal cell carcinoma (nccRCC) in the Kidney and Bladder Poster Discussion session at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Deepak Kilari provided a discussant overview of these data and the rapidly moving disease space of non-clear cell renal cell carcinoma.

He emphasized that, in the post-cytokine era, we have seen a rapid proliferation of treatment options for patients with clear-cell renal cell carcinoma.


In contrast, in patients with non-clear cell histology, we have not seen a single new agent approved. Thus, treatments used for these patients are extrapolated from more general approvals in advanced RCC, with the data predominately driven by patients with clear cell disease. Thus, the most recent National Comprehensive Cancer Network (NCCN) guidelines still recommend sunitinib as a preferred choice for patients with nccRCC. He then highlighted four of what he deemed landmark trials in nccRCC, SUPAP, ASPEN, ESPN, and RECORD-3. These trials compared sunitinib to everolimus for the most part. These studies demonstrated some benefits of sunitinib and thus, it has become the standard of care.


However, very recently, the SWOG 1500 (PAPMET) trial compared sunitinib and cabozantinib among patients with papillary disease demonstrating improvements in objective response rate and progression-free survival for those receiving cabozantinib, establishing this as a new standard of care.

He first reviewed the results of the phase II trial of nivolumab and cabozantinib in patients with nccRCC, presented by Dr. Lee. This trial included patients with nccRCC who had received at most one prior line of systemic therapy. The patients then received nivolumab and cabozantinib 40mg daily. This study was split into two cohorts: cohort two included only chromophobe disease while cohort one included other non-clear cell histologies. Calling the results “impressive”, Dr. Kilari highlighted the objective response rate of 48% and disease control rate of 98% in cohort one. Further, in cohort one, the median progression-free survival (PFS) was 12.5 months.

He then made a cross-trial comparison, acknowledging the limitation of this approach, with the outcomes observed from single-agent sunitinib and cabozantinib observed in the SWOG 1500 trial. Acknowledging the limitations of such an approach, he emphasized that the results of the present approach utilizing combination therapy with nivolumab and cabozantinib appear to be favorable regardless of the outcome considered. It also compares relatively favorably to other VEGF-IO combinations including atezolizumab and bevacizumab and atezolizumab and cabozantinib.


He emphasized that the takeaway from this study demonstrates that nivolumab and cabozantinib demonstrate promising efficacy and manageable toxicity in patients with nccRCC though it does not change the standard of care currently. Instead, such an approach warrants ongoing study including, for example, the phase II PAPMET2 trial being led by SWOG.

He then transitioned to discussing Cohort B of HCRN GU16-260 which was a phase II study of nivolumab and salvage nivolumab and ipilimumab in nccRCC. Both retrospective and prospective single-arm studies have suggested some activity to both IO monotherapy and IO-IO combination therapy in advanced nccRCC. Thus, the HCRN GU16-260 examined a sequential approach with nivolumab monotherapy (part A) followed by ipilimumab and nivolumab salvage (part B) for those with progressive disease or stable disease at 48 weeks. While 124 patients were accrued to the ccRCC cohort, 35 were treated in the nccRCC cohort, of whom only 17 patients were eligible for salvage. The objective response rate (ORR) for single-agent nivolumab was 14%, in keeping with prior studies. However, in part B, he emphasized that 43% of patients who had progressive or stable disease who in theory should have been eligible for salvage therapy were unable to be enrolled due to a combination of toxicity from nivolumab monotherapy and symptomatic progressive disease. Only one patient had a partial response with salvage therapy. Compared to an upfront combination approach, he emphasized that this approach is associated with much worse outcomes compared to CheckMate 920 and other studies. He, therefore, concluded that nivolumab monotherapy had modest efficacy in nccRCC and that ipilimumab has minimal role or efficacy in salvage. However, this trial offers the opportunity for extensive ongoing correlative work. The ongoing SUNNIFORECAST trial will assess the role of combination immunotherapy in nccRCC.

Finally, he discussed Abstract 4511, examining the combination of durvalumab and savolitinib in patients with MET-driven, metastatic papillary RCC. He began by emphasizing that MET alternations are found in a large proportion of patients with papillary RCC: 81% of those with type-1 disease and 46% of those with type-2 disease. There are a number of MET inhibitors, though savolitinib is a selective MET inhibitor. A number of prior studies have shown that targeting MET is effective in patients with papillary RCC.


The CALYPSO trial includes a number of different RCC histologies though the present analysis focused on patients with MET-driven papillary RCC, defined based on chromosome 7 gain, MET amplification, MET kinase domain variations, or hepatocyte growth factor (HGF) amplification. This included 34% of patients with papillary disease. While ORR was 29% in the overall papillary RCC cohort, it was 57% among those who had MET-driven disease. Similarly, PFS and OS were better in the MET-driven subset.
In comparison to other treatment approaches, Dr. Kilari emphasized that these data show similar efficacy of this combination approach as to the combination of cabozantinib and nivolumab.


Again, he suggested that these data do not change the standard of care. However, they support the strong preclinical rationale for MET targeting. The ongoing SAMETA trial will provide a randomized comparison of durvalumab and savolitinib, durvalumab alone, and sunitinib alone.

He closed by emphasizing that patients with lung cancer have many actionable mutations. While there are many identified mutations in nccRCC, these are not yet actionable. Considering again the NCCN guidelines, he suggested that cabozantinib and potentially VEGF-IO combinations should become preferred treatment approaches in nccRCC.

Presented by: Deepak Kilari, MD, Associate Professor in the Division of Hematology and Oncology at The Medical College of Wisconsin in Milwaukee

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021.
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