ASCO21 – Key Updates for Kidney Cancer Patients

ABSTRACT

Over the last decade, novel immunotherapies and targeted therapies have revolutionized the kidney cancer treatment landscape. ASCO Annual Meeting, 2021, was yet another success against this battle, and in this commentary, we will focus on a few critical abstracts presented at the meeting pertinent to kidney cancer.

Dr. Toni K. Choueiri, Dana-Farber Cancer Institute, Boston, MA, presented the data of phase 3, randomized, double-blinded study of pembrolizumab (pembro) vs. placebo among early-stage clear cell renal cell carcinoma (ccRCC). In this landmark adjuvant study, Dr. Choueiri reported improved disease-free survival (DFS) with pembro (N-496) vs. placebo (N-498), HR 0.68 (95% CL, 0.53, -0.87), p-0.01. The one year and two-year DFS rate was 86% vs. 76% and 77% vs. 68%, respectively. Overall survival (OS) was not mature at the study cut-off timepoint. The findings in this trial are encouraging as many previous adjuvant trials with targeted therapy, including ASSURE1, PROTECT2, ATLAS3, and SOURCE4, failed to show improvement in DFS. The STRAC trial with adjuvant sunitinib vs. placebo also showed improved DFS5 HR, 0.74 (95% 0.55- 0.99, P 0.04). The trial noted substantially increased treatment-related adverse events (AE - grade 3 48%) and was associated with worse quality of life scale. Also, it failed to demonstrated OS benefit6 compared to placebo HR 0.92, (95%, CL 0.66- 1.28, P 0.61). Thus, even though sunitinib is FDA approved, it is less utilized in clinical practice. The present study, Keynote-564, was is also associated with 19% grade ≥3 treatment related AEs. Thus, DFS data from KEYNOTE-564 is promising, but it is critical to follow OS data and monitor long-term toxicity.

Dr. Chung-Han Lee, Memorial Sloan Kettering Cancer Center, NY, presented phase 2, a single-center study of cabozantinib plus nivolumab in non-clear cell RCC patients (nccRCC). Lee et al. noted an objective response rate (ORR) of 47.5% (19/40), median progression-free survival (PFS), and OS of 12.5 and 28.0 months respectively among papillary, unclassified, and translocation associated RCC patients. Suarez C et al. reported data from the CALYPSO multi-arm study of durvalumab and savolitinib in RCC with variant histology. Among 41 patients with papillary RCC (PRCC), 14 patients had MET-driven PRCC. The ORR, PFS, and OS in the entire population and MET-driven PRCC patients was 29% vs. 57%, 4.9 vs. 10.5 months, and 14.1 vs. 27.4 months. Both studies have shown improved ORR compared to ASPEN7 and PAPMET8 trials. Both cabozantinib plus nivolumab and durvalumab plus savolitinib appear promising treatments for non-clear cell RCC patients. However, larger sample size and randomized studies are needed to validate the findings.

Dr. Michael B. Atkins, Lombardi Comprehensive Cancer Center, Georgetown, DC, reported data of phase II, multicenter study of nivolumab (nivo) followed by salvage ipilimumab(ipi) plus nivolumab (ipi/nivo) in nccRCC patients (N-35). The ORR and PFS of single-agent nivo among treatment naïve nccRCC was 14.3% (5/35) and 3.4 months, respectively. Only 57% (17/30) patients were able to receive salvage ipi/nivo. The ORR and PFS among this salvage cohort were poor 6% (1/17) and 2.8 months, respectively. Unfortunately, single-agent nivolumab and salvage ipi/nivo showed modest efficacy among ncc-RCC patients.

Luis A Meza and Sumanta K Pal, City of Hope Comprehensive Cancer Center, Duarte, CA, reported first in class, single-center, randomized prospective study of ipilimumab plus nivolumab with or without a live bacterial product CBM-588 among clear-cell RCC patients (N-29). They noted improved PFS of 55 vs. 10.7 months, and ORR 58% vs. 20% among ipi/nivo plus CBM-58 (N-19) and ipi/nivo plus placebo (N-10), respectively. They also noted a trend toward increased Bifidobacterium levels among patients who responded to treatment with ipi/nivo. Although the study sample size was small, the results were quite striking and warrant further investigation.

In summary, ASCO annual meeting 2021 was successful in delivering promising treatment for patients with kidney cancer. Treatment with pembrolizumab in a post-nephrectomy adjuvant setting is very promising for clear cell RCC patients. For ncc-RCC patients, cabozantinib plus nivolumab and durvalumab plus savolitinib appear to be effective. Single-agent nivolumab and salvage ipi/nivo has a modest effect on nccRCC patients. Treatment with a live bacterial product CBM-588 can boost the impact of ipi/nivo among ccRCC patients.

REFERENCES

1. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. The Lancet 2016;387:2008-16.

2. Motzer RJ, Haas NB, Donskov F, et al. Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma. J Clin Oncol 2017;35:3916-23.

3. Gross-Goupil M, Kwon TG, Eto M, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Annals of oncology : official journal of the European Society for Medical Oncology 2018;29:2371-8.

4. Eisen T, Frangou E, Oza B, et al. Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial. 2020;38:4064-75.

5. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. The New England journal of medicine 2016;375:2246-54.

6. Motzer RJ, Ravaud A, Patard JJ, et al. Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results. Eur Urol 2018;73:62-8.

7. Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-388. doi: 10.1016/S1470-2045(15)00515-X. KEYWORDS: • cancer genomics • cancer evolution • intratumoral heterogeneity • next-generation sequencing • somatic mutation, clonality •

REFERENCES

1. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. The Lancet 2016;387:2008-16.

2. Motzer RJ, Haas NB, Donskov F, et al. Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma. J Clin Oncol 2017;35:3916-23.

3. Gross-Goupil M, Kwon TG, Eto M, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Annals of oncology : official journal of the European Society for Medical Oncology 2018;29:2371-8.

4. Eisen T, Frangou E, Oza B, et al. Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial. 2020;38:4064-75.

5. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. The New England journal of medicine 2016;375:2246-54.

6. Motzer RJ, Ravaud A, Patard JJ, et al. Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results. Eur Urol 2018;73:62-8.

7. Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2