ASCO21 Kidney Cancer Roundup
Robert A Figlin, MDCorrespondence to: Robert.Figlin@cshs.org
Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Health System, Los Angeles, CA
The COVID-19 pandemic has exposed fundamental disparities in the provision of health care across our nation and exacerbated the differences in health outcomes associated with race, socioeconomic and other demographic factors. A silver lining however is that pandemic precarity has inspired tremendous scientific collaboration among clinicians, researchers, and key opinion leaders. In this line, this year’s Annual Meeting of the American Society of Clinical Oncology (ASCO21) which was kicked off virtually on June 4 through June 8, not only celebrated latest breakthroughs in cancer research, treatment and patient care, but also focused on health equity in cancer care. ASCO21’s fitting theme - Health equity “doing right by the patients for whom we care” reflected addressing complex forces and systems that have created disparities in cancer care, treatment, and research and identifying ways to ensure that all patients have access to and benefit from the latest cancer advances and high-quality cancer care.Let’s recap the key developments from some of the highest-profile clinical trials presented in the ASCO21 conference. The results from KEYNOTE-564 trial presented during plenary session of ASCO21 have demonstrated that post-surgery treatment with pembrolizumab extends DFS for clear cell renal cell carcinoma (RCC) patients. This is the first phase III study based on adjuvant immunotherapy to demonstrate an improvement in DFS with a favorable safety profile as compared to S-TRAC and sunitinib. KEYNOTE- 564’s findings support adjuvant pembrolizumab as a potential new standard of care to reduce disease recurrence in patients with fully resected intermediate to high-risk RCC. However, further works remains to be seen especially confirmation of an overall survival benefit, usability in other RCC histologies, and the implications regarding treatment choices in advanced RCC. Additionally the trial included M1 patients post treatment of the oligometastatic disease. This is not a usual cohort of patinets included in classical adjuvant trials and may affect the DFS reported. Currently, there are four IO combinations available for the first-line treatment of metastatic RCC viz. nivolumab plus ipilimumab, pembrolizumab plus axitinib, avelumab plus axitinib, and nivolumab plus cabozantinib. The latest outcome of CLEAR trial adding lenvatinib plus pembrolizumab combination to the growing armamentarium of first-line treatments for RCC patients. CLEAR met its primary endpoint, with lenvatinib plus pembrolizumab significantly improving progressionfree survival compared to sunitinib. This combination also achieved favorable objective response rate compared to sunitinib with an impressive complete response rate. Lenvatinib + everolimus combination resulted in similar or worse HRQoL and symptom scores compared with patients treated with sunitinib. The additional data builds on previous findings of a phase 3 KEYNOTE-581 trial has shown (Abstract 4502); PD-1 inhibitor pembrolizumab plus lenvatinib improved outcomes versus sutent on a measure of health-related quality of life in first-line renal cell carcinoma (RCC). The additional data showed an improvement of specific health-related quality of life measures including favorable disease-related symptoms scores, as well as better HRQoL and disease-related symptoms scores for physical functioning, fatigue, dyspnea and constipation versus sutent. Results from KEYNOTE-426’s prespecified final analysis with a 42.8-month median follow-up and a 35.6-month minimum follow-up show that pembrolizumab + axitinib continues to demonstrate superior efficacy over sunitinib with respect to OS, PFS, and objective response rate. KEYNOTE-426 represents the longest follow-up of an anti- PD–1/L1 immunotherapy combined with a VEGF/VEGFR inhibitor for first line RCC and indicate pembrolizumab + axitinib as standard of care for patients with previously untreated advanced clear cell RCC. Results from CANTATA study shows that the addition of telaglenastat did not improve the efficacy of cabozantinib in mRCC as there was no significant difference in PFS between the arms. While the addition of telaglenastat did not improve outcomes with cabozantinib in this unselected population of patients with clear cell RCC, future studies are warranted to determine the impact of glutaminase inhibition in biomarker-selected patient populations with high dependence on glutamine/ glutaminase, and in combination with other therapeutic partners. A study involving Cabozantinib plus nivolumab (CaboNivo) combination showed that CaboNivo had an acceptable safety profile and showed promising efficacy in metastatic non-clear cell RCC pts with papillary, unclassified, or translocation associated histologies whereas activity in patients with chromophobe RCC was limited. Latest results from phase 2 study of belzutifan (MK-6482) shown clinical benefit and has a favorable safety profile in patients with VHL disease–associated ccRCC, pNETs, and hemangioblastomas.. In the phase 3 CheckMate (CM) 9ER trial, Nivolumab in combination with cabozantinib (N+C) has demonstrated significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS), compared with sunitinib as a first-line (1L) treatment for aRCC. In this issue, an exclusive roundtable discussion which I have moderated, participated by three distinguished kidney cancer and genitourinary investigators from across the country focusing on the current challenges in cancer trials post COVID-19 pandemic. These renowned experts also brainstormed various important topics including cancer therapy delivery in the COVID-19 era, telemedicine, new COVID-19 guidelines, evolving clinical trial design, vaccination efforts in cancer patients, adverse events associated with vaccination, and other newly developed measures and recommendations to manage COVID-19 issues in the provision of cancer care. In the review work, Eric et al evaluated the current literature regarding the epidemiology, clinical course, screening guidelines, and management of localized and metastatic disease of krebs cycle deficient RCCs such as hereditary leiomyomatosis and RCC (HLRCC) and hereditary paraganglioma and pheochromocytoma and also summarized therapeutic targeting strategies germline mutations in the fumarate hydratase (FH) and succinate dehydrogenase (SDH) genes participating in the krebs cycle metabolism. A seminal work by DiNatale et al proposed a pooled multiregional DNA sequencing strategy to boost translational value by addressing ITH while preserving valuable residual tissue for secondary analysis in RCC like solid tumors.