In the past decade we have witnessed dramatic changes in the understanding and treatment of renal cell carcinoma (RCC), which is the most common type of kidney cancer. Although, a number of targeted therapies have revolutionized the management of this disease, improved survival remains the most important unmet need in the treatment of advanced RCC.
According to this year’s 18th ECCO - 40th ESMO European Cancer Congress in Vienna, there is a hope for RCC, as two new heroes enter the scene with potentially practice-changing results.
Actions of first hero, programmed death 1 (PD-1) checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) were presented during the first Presidential Session by Professor Padmanee Sharma from the MD Anderson Cancer Center, USA.
- The CheckMate 025 Phase III trial evaluating nivolumab versus everolimus in advanced RCC patients pretreated with one or more anti-angiogenic agents was stopped early after meeting the primary overall survival (OS) endpoint. This is the first trial in which immunotherapy shows an OS benefit versus standard therapy in RCC patients who failed previous treatment.
- Data from this trial showed that at a minimum follow-up of 14 months, nivolumab significantly prolonged OS compared with everolimus (25.0 months versus 19.6 months, respectively). The OS benefit was consistent across patient subgroups, and irrespective of PD-L1 expression.
- The analysis showed also that the objective response rate (ORR) was higher in the nivolumab arm (25%) than in the everolimus arm (5%). Complete responses (CR) were observed in 1% of patients (n=4) in the nivolumab group and in <1% (n=2) in the everolimus group. The median time to response was 3.5 months and 3.7 months, respectively; the median duration of response was 12 months in both arms.
- The median progression-free survival (mPFS) was 4.6 and 4.4 months with nivolumab and everolimus, respectively. In a post-hoc analysis of patients who had not progressed or died at 6 months, mPFS was 15.6 months in the nivolumab group and 11.7 months in the everolimus group.
- The CheckMate 025 study reported also that nivolumab had favorable safety profile, and the most common treatment-related adverse events were fatigue (33%), nausea (14%), and pruritus (14%). Grade 3/4 adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients treated with everolimus. Treatment discontinuation due to adverse events was reported for 8% of patients receiving nivolumab and 13% of patients receiving everolimus.
- In September 2015, based upon the results of this study, nivolumab received FDA Breakthrough Therapy Designation for advanced RCC.
Another highlight of the first Presidential Session at the 2015 ECCO - ESMO European Cancer Congress was presentation of Professor Toni Choueiri from the Dana Farber Cancer Institute, USA who revealed clinical data on the second RCC hero, cabozantinib (Cometriq, Exelixis). Cabozantinib is a multi-tyrosine kinase inhibitor that targets MET, VEGF receptors, AXL, and RET, which have been implicated in the pathobiology of advanced RCC or in the development of resistance to anti-angiogenic drugs.
- The METEOR Phase III trial is comparing cabozantinib versus everolimus in subjects with mRCC that has progressed after VEGFR-targeted therapy.
- The study met the primary endpoint of PFS, which was almost doubled in patients receiving cabozantinib compared with everolimus (7.4 months versus 3.8 months). In a post-hoc analysis of patients who received sunitinib as their only prior VEGFR inhibitor, mPFS was 9.1 months in the cabozantinib group and 3.7 months in the everolimus group.
- The study revealed also that the secondary endpoint (ORR) was 21% with cabozantinib and 5% for everolimus. Stable disease (SD) was reported in 62% of patients in each group, while a progressive disease (PD) occured among 14% patients receiving cabozantinib versus 27% in patients assigned to everolimus.
- At the interim analysis, median OS could not yet be estimated, but a strong trend in OS benefit over everolimus was observed.
- The incidence of serious adverse events was similar for both arms, with 68% in the cabozantinib group and 58% in the everolimus group. The most common grade 3/4 adverse events in the cabozantinib arm were hypertension (15%), diarrhea (11%), and fatigue (9%). Treatment-related adverse events leading to treatment discontinuation occurred in 9% of patients treated with cabozantinib and in 10% of patients treated with everolimus.
- In August 2015, cabozantinib received a Breakthrough Therapy Designation by the FDA for patients with advanced RCC who have received one prior therapy. The decision was based on the data from the METEOR study.
These data show how much promise we hold for combatting renal cell carcinoma. The majority of participants of this year’s ECCO – ESMO European Cancer Congress were heartened by the growing body of exciting clinical data around two new RCC heroes, nivolumab and cabozantinib, Although Phase III data for these drugs are promising, physicians are hopeful that a translational biomarker will find a way to successfully identify biological subsets of patients most likely to respond to each of these agents. Unfortunately, association between PD-L1 expression and improved outcomes with nivolumab therapy observed previously with melanoma or non-small cell lung cancer patients, has not been noted in subjects with advanced RCC. For cabozantinib, it remains to be seen if observed clinical activity is mainly a result of inhibition of MET, AXL, or RET, or simply it is caused by VEGFR-inhibitory effect. Additional questions also persist; for example, will only patients that have been previously treated with anti-angiogenic agents benefit from either nivolumab or cabozantinib? How will these two new RCC drugs integrate into the present treatment paradigm for advanced RCC, whose disease has progressed on prior treatment? Will they be cost-effective? Undeniably, further work needs to be undertaken to find answers to some of these questions. Decision Resources Group will certainly continue to follow the developments for Opdivo and Cometriq in RCC and will keep you up to date with the latest news in this exciting field of research.
Izabela Ammermann is a business insights analyst with the Oncology team at Decision Resources Group.
Motzer RJ, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015 Sep 25.
Choueiri TK, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015 Sep 25