Safely administering the combinations – through use of education, judicious patient selection, and attention to logistics – is a challenge, she maintained. “I tell the residents, you can probably give cisplatin/gemcitabine to 10 patients and you can probably give sunitinib to 20 patients and get a good sense of what’s going to happen. But every single patient that I have put on immune therapy, I learn something new.”
Evolving issues, such as nuanced differences among the immune checkpoint inhibitors and whether the doses used in trials are really needed, have yet to be worked through. But combining these agents is likely better than sequencing them because only about half of RCC patients given first-line therapy go on to get second-line therapy, “so we might as well use our best therapy up front,” Dr. Wood said. Finally, it’s unclear whether cytoreductive nephrectomy is needed to achieve a complete response with these combinations because all trials predated the CARMENA trial (NCT00930033), so most patients underwent this surgery.
“These are exciting times. I think that for the first-line metastatic renal cell patient with favorable-, intermediate-, or poor-risk disease, a checkpoint inhibitor/axitinib combination will be a new standard of care in many parts of the world, not all,” she summarized. “For intermediate- and poor-risk patients, there’s no clear winner in my mind at this current time between ipilimumab/nivolumab and checkpoint inhibitor/axitinib. Decisions will need to be based on overall survival, complete response rates, toxicities, and then practical aspects, as well as costs.”
“But we cannot safely and effectively deliver this new standard of care without true infrastructure and system changes to accommodate more doctor and nurse visits, more infusion time, all of these extra visits, and more education for everybody who is both delivering and receiving these agents,” Dr. Wood concluded.
Study details
The subgroup analyses showed that, compared with sunitinib, avelumab/axitinib yielded better progression-free survival across patients differing with respect to IMDC risk group (range of hazard ratios, 0.539-0.736), MSKCC risk group (range of HRs, 0.495-0.715), tumor PD-L1 status (range of HRs, 0.626-0.827), prior nephrectomy status (range of HRs, 0.673-0.748), smoking status (range of HRs, 0.663-0.711), and body mass index (range of HRs, 0.667-0.674), Dr. Choueiri reported at the symposium. However, the 95% confidence intervals crossed 1 in some cases.
Overall, 20.8% of the avelumab/axitinib group and 39.2% of the sunitinib group went on to receive a follow-up anticancer drug therapy. The most common was cabozantinib (Cabometyx) in the former and nivolumab (Opdivo) in the latter.
The rate of progression-free survival 2 could not be estimated for the avelumab/axitinib group and was 18.4 months for the sunitinib group (HR, 0.56). “In theory, the first-line treatment could change the biology of the disease and therefore lead to substantially shorter benefit of second-line treatment, and progression-free survival 2 is actually a potentially important endpoint for regulatory and reimbursement evaluation,” Dr. Choueiri explained. “This suggests at least no negative impact of first-line treatment with the combination on subsequent benefit from second-line treatment.”
Compared with sunitinib, avelumab/axitinib also yielded better odds of objective response regardless of IMDC risk group (range of odds ratios, 3.099-3.556), MSKCC risk group (range of ORs, 3.061-4.686), PD-L1 status (range of ORs, 2.240-3.594), prior nephrectomy status (range of ORs, 2.592-3.249), smoking status (range of ORs, 2.649-3.798), and body mass index (range of ORs, 3.086-3.292). Here, virtually all 95% confidence intervals excluded 1.