Robert A. Figlin, MD, FACP
The emergence of immunotherapy in renal cell carcinoma (RCC) has led to promising approaches to combat the disease, but investigators are still trying to determine how this class of agents compares with others and how to choose between combination strategies, said Robert A. Figlin, MD.
At the 2019 Genitourinary Cancers Symposium, data presented included combination regimens of checkpoint inhibitors and VEGF TKIs. Pivotal findings from the phase III KEYNOTE-426 trial showed that the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) reduced the risk of death by 47% compared with standard sunitinib (Sutent). Furthermore, the median progression-free survival was 15.1 months with the combination compared with 11.1 months in patients treated with TKI monotherapy. The median overall survival had not been reached in either arm at the time of the presentation.
Based on these data, the FDA granted a priority review designation in February 2019 to a supplemental biologics license application for pembrolizumab/axitinib as a frontline treatment for patients with advanced RCC.
Despite these promising findings, Figlin, director of the Division of Hematology/Oncology and the Steven Spielberg Professor of Biomedical Sciences and Medicine at Cedars-Sinai Medical Center, said that there is still much work to be done with immunotherapy; several unanswered questions still need to be addressed to further progress the field.
“We need to discover [more] novel targets and novel approaches because the fight in RCC has not been won just by the use of immuno-oncology drugs alone or in combination,” he said.
In an interview with OncLive
, Figlin highlighted advances made with immunotherapy in RCC and shed light on the challenges that remain.
OncLive: What recent updates in RCC do you find to be practice changing?
: The continued evolution of combination therapy with immunotherapy approaches and targeted therapy were the real focus of the plenary session at the 2019 Genitourinary Cancers Symposium. We heard about pembrolizumab and axitinib when combined together. These data come on the heels of learning about other checkpoint inhibitors and targeted agents, as well as [immunotherapy agents plus immunotherapy]. The good news is that we continue to see both robust activity—an improvement in the hazard ratio, as illustrated by the abstract—as well as benefit in patients. Therefore, what are the unanswered questions?
The good news is that these drugs seem to be combinable. The reality is that we have used these agents in the clinic at my own practice at Cedars-Sinai Medical Center. We found them to be acceptable in terms of toxicity. What patients want to know is whether the toxicity is acceptable and if there is a tail of the [survival] curve where patients achieve long-term disease control. The things we don't have answers to are how we would compare them with other combinations in the clinic. And, how we would choose one combination over another immunotherapy/targeted therapy or immunotherapy/immunotherapy combo? Unfortunately, those questions [remain unanswered] because we really don't have cross-trial comparisons.
Could you discuss the toxicity observed when combining checkpoint inhibitors with VEGF TKIs?
What we see in terms of the adverse event (AE) profile is what we'd expect and hope for: separate immune-related AEs with the immunotherapy agent, plus hypertension, hand-foot syndrome, diarrhea, fatigue, and loss of appetite with the VEGF TKI. Luckily, we have not seen enhancement or synergy of the toxicities when these agents are combined. As long as the doctors are familiar with immune-related AEs and their time course, as well as those of TKIs, they should be able to manage these patients quite well.
Where do we stand in terms of biomarkers of immunotherapy response in these patients?
While we all are interested in using data sets to identify biomarkers in prospective trials and validate them—whether that happens to be an angiogenic profile, immunotherapy profile, or PD-L1 staining—we are not at a place in RCC where that is applicable in the standard management of these patients.
Based on these recent advances, what can be accomplished in the near future?
We can accomplish several things. First, we need to nail down the true accomplishments of immunotherapy approaches and try to identify which ones are optimal. What offers the patient the greatest value of care—meaning control of risk, control of AEs, long-term benefit, possible tail of the [survival] curve, and possible maintained remissions? That's the first step, and whether that means immunotherapy/immunotherapy combinations or immunotherapy/TKI combinations remains to be seen.
Secondly, even if we are hugely successful with immunotherapy approaches in RCC, there are still going to be large populations of patients who don't benefit. We need to continue to identify novel targets, novel approaches, and investigate them with vigor. That could happen to be an agent like bempegaldesleukin (NKTR-214), a pro interleukin (IL)-2 drug, in combination with an immunotherapy drug. This is bringing IL-2 back into the equation. We could also be looking at agents that inhibit glutamine; in fact, some are already being evaluated in ongoing trials. These are examples of novel approaches that we hope will extend observations that have occurred to date.
Powles T, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. J Clin Oncol. 2019;37(suppl 7; abstr 543). doi: 10.1200/JCO.2019.37.7_suppl.543.