Negative Trials Fail to Dampen Enthusiasm for Adjuvant, Combination Therapy in RCC

Toni K. Choueiri, MD

With three negative neoadjuvant and adjuvant trials in renal cell carcinoma (RCC)––CheckMate-914 (NCT03138512), IMmotion010 (NCT03024996) and PROSPER (NCT03055013)––it is difficult not to question the legitimacy of bringing proven, effective systemic therapies from the metastatic setting to the localized setting. However, without definitive proof explaining why the trials were negative, one can only focus on the known: that checkpoint inhibition has shown preliminary benefit deserving of additional follow-up in the adjuvant setting, explained Toni K. Choueiri, MD.

“Today, we have to build on pembrolizumab as a standard, but again, this is based on disease-free survival data,” Choueiri said. “I remain quite enthusiastic because the overall survival [OS] data at 24 and 30 months is intriguing despite not having met the rigorous statistical significance that we wanted.”

In an interview with OncLive^® during the 2022 ESMO Congress, Choueiri, director, Lank Center for Genitourinary Oncology, director, Kidney Cancer Center, senior physician, Dana-Farber Cancer Institute, Jerome and Nancy Kohlberg Chair and Professor of Medicine, Harvard Medical School, provided perspective on key research in RCC that was presented at the meeting, including the first demonstration of benefit with triplet therapy in metastatic clear cell disease, the expansion of HIF-2α inhibition into the first line, and success with VEGF/immune-oncology approaches in the non–clear cell population.

OncLive^®: The results from the combination arm of CheckMate-914 were ultimately negative but a large percentage of patients did not complete the intended 6 months of therapy. Similarly, negative results were observed with adjuvant atezolizumab (Tecentriq) in IMmotion010 and neoadjuvant nivolumab (Opdivo) in PROSPER. How do you interpret these findings, and what might the next steps be for neoadjuvant and adjuvant therapy in high-risk RCC?

Choueiri: We now have three negative adjuvant trials and one positive trial in KEYNOTE-564 [NCT03142334] that we presented last year with Thomas Powles, MBBS, MRCP, MD, of Barts Cancer Centre, and colleagues at the 2021 ASCO Annual Meeting plenary. I don’t have a [clear] explanation of why the other trials are negative, but they’re different. The study designs are different, and the patients’ risks are different. CheckMate-914, which [was presented by] Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center [MSK], didn’t enroll patients with M1NED disease. It seemed to include a bunch of T1 patients, and the regimen was given for only 6 months, so it’s very plausible that patients didn’t get enough immunotherapy. It [is also] plausible that they received steroids for immune-related adverse effects [AEs] that probably affected the outcome, although we don’t know that [for certain].

Atezolizumab is a drug that has not panned out in the first-line setting in metastatic RCC, or in bladder cancer, so it’s possible that the PD-1 and PD-L1 inhibitors are different.

You presented the results of the COSMIC-313 trial (NCT03937219), which showed a significant improvement in progression-free survival (PFS) with cabozantinib plus nivolumab and ipilimumab (Yervoy) vs the immunotherapy combination alone in advanced, untreated RCC. What is the significance of the control arm? Can you explain what the ramifications of this study are on the frontline landscape?

This is the first trial [to use] a modern control arm. The control arm is contemporary; this is not sunitinib [Sutent], but rather, the combination of nivolumab [Opdivo] and ipilimumab that beat sunitinib hands down with a hazard ratio of 0.06; that stood the test of time from 17 to 60 months of follow-up. [We showed that] adding cabozantinib [Cabometyx] 40 mg once a day resulted in a statistically significant and clinically meaningful PFS benefit. The OS [data are] immature, with only 17 months of follow-up. Responses were numerically higher. I’d love to see them be even higher, but we must see.

One of the [questions] is, how do you manage AEs? You’re adding a TKI. We saw a higher risk of higher AEs overall in the triplet arm especially [in terms of] diarrhea and rash, although they were mostly all-grade. [However,] LFTs [liver function tests] also increased, so we’re learning how to manage [the AEs of] this regimen and we still have to find it a place [in the paradigm]. It is too early [to say where that might be, as] these are interim results, but more analyses are to come.

Novel agents are beginning to enter the frontline setting as well, and results from the LITESPARK-003 trial (NCT03634540) with belzutifan and cabozantinib were reported. With so many combinations in the frontline setting, which patients do you see benefitting from this regimen the most?

This was a study we launched in the frontline setting. The response rates with cabozantinib and belzutifan were quite intriguing, reaching almost 60%. The PFS is also quite long, although the median follow-up is short. The regimen is moving to the frontline and second line. In the second line, belzutifan and lenvatinib [Lenvima] is being compared with cabozantinib in previously treated patients. In the front line, this regimen is not moving. What’s moving is belzutifan and lenvatinib plus pembrolizumab, which is being evaluated in one of the three arms of the large LITESPARK-012 study [NCT04736706].

In non–clear cell RCC, based on the results of the KEYNOTE-B61 trial (NCT04704219) with pembrolizumab and lenvatinib, could combinations redefine the frontline landscape in this population as in the clear cell population?

Absolutely. In kidney cancer, the motto is no kidney cancer left behind. Non–clear cell RCC is a rare variant of kidney cancer that encompasses probably 20% [of all kidney cancers]. There are maybe 20 types [of non–clear cell RCC]; some of them tend to be very aggressive and others are not aggressive at all. Laurence Albiges, MD, PhD, of Gustave Roussy, presented results on the combination of pembrolizumab and lenvatinib.

We have a lot of phase 2 data with VEGF/immune-oncology approaches from atezolizumab/bevacizumab [Avastin] with Bradley McGregor, MD, of Dana-Farber Cancer Institute, cabozantinib/nivolumab from Chung-Han Lee, MD, PhD, from MSK, atezolizumab/cabozantinib from Sumanta Pal, MD, FASCO, of City of Hope, and on and on. But this is new­—this combination of pembrolizumab and lenvatinib, which has an approved indication in frontline clear cell RCC. [In non–clear cell RCC] Dr Albiges [reported] a response rate close to 50%, which is quite impressive, and there were no new safety signals.

The question is: Do we need the randomized phase 3 trial, or do we accept this phase 2 data since the combination is already approved? Certainly, this is a valid combination. We must look more at the data and tease out the subgroups that respond vs those that do not respond.