Immunotherapy Combinations Dominate Frontline Discussions in Advanced RCC

Recently updated data from clinical studies evaluating immunotherapy-based combination regimens in renal cell carcinoma (RCC) have shown that upcoming regimens are poised to offer additional treatment options personalized to patients’ therapeutic needs and have confirmed the benefit of entrenched regimens.

“With more and more options available for kidney cancer, we’re starting to get to the point where patients are going to have [a] choice,” Wenxin “Vincent” Xu, MD, said. “Not every patient is going to need every treatment option. We not only have advances in biomarkers, which are important for choosing [therapy], but we have [made] advances where patients can choose which mechanisms, adverse effects [AEs], and effects on quality of life are most important to them. We now have 5 tyrosine kinase inhibitor [TKI] choices, TKI and immunotherapy [combinations], and HIF2α inhibitors. [For example], a patient who is struggling with AEs now has an opportunity to experience a TKI break and still [receive] active therapy.”

During an OncLive Peer Exchange^®, a panel of RCC clinicians discussed recent updates in non–clear cell and clear cell RCC. They highlighted new data regarding front-line treatment approaches in advanced clear cell RCC, including that from the phase 3 CheckMate 214 (NCT02231749) and CheckMate 9ER (NCT03141177) trials, which investigated nivolumab (Opdivo) plus ipilimumab (Yervoy) and nivolumab plus cabozantinib (Cabometyx), respectively, and the phase 3 CLEAR study (NCT02811861) of lenvatinib (Lenvima) plus pembrolizumab (Keytruda).

The panelists then transitioned to the second-line and later settings of clear cell RCC, discussing updated data from studies such as the phase 3 CONTACT-03 trial (NCT04338269) of atezolizumab (Tecentriq) plus cabozantinib and the phase 3 KEYNOTE-564 trial (NCT03142334) of pembrolizumab monotherapy. The investigators concluded their discussion by briefly taking stock of the evolving landscape of non–clear cell RCC, spotlighting results from the phase 2 PAPMET trial (NCT02761057), which compared sunitinib (Sutent) with cabozantinib, crizotinib (Xalkori), or savolitinib (Orpathys) in advanced papillary RCC and led to the initiation of the phase 2 PAPMET2 trial (NCT05411081) of cabozantinib with or without atezolizumab in this patient population.

Combination Regimens Remain at the Forefront of Advanced Clear Cell RCC

In recent years, the FDA has approved multiple combination regimens for the first-line treatment of patients with clear cell RCC. The long-term follow-up data that have matured since these regimens’ approvals have afforded a more comprehensive understanding of each combination’s benefits.

“We’ve seen huge advancements in terms of landscape changes and how new therapies for the frontline setting are now considered,” Pedro Barata, MD, MSc, said. “For the majority of patients, we often [consider] an immunotherapy-based combination regimen. We have immunotherapy combined with another immunotherapy agent—nivolumab plus ipilimumab—but we also have combinations of immune checkpoint inhibitors with targeted therapies.”

Data from CheckMate 214 supported the 2018 FDA approval of the combination of nivolumab and ipilimumab for patients with previously untreated or intermediate- or poor-risk RCC. The study compared nivolumab plus ipilimumab followed by nivolumab monotherapy with sunitinib in adult patients with previously untreated RCC with a clear cell component. The primary end points of the study were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in patients with International Metastatic RCC Database Consortium (IMDC) intermediate- or poor-risk disease.^1,2

During the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), investigators presented long-term follow-up data from CheckMate 214. At a median follow-up of 99.1 months (range, 91.0-107.3), patients in the intent- to-treat population who received the combination (n = 550) achieved a median OS of 52.7 months (95% CI, 45.8-64.5) compared with 37.8 months (95% CI, 31.9- 43.8) among those treated with sunitinib (n = 546; HR, 0.72; 95% CI, 0.62-0.83). The median PFS was 12.4 months (95% CI, 9.9-16.8) vs 12.3 months (95% CI, 9.8-15.2), respectively (HR, 0.88; 95% CI, 0.75-1.03). The HR for OS and PFS remained stable in the intermediate- and poor-risk population (OS: HR, 0.69; 95% CI, 0.59-0.81; PFS: HR, 0.73; 95% CI, 0.61-0.87) and improved over time in the favorable-risk population (OS: HR, 0.82; 95% CI, 0.60-1.13; PFS: HR, 1.76; 95%CI, 1.25 2.48).²

“The question through the years has always been, ‘How have the data matured, and what happens to patients, long term?’ This is the longest follow-up we had for any immunotherapy combination,” Martin H. Voss, MD, said. “In my mind, the most striking data are the duration of response [DOR] data. Fifty percent of patients who are still being tracked after achieving a response to ipilimumab/nivolumab remain in response. The median DOR for this regimen is [greater than] 80 months, which stands out across all the data and is something that I think of when I consider this for my patients.”

CheckMate 9ER also evaluated a nivolumab-containing combination regimen, but with cabozantinib as its partner, vs sunitinib in patients with previously untreated clear cell RCC belonging to any IMDC risk group. Prior findings from the study supported the January 2021 FDA approval of the combination as a frontline treatment for these patients. The study’s primary end point was PFS by blinded independent central review (BICR) and OS was the key secondary end point.^3,4

Updated findings from CheckMate 9ER presented during ASCO GU 2024 showed that patients who received the combination (n = 323) achieved a median PFS per BICR of 16.4 months (95% CI, 12.5- 19.3) compared with 8.4 months (95% CI, 7.0-9.7) among patients treated with sunitinib (n = 328; HR, 0.58; 95% CI, 0.49-0.70). At a median follow-up for OS of 55.6 months (range, 48.1-68.1), the median OS figures were 46.5 months (95% CI, 40.6-53.4) vs 36.0 months (95% CI, 29.2-42.8), respectively (HR, 0.77; 95% CI, 0.63-0.95). Notably, PFS and ORR data favored the combination arm regardless of patient IMDC risk group.⁴

“In contrast to CheckMate 214, patients received a time-limited amount of nivolumab on this trial; however, cabozantinib was continued and was started at lower than the maximal dose [than what is] used as monotherapy, but we [still] see preservation of the clear improvement in meaningful cancer control outcomes as we see continued follow-up,” Elizabeth Wulff-Burchfield, MD, explained. “Treatment-free survival [TFS] is 1.5 times [that with] sunitinib in the nivolumab/cabozantinib arm. One of our patients’ main goals is to have the life that they envision for themselves, which is TFS, and we’re seeing that they can attain that at a greater rate [with nivolumab plus cabozantinib].”

Later in 2021, findings from CLEAR supported the approval of frontline pembrolizumab plus lenvatinib for patients with advanced RCC. The combination led to a significant PFS (HR, 0.39; 95% CI, 0.32-0.49; P < .0001) and OS (HR, 0.66; 95% CI, 0.49-0.88; P = .0049) benefit compared with sunitinib.⁵

During the 2024 ASCO Annual Meeting, investigators presented findings from a biomarker analysis of CLEAR that demonstrated that the PFS benefit observed with pembrolizumab plus lenvatinib vs sunitinib was maintained in the analysis sets for PD-L1 expression per immunohistochemistry (HR, 0.47; 95% CI, 0.37-0.60), gene expression via RNA sequencing (HR, 0.52; 95% CI, 0.41-0.68), and gene alterations with whole-exome sequencing (HR, 0.49; 95% CI, 0.38-0.63). The HRs for PFS also favored the combination across RCC driver mutation (mutant or wild-type VHL, PBRM1, SETD2, BAP1, and KDM5C) and gene signature (high vs low) subgroups.⁶

“In the biomarker analysis, we [examined] several different categories of biomarkers, including PD-L1 tumor mutations and transcriptomic signatures,” Xu said. “No matter which way you slice the data, lenvatinib/pembrolizumab [performs] significantly better than sunitinib. We can’t tell a patient that [they’re] the 1 patient who needs this regimen, but we can tell [them] that it seems, with the data that we have, these combination therapies are better and are the appropriate choice for most patients.”

Options in Clear Cell RCC Expand After Disease Progression, but Questions Linger

When selecting a regimen in the second line and beyond in clear cell RCC, several factors, such as safety profile, treatment goals, and patients’ disease characteristics, must be weighed. However, how to best select and, if necessary, sequence available regimens in this space remains an open question. “The way I [consider] the refractory setting is impacted by the frontline regimen that I chose. Another aspect that I now [consider is] the CONTACT-03 data,” Barata said.

CONTACT-03 enrolled patients with clear cell or non–clear cell RCC with or without a sarcomatoid component who experienced disease progression following treatment with an immune checkpoint inhibitor. Patients were randomly assigned 1:1 to receive atezolizumab plus cabozantinib or cabozantinib monotherapy. The co–primary end points were independent centrally assessed PFS and OS; secondary end points included ORR, DOR, and safety.⁷

Findings presented during the 2023 ASCO Annual Meeting demonstrated that patients who received atezolizumab plus cabozantinib (n = 263) did not experience improved outcomes vs those treated with cabozantinib alone (n = 259); in the overall population, the median PFS was 10.6 months (95% CI, 9.8-12.3) vs 10.8 months (95% CI, 10.0-12.5), respectively (stratified HR, 1.03; 95% CI, 0.83-1.28; P = .784), and the median OS was 25.7 months (95% CI, 25.1-not estimable [NE]) vs NE (95% CI, 21.1-NE), respectively (stratified HR, 0.94; 95% CI, 0.70-1.27; P = .690).

“The question that CONTACT-03 raises is how far to take this result; atezolizumab is a PD-L1 inhibitor, which [as a class is] not commonly used in RCC,” Xu said. “[These results] tell us that stimulating the tumor more with PD-L1 inhibitors is not having a strong clinical effect on tumor response. The real unanswered question here is whether we can extrapolate that to the postadjuvant setting. We now have an approved adjuvant therapy in RCC—pembrolizumab—which improves DFS [disease-free survival] and OS. The first-line treatment landscape after progression on adjuvant pembrolizumab is a big question for the field. Based on CONTACT-03, many [of us] are worried that we shouldn’t be giving additional PD-L1 inhibitors right after adjuvant pembrolizumab. But what is the definition of ‘right after’—how many months, is it a year? Do we challenge some patients and not others? These are questions that need to be answered in the coming years.”

Defining Pembrolizumab’s Role in the Adjuvant Setting

Findings from KEYNOTE-564 supported the November 2021 FDA approval of adjuvant pembrolizumab in patients with RCC at intermediate-high or high risk of recurrence after nephrectomy alone or after resection of metastatic lesions. KEYNOTE-564 randomly assigned patients 1:1 to receive adjuvant pembrolizumab or placebo. The primary end point was investigator-assessed DFS and OS was the key secondary end point.⁸

Updated findings from KEYNOTE-564 presented during ASCO GU 2024 showed that, at a median follow-up of 57.2 months (range, 47.9-74.5), patients in the pembrolizumab arm (n = 496) experienced a significant OS benefit compared with those in the placebo arm (HR, 0.62; 95% CI, 0.44-0.87; P = .002). Pembrolizumab also displayed a significant DFS benefit vs placebo (HR, 0.72; 95% CI, 0.59-0.87). The findings made KEYNOTE-564 the first study to demonstrate significant and clinically meaningful improvement with an adjuvant treatment in RCC.⁹

“The KEYNOTE-564 [regimen], once it demonstrated an OS benefit, was clearly seen as a new standard in the postnephrectomy setting,” Voss said. “[These findings] created this new space that we must think through and that we must address with dedicated clinical trials. A lot of the trials that we’ve recently [performed], and some of the trials that we are seeing now, are allowing patients to [enroll] if they’ve had prior adjuvant therapy. I would argue we need dedicated trials that not only allow for it, but where the requirement must be that the progression occurred after adjuvant [therapy] to address this question.”

If Not a Checkpoint Inhibitor, Then What? Alternative Options in the Refractory Setting

The panelists ended their discussion of treatment options in the second and later lines of clear cell RCC therapy by offering their perspective on treatment sequencing following treatment with a checkpoint inhibitor.

The HIF2α inhibitor belzutifan (Welireg) is approved by the FDA for treating patients with advanced RCC following treatment with a PD-L(1) inhibitor and a VEGF TKI. The regulatory decision was supported by findings from the phase 3 LITESPARK-005 (NCT04195750) study, which compared the agent with everolimus (Afinitor) in this patient population.¹⁰

Updated findings from LITESPARK-005 presented during ASCO GU 2024 demonstrated that belzutifan continued to offer a PFS (HR, 0.74; 95% CI, 0.63-0.88) and an OS (HR, 0.88; 95% CI, 0.73-1.07; P = .099) benefit vs everolimus. Additionally, findings from a patient-reported outcomes analysis showed prolonged time to confirmed deterioration by Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease Related Symptoms (HR, 0.53; 95% CI, 0.41-0.69; 2-sided nominal P < .0001) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (HR, 0.75; 95% CI, 0.58-0.96; 2-sided nominal P = .0185) with belzutifan. The respective difference in scores from baseline to week 17 were 1.45 (95% CI, 0.70-2.19; 2-sided nominal P = .0002) and 6.83 (95% CI, 3.21-9.55; 2-sided nominal P < .0001) in favor of the belzutifan arm.¹¹

“We’re getting more follow-up data to help us understand patient experiences [with these agents],” Wulff-Burchfield said. “I personally prescribe belzutifan, and I [also] prescribe tivozanib [Fotivda, but] I use them differently. I consider belzutifan as a TKI break for my patients, but because it has a slower onset of action, I have to be thoughtful about the most appropriate patient for that [agent] depending on their disease [characteristics]. We learn something from [all these studies]; these are valid therapies, and [there are] more to come.”

Immunotherapy Looks to Carve Out Its Place in Non–Clear Cell RCC

Although non–clear cell RCC is less common than clear cell disease, research in this area has seen significant gains in recent years, with an emphasis on adding immunoncology agents to the treatment arsenal. “[We] are starting to realize that non–clear cell RCC is not just an afterthought to clear cell RCC but is its own set of biologically distinct diseases. Non–clear cell RCC is not just 1 entity but is over a dozen entities, with some more common than others. Approximately 30% of all RCCs are non–clear cell,” Wulff-Burchfield noted.

The phase 2 PAPMET trial (NCT02761057) compared the existing standard-of-care treatment, sunitinib, with cabozantinib, crizotinib, or savolitinib in adult patients with papillary RCC. Data from the study demonstrated that patients who received cabozantinib (n = 44) achieved a median PFS of 9.0 months (95% CI, 5.6-12.4) compared with 5.6 months (95% CI, 2.9-6.7) among patients who received sunitinib (n=46; HR, 0.60; 95% CI, 0.37- 0.97; 1-sided P = .019), 2.8 months (95% CI, 2.6-3.6) in the crizotinib arm (n = 28), and 3.0 months (95% CI, 2.8-7.2) in the savolitinib arm (n = 29). The respective median OS values were 20.0 months (95% CI, 11.3-not reached [NR]), 16.4 months (95% CI, 12.8-21.6), 19.9 months (95% CI, 11.2-NR), and 11.7 months (95% CI, 6.7-28.9); cabozantinib led to a 16% reduction in the risk of death vs sunitinib (HR, 0.84; 95% CI, 0.47-1.51).¹²

Considering the positive findings with cabozantinib reported in PAPMET, investigators launched and subsequently presented the design of the phase 2 PAPMET2 study (NCT05411081) during ASCO GU 2024. PAPMET2 is the first randomized study of immunotherapy in papillary RCC; patients will be randomly assigned 1:1 to receive cabozantinib monotherapy or cabozantinib in combination with atezolizumab. The primary end point is a comparison of the median PFS between the 2 arms, and secondary end points include ORR, OS, and safety.¹³

Another phase 2 study, KEYNOTE-B61 (NCT04704219), is examining the combination of pembrolizumab with lenvatinib for the frontline treatment of patients with advanced or metastatic non–clear cell RCC. The primary end point of the study is ORR by BICR per RECIST 1.1; secondary end points included DOR, PFS, OS, and safety.¹⁴

At a median follow-up of 22.8 months (range, 16.6-27.6), updated findings from KEYNOTE-B61 presented during ASCO GU 2024 showed that pembrolizumab plus lenvatinib displayed durable efficacy; the ORR among patients who received the combination (n=158) was 50.6% (95% CI, 42.6%- 58.7%), including an 8.2% complete response rate, and the Kaplan-Meier estimated median DOR was 19.5 months (range, 1.5+to 23.5+). The Kaplan-Meier estimated median PFS and OS figures were 17.9 months (95% CI, 15.1-22.1) and NR (95% CI, NR-NR), respectively.

“[Patients with] translocation type [disease] did well with lenvatinib plus pembrolizumab and had the highest ORR,” Wulff-Burchfield said. “The disease control rate [DCR] was [approximately] 80%, which is wonderful because it’s such an aggressive biology in adult patients. Patients with papillary disease [also] did very well, with an ORR of [approximately] 50% and a DCR of approximately 80%. The chromophobe [subgroup] did not perform as well, with an ORR of approximately 35%, but we still saw disease control. I’m hopeful that we will have meaningful correlatives that will help us understand the mechanistic underpinnings of why this [regimen] is helping [patients], especially with chromophobe disease, because [we had thought] it doesn’t respond to anything until we saw [these data].

References

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