Toolbox Overflows With First-Line Combination Regimens for Advanced RCC

Oncology Live®Vol. 23/No. 11
Volume 23
Issue 11

In Partnership With:

Mehmet A. Bilen, MD, and a panel of renal cell carcinoma experts discuss the preferred treatment options for patients with intermediate-risk or high-risk advanced renal cell carcinoma and the clinical features that may influence their decisions.

Mehmet A. Bilen, MD

Mehmet A. Bilen, MD

Systemic treatment options for patients with advanced clear cell renal cell carcinoma (RCC) have expanded in the first line, with combination strategies headlining as preferred regimens across guidelines. Leveraging the synergistic effects of immune checkpoint inhibitors (ICIs) with tyrosine kinase inhibitors (TKIs) and other ICIs, several approved options set up a crowded landscape for clinicians to navigate.1

“We have at least 4 very effective regimens in our toolbox,” Mehmet A. Bilen, MD, said during a recent OncLive Peer Exchange®. “[Clinic] visits tend to be longer each year because we need to cover all these important data and then make a final decision.” He added that without a validated predictive biomarker for patients with RCC, selecting a frontline treatment option must consider a variety of clinical features. Risk stratification models, prognostic factors, and agent-specific concerns all play a role in identifying the right patient for the right combination.1

Bilen and a panel of RCC experts discussed the preferred treatment options for patients with intermediate-risk or high-risk advanced RCC and the clinical features that may influence their decisions.

Nivolumab Plus Ipilimumab

The combination that paved the way for frontline regimens is one that moderator Tian Zhang, MD, refers to as the “oldie but goodie” combination of nivolumab (Opdivo) plus ipilimumab (Yervoy). The dual PD-1/CTLA-4 blockade was the first ICI combination to tackle the previous standard of care in the space, sunitinib (Sutent). Results of the phase 3 CheckMate 214 trial (NCT02231749) led to the approval of the combination for patients with intermediate-risk or poor-risk advanced RCC in 2018.2

“It really was superior to sunitinib on all accounts at the time [the data were] originally published the in the landmark New England Journal of Medicine article in 2018,” David A. Braun, MD, PhD, said, adding that the updated analysis with 5-year follow-up confirmed this response and provided key information regarding the durability of the regimen. “Something that we’re hoping for is not just a response but long-lasting response. Sometimes responses might last indefinitely. This really provides a window into that.”

At the time of the updated analysis, 74 patients from the nivolumab/ ipilimumab arm and 65 patients from the sunitinib arm were included. The median overall survival (OS) for patients in the combination arm was 48.6 months (95% CI, 25.2-not estimable [NE]) vs 14.2 months (95% CI, 9.3-22.9) in the sunitinib arm (HR, 0.46; 95% CI, 0.29-0.71; P = .0004). The 60-month OS rates were 47% and 21%, respectively. In terms of progression-free survival (PFS), the median PFS with nivolumab/ipilimumab was 26.5 months (95% CI, 7.2-NE) vs 5.5 months (95% CI, 4.1-6.9) with sunitinib (HR, 0.50; 95% CI, 0.32-0.80; P = .0036). The 60-month PFS rates were 46% and 12%, respectively.3

Lenvatinib Plus Pembrolizumab

Data from the phase 3 CLEAR trial (NCT02811861) solidified the role of lenvatinib (Lenvima) in combination with pembrolizumab (Keytruda) for the first-line treatment of patients with advanced RCC, garnering FDA approval in August 2021.4,5 The combination of lenvatinib plus pembrolizumab outperformed 2 other regimens: lenvatinib plus everolimus (Afinitor) and sunitinib alone.

The median PFS was 23.9 months (95% CI, 20.8-27.7) with lenvatinib/pembrolizumab vs 14.7 months (95% CI, 11.1-16.7) with lenvatinib/everolimus, vs 9.2 months (95% CI, 6.0-11.0),with sunitinib. Lenvatinib plus pembrolizumab improved the risk of disease progression by 61% vs standard-of-care sunitinib (HR, 0.39; 95% CI, 0.320.49; P < .001).4

In terms of safety, adverse effects (AEs) were more prevalent in the combination arms. However, investigators noted that the median time to discontinuation due to AEs was 8.97 months in the lenvatinib/pembrolizumab arm compared with 5.49 months in the lenvatinib/everolimus arm, and 4.57 months in the sunitinib arm.4

The approved dose of lenvatinib plus pembrolizumab is 20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks or 400 mg administered as an intravenous infusion over 30 minutes every 6 weeks.5 However, Bilen noted that patient fitness may influence starting dose considerations.

“If this is not a frail patient, I start with 20 mg of lenvatinib, which is the dose that was used in the CLEAR trial,” Bilen said. “Based on tolerance, dose reductions and [treatment pauses] are helpful. This is [applicable for] approximately 60% to 70% of the patients I see in the clinic. Lenvatinib doesn’t have a very long halflife [and] because of this reason, if an AE occurs after holding the dose, we see improvement relatively quickly.”

Axitinib Plus Pembrolizumab

Axitinib (Inlyta) has demonstrated efficacy in combination with immune checkpoint inhibitors for the treatment of patients with advanced RCC. The TKI was first approved by the FDA in combination with pembrolizumab in 2019 based on data from the phase 3 KEYNOTE-426 study (NCT02853331).6 A second approval was granted in May 2019 to the combination of axitinib plus avelumab (Bavencio) based on data from the JAVELIN Renal 101 trial (NCT02684006).7 Both studies were designed to evaluate the combinations vs single-agent sunitinib.6,7

The preferred regimen for patients with intermediate-risk or high-risk disease is axitinib plus pembrolizumab.1 An updated analysis of KEYNOTE-426 demonstrated that the combination maintained the efficacy and safety profile at 42.8-month follow-up. Compared with sunitinib, axitinib/pembrolizumab reduced the risk of death by 27% with median OS of 45.7 months (95% CI, 43.6-not reached) vs 40.1 months (95% CI, 34.3-44.2) with sunitinib (HR, 0.73; 95% CI, 0.60-0.88; P < .001). The median PFS was 15.7 months (95% CI, 13.6-20.2) vs 11.1 months (95% CI, 8.9-12.5), respectively (HR, 0.68; 95% CI, 0.58-0.80; P < .0001). In terms of response, the combination elicited an objective response of 60.4% (95% CI, 55.6%-65.1%) among 432 patients treated with axitinib/pembrolizumab vs 39.6% (95% CI, 35.0%-44.4%) among the 429 patients who received sunitinib. The complete response (CR) rates were 10.0% and 3.5%, respectively.8

“From the efficacy perspective, the updated data [provided] confirmation of very interesting results with a high response rate of approximately 60%, including approximately 10% of responses being complete responses,” Pedro C. Barata, MD, MSc, said. “According to what we saw early on, I would say from the efficacy profile [that] this combination regimen continued to demonstrate value and continued to help patients in this first-line setting.”

Barata also discussed the safety profile of the combination noting that no unexpected toxicities were observed. “I should just mention that it was clever the way [investigators] designed this study because they allowed for dose titration specifically for the TKI,” Barata said. “You could go up on the dose and you could also down, titrate it down, to 3 and then 2 mg orally once daily, which allowed patients to remain on treatment [while] the regimen was active.”

Cabozantinib Plus Nivolumab

Approved by the FDA in January 2021, cabozantinib (Cabometyx) and nivolumab introduced the multikinase inhibitor and ICI combination to the treatment landscape.9 The approval was supported by data from the phase 3 CheckMate 9ER trial (NCT03141177).

At the 2022 American Society of Clinical Oncology Genitourinary Symposium (ASCO GU) the final OS analysis of CheckMate 9ER was presented with a median follow-up of 32.9 months. The median OS for patients who received the combination was 37.7 months (95% CI, 35.5-NE) compared with 34.3 months (95% CI, 29.0-NE) with single-agent sunitinib (HR, 0.70; 95% CI, 0.55-0.90).10 The median PFS was 16.6 months (95% CI, 12.819.8) vs 8.3 months (95% CI, 7.0-9.7), respectively (HR, 0.56; 95% CI, 0.460.68). Confirmed objective responses, including CRs, were nearly double among patients who received cabozantinib/nivolumab (n = 323) vs those who received sunitinib (n = 328). The objective response rate was 55.7% (95% CI, 50.1%-61.2%) vs 28.4% (95% CI, 23.5%33.6%), respectively, with CR rates of 12.4% and 5.2%, respectively.10

“Looking at these landmark OS and PFS analyses, notably the 24-month mark, is important because it really gives you a sense of what you can tell a patient to expect at 2 years,” Moshe C. Ornstein, MD, MA, said. The 24-month OS and PFS rates with cabozantinib/nivolumab were 70.3% and 39.5%, respectively, compared with 60.3% vs 20.9% with sunitinib.10

“What we see from the updated analysis is not only are the efficacy results holding up but the [regimen] seems to be tolerable. The OS holds up at landmark analyses and the CR rates look very impressive for cabozantinib and nivolumab. Taken together these data establish it as one of the standards of care for patients [with] treatment-naïve metastatic RCC,” Ornstein said.

AE Mitigation Strategies

Despite investigators reporting no unexpected safety signals across these trials, AEs associated with ICIs and TKIs were common. “These drugs have been around now for a long time and some of the AEs are easily recognizable,” Ornstein said.

Regarding a clinical scenario for managing treatment-emergent AEs, Ornstein noted, “You’re either giving steroids for the immune-related AE or you’re giving supportive care, breaks in therapy, dose reductions, etc, for a TKI-mediated toxicity. For AEs that have potential overlap, say diarrhea or elevated liver enzymes, one option is to hold both agents, or especially the TKI, and to wait a couple of days to see if there’s resolution. It’s important with all these combinations to really pay attention to the toxicity because we know that patients need to be on these drugs for longer period of time.”

Creating a Road Map for Treatment Selection

Results from several molecular analyses were presented during 2022 ASCO GU marked the slow and steady progress toward identifying predictive biomarkers. In a review of the data, Braun said that early signals across studies were not robust or conclusive, but ongoing efforts are exciting and encouraging for future exploration.

“The overall answer is that I hope we get there someday,” Braun said. “We’re making progress, but we’re definitely not there in terms of molecular biomarkers helping us choose the right drug for the right patient. What’s needed is more sophisticated analyses—high-dimensional analyses, single-cell RNA sequencing, and spatial technologies. [We also need] better approaches to incorporate these data. Not looking at 1 feature at a time, 1 gene, or 1 protein, but intubating a lot of things, including clinical factors, to create an integrative analysis. Those are going to be the key.”

In the absence of these markers, the panel turned to the agent- and patient-specific factors that influence their treatment decisions in clinical practice (Table3,4,8,10).

Table. Select Outcomes of Preferred Combination Regimens for Advanced RCC3,4,8,10

Table. Select Outcomes of Preferred Combination Regimens for Advanced RCC3,4,8,10

For example, Ornstein noted that the half-life of agents may aid in identifying toxicities faster. “There’s a benefit to the axitinib and pembrolizumab combination because the axitinib has the shortest half-life so it’s easiest to stop it and to tease out the toxicity,” he said.

Braun noted that considering the durability of the regimens boils down to the available data. “For some of the immuno-oncology/TKI combinations there’s at least the question of whether that durability holds up to the same degree. I know some [individuals] have been following the hazard ratios for OS or PFS and maybe they start to trend up a little bit. I think that’s an open question,” he said, adding that the robust data from CheckMate 214 offers the durability clinicians may be looking for when making a selection.

He highlighted the fact that the hazard ratio for the nivolumab/ipilimumab combination held up in the 5-year analysis. “Here’s a situation where we really have extensive follow-up, so we can see how [data] compare over time. If we go back to 2018, the hazard ratio for overall survival for the [patients who are intermediate risk or poor risk] was 0.63. Now it’s 0.68. Thus, [it is] really stable…The PFS looks like it’s gotten better—the hazard ratio was 0.82 when it was f irst reported in 2018 and now it is improved to 0.73 in favor of nivolumab/ipilimumab. To me that’s just [an] incredible statistic.”

Ornstein concluded that head-to-head trials of the combinations will never come to fruition; however, when making treatment decisions for his patients he compares the efficacy and safety the benefits of each. “If I have an elderly patient with multiple comorbidities and I know that I need to stop the toxicity right away if it happens, I’m more likely to use axitinib and pembrolizumab. But for the patient who is highly symptomatic and I need that response rate regardless of toxicity, I’m more inclined to use lenvatinib and pembrolizumab because the response rate is 71% and the PFS is close to 2 years,” he said.

“It goes back to being able to [treat] patients on any one of [the combinations] because the toxicities can be similar and the one that we’re most comfortable with keeping the patients on for the longest duration of time is probably the option that’ll provide the most benefit to an individual patient,” Ornstein said.


  1. George DJ, Lee CH, Heng D. New approaches to first-line treatment of advanced renal cell carcinoma. Ther Adv Med Oncol. 2021;13:17588359211034708. doi:10.1177/17588359211034708
  2. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed May 17, 2022.
  3. Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and safety of nivolumab plus ipilimumab (N+I) versus sunitinib (S) for first-line treatment of patients with advanced sarcomatoid renal cell carcinoma (sRCC) in the phase 3 CheckMate 214 trial with extended 5-year minimum follow-up. J Clin Oncol. 2022;40(suppl 6):352. doi:10.1200/JCO.2022.40.6_suppl.352
  4. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716
  5. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. Updated August 11, 2021. Accessed May 16, 2022.
  6. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA. Updated April 22, 2019. Accessed May 17, 2022.
  7. FDA approves avelumab plus axitinib for renal cell carcinoma. FDA. Updated May 15, 2019. Accessed May 17, 2022.
  8. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500
  9. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed May 17, 2022.
  10. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(suppl 4):350. doi:10.1200/JCO.2022.40.6_suppl.350
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