Evaluating First-Line Treatment Options for Metastatic ccRCC

Case-Based Roundtable Meetings Spotlight, Case-Based Roundtable Meetings Spotlight: June 2022,
Pages: 26

During a Targeted Oncology case-based roundtable event, Chandler Park, MD, discussed the preferred first-line treatment options including tyrosine kinase inhibitor/immunotherapy combinations for metastatic clear cell renal cell carcinoma.

Targeted OncologyTM: What do the current National Comprehensive Cancer Network (NCCN) guidelines say about first-line systemic therapy for relapsed or stage IV ccRCC?

PARK: First, for patients with favorable-risk disease, the NCCN recommends the following category 1 combinations: pembrolizumab [Keytruda] plus axitinib [Inlyta], cabozantinib [Cabometyx] plus nivolumab [Opdivo], and lenvatinib [Lenvima] plus pembrolizumab.1 Now, if you look at the subgroup analysis for the different studies, the study that had slightly more [patients with favorable risk in its study population] was the study of lenvatinib plus pembrolizumab [CLEAR; NCT02811861], so I do consider that as an option here. The recommended regimen I don’t consider [for patients with favorable risk] is the combination of ipilimumab [Yervoy] and nivolumab. This combination is [a preferred regimen] for [patients with] poor [or] intermediate risk.1

There are some patients who only have 1 pulmonary metastasis and are asymptomatic. For some of those patients, you can consider localized treatment. The NCCN recommendations for patients of poor or intermediate risk are the [category 1] combinations of axitinib plus pembrolizumab, cabozantinib plus nivolumab, ipilimumab plus nivolumab, and lenvatinib plus pembrolizumab.1 There are still some patients for whom I consider cytoreductive nephrectomy, especially patients in the intermediate-risk category. The CARMENA study [NCT00930033] that was released 3 years ago tested the tyrosine kinase inhibitor [TKI] sunitinib [Sutent], but today we live in an immune checkpoint inhibitor world, so for some of those patients with intermediate risk, [and who are candidates for cytoreductive nephrectomy], I start treatment with ipilimumab plus nivolumab. Then once the surgeon gets on board to do the cytoreductive nephrectomy, I continue with that same combination.

Can you summarize the studies upon which these recommendations were based?

The study with the most mature data is CheckMate 214 [NCT02231749], which studied ipilimumab plus nivolumab. Of this patient population, 23% had favorable risk, 61% had intermediate risk, and 17% had poor risk.2,3 Compare that with the CLEAR study of lenvatinib plus pembrolizumab: 31% favorable, 58% intermediate, and 9% poor.4 Then in the CheckMate 9ER study [NCT03141177] of cabozantinib plus nivolumab, the respective values were 23%, 58%, and 19%.5 The KEYNOTE-426 study [NCT02853331] of axitinib plus pembrolizumab was pretty balanced at 32%, 55%, and 13%, respectively.6,7 [Note that all of the comparison arms were sunitinib].

Now let’s consider the median follow-up periods. For CheckMate 214, [the] median follow-up was 67.7 months.2,3 KEYNOTE-426 was 42.8 months,6 CheckMate 9ER [was] 23.5 months,5 and CLEAR [was] 33.7 months.4 Median overall survival [OS] for CheckMate 214 was 55.7 months in the experimental arm vs 38.4 months in the comparator arm.2,3 [For] KEYNOTE-426, it was 45.7 months vs 40.1 months, respectively.6 In CheckMate 9ER, the respective values were not reached vs 29.5 months.8 In CLEAR, median OS was not reached in either arm.4 You can’t say much about the differences between these studies because of the differences in the patient profiles with respect to [risk status].

You also have to consider the probability of OS. If you have a newly diagnosed patient tomorrow and you start the treatment, what is the [likelihood] that the patient will be alive 1 year from now? For the CheckMate 214 trial, the probability of survival at 12 months was 83% in the experimental arm.2,3 In the KEYNOTE-426 trial, the probability at 12 months was 90%,6 and in the CLEAR trial, it was 90% also.4 In the CheckMate 9ER trial, the value was 86%.5

Another thing to consider is the HR for progression-free survival [PFS]. The HR for CheckMate 214 was 0.86 [95% CI, 0.73-1.01],2,3 KEYNOTE-426 [was] 0.68 [95% CI, 0.58-0.80],6 CheckMate 9ER [was] 0.52 [95% CI, 0.43-0.64],5 and CLEAR [was] 0.39 [95% CI, 0.32-0.49],4 a 61% reduction in the risk of death. The objective response rates [ORRs] in the experimental and comparator arms, respectively, were 39% vs 32% for CheckMate 214,2,3 60% vs 40% for KEYNOTE-426,6 55% vs 27% for CheckMate 9ER,5 and 71% vs 36% for CLEAR.4

That’s something I think about. Finally, the percentage of patients demonstrating complete response [CR] was 12% in CheckMate 214,2,3 10% in KEYNOTE-426,6 8% in CheckMate 9ER,5 and 16% in CLEAR.4 There is [an obvious] difference here. The follow-ups are all different, but this 16% is something I think about.

[On the basis of these results], the FDA approved nivolumab plus cabozantinib for advanced RCC in January 2021,9 then approved lenvatinib plus pembrolizumab in August 2021.10

Could you describe the patient population, design, and goals of the phase 3 CLEAR trial that explored the combination of lenvatinib plus pembrolizumab, the combination of lenvatinib plus everolimus [Afinitor], and single-agent sunitinib as frontline therapies?

The eligibility criteria included advanced ccRCC, a Karnofsky performance status score greater than 70, measurable disease, and adequate organ function. All patients were treatment-naive. Stratification factors included geographic region—western Europe and North America [combined] vs the rest of the world—and Memorial Sloan Kettering Cancer Center [MSKCC] risk category. The first study arm was lenvatinib [20 mg oral daily] plus pembrolizumab [200 mg intravenous every 3 weeks]. The second arm was lenvatinib at 18 mg plus everolimus at 5 mg, and the third arm was sunitinib. The primary end point was PFS [Figure4]. Secondary end points included OS, ORR, and health-related quality of life. The key exploratory end points were duration of response and biomarkers.4

[At a median follow-up of 26.6 months], there was a clear separation of all 3 survival outcomes. The survival probability in the lenvatinib plus pembrolizumab arm was [approximately] 50%, and the HR was very impressive [at] 0.39 [95% CI, 0.32-0.49; P < .001]. [This combination was favored in] all the subgroups analyzed in the CLEAR study, including those defined by age [younger than 65 years vs 65 years or older], geographic region, sex, MSKCC risk category, International Metastatic RCC Database Consortium [IMDC] risk group, and Karnofsky score [100-80 vs 80-70]. There were also subgroups defined by PD-L1 combined positive score [≥1 vs <1], although I don’t use PD-L1 in my practice.4

A prespecified analysis of adverse prognostic features, such as bone metastases, was performed. This is very intriguing to me because in the CheckMate 9ER study, patients with bone metastases tended to favor cabozantinib plus nivolumab.5 However, in this study, patients with bone metastases favored lenvatinib plus pembrolizumab. The patients with liver and lung metastases are the ones you have to think about, because those [metastases are] very poor prognostic factors. But in this study, patients with liver metastases [favored lenvatinib plus pembrolizumab]. The subgroups also favored this combination regardless of PD-L1 status, prior nephrectomy status, and presence of sarcomatoid component.4

At the 26.6-month follow-up, the OS analysis showed [an initial] separation of the survival curves, then the curves converged at the 33-month mark.4

Could this convergence be attributable to a crossover in the study design?

No, there was no crossover. I think most physicians were puzzled by this result, because there was such a separation of the 3 arms on the PFS curves, [and yet the OS curves converged. It is notable that at 33 months], the sample size is very small here—[26 or fewer patients per arm]4—so it’s hard to interpret this result. But we have to follow up on this, because this isn’t something we expected.

What were the response rates among the arms of the CLEAR trial?

In the lenvatinib plus pembrolizumab arm, the percentage of patients with a CR was 16.1%. Another 54.9% had a partial response [PR], so there was a combined ORR of 71% [95% CI, 66.3%-75.7%]. For the lenvatinib plus everolimus arm, the ORR was 53.5% [95% CI, 48.3%-58.7%], and the sunitinib arm value was 36.1% [95% CI, 31.2%-41.1%].4

Would I still consider lenvatinib plus everolimus in the first line here, [as] it seems like it had a higher response rate than sunitinib in this study? The answer is no. In the first-line setting, I still consider either the combination of nivolumab plus ipilimumab or a TKI plus immune checkpoint inhibitor.

What did the exposure, safety, and discontinuation analysis reveal?

The median duration of treatment for the lenvatinib plus pembrolizumab arm was 17.0 months. For the lenvatinib plus everolimus arm, the value was 11.0 months, and for the sunitinib arm [was] 7.8 months. The [percentages of patients with] grade 3 toxicities were similar [among the arms], with the lenvatinib plus pembrolizumab arm and the lenvatinib plus everolimus arm demonstrating slightly higher percentages than the sunitinib arm.

The possibility of adverse effects [AEs] leading to dose reductions is something we have to manage very carefully with the lenvatinib plus pembrolizumab regimen. In this arm, 68.8% of patients required a dose reduction.4 We have a clinical study at the Norton Cancer Institute in Louisville, [Kentucky], wherein patients receive lenvatinib plus pembrolizumab and a hypoxia-inducible factor-2α [inhibitor]. In this setting we do a quick dose reduction of the lenvatinib from 20 mg to 18 mg. If you have any toxicity at all, it’s very important you do a quick dose reduction.

In this study, treatment-related AEs included diarrhea, which affected 54.5% of the lenvatinib plus pembrolizumab population. Grade 3 diarrhea affected 8.2% of this population. Hypertension affected 52%; grade 3, 25.3%. [The values for stomatitis and other AEs] were similar, although the hypertension and diarrhea were more pronounced.4 We know the hypothyroidism and fatigue [are associated] with the pembrolizumab, [and] lenvatinib does have some activity in the thyroid, as well, which is why it has the indication for thyroid cancer.

What are some practical considerations for physicians who use the lenvatinib plus pembrolizumab regimen?

The recommended dosage of lenvatinib is 20 mg [daily], and the dosage of pembrolizumab is 200 mg every 3 weeks for up to 2 years. At the completion of 2 years of the combination, lenvatinib is administered as a single agent until progressive disease or toxicity. Lenvatinib is available in 4-mg and 10-mg capsules. So, [if you start] at 20 mg, you could go down to 14 mg, but I try 18 mg. The second reduction is to 10 mg, and the third reduction is to 8 mg.11,12

Please describe the patient population, design, and goals of the phase 3 CheckMate 9ER study, which compared the combination of nivolumab plus cabozantinib with single-agent sunitinib.

CheckMate 9ER included patients [who] had advanced or metastatic RCC with a clear cell component, and any International Metastatic RCC Database Consortium [IMDC] risk profile was permitted. After stratification [according to IMDC risk score, tumor PD-L1 expression, and geographic region], patients were assigned to receive either nivolumab at 240 mg plus cabozantinib at 40 mg, instead of the 60 mg we’re used to, or the comparator, which was sunitinib at 50 mg daily. Patients were treated until RECIST-defined progression [or unacceptable toxicity]. The primary end point was PFS, and the secondary end points were OS, ORR, and safety.5

The median PFS of the nivolumab plus cabozantinib arm was 16.6 months [95% CI, 12.5-24.9] vs 8.3 months [95% CI, 7.0-9.7]. There was a strong HR of 0.51 [95% CI, 0.41-0.64; P < .0001]. [The survival curves remained widely separated] at the 3-month mark.5 At the 2-year follow-up, median PFS was 17.0 months for the experimental arm vs 8.3 months for the comparator arm [HR, 0.52; 95% CI, 0.43-0.64]—very strong data.8 In the subgroup PFS analysis, every subgroup—[including those defined by IMDC risk status, PD-L1 expression, and by the presence or absence of bone metastases]—favored the nivolumab plus cabozantinib combination.5

When OS was analyzed after a median follow-up of 18.1 months, [median OS was not reached for either arm], but there was a separation of the survival curves [HR, 0.60; 98.89% CI, 0.40-0.89; P = .001].5 At the 2-year follow-up, median OS was not reached for the nivolumab plus cabozantinib arm vs 29.5 months for the sunitinib arm [HR, 0.66; 95% CI, 0.50-0.97; P = .0034].8

What were the response rates among the arms of the CheckMate 9ER trial?

The ORR was 55.7% [95% CI, 50.1%-61.2%] for the nivolumab plus cabozantinib arm and 27.1% [95% CI, 22.4%-32.3%] for the sunitinib arm.13 [For comparison,] the ORR with nivolumab plus ipilimumab was [approximately] 40%,2,3 [approximately] 60% with axitinib plus pembrolizumab,6 and [approximately] 70% with pembrolizumab plus lenvatinib.4 The CR rate was 8.0% vs 4.6% in the experimental and comparator arms, respectively.13 The respective PR rates were 47.7% and 22.6%. One caveat is that there was a higher percentage of patients [with poor risk] in this study [than in other studies].3-6

What were the results of the safety analysis?

At a minimum follow-up of 10.6 months, the median duration of therapy was 14.3 months in the nivolumab plus cabozantinib arm and 9.2 months in the sunitinib arm. The percentage of patients with at least 1 dose reduction of cabozantinib from 40 mg to 20 mg was 56.3%, and 51.6% of patients in the comparator arm required at least 1 dose reduction of sunitinib. The percentage of patients requiring treatment discontinuation was 44% for the nivolumab plus cabozantinib arm [and] 71.3% for the sunitinib arm.

Treatment discontinuation due to disease progression affected 27.8% vs 48.1% of patients in the respective arms, so [the experimental combination] does get the disease under control, and treatment discontinuation due to treatment-related AEs of any grade occurred in 15.3% vs 8.8% of patients in the respective arms.13

One disadvantage of the nivolumab plus cabozantinib combination is that [because] cabozantinib has such a long half-life, if a patient has colitis or diarrhea, you can’t just stop the cabozantinib. In contrast, if somebody is on a very short-acting TKI, such as axitinib, if you stop the axitinib and the patient gets better within 2 or 3 days, [you can conclude] it was not the checkpoint inhibitor that caused the colitis or diarrhea, it was the axitinib.

The other disadvantage of the cabozantinib is that if you know a patient is going to have surgery for any reason, you [must stop] the cabozantinib up to 3 weeks before the surgery. In contrast, with axitinib and [with] lenvatinib, you only have to [stop treatment for approximately] 7 days before surgery.

Among the observed AEs, diarrhea affected 57% of patients in the experimental arm and 43% of patients in the comparator arm. The disadvantage of the cabozantinib plus nivolumab combination is that you don’t know which one is causing the diarrhea. You can treat with loperamide [Imodium], but it [usually] ends up being the cabozantinib that caused the diarrhea.

Hand-foot disease affected 38% vs 40% of patients in the respective arms. Elevation of both aspartate aminotransferase [AST] and alanine transaminase [ALT] levels was more pronounced in the experimental arm than in the comparator arm.13 Of all the TKIs, axitinib [causes] the highest AST and ALT levels, but cabozantinib also causes slight elevation.


1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 4.2022. Accessed May 14, 2022. https://bit.ly/39EA3mY

2. Motzer RJ, Tannir NM, McDermott DF, et al. Conditional survival and 5-year follow-up in CheckMate 214: first-line nivolumab + ipilimumab (N + I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). Presented at: European Society for Medical Oncology Congress 2021; September 16-21, 2021; virtual. Accessed May 15, 2021. https://bit.ly/3wvYfBk

3. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi:10.1136/ esmoopen-2020-001079

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. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa202698

6. 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

7. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE- 426): extended follow-up from a randomised, open-label, phase 3. Lancet Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8

8. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. Presented at: American Society of Clinical Oncology Genitourinary Cancers Symposium; February 11-13, 2021; virtual. Accessed May 16, 2022. https://bit.ly/3PAWzxY

9. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed May 15, 2022. https://bit.ly/3LoVdmB

10. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. Updated August 11, 2021. Accessed May 15, 2022. https://bit.ly/3lrHpgo

11. Lenvima. Prescribing information. Eisai Inc; 2021. Accessed May 16, 2022. https://bit.ly/39C3y92

12. Keytruda. Prescribing information. Merck Sharp & Dohme Corp; 2022. Accessed May 16, 2022. https://bit.ly/3LsMpfl

13. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2020;31(suppl 4):S1159. doi:10.1016/j. annonc.2020.08.2257