During a Targeted Oncology™ Case-Based Roundtable™ event, Pedro Barata, MD, MSc, discussed the CheckMate 9ER, KEYNOTE-426, and CLEAR trials of frontline combination therapies for patients with renal cell carcinoma.
Can you go over the update to the CheckMate 9ER [NCT03141177] trial in regard to this patient’s treatment?
BARATA: At the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium [ASCO GU], there was [an update to the CheckMate 9ER data]. This patient was started on cabozantinib/nivolumab. You start with 40 mg of cabozantinib [every day] and the standard dose of nivolumab every 2 weeks, but a lot of folks are doing it every 4 weeks.1
CheckMate 9ER is a phase 3 trial for patients with advanced ccRCC randomly assigned 1:1 to cabozantinib/nivolumab vs sunitinib [Sutent]. The primary end point was progression-free survival [PFS], and the secondary end points were overall survival [OS], objective response rate [ORR], and safety. This trial was positive. The important stratification factors were the IMDC [International Metastatic RCC Database Consortium] risk score; geography, because it was an international trial; and PD-L1 expression.
The data that Mauricio Burotto, MD, presented are the longest follow-up data we’ve seen for cabozantinib/nivolumab—3.5 years, or 44 months.2 The primary end point, PFS, doubles—8.4 months with sunitinib, going to 16.6 months with cabozantinib/nivolumab [HR, 0.58; 95% CI, 0.48-0.71]. The Kaplan-Meier curves separated quite early and remained separated, with a risk reduction of 42%.
Then the OS in the intention-to-treat population were absolute numbers. There’s a 14-month absolute difference in OS. Patients are living longer on cabozantinib/nivolumab. We’re talking close to 50 months—more than 4 years—vs 35 months or so with sunitinib—approximately 3 years. So, over a year difference [HR, 0.70; 95% CI, 0.56-0.87]. The curves separate quite early, and a bunch of events happen beyond the 3-year mark, and still, those curves are separated there.
How did the survival differ for intermediate- and poor-risk RCC vs favorable risk?
The median OS was 49.5 months with cabozantinib/nivolumab vs 29.2 months with sunitinib for the intermediate- and poor-risk groups [HR, 0.65; 95% CI, 0.51-0.83].2 Thus far, [there is] not much difference in OS for favorable risk [median OS, not reached with nivolumab/cabozantinib vs 47.6 months with sunitinib]. Part of the reason for that is because patients with favorable risk do much better. You need a much longer follow-up.
The median PFS for intermediate- and poor-risk groups was 16.4 months vs 7.1 months with nivolumab/cabozantinib vs sunitinib, respectively [HR, 0.55; 95% CI, 0.45-0.69].2 For the favorable-risk group, patients progressing shy of 2 years, [it was] 21.4 months for cabozantinib/nivolumab and 13.9 months for sunitinib [HR, 0.75; 95% CI, 0.50-1.13].2 [This is] not surprising, but it’s interesting to see the breakdown by risk group.
We also have the ORR, which is another end point. The ORR was 55.7% vs 28.4% responses for cabozantinib/nivolumab vs sunitinib, respectively.3 There were more than 12% complete responses [CR] and 6% progressive disease [PD] for cabozantinib/nivolumab. I think sunitinib…performed as expected—28.4% ORR is about right, 5.2% CR is about right, and PD in 13.7% of patients.
Time to response was 2.8 months for cabozantinib/nivolumab and 4.2 months for sunitinib. The median duration of response, meaning [whether] you’re responding, was close to [2 years] on cabozantinib/nivolumab vs shy of 1.5 years for sunitinib.
The data at ASCO GU showed the ORRs in intermediate-/poor-risk groups were 52.6% vs 23.8%, CRs were 12% vs 3.5%, and PD was 7.2% vs 16.8% for cabozantinib/nivolumab vs sunitinib, respectively.2 It seems that cabozantinib/nivolumab performed well, irrespective of the risk group.
What do you think of the subgroup OS analysis in CheckMate 9ER?
The schema [for the subgroup analysis] is a proof of concept, or a hypothesis generator.3 Most of the subgroups favored cabozantinib/nivolumab. Some of them are close in the middle—according to the breakdown by age, region, [and] race—although there are smaller numbers there. These were not surprising signals in [this analysis].
The CI was from 0.6 to more than 9.0 [HR, 2.37; 95% CI, 0.61-9.15]. I’m not sure how much we’ll make out of that because of the line being so wide.
Looking at the baseline IMDC score…the way I interpret this is: the sicker the patient is, the more it seems the patient will benefit from cabozantinib/nivolumab. In this case, the use of IO [immunotherapy]/TKI [tyrosine kinase inhibitor] can speak somewhat to the sense that we have in clinic. We have patients who present very differently: those who are in trouble quickly and those who do well. I think this shows us [what we might see] in the clinic.
What is interesting to me is to see all the factors benefiting the IO/TKI, cabozantinib/nivolumab. They gave data for bone metastasis and liver metastasis, and the benefit seems to be there. Again, this is a hypothesis generator, because the study has not been powered to answer the question for these factors, but it gives you an idea of how much the cabozantinib/nivolumab performed in these 2 groups.
Now we have the breakdown by location of metastasis. You have liver on top, bone in the middle, and lung at the bottom.4 I think it’s fair to say that across all those tumor types, you see a benefit for patients receiving cabozantinib/nivolumab, with the curves separating in all these scenarios for both PFS and OS. Again, they’re not powered to answer differences, but you do see the curves separating. I think that might be reassuring for a patient with liver, lung, or bone metastasis, for those end points.
What were other noteworthy outcomes from the CheckMate 9ER trial?
The other question that a lot of folks have has to do with time to subsequent therapy. It was 20.6 months.2 I should clarify that this is for patients who completed 2 years of nivolumab. Per protocol, they completed 2 years of nivolumab and then discontinued, and 88% of those patients continued on cabozantinib. The time to subsequent therapies was for patients who completed nivolumab, that specific end point. The reason why this came up is [because] a lot of [physicians] were asking, “What’s happening to patients who reached to the 2-year mark?” So the company and the investigators decided to run that analysis. This was presented at ASCO GU.
There were no new safety signals.5 There were a lot of the TKI-based [and IO-based] adverse events [AEs]. Treatment discontinuations of 27.2% were seen with either cabozantinib and/or nivolumab. For nivolumab, 10.6% of patients discontinued treatment [compared with] 9.6% for cabozantinib, and both discontinued at 7.5% compared with 10% of patients who discontinued sunitinib. Approximately half of the patients got at least 1 if not more dose reductions. I think we can say it was manageable toxicity. These safety data were presented last year. Then the grade 3 or higher AEs were at 65.0% for cabozantinib/nivolumab vs 54.0% for sunitinib.5
Can you discuss the KEYNOTE-426 trial (NCT02853331) efficacy in patients with RCC?
KEYNOTE-426, which investigated axitinib [Inlyta]/pembrolizumab [Keytruda] vs sunitinib, randomly assigned the patient population 1:1. The primary end points were OS and PFS, a composite end point. It was a positive trial. The intention-to-treat population median OS curves remain separated, at 45.7 months vs 40.1 months [HR, 0.73; 95% CI, 0.60-0.88; P< .001].6,7 Interestingly, there was 5 months’ difference between the 2 arms, and the risk reduction was 27%.
I think it’s fair to say that the different factors considered all seemed to favor axitinib/pembrolizumab [by subgroup for OS].6 Some with wider CIs, so I’m not sure we can take a lot out of that other than seeing that axitinib/pembrolizumab seemed to perform better than sunitinib in different groups.
The PFS and coprimary end point had curves separating relatively early at the 3-month marker and remains separated.6,7 It was 15.7 months vs 11.1 months for sunitinib. So it was close to a 5-month difference favoring axitinib/pembrolizumab, [and the] risk reduction was 32% [HR, 0.68; 95% CI, 0.58-0.80; P< .0001].
When we look at the confirmed responses, which was another efficacy end point, it was 60.4% vs 39.6%. [Again], I don’t think sunitinib underperformed. We’re talking about 3.5% CR and 17.0% PD with sunitinib compared with 10.0% CR and 11.3% PD with axitinib/pembrolizumab.
What was the toxicity seen with axitinib/pembrolizumab in this patient population?
Most have seen the safety data, and this is published. We have treatment-related AEs that led to…close to half of the patients discontinuing axitinib or pembrolizumab—21% for pembrolizumab, 20% for axitinib, and 7% for both compared with 12% for sunitinib. That number seems to be about right.
For dose interruptions, there was 44% for pembrolizumab, 62% for axitinib, [and 30% for] axitinib/pembrolizumab compared with 44% for sunitinib. In reality, you expect TKI-based [and IO-based] AEs. The significant AEs, grades 3 to 5, were in approximately two-thirds of the population, as expected.
How did the CLEAR trial [NCT02811861] investigate the RCC population?
Lenvatinib [Lenvima]/pembrolizumab [was investigated] relatively recently.8 This was a 3-arm study. A similar patient population [to the previous trials] was randomly assigned 1:1:1 to lenvatinib/pembrolizumab, lenvatinib/everolimus [Afinitor], or sunitinib. For lenvatinib/pembrolizumab, 20 mg of lenvatinib was used, so a higher dose of lenvatinib. Lenvatinib/everolimus was given at 18 mg and 5 mg, respectively, which is the standard. Sunitinib was also standard dose. PFS was the primary end point.
Median follow-up was shy of 3 years, and the PFS curves separate early and remain nicely separated.9 The median was 23.3 months vs 9.2 months favoring lenvatinib/pembrolizumab [HR, 0.42; 95% CI, 0.34-0.52]. The breakdown by risk showed the benefit is there, irrespective of the risk group, with poor, intermediate, and favorable risk favoring lenvatinib/pembrolizumab compared with sunitinib.
The subgroups seemed to benefit across the board for all the factors considered.8,10 Specific variables of interest, such as bone metastasis, liver metastasis, prior nephrectomy, and sarcomatoid features…had a benefit with lenvatinib/pembrolizumab compared with sunitinib. That’s reassuring for those subgroups.10
For OS, the curves separated around the 3-month mark.9 For intermediate- and poor-risk patients, it does cross 1.0, so it’s not statistically significant. This trial was not powered to answer that question, but nonetheless, you can see the curves get closer toward the end. The OS was still positive for patients enrolled in the CLEAR trial.
Similar to what I said previously for cabozantinib/nivolumab, there were patients who completed 2 years on pembrolizumab, stopped pembrolizumab, and then continued on lenvatinib as monotherapy.9 [A total of] 94.5% of patients were alive 3 years later. The risk breakdown was: intermediate/poor in 65 patients and favorable in 36 patients. We’re talking approximately 101 patients, so it’s a little less than one-third of the patient population who were able to complete 2 years of pembrolizumab and go on lenvatinib.
The ORRs were 71.0% for lenvatinib/pembrolizumab compared with 36.1% for sunitinib.9 For the experimental arm, the CR rate was at 17.2%...and there was very little PD—in the 5% range—compared with 14.0% for sunitinib. There was a median duration of response of more than 2 years compared with 14.7 months with sunitinib.
There were no surprising safety signals.8 Treatment-related discontinuations for lenvatinib was 25.6%, 28.7% for pembrolizumab, and 13.4% for both compared with 14.4% for sunitinib.8 For dose reductions, two-thirds dose reduced lenvatinib/pembrolizumab compared with half of the patients who dose reduced sunitinib. Finally, 78.4% had treatment interruptions with lenvatinib/pembrolizumab compared with 50.3% for sunitinib.
1. 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/NEJMoa2026982
2. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl 6):603. doi:10.1200/JCO.2023.41.6_suppl.603
3. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(7):888-898. doi:10.1016/S1470-2045(22)00290-X
4. Apolo AB, Powles T, Burotto M, et al. Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial. J Clin Oncol. 2021;39(suppl 15):4553. doi:10.1200/JCO.2021.39.15_suppl.4553
5. 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 6):350. doi:10.1200/JCO.2022.40.6_suppl.350
6. 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 trial. Lancet Oncol. 2020;21(12):1563-1573. Published correction appears in Lancet Oncol. 2020;21(12):e553.
7. 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
8. 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
9. Porta CG, Eto M, Motzer RJ, et al. Updated efficacy of lenvatinib (LEN) + pembrolizumab (PEMBRO) vs sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in the CLEAR study. Ann Oncol. 2022;33(suppl 7):S660-S680. doi:10.1016/annonc/annonc1072
10. Choueiri TK, Eto M, Kopyltsov E, et al. Phase III CLEAR trial in advanced renal cell carcinoma (aRCC): outcomes in subgroups and toxicity update. Ann Oncol. 2021;32(suppl 5):S678-S724. doi:10.1016/annonc/annonc675