Park Considers Long-Term Data for Frontline Metastatic ccRCC Treatment

Peers & Perspectives in OncologyNovember II, 2023
Volume 1
Issue 9
Pages: 36

During a Targeted Oncology™ Case-Based Roundtable™ event, Chandler Park, MD, reviewed the latest updates of the pivotal trials of frontline combination therapies for advanced clear cell renal cell carcinoma.

Park headshot

Chandler Park, MD

Medical Oncologist

Norton Cancer Institute

Louisville, KY


  • Patient is a 59-year-old Black woman with a left renal mass.
  • She underwent left radical nephrectomy in December 2019 that revealed clear cell renal cell carcinoma (ccRCC).
  • Nine months later, she developed nodules in both lungs, with mediastinal (35 × 38 mm) and retroperitoneal lymph node involvement.
  • Lung biopsy confirmed stage IV RCC, clear-cell histology.
  • Karnofsky Performance Status: 90%
  • Hemoglobin level: 11.1 g/dL
  • Corrected calcium level and neutrophil and platelet counts were within normal limits.

Targeted Oncology: What data support the use of dual immunotherapy in patients with advanced ccRCC?

PARK: CheckMate 214 [NCT02231749] was a phase 3 clinical study. The primary end points were objective response rate [ORR], overall survival [OS], and progression-free survival [PFS] in intermediate- and poor-risk patients—notice favorable risk is not included. Secondary end points [included] ORR, [PFS, and OS in patients with any risk]. Patients were randomly assigned to the dosing of nivolumab [Opdivo] 3 mg/kg and ipilimumab [Yervoy] 1 mg/kg every 3 weeks, then nivolumab 3 mg/kg every 2 weeks. The comparison arm was sunitinib [Sutent].

It’s very interesting because in terms of the general oncologist’s [experience], the nivolumab/ipilimumab dose was slightly different from the other tumor types.1,2 For melanoma, it’s the opposite. We use ipilimumab 3 mg/kg and nivolumab 1 mg/kg. For patients who use nivolumab/ipilimumab for lung adenocarcinoma and squamous cell carcinoma, you give nivolumab/ipilimumab on day 1, and then 2 weeks later you give nivolumab on day 15, and then [you give] nivolumab on day 29. You end up giving ipilimumab every 6 weeks. That was also in the adjuvant nivolumab/ipilimumab study [CheckMate 914; NCT03138512]. The reason they did this is because in the original study [CheckMate 016; NCT01472081], they had an arm of 3-mg ipilimumab and 1-mg nivolumab and it had much higher toxicity.3 That’s why they came up with this arm.

At 67.7 months median follow-up, the median OS [in the intermediate- and poor-risk populations in CheckMate 214] was 47 months with nivolumab/ipilimumab vs 26.6 months with sunitinib. There’s a clear separation there, especially after 6 months. Then looking at the PFS, there is a complete drop in the first 6 months, [with] a median PFS of 11.6 months with nivolumab/ipilimumab vs 8.3 months with sunitinib.4

How does the durability of response on dual immunotherapy contribute to long-term OS?

If the patients survive, in terms of getting a response, they tend to have a durable response, with 31% vs 11% [OS rate at 60 months for nivolumab/ipilimumab and sunitinib respectively].4 If you look at the [waterfall plot], you might think 31% of the patients have a durable response after starting treatment, [but that] might not necessarily be the truth. At the very beginning where the X and Y cross, 425 patients started on nivolumab/ipilimumab. And in terms of the X axis at 60 months, now you have 48 patients, [which] is not 30% of 425. Thirty percent of 425 is closer to 130. How can you have a 31% [OS rate] and only have 48 patients? The answer is censoring. A lot of the patients dropped off. It could be higher than 31%, but it could also be lower. Be aware that even though it says 31%, that might not be the full story.

Can you summarize the outcomes of the immune checkpoint inhibitor and tyrosine kinase inhibitor (TKI) combination trials?

Here is a summary of the first-line immune checkpoint combination regimens for intermediate- and poor-risk metastatic renal cell carcinoma. I’ll start with the very first study, CheckMate 214. We always say it’s hard to make a comparison [between] different studies. How can you compare [patients] if one is halfway and the other is at the full [60 months]? That’s one reason why it’s difficult to compare trials. The second one is the comparison arm of sunitinib. In theory, all of the sunitinib arms should have the same PFS and OS, but they do not. Another reason is they have different inclusion criteria and so on.

The CheckMate 214 trial had a median follow-up of 67.7 months, and median OS [in the intent-to-treat (ITT) population was] 55.7 months [with nivolumab/ipilimumab] vs 38.4 months [with sunitinib]. [The HRs were] [0.72 for OS] and 0.86 for PFS [in the ITT population] and 0.68 [for] OS and 0.73 [for] PFS for [intermediate- and poor-risk patients].

[Approximately] 4 out of 10 patients are going to get a response [with nivolumab/ipilimumab]. Twelve out of 100 people get a complete response [CR], [but] 18% of patients—close to 1 out of 5 patients—are going to progress [by] their first CT scan. The ORR is 42%, and [the CR is] 11% [with nivolumab/ipilimumab vs [only] 1% [with sunitinib] in the intermediate- and [poor-risk] population.4,5

The second study, KEYNOTE-426 [NCT02853331], [investigated] pembrolizumab [Keytruda]/axitinib [Inlyta]. At the median follow-up of 42.8 months…median OS [in the ITT population] was 45.7 months [in the study arm] vs 40.1 months [for sunitinib]. The OS HR was 0.64 for the intermediate- to [poor-risk] population. If you look at the PFS, [intermediate- and poor-risk groups were] very similar. Six out of 10 [participants] responded [to pembrolizumab/axitinib], with a CR rate of [10%]. Eleven percent ended up with progressive disease [PD] on the first CT scan, [which was better than [nearly] 1 out of 5 with ipilimumab/nivolumab. The ORR was 57% [in the combination arm] vs 35% for sunitinib [in the intermediate-/poor-risk population], and the CR rate was 9% vs 2%, respectively.6,7

The third combination is cabozantinib [Cabometyx]/nivolumab. [Median follow-up] was 32.9 months, which means it’s about halfway [to 60 months], [with median OS of 37.7 months [for cabozantinib/nivolumab] vs 34.3 months [for sunitinib]. The OS HR was [0.74 in intermediate-risk and 0.45 in poor-risk patients]. In terms of the PFS, the HRs were 0.58 [for intermediate risk and] 0.36 [for poor risk], [which are] very comparable. The ORR was 56% [for cabozantinib/nivolumab] vs 28% [for sunitinib], with a CR rate of 12% vs 5%, respectively. If you look at PD, 6% of the patients on the scan have PD [with cabozantinib/nivolumab]. That’s so much better than KEYNOTE-426 and CheckMate 214. [In the patients with intermediate risk,] ORR was 56% with cabozantinib/nivolumab vs 29% with sunitinib, with a CR rate of 11% vs 3%, respectively.8-11

The CLEAR study [(NCT02811861) of lenvatinib (Lenvima) plus pembrolizumab] had an OS HR of 0.72, a PFS HR of 0.42, a PFS HR of 0.41 for intermediate risk and 0.30 for poor risk.12-15 The ORR was 71%, and 17% had a CR. Very similarly to CheckMate 9ER [NCT03141177], PD rate was 5%, which means 19 out of 20 patients on their first CT scan have stable disease or better. The ORR that was updated [in 2023] was 72% with lenvatinib/pembrolizumab vs 30% for sunitinib for the intermediate- and poor-risk patients, with a CR rate of 14% vs 4%, respectively.15

What data support the use of lenvatinib/pembrolizumab for ccRCC?

The phase 3 CLEAR study [investigated] frontline lenvatinib/pembrolizumab vs sunitinib. There were 3 arms: lenvatinib 20 mg daily orally with pembrolizumab 200 mg intravenous every 3 weeks vs [lenvatinib 18 mg daily plus everolimus (Afinitor) 5 mg daily vs sunitinib 50 mg daily 4 weeks on, 2 weeks off]. The primary end point was PFS. The secondary end points included OS and ORR. Subsequent therapies received [by the lenvatinib/pembrolizumab and sunitinib arms included] anti-VEGF in 30% vs 34%, anti–PD-1/PD-L1 in 8% vs 43%, and “other” in 7% vs 15%, respectively.16

Subgroup analysis across all MSKCC [Memorial Sloan Kettering Cancer Center] and IMDC [International Metastatic RCC Database Consortium] risk groups favored lenvatinib/pembrolizumab. If you look at the poor-risk [population], PFS [by independent review committee] favored lenvatinib/pembrolizumab with an HR of 0.18; [the] HR [was] 0.46 for intermediate risk.15

[Looking at] OS…the HR for [MSKCC] poor risk was 0.5, intermediate [risk was] 0.71, and favorable risk was 1.0, [whereas for those with IMDC favorable risk, it was] 1.22.15

What does favorable-risk status vs intermediate-/poor-risk status suggest about response to immunotherapy/TKI therapy?

There are emerging data for metastatic ccRCC, and there tend to be 2 main drivers. One driver is VEGF, [targetable with] sunitinib, cabozantinib, or lenvatinib. You also have the immunogenic driver; these patients tend to have more response to immunotherapy. Classically, if you have poor risk, you tend to respond better to immunotherapy. That’s why you see such a great response with ipilimumab/nivolumab in the patients with poor risk and you don’t see that much data for tyrosine kinase inhibitor monotherapy in the patients with poor risk. On the other hand, if you look at the favorable risk, when the [data] first came out for KEYNOTE-426, the combination of pembrolizumab and axitinib showed a separation. But…over time, the sunitinib is looking better or the same as pembrolizumab/axitinib.

So if a patient has intermediate or poor risk, that’s where there is convergence of 2 different mechanisms of action. If they’re favorable risk, technically speaking, that’s not an immunogenic kind of cancer. Brian I. Rini, MD, [of Vanderbilt-Ingram Cancer Center] is actually doing a study right now where he’s looking at the sequencing of the different intermediate-, poor-, and favorable-risk [populations] and coming out with a biomarker to [find] the best regimen for this situation.

What has more recent follow-up on the CLEAR trial showed about this combination?

At 33.7-month follow-up, if you look at the CR rate, it was 17.2% vs 4.2% with lenvatinib/pembrolizumab vs sunitinib, respectively.16

The 2023 American Society of Clinical Oncology Annual Meeting [ASCO] update was at a median follow-up of 49.8 months. What’s new here is overall survival at 24, 36, and 48 months.17 If you look at the lenvatinib/pembrolizumab arm, 55.9% of the patients are still alive at 4 years. Sunitinib is pretty comparable at 52.5%, but that’s very strong there. The PFS HR is 0.47 [favoring the combination]. In terms of the ORR, it was 71.3% for lenvatinib/pembrolizumab vs 36.7% for sunitinib, and then median duration of response was 26.7 months [vs 14.7 months, respectively]. My take-home message at the 4-year follow-up from ASCO [is that] everything [has] pretty much kept in place in terms of the ORR, PFS, and OS.

[Looking at] the treatment exposure, safety, and discontinuation…the key point here is that [the rate of any-grade] treatment-emergent adverse events [AEs] is pretty much similar [at 99.7%, 99.7%, and 98.5% in the lenvatinib/pembrolizumab, lenvatinib/everolimus, and sunitinib arms, respectively].12 What about patients with any-grade AEs leading to discontinuation? That’s where all of us, if we decide to use lenvatinib/pembrolizumab, have to put in some work because 37.2% [of patients required] discontinuation, [with many cases related to] lenvatinib. [Other patients may require dose reduction] from 20 mg to 14 mg and watching the blood pressure and diarrhea.


1. Opdivo. Prescribing information. Bristol Myers Squibb; 2023. Accessed October 13, 2023.

2. Yervoy. Prescribing information. Bristol Myers Squibb; 2023. Accessed October 13, 2023.

3. Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol. 2017;35(34):3851-3858. doi:10.1200/JCO.2016.72.1985

4. 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). Ann Oncol. 2021;32(suppl 5):S685-S687. doi:10.1016/j.annonc.2021.08.057

5. 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

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 trial. Lancet Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8

8. 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

9. 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

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 6):350. doi:10.1200/JCO.2022.40.6_suppl.350

11. 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

12. 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

13. Grünwald V, Powles T, Kopyltsov E, et al. Analysis of the CLEAR study in patients (pts) with advanced renal cell carcinoma (RCC): depth of response and efficacy for selected subgroups in the lenvatinib (LEN) + pembrolizumab (PEMBRO) and sunitinib (SUN) treatment arms. J Clin Oncol. 2021;39(suppl 15):4560. doi:10.1200/JCO.2021.39.15_suppl.4560

14. Choueiri TK, Powles T, Porta C, et al. A phase 3 trial of lenvatinib plus pembrolizumab versus sunitinib as a first-line treatment for patients with advanced renal cell carcinoma: overall survival follow-up analysis (the CLEAR study). Abstract presented at: Kidney Cancer Research Summit; October 7-8, 2021; Philadelphia, PA.

15. 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):S1205-S1206. doi:10.1016/j.annonc.2022.07.1552

16. Voss MH, Powles T, McGregor BA, et al. Impact of subsequent therapies in patients (pts) with advanced renal cell carcinoma (aRCC) receiving lenvatinib plus pembrolizumab (LEN + PEMBRO) or sunitinib (SUN) in the CLEAR study. J Clin Oncol. 2022;40(suppl 16):4514. doi:10.1200/JCO.2022.40.16_suppl.4514

17. Motzer RJ, Porta CG, Eto M, et al. Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2023;41(suppl_16):4502. doi:10.1200/JCO.2023.41.16_suppl.4502

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