Sosman Weighs the Benefits of Combination Therapies in Multiple Lines of Treatment in RCC

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Jeffrey A. Sosman, MD leads a discussion about a 59-year-old Black who woman received a diagnosis of clear cell renal cell carcinoma.

Jeffrey A. Sosman, MD

Jeffrey A. Sosman, MD

During a Targeted OncologyTM Case-Based Roundtable event, Jeffrey A. Sosman, MD, professor
of Clinical Medicine, director, Thoracic Oncology, and director, Clinical Cancer Genomics at the Albert Einstein College of Medicine/ Montefiore Medical Center, lead a discussion about a 59-year-old Black who woman received a diagnosis of clear cell renal cell carcinoma.

Targeted OncologyTM: What is the current guidance on first-line therapy for relapsed or stage IV ccRCC?

SOSMAN: The most recent National Comprehensive Cancer Network [NCCN] guidelines [for systemic therapy] are divided into recommendations for favorable and poor/intermediate risk groups. All the tyrosine kinase inhibitors [TKIs] that have been approved are on this list.1

According to these guidelines, the regimens recommended for favorable- vs intermediate- or poor-risk patients are very much the same. What is the purpose of separating the recommendations according to risk group?

[The regimens are split because] the ipilimumab [Yervoy] and nivolumab [Opdivo] combination did not show a benefit for favorable-risk patients.2 Also, cabozantinib [Cabometyx] has not been evaluated in that group of patients. The 3 other regimens, axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib plus nivolumab, and lenvatinib [Lenvima] plus pembrolizumab, are recommended for both risk groups.1

What is the rationale for targeted therapy in patients with ccRCC?

A key factor in ccRCC is the frequent loss of von Hippel- Lindau disease [VHL], which leads to the derepression of several growth factors; among these is VEGF, an important target of TKIs [such as cabozantinib and lenvatinib]. There are some additional specificities to these therapies; cabozantinib also targets MET and AXL, and lenvatinib also targets FGFR.3 So that may suggest why there might be differences [between the therapies] and there are certainly clinical data to support that. Finally, mTOR [mechanistic target of rapamycin, is another important target]; it can become activated by mutation or by other means, and the mTOR pathway affects the translation of relevant genes [and processes of] metabolism and migration.4,5

For most tumors treated with inhibitors of the PD-1 pathway, objective response rate [ORR] usually correlates with the tumor mutational burden [TMB]. Renal cancer is one of the only tumors that does not fit [this model]; it does not have a high TMB, but patients can have very good responses [to PD-1 inhibition with therapies such as pembrolizumab and nivolumab].

[In a comparison of trials of first-line immune checkpoint inhibitor combinations], median follow-up ranged from 23.5 months in the CheckMate 9ER trial of cabozantinib plus nivolumab [NCT03141177] to 55 months in the CheckMate 214 trial of ipilimumab plus nivolumab [NCT02231749].6 Other trials were the KEYNOTE-426 trial of axitinib plus pembrolizumab [NCT02853331], with a median follow-up of 42.8 months, and the CLEAR trial of lenvatinib plus pembrolizumab [NCT02811861], with a median follow-up of 27 months.7,8

In all groups, there was an overall survival [OS] benefit, but the longer follow-up with ipilimumab plus nivolumab gives you [a better] idea of the median OS [not reached vs 38.4 months with the comparator (HR, 0.69; 95% CI, 0.59- 0.81), offering some] comfort that this survival advantage [will persist].2 The objective response rate was highest in patients with lenvatinib and pembrolizumab [71.0% (95% CI, 66.3%-75.7%) vs 36.1% (95% CI, 31.2%-41.1%) for the control]. However, the complete response [CR] rate was about the same [for the experimental groups in all 4 trials].9 Additionally, progression-free survival [PFS] appears to favor the lenvatinib plus pembrolizumab [23.9 months for the experimental arm vs 9.2 months for the comparator arm; HR, 0.39; 95% CI, 0.32-0.49] and the axitinib plus pembrolizumab [15.7 months for the experimental arm vs 11.1 months for the comparator arm; HR, 0.68; 95% CI, 0.58-0.80]. However, the median PFS of cabozantinib plus nivolumab was 17 months vs 8.3 months [HR, 0.52; 95% CI, 0.43-0.64].10

What additional data from this clinical trial support the use of the cabozantinib plus nivolumab combination?

This clinical trial is the phase 3 CheckMate 9ER trial, [which] included untreated patients with metastatic or advanced unresectable RCC. The patients had [a] clear cell component [to their disease], and…favorable-, intermediate-, and poor-risk patients were included. [Patients were stratified according to] risk category, expression of PD-L1, and…geographic region [of origin]. The comparator was sunitinib [Sutent] at 50 mg daily for 4 out of 6 weeks; the [experimental] therapy involved cabozantinib [40 mg daily] plus nivolumab [240 mg every 2 weeks]. The median follow-up was 18.1 months [range, 10.6-30.6] and the primary end point was PFS. OS, objective response, and safety were secondary end points.10

Cabozantinib plus nivolumab was superior to sunitinib with respect to PFS [16.6 months vs 8.3 months, respectively; HR, 0.51; 95% CI, 0.41-0.64; P < .001]. When PFS was analyzed by subcategories, as specified by risk group, age, gender, Karnofsky score, and others, the experimental immunotherapy combination arm [was consistently favored].11

An interim analysis of OS lead to unblinding [in this study]; the HR was 0.60 [98.89% CI, 0.40-0.89; P = .001]. At the 2-year follow-up, the results were equally good, with an HR of 0.66 [95% CI, 0.50-0.87].

[Although] the cabozantinib plus nivolumab combination did not [produce] a very high CR rate [8.0%], the objective response rate was 55.7% [95% CI, 50.1%-61.2%], while in the sunitinib group, it was 27.1% [95% CI, 22.4%-32.3%].11 In the combination arm, the median time to response was 2.8 months [vs 4.2 months in the comparator arm] and the median duration of response [DOR] was 20.2 months [vs 11.5 months; 95% CI, 17.3–not estimable and 95% CI, 8.3-18.4, respectively].9 At 23.5 months of follow-up, there was still benefit with respect to the rates of objective response [54.8% vs 28.4%], CR [9.3% vs 4.3%], and disease control [88.2% vs 69.9%].

There was some discontinuation of treatment [in this trial, and it was] similar in both arms [44.4% in the combination arm and 71.3% in the comparator arm]. Usually the patients received more therapy with cabozantinib and nivolumab [median duration, 14.3 months] than with the comparator [median duration, 9.2 months]. Discontinuation in many cases was due to disease progression, [among 27.8% of patients in the combination arm vs 48.1% in the comparator arm].10 Many of the toxicities were comparable. There was certainly more diarrhea [of any grade] in the group receiving the combination [57% vs 43%] and also more hypothyroidism [33% vs 28%]. But many of the other toxicities were similar in both groups. And based on this study, the FDA approved nivolumab and cabozantinib in January 2021.11

What options exist for subsequent therapy?

The NCCN guidelines take a conservative approach. The preferred regimens are cabozantinib, lenvatinib plus everolimus [Afinitor], and nivolumab; those are all category 1. Axitinib is a category 1 therapy listed among “other recommended regimens.” Nivolumab and axitinib are not regimens that I favor, and I don’t think most people do, but the other regimens would be options. Everolimus, bevacizumab [Avastin], and high-dose IL-2 [Proleukin] are listed as “useful in certain circumstances.” I don’t think anyone would use everolimus [alone but would use] everolimus plus lenvatinib. Bevacizumab is certainly a regimen to be considered in subsequent therapy when you run out of options. High-dose IL-2 is not what I, or even most people, [consider] a subsequent therapy, but certainly some would say that it is the only therapy with a 10-year follow-up [that shows that treated] patients are still in remission. The NCCN lists several other recommendations as well.1

The NCCN’s recommendations for preferred regimens were based on several studies. In a trial of nivolumab vs everolimus [CheckMate 025; NCT01668784], nivolumab was far superior in response rate and OS.12 Cabozantinib was compared with everolimus [METEOR; NCT01865747] and again showed superior benefit. Finally, lenvatinib plus everolimus was compared with single-agent lenvatinib and single-agent everolimus [NCT01136733], and this showed that the combination arm was superior to single-agent everolimus.13

Which data support this combination?

This is based on these data, which showed the effectiveness of the use of lenvatinib plus everolimus vs each agent used by itself. All patients in this trial had experienced progression of ccRCC following treatment with a single VEGF-targeted therapy. The treatments…were administered daily on 28-day cycles [lenvatinib (18 mg) plus everolimus (5 mg); single-agent lenvatinib (24 mg); and single-agent everolimus (10 mg)]. Patients were stratified according to hemoglobin and corrected serum calcium levels; PFS was the primary end point.14

The combination arm was far superior vs everolimus in terms of median PFS [14.6 months vs 5.5 months; HR, 0.40; 95% CI, 0.24-0.68; P = .0005]. The objective response rate with the combination vs with everolimus alone was greater [43% vs 6%; rate ratio, 7.2; 95% CI, 2.3-22.5; P < .0001]; likewise, the median DOR was superior [13.0 months (95% CI, 3.7–not evaluable) vs 8.5 months (95% CI, 7.5-9.4)]. In the post hoc analysis, OS was favored by the combination vs single-agent everolimus [25.5 months vs 15.4 months; HR, 0.51; 95% CI, 0.30-0.88; P = .024]. The data are overwhelming: If you’re going to use everolimus, it probably makes more sense to combine it with lenvatinib.

About 70% of patients who received the combination [developed] treatment-emergent adverse events of grade 3 or 4, but [that is similar to the percentage] in the lenvatinib-only group [79%] and is only somewhat higher than that in the everolimus-only group [50%]. Everolimus as a single agent is clearly not as toxic, though I usually have a lot of difficulty with pulmonary complications, and the combination produced more grade 3 and grade 4 fatigue and diarrhea. [Other than that], the percentages of patients with grade 3 and 4 toxicities were generally similar between groups.

I think it is very important to consider lenvatinib dosage modifications, because my experience is that the frequency of toxicity at [a dosage of] 18 mg daily is very high. Reducing it by even a small amount seems to make a big difference. However, you may have to go down to just 8 mg.14 And [in the study described, if a patient in the combination group experienced a] toxicity thought to be caused by the everolimus, the [dosage was permanently reduced] to 5 mg every other day.15


1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2022. Accessed August 17, 2021.

2. 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

3. Grüllich C. Cabozantinib: multi-kinase inhibitor of MET, AXL, RET, and VEGFR2. Recent Results Cancer Res. 2018;211:67-75. doi:10.1007/978-3-319-91442-8_5

4. Hsieh JJ, Purdue MP, Signoretti S, et al. Renal cell carcinoma. Nat Rev Dis Primers. 2017;3:17009. doi:10.1038/nrdp.2017.9

5. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377(25):2500-2501. doi:10.1056/NEJMc1713444

6. 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

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. 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. Paper presented at: American Society of Clinical Oncology Genitourinary Cancers Symposium; February 11-13, 2021; Virtual. Accessed August 17, 2021.

10. 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):S1142-S1215. doi:10.1016/annonc/annonc325

11. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed August 18, 2021.

12. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665

13. Choueiri TK, Escudier B, Powles T, et al; METEOR Investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917-927. doi:10.1016/S1470-2045(16)30107-3

14. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-1482. doi:10.1016/S1470-2045(15)00290-9

15. Lenvima. Prescribing information. Eisai Inc; 2021. Accessed August 18, 2021.

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