Late-breaking results of the phase III CheckMate 9ER trial, presented at ESMO Virtual Congress 2020, have provided a new first-line treatment option for patients with advanced clear cell renal cell carcinoma (aRCC). 
The study, funded by Bristol-Myers Squibb (Princeton, NJ), ONO Pharmaceutical Company (Osaka, Japan), and Exelixis (Alameda, CA), included the checkpoint inhibitor nivolumab (Opdivo®; Bristol-Myers Squibb) and the tyrosine kinase inhibitor cabozantinib (Cabometyx®; Exelixis), two drugs used as monotherapies in the second-line treatment of aRCC, and combined them for use as a first-line treatment against the standard of care, sunitinib (Sutent®; Pfizer), an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor.
Efficacy and Safety
As monotherapies, nivolumab and cabozantinib have demonstrated efficacy and a manageable safety profile in the treatment of patients with aRCC. Cabozantinib, which targets include VEGF receptor, MET, and the TAM receptor family, has demonstrated immunomodulatory properties that may counteract tumor-induced immunosuppression, suggesting that the drug may be synergistic with immune checkpoint inhibitors. This understanding, in part based on a phase I study and expanded cohorts of nivolumab and cabozantinib, showed encouraging antitumor activity in pretreated patients with aRCC, metastatic urothelial carcinoma, and other genitourinary malignancies and other advanced genitourinary tumors, providing a rationale for combining nivolumab with cabozantinib.
The investigators noted that the combination of the two drugs was superior to sunitinib for progression-free survival (PFS), overall survival (OS), and response rate. They also observed a consistent benefit of the combination over sunitinib in numerous subgroups including age, sex, PD-L1 expression, bone metastases, International Metastatic RCC Database Consortium (IMDC) risk group, and region of the world.
Participating patients were randomized 1:1 (stratified by IMDC risk score, tumor PD-L1 expression, region) to nivolumab 240 mg flat dose IV Q2W + cabozantinib 40 mg PO QD versus sunitinib 50 mg PO for 4 wk (6-wk cycles) until disease progression or unacceptable toxicity (maximum nivolumab treatment was 2 years). The primary endpoint was progression-free survival (PFS; α = 0.05 final) by blinded independent central review (BICR). The secondary endpoints (hierarchical testing) were overall survival (OS; α = 0.011 first interim analysis), objective response rate (ORR; α = 0.05 final) by BICR, and safety.
The study enrolled a total of 651 patients (22.6% favorable risk, 57.6% intermediate risk, 19.7% poor risk; 24.9% PD-L1 ≥1%). Participating patients were randomized to nivolumab + cabozantinib (n = 323) or sunitinib (n = 328).
With 18.1 months median (10.6 month minimum) study follow-up, all 3 efficacy endpoints were met.
The investigators observed that nivolumab + cabozantinib significantly improved PFS (HR 0.51 [95% CI 0.41–0.64], P < 0.0001; median, 16.6 v 8.3 mo) and OS (HR 0.60 [98.89% CI 0.40–0.89]; P = 0.0010; medians not reached) versus sunitinib. These results were consistent across prespecified IMDC risk and PD-L1 subgroups.
The objective response rate (95% CI) was significantly higher with nivolumab in combination with cabozantinib compared to sunitinib (55.7% [50.1–61.2] v 27.1% [22.4–32.3]; P < 0.0001), and 8.0% v 4.6% of patients achieved complete response. Median duration of response was 20.2 months for patients treated with nivolumab + cabozantinib compared to 11.5 months for patients treated with sunitinib.
In the study, more than 50% of patients in the combination arm needed a dose reduction of cabozantinib due to adverse events. But only 3% had to stop both drugs because of toxicity compared to 9% of patients in the sunitinib arm.
Any-grade treatment-related adverse events (TRAEs) occurred in 96.6% v 93.1% of patients treated with nivolumab + cabozantinib v sunitinib . One treatment-related death occurred with nivolumab + cabozantinib and 2 patients died with sunitinib.
The overall rate of serious treatment-related adverse events was similar between arms (60.6% v 50.9% grade ≥3), but liver toxicity was more common in the combination arm. As for immune-related side-effects, 19% of patients in the experimental arm needed corticosteroids with just 4% of participating patients needing corticosteroids for 30 days or longer.
Treatment-related adverse events led to discontinuation in 8.8% of the participating patients treated with sunitinib, nivolumab or cabozantinib in 15.3%, nivolumab with cabozantinib in 3.1%, nivolumab only in 5.6%, and C only in 6.6% of patients.
Advantages of combination therapies
These findings add to mounting evidence showing the advantages of combination therapy over single drugs. Similar to the CheckMate 9ER trial, the KEYNOTE-426 and JAVELIN Renal 101 trials  combined an immune checkpoint inhibitor with an anti-angiogenic drug, whereas CheckMate 214 combined two immune checkpoint inhibitors. 
“The results with combination therapy were statistically significant and clinically meaningful. The risk of progression or death was cut by almost 50%, death was cut by 40%, and the response rate doubled,” noted study author Toni K. Choueiri, M.D., the of Director of The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and The Jerome and Nancy Kohlberg Chair and Professor of Medicine, Harvard Medical School, Boston.
“This will become an important treatment option to choose from. The various combination treatments will unlikely be compared head-to-head, but I think the (health-related) Quality of Life (hrQoL) could differentiate this new therapy, as there was a statistical significance favoring the combination arm with both questionnaires we used. Another factor to consider is that clinicians are familiar with both of these drugs.” 
“CheckMate 9ER met its efficacy endpoints and the combination can be considered a new first-line treatment option,” said Dominik Berthold, M.D., Head, Specialised Consultation for Urological Cancers Medical Oncology Service, Department of Oncology, Lausanne University Hospital, Switzerland, commenting on the findings of the study.
“However, the medical community is divided about whether two immunotherapies or immunotherapy plus an anti-angiogenic drug is the better choice since the different combinations appear to have similar effectiveness,” Berthold added.
Berthold further moted that longer-term data are needed for CheckMate 9ER.
“The 18 months of follow-up is still quite short. The question is whether the responses to treatment are durable or patient’s progress at some point. It would also be useful to learn whether the combination of cabozantinib and nivolumab is effective in non-clear cell carcinoma,” added Berthold.
“This is a minority of patients with advanced kidney cancer which are not well studied and were excluded from this trial,” he said.
Berthold explained that when using drugs with specific mechanisms of action, the first-line treatment choice will also determine the selection of second-line therapy.
“If you start with a combination of immune therapy only, it becomes an automatic choice to use an anti-angiogenic drug in the second line. But if you begin with a combination of two mechanisms of action, such as immune therapy and an anti-angiogenic drug, then the second-line choice is less clear. More data are needed on the most suitable order of therapy for the entire population as well as specific groups such as high tumor burden versus slow-growing disease,” he concluded.
A Study of Nivolumab Combined With Cabozantinib Compared to Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 9ER) – NCT03141177
Cabozantinib S-malate and Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Genitourinary Tumors – NCT02496208
Study to Evaluate the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Axitinib Versus Sunitinib Monotherapy in Participants With Renal Cell Carcinoma (MK-3475-426/KEYNOTE-426) – NCT02853331
A Study of Avelumab With Axitinib Versus Sunitinib In Advanced Renal Cell Cancer (JAVELIN Renal 101) – NCT02684006
Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214) – NCT02231749
Highlights of prescribing information
Nivolumab (Opdivo®; Bristol-Myers Squibb)[Prescribing Information]]
Cabozantinib (Cabometyx®; Exelixis) [Prescribing Information]]
Sunitinib (Sutent®; Pfizer)[Prescribing Information]
 Choueiri TK Powles T, Burotto M, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. Presented by Toni K. Choueiri during the Presidential Symposium I on Saturday, 19 September, 18:30 – 20:10 CEST. Annals of Oncology, Volume 31 Supplement 4, September 2020 Abstract 696O_PR
 Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380:1116–1127.
 Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380:1103–1115.
 Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378:1277–1290.
 Quality of life was assessed using the Functional Assessment for Cancer Therapy – Kidney Symptom Index (FKSI) and the revised FKSI scale (FKSI-19).
Featured image: General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.