CheckMate 9ER offers RCC new frontline option; perspectives from the study’s principle investigator

Prof. Toni Choueiri (Dana Farber Cancer Institute, Harvard University, Boston, USA) presented the late-breaking results of the phase III CheckMate 9ER trial evaluating the combination of nivolumab and cabozantinib compared to sunitinib in untreated patients with advanced or metastatic renal cell carcinoma (RCC) at the ESMO Virtual Congress 2020 held 19-21 September, 2020 [1]. All endpoints were met, making this combination the newest frontline therapy option likely to be added to guidelines. Prof. Choueri discussed the implications with our journalist.

Efficacy results

Each of these treatments has proven survival benefit as single agents for metastatic RCC. CheckMate 9ER is a phase III, open-label, international randomised controlled trial in patients with previously untreated, advanced or metastatic clear cell RCC. Unlike some studies previously, patients whose tumors had sarcomatoid features were also allowed to enrol. Participants (n=651) were randomized to standard dose nivolumab + 40mg daily cabozantinib (n=323) or to single agent 50 mg daily sunitinib with a 4 weeks on 2 weeks off schedule (n=328). Randomization was stratified by tumor risk score, the presence of tumour PD-L1 receptors, and region. Patients continued on the study until the disease progressed or there was unacceptable toxicity. Progression-free survival (PFS) was the primary endpoint. Secondary outcomes were overall survival (OS), objective response rate (ORR), and safety/toxicity.

With a median follow-up of 18.1 months (all patients >10.6 months), all 3 efficacy endpoints were met. Nivolumab + cabozantinib significantly improved PFS (16.6 vs 8.3 months; HR 0.51; 95% CI 0.41–0.64; P<0.0001) and OS (medians not reached; HR 0.60; 98.89% CI 0.40–0.89; P=0.0010) when compared with the sunitinib arm. These results were consistent across prespecified risk and PD-L1 subgroups.

The objective response rate was significantly higher with nivolumab/cabozantinib compared with sunitinib (55.7% vs 27.1%; P<0.0001). The number of patients achieving complete response was nearly doubled in the nivolumab/cabozantinib arm (8.0% v 4.6%). Median duration of response was 20.2 months for patients treated with nivolumab/cabozantinib compared with 11.5 months for patients treated with sunitinib.

Adverse events

Toxicity was similar in both groups but manageable. High grade events (severe or greater) were higher among those receiving nivolumab plus cabozantinib (60.6% vs 50.9%). A single patient died with nivolumab/cabozantinib, whereas 2 patients died with sunitinib. In the nivolumab/cabozantinib group, 19% required corticosteroids to manage specific immune-related adverse events, with just 4% needing corticosteroids for 30 days or longer. In the study, >50% of patients in the nivolumab/cabozantinib arm needed a dose reduction of cabozantinib due to toxicity. Nevertheless, this approach was easily adaptable, and only 3% of the participants stopped treatment in the nivolumab/cabozantinib arm because of toxicity, compared with 9% of patients in the sunitinib arm.

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.

Dr Choueiri concluded that these data from CheckMate 9ER demonstrate the superiority of nivolumab plus cabozantinib to sunitinib in the first-line treatment of patients with advanced RCC and supports this approach as a new treatment option for these patients.

CheckMate 9ER senior investigator Prof. Toni Choueiri provided some additional information in an interview:

Quality of life data

“Overall, these data provide a quite strong message. The trial was positive for all endpoints, both by central review and investigator assessment which is a testimony for the robustness of the results overall. Although there was definitely toxicity in both arms, as evidenced by dose reductions, the treatment discontinuation was low for both arms, which meant that the investigators could keep the patient on therapy. One interesting feature of CheckMate 9ER is the quality of life data. These data were only partly presented at ESMO, and we expect to take a deeper dive into the parameters measured. We used two questionnaires, the Functional Assessment of Cancer Therapy Kidney Symptom Index (FKSI)-19 and the nine-item FKSI-Disease-Related Symptoms (FKSI-DRS). Both strongly favored, in a statistically significant fashion, the higher quality of life with the combination nivolumab/cabozantinib over sunitinib. I think this is important because this is part of the patient-reported outcome, the patients themselves telling us how they feel and what they think, and even if we grade, we have the grading for toxicity, it does not always go hand in hand with how the patient feels overall about their therapy. I think if you take the whole package together, you will find that these are very important overall results that are quite positive and certainly put the combination of cabozantinib and nivolumab as a very solid option for front line metastatic RCC.”

Toxicity

“It is important to note that as opposed to the METEOR trial where cabozantinib monotherapy was 60 mg [2], CheckMate 9ER used 40 mg starting dose of cabozantinib. It is therefore amazing that with the lower 40 mg dose, the efficacy doubles the PFS while maintaining the quality of life. In CABOSUN, which is the only head-to-head study looking at frontline sunitinib versus cabozantinib, there was no quality of life data [3]. In CABOSUN, the frequency of high grade adverse events was similar across arms. Therefore, we were not entirely surprised that the toxicity results with lower-dose cabozantinib were quite manageable with combined with nivolumab. Of course, the fact that the combination of nivolumab/cabozantinib controlled the disease better, would naturally improve disease-related symptoms, and that could have contributed also.”

Next perspectives?

“I think the field is moving very fast, almost like drinking from a hose. In my mind, I think we need to integrate tyrosine kinase inhibitors with immunotherapy either as a triplet or as a sequence. Cabozantinib is being further investigated in two trials. Firstly, COSMIC-313 (NCT03937219) is interrogating cabozantinib compared with nivolumab/ipilimumab, where cabozantinib is a modern control, as opposed to sunitinib. Secondly, PDIGREE (NCT03793166) uses a response-adapted design to nivolumab/ipilumumab treatment; if complete response is achieved, the patient continues on nivolumab, but should the patient develop progressive disease, you switch them to cabozantinib. For the estimated 70% of patients who do not have a complete response or progressive disease, but show stable disease, this study will address the question of whether adding cabozantinib to maintenance nivolumab does anything to OS. While we wait on these results, the CLEAR study (NCT02811861) is also quite interesting, because despite sunitinib being a somewhat outdated control, that study compares pembrolizumab plus lenvatinib in addition to lenvatinib/everolimus in the non-immunooncology arm, and it is powered for OS. So it is quite exciting to see what is going to happen in the next few years.”

“We want patients to be partners in their care, fully equal partners, and today I think that patient-reported outcomes play the most important role in whether we can all be partners in our care. I hope we can count on some studies where the primary endpoint is quality of life because when we do competitive effectiveness research, the voice of the patient will lead our choices.”

Sources:

1. Choueri TK, et al. Abstract 696O_PR. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
2. Choueiri TK et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015 Nov 5;373(19):1814-23.
3. Choueiri TK, et al. J Clin Oncol. 2017 Feb 20;35(6):591-597.

Posted on 15 December 202015 December 2020