Christopher Wallis: Hello and thank you for joining us for this UroToday Journal Club discussion. Today, we're talking about a recent publication titled, 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, randomized, phase III trial. I'm Chris Wallis, an assistant professor in the Division of Urology at the University of Toronto, and with me today is Zach Klaassen, and assistant professor in the Division of Urology at the Medical College of Georgia. You can see here, the citation for this recent publication in Lancet Oncology.

The treatment landscape for metastatic kidney cancer has advanced significantly over the past decade and a half. We've seen a transition from the target therapy era into the immune checkpoint era, and we first saw that with single-agent immune checkpoint inhibitors in later lines of therapy, followed by combined checkpoint blockade and first-line therapy with nivolumab and ipilimumab, and now more recently, the combination of immune checkpoint inhibitors and targeted therapies.

CheckMate 9ER is one of the later studies in this disease space, assessing the role of first-line cabozantinib with nivolumab in metastatic or advanced renal cell carcinoma. As you can see here from the primary publication, this combination improved overall survival compared to sunitinib, with a median follow-up of 18 months. In the first publication, the endpoint assessed included a final analysis of progression-free survival, the first interim analysis of overall survival, and a final analysis of objective response. On the basis of these data, cabozantinib and nivolumab was recommended as a new standard of care in first-line advanced renal cell carcinoma.

In this analysis, the authors present updated results of this trial with a pre-planned final analysis of overall survival data, as well as updated results for progression-free survival, objective response, and safety outcomes. In comparison to the primary publication that had a median follow up of 18 months, median follow-up now is nearly 33 months, and the authors further provide subgroup analyses, including both pre-planned and post-hoc analyses defined based on clinical subgroups and tumor response.

To summarize the study design of CheckMate 9ER, this is an open-label, randomized, phase III trial. Key inclusion criteria include age over 18 years, previously untreated advanced or metastatic renal cell carcinoma with a clear cell component, in any IMDC risk group, Karnofsky performance status of at least 70, measurable metastatic disease according to RECIST criteria, and tumor tissue available for PD-L1 testing. As you can see here, key exclusion criteria include prior systemic therapy for renal cell carcinoma, lack of tissue for analysis, active central nervous system disease or autoimmune disease, recent immunosuppression, or a lack of organ function to allow treatment.

As mentioned, this is a randomized, open-label, phase III trial, and there was 1:1 randomization to the intervention arm of nivolumab and cabozantinib, or sunitinib, the control arm. The randomization was stratified according to MSKCC risk group, geographic region, and tumor PD-L1 expression. The agents were given in their standard doses of nivolumab at 240 milligrams IV, and cabozantinib at 40 milligrams PO daily. Sunitinib was given in the 50-milligram daily dosing for 4 weeks, with 2-week drug holidays in 6 weeks cycles. Treatment continued until there was progression on acceptable toxicity, and nivolumab exposure was capped at 2 years.

Patients were assessed with a CT or MRI of the chest, abdomen, and pelvis, as well as the brain at baseline, and then CT chest, abdomen, and pelvis at 12 weeks, and then every six weeks until weeks 60, and then every 12 weeks until progression. PD-L1 status was assessed using a validated assay at baseline, and adverse events were assessed using the CTCAE criteria at each study visit until patients had, had at least 100 days from their last dose of study medication.

The primary endpoint of this trial was progression-free survival, and they also included key secondary endpoints, including overall survival, objective response rate, and safety and tolerability. Further exploratory endpoints included secondary PFS, health related quality of life, and biomarkers. As we mentioned before, this present report focuses on updated results of the overall survival data, as well as an update on progression-free survival, objective response, and safety and tolerability. This, again, highlights the study schema of this trial.

In terms of analysis, the authors expected to enroll 638 patients. An overall alpha 0.05 was used with the hierarchical testing approach, progression-free survival is the first endpoint, and the entire alpha 0.05 was spent here, with a single final analysis allowing power greater than 95%, where PFS was positive. The alpha was then shifted to overall survival, and this allowed 80% power. In this case, the alpha was split based on first, second, interim analyses, as well as the final analyses. Because this first analysis in the primary publication was positive, alpha spending kind of ceases here, and further formal analyses are not performed. Efficacy analyses are conducted in the intention-to-treat population, and safety analyses include all patients who received at least one dose. As mentioned before, subgroup analyses were performed based on disease and demographic characteristics, including both pre-specified in post-hoc groups. There's also a post-hoc analysis of the depth of response to target lesions by organ site.

At this point in time, I'm going to hand it over to Zach to walk us through these updated results of the CheckMate 9ER trial.

Zachary Klaassen: Thanks so much for that great introduction, Chris. This is the trial profile for the CheckMate 9ER study, and you can see here that there was 651 patients that were randomized, including 323 to nivolumab plus cabozantinib and 328 that were randomized to sunitinib. Ultimately, at the time of this follow up analysis, as Chris mentioned with extended follow-up, there was 92 patients that remained on treatment for nivolumab plus cabozantinib, and 46 patients that remained on treatment for sunitinib.

This is the demographic and clinical characteristics at baseline in the intention-to-treat population. As you can see here, on the right of the screen is the characteristics stratified by nivolumab plus cabozantinib and sunitinib. These were a well balanced group. As you can see, the age was just over 60 years, just over three-quarters were male, and the majority of which were white patients. If we go down to Karnofsky performance status, these patients all had excellent performance status, with more than three-quarters having a 90-100% KPS. Looking at the IMDC prognostic risk groups, roughly about one-quarter were favorable risk, just over half were intermediate, and around 20% were poor risk. So good breakdown between the IMDC prognostic scores. In terms of tumor PD-L1 expression, about three-quarters of these patients had less than 1% or indeterminate expression, and most commonly, in terms of organ sites, was more than or equal to two in roughly 80% of these patients.

This is the updated overall survival and the intention-to-treat population. You can see nivolumab plus cabozantinib in blue and sunitinib in red. The median overall survival for nivolumab plus cabozantinib was 37.7 months, with a 95% confidence interval of 35.5 to not evaluable. And in sunitinib, was 34.3 months, with a 95% confidence interval of 29.0 to not evaluable. This resulted in a hazard ratio favoring nivolumab plus cabozantinib of 0.70, and a significant 95% confidence interval of 0.55 to 0.90.

This is the Kaplan-Meier curve for progression-free survival in the same population. Median PFS for nivolumab plus cabozantinib was 16.6 months, compared to 8.3 months sunitinib, with the hazard ratio favoring nivolumab plus cabozantinib of 0.56, and a 95% confidence interval 0.46 to 0.68. This Kaplan-Meier curve looks at duration of response in the intention-of-treat population. Median duration of response in the nivolumab plus cabozantinib arm was 23.1 months, with a 95% confidence interval of 20.2 to 27.9. And sunitinib, was 15.1 months, with a 95% confidence interval of 9.9 to 20.5 months.

This table basically summarizes the confirmed objective response rates stratified by nivolumab plus cabozantinib versus sunitinib. If you look at the top of this table, you can see the confirmed objective response was 56% in nivolumab plus cabozantinib, compared to 28% sunitinib. If we look at some of the confirmed best overall responses, the complete response rate for nivolumab plus cabozantinib was 12%, compared to 5% for sunitinib. Partial response, 43% for nivolumab plus cabozantinib, compared to 23% for sunitinib. If we go down to progressive disease, only 6% for cabozantinib plus nivolumab, compared to 14% for sunitinib.

The median time to response was 2.8 months for nivo plus cabo, compared to 4.2 for sunitinib, and as mentioned on the previous slide, median duration of response, 23.1 months for nivo/cabo, compared to 15.1 for sunitinib.

This is the updated treatment related adverse events in either treatment group. As you can see here, the possible events are on the left, stratify nivo/cabo versus sunitinib. Just a couple of highlighting points here, in terms of any grade 4 adverse events, 7% for nivo/cabo, compared to 6% for sunitinib, with no real difference in major adverse events between these two groups. If we look at the grade 3 adverse events, any grade 3 adverse events are nivo plus cabo was 58%, compared to 48% for sunitinib. I've highlighted two of the major differences between these adverse events, with increased LFTs for nivo plus cabo being slightly more common than the sunitinib group. Otherwise, these are relatively comparable with regards to grade 3 adverse events between these two groups, and these specific adverse events between these two.

Several good discussion points from the CheckMate 9ER updated analysis. With longer follow-up in this trial, as Chris mentioned, a median of 32.9 months for overall survival, there was superior and continued superior efficacy of the nivolumab plus cabozantinib versus sunitinib. As we discussed, this resulted in longer overall survival, 37.7 versus 34.3 months, as well as more than doubled median PFS, at 16.6 versus 3.3 months, both of these favoring nivo/cabo combination therapy. Additionally, there was a higher objective response and duration of response for the combo therapy.

The combination of nivo plus cabo is being explored further. There's been previous studies that have showed promising efficacy for patients with papillary, unclassified, or translocation-associated histology, specifically reported median progression-free survivals of 12.5 months, median overall survivals of 28 months, and objective responses of 47.5%. Several upcoming trials that we look forward to specifically with this combination therapy is the phase II CA209-9KU trial. This is looking at combination therapy in advanced non-clear cell RCC patients who have not received previous PD-1 or PD-L1-directed therapy. The phase III PDIGREE trial is looking at nivo plus cabo in patients with clear cell RCC and intermediate or poor risk disease without a complete response or with progressive disease after first-line nivo plus ipi. And finally, the COSMIC-313 trial is looking at triplet therapy with nivo plus cabo plus ipilimumab in patients with clear cell RCC and IMDC intermediate poor risk disease being assessed in the first-line therapy.

In conclusion, with extended follow-up and a pre-planned final overall survival analysis per protocol, nivolumab plus cabozantinib demonstrated approved efficacy versus sunitinib. And finally, this further supports this combination in the first-line treatment of advanced renal cell carcinoma.

We thank you very much for your attention. We hope we enjoyed this UroToday Journal Club discussion of the updated survival and safety analysis of the CheckMate 9ER trial.