Christopher Wallis: Hello and thank you for joining us for UroToday Journal Club. Today, we're discussing a recently published paper entitled "Nivolumab plus Ipilimumab versus Sunitinib for First-Line Treatment of Advanced Renal Cell Carcinoma: Extended Four-Year Follow-Up of the Phase III CheckMate 214 Trial". I'm Chris Wallace, a Fellow in Urological Oncology at Vanderbilt. And with me today is Zack Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia. This is a citation for the paper we're going to be discussing today, published in ESMO Open.

So, most people who subscribe to UroToday will know, but the treatment landscape for metastatic renal cell has changed dramatically. We began with an immunotherapy era with interferon and interleukin and then as of 2005 entered the targeted therapy era. And we remained there for approximately 10 years. And then in 2015 we had the introduction of immune checkpoint approaches in more advanced lines of therapy for patients with metastatic renal cell carcinoma.

In 2018, we had the publication of the first data from CheckMate 214 demonstrating the superiority of nivo/ipi compared to sunitinib in patients with intermediate and poor-risk RCC. And this has really opened the flood gates to a number of new trials and approvals such that a treatment approach with an immune checkpoint inhibitor backbone has now become the standard of care for patients with advanced kidney cancer. However, to date, we've had a relatively short follow-up of these trials. And so the data we're discussing today provides a longer follow-up and some really useful information.

Most people will know but this is the design of the CheckMate 214 trial. This is a superiority design with a 1:1 randomization between nivo/ipi or sunitinib. Patients were enrolled if they had advanced clear cell RCC without prior systemic therapy and had measurable disease by RECIST criteria and had a decent performance status. There were a variety of endpoints. Notably, this was a stratified approach with primary endpoints assessed in the intermediate and poor-risk patients. We'll go through this in a little bit more detail now.

So this is the initial publication of the CheckMate 214 trial, which led to its approval. And so this shows in the intermediate and poor-risk patients that the nivo/ipi approach in yellow is associated with improvements in overall and progression-free survival compared to sunitinib with hazard ratio 0.63 and 0.82 respectively and notably this effect was relatively consistent across subgroups, but it does bear mention that this is a restricted to the intermediate and poor-risk patient population and did to date have not demonstrated benefit to the use of nivo/ipi compared to sunitinib in patients with favorable-risk disease.

However, we should note that at the time of this publication in 2018 median follow-up was 25 months, just over two years, and minimum follow-up was 18 months. So to briefly recap the study again, including adult patients with previously untreated advanced renal cell carcinoma with at least a clear cell component and measurable metastatic disease based on RECIST criteria. Patients were excluded if they had a CNS metastasis auto-immune disease requiring a glucocorticoid use or Immunosuppressants. Patients were randomized in a one-to-one fashion in this open-label Phase III trial, either nivo/ipi or sunitinib with stratification according to their IMDC risk group, as well as to their geographic region. Nivo/ipi was administered in a fairly standard fashion with three milligrams per kilogram in nivo, and one milligram per kilogram of ipilimumab in three weeks cycles for four cycles. And during the induction phase followed by nivolumab monotherapy maintenance. Sunitinib was given in the standard four weeks on two weeks off fashion.

The primary endpoint as mentioned before it was overall survival, progression-free survival, and objective response rates among patients with intermediate and poor-risk disease. Secondary endpoints included these same outcomes among the intention to treat population, including those with favorable-risk disease, as well as safety among all patients who receive study drug. There were further exploratory endpoints, including the three primary endpoints among the subgroup of patients with favorable-risk disease, as well as stratified outcomes according to PD-L1 status and health-related quality of life. Assessments for these outcomes were performed with CT and MRI at baseline week 12, every six weeks for the next year. And then every 12 weeks thereafter.

In terms of statistical analysis, this role leads primarily to the paper which was published in 2018. They used an alpha splitting strategy for their three primary outcomes. However, because the first analysis met the overall survival endpoint, it's considered the final analysis and these updated data are simply a descriptive update providing longer follow-up and not part of the formal analytic approach. The authors did use a Kaplan-Meier technique and stratified Cox models hearing. And so now I'm going to pass it over to Dr. Klassen to walk us through these data.

Zachary Klaassen: Excellent. So this is the consort diagram from the original publication, as Chris mentioned in 2018, but just to recap, they screened 1,390 patients for enrollment and ultimately 1,096 were eligible and enrolled. This include included 550 that were assigned to the nivo+ipi arm and 546 that were assigned to the sunitinib arm.

Another table from the baseline characteristics from the original study, just to recap once again. So the median age of both groups was 62 years. Three-quarters of these patients were males. And if you look at the IMDC prognostic score, the majority were intermediate risk, 17% were poor risk, and about one-quarter of these were favorable risk. In terms of regions of the world, you can see that there's a pretty even split between the US, Canada, Europe, and the rest of the world. Notably, roughly 80% of patients had a prior nephrectomy. And you can see that the quantifiable tumor PD-L1 expression was greater than 1% in about one-quarter of these patients.

So this is the overall survival intention to treat population. You can see nivo/ipi is in the orange figure or in the orange outline and sunitinib is in the gray line. And in the intention to treat population, there was a median overall survival for nivo/ipi of not reached and for sunitinib of 38.4 months. So this hazard ratio, you can see here an early split in the curves hazard ratio of favoring nivo/ipi of 0.69 with a 95% confidence interval of 0.59 to 0.81. And once again, at 48 months, sort of this four-year follow-up, you can see that 53.4% of patients in the nivo/ipi group were alive compared to the 43.3 in sunitinib.

This is the Kaplan-Meier curve for overall survival, for intermediate and poor-risk patients. You can see once again, an early split in the curves, 50% of patients alive in the nivo/ipi group at 48 months compared to the 35.8% in sunitinib. Median overall survival of 48.1 months in the nivo/ipi group and 26.6 in the sunitinib group. For the hazard ratio, once again, favoring a nivo/ipi of 0.65 with a 95% confidence interval of 0.54 to 0.78.

The last overall survival Kaplan-Meier curve includes the favorable risk population. Chris already mentioned that we had not seen a signal in this group in the 2018 publication. And once again, there is no difference in overall survival between these two groups. You can see a median overall survival not reached in both the nivo/ipi and the sunitinib and the arms and non-significant hazard ratio of 0.893 with a 95% confidence interval of 0.62 to 1.40. Moving to the progression-free survival, the attention to treat population, median PFS of 12.2 months in nivo/ipi group and sunitinib 12.3 months with an insignificant hazard ratio of 0.89. When we moved to the intermediate and poor-risk group, we do see a benefit for nivo/ipi in terms of progression-free survival or the median PFS in the nivo/ipi group of 11.2 months compared to sunitinib of 8.3 months and a hazard ratio of 0.74, 95% confidence interval of 0.62 to a 0.88.

Once again, in the progression-free survival favorable risk population actually benefiting sunitinib, you can see here a median progression-free survival for sunitinib and the patients at 28.9 months versus only 12.4 months in the nivo/ipi group and a hazard ratio of 1.8 for favoring sunitinib in this instance as you can see by the curve as well.

Looking at this table, this is the objective response rates and best objective response at a four-year minimum follow-up. So on the left-hand column here, you can see from my cursor, this is intention to treat population that confirmed objective response rate for nivo/ipi patients was 39.1% compared to 32.4%. For sunitinib their best overall response in terms of complete responders, 10.7% for nivo/ipi and 2.6% for sunitinib in terms of ongoing response, 65.1% for nivo/ipi and 52% for sunitinib. When we get to the intermediate poor-risk patients as a significant benefit for nivo/ipi confirmed objective response rate of 41.9% compared to 26.8% for sunitinib, a complete response sort of 10.4% for nivo/ipi and 1.4% for sunitinib with 65.2% of patients in the nivo/ipi arm, having an ongoing response compared to 49.6% in the sunitinib group.

Finally, on the right side of the table, this is the favorable risk population. We still continue to see the signal for sunitinib, in this group with 51.6% of patients in the sunitinib arm with favorable-risk disease having an objective response and a 29.6 in the nivo/ipi group. Interestingly, though, if you look at the complete responders, it's 12% in the nivo/ipi group compared to only 6.5% in the sunitinib group. And then groups of certainly there is a fraction of these popular of this population of favorable-risk disease that will have a complete response with nivo/ipi.

Several other final capital markers looking at the duration of response and the intention to treat the population. We see an excellent duration of response with a median not reached in the nivo/ipi group compared to sunitinib and at 23.7 months, median duration of response. And this was a significant hazard ratio of favoring nivo/ipi of 0.51 with a 95% confidence interval of 0.36 to 0.71. In the intermediate and poorest population-wide split of the Kaplan Meier curves from a very early up median is not reached in the nivo/ipi group and is 19.7 in this group with a strong hazard ratio of 0.45, 95% confidence interval of 0.31 to 0.65.

And finally, in the favorable risk population, a median duration of response has not reached in nivo/ipi, but is 33.2 months in sunitinib with an insignificant hazard ratio of 0.79. Several other results in this long-term follow-up that are notable. So 59 patients received had achieved a complete response with nivo and ipi, 32.2% were still on therapy, 45.8% discontinued and did not require subsequent systemic therapy. And 22% received subsequent systemic therapy. Comparatively only 14 patients achieved complete response with sunitinib, then including 21.4% is still on therapy, 21.4% discontinued and did not require additional systemic therapy, and 57.1% of patients that received subsequent systemic therapy.

This table here looks at the subsequent therapy that the patients got. I'll point out several important points in this table at the top row here, any subsequent therapy you can see in the attention to treat population, 60% of those receiving nivo/ipi and 70% of those are students receiving sunitinib in the intermediate and poor-risk population, 58.6% of nivo/ipi patients received subsequent therapy compared to 68.5% of patients in the sunitinib arm. We look at the PD-L1 inhibitors that were subsequently received, not surprisingly in the intention to treat population 40.1% of patients in the sunitinib arm subsequently received nivolumab. And if you look down here to the VEGF receptor inhibitors, most commonly received subsequently was axitinib, 18% in the nivo/ipi arm of the intention to treat population and 24.9% in the sunitinib arm.

Several important discussion points from this updated analysis of the CheckMate 214 study with a minimum of follow-up of four years. This is the longest follow-up in a Phase III trial of checkpoint inhibitor-based combinations for those in the first line for advanced renal cell carcinoma. Nivo/ipi continues to demonstrate superior long-term benefits to sunitinib, particularly in the intention to treat population and in those with intermediate and poor-risk disease.

And you can see that as Chris mentioned in the previous publication in 2018, there is a stable hazard ratio for overall survival for nivo/ipi, compared to sunitinib in the intention to treat population and the intermediate and poor-risk population. So in the original publication, minimum follow-up of 17.5 months, the hazard ratio for overall survival and the intention to treat population was 0.68 and was 0.63 in the intermediate and poor-risk population. And at 48 months you can see here very stable hazard ratios in both of these groups at 0.69 for the intention to treat population, 0.65 for those with intermediate and poor-risk disease. In terms of favorable-risk disease, the OS benefit for either arm was inconclusive at four years. However, there are some interesting findings, certainly PFS objective response rate favor sunitinib. However, as I mentioned previously, there's double the complete response rate for those patients receiving nivo/ipi.

So in conclusion, with extended follow-up report in the CheckMate 214 study, there's further evidence for clinically meaningful and durable benefits of first-line nivo/ipi in patients with advanced renal cell carcinoma. And this continues to support nivo/ipi as a first-line treatment option for patients with advanced renal cell carcinoma. Thank you very much. And we hope you enjoy this Journal Club on the CheckMate 214 study.