OMNIVORE - Optimized Management of Nivolumab and Ipilimumab in Advanced Renal Cell Carcinoma, Journal Club - Christopher Wallis & Zachary Klaassen

September 25, 2022

Christopher Wallis and Zachary Klaassen discuss the OMNIVORE study published in the Journal of Clinical Oncology. This phase II response-adaptive trial investigated the rational application of immune checkpoint blockade in renal cell carcinoma.

Biographies:

Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto.

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center


Read the Full Video Transcript

Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club. Today, we are discussing a recently published paper, entitled, Optimized Management of Nivolumab and Ipilimumab in Advanced Renal Cell Carcinoma: A Response-Based Phase 2 Study. This is the OMNIVORE study. I'm Chris Wallis, a Fellow in Urologic Oncology at Vanderbilt. With me today is Zach Klaassen, an Assistant Professor in the division of Urology at the Medical College of Georgia.

Here is the citation for this recent publication in the Journal of Clinical Oncology, led by Dr. Rana McKay. By way of background, the treatment of advanced kidney cancer has changed dramatically in the last 15 years, beginning with the introduction of sorafenib, which heralded the targeted therapy era. Subsequently, about 5 years ago, we had the introduction of immunotherapy and subsequent immunotherapy combinations. This has now become the current standard of care for most patients with this first-line disease.

The study, which initially led to this combination approach, was CheckMate 214, and in this study, patients were randomized to receive combination immunotherapy with nivolumab and ipilimumab or sunitinib. This demonstrated a significant benefit, particularly in those patients with intermediate and poor-risk disease with the receipt of combination immunotherapy. Here are the results of the publication of this trial, demonstrating improvements in both overall and progression-free survival, and findings that were consistent across many subgroups.

However, we can also look at the toxicity associated with this regime, as evidenced by the CheckMate 214 data. In particular, with the use of combination immunotherapy, we see significant rates of immune-related adverse events. These are both relatively common and may be life-threatening. Further, compared to the relatively predictable and dose-related adverse events associated with tyrosine kinase inhibitors, immune-related adverse events may be unpredictable, often require steroids for treatment, and may, in some cases, not be reversible. Further, the use of combination immunotherapy approaches is associated with a significantly higher rate of immune-related adverse events. For example, compared to nivolumab immunotherapy as monotherapy, which is associated with a 21% rate of grade 3 or 4 events, the combination is associated with a 47% rate. Further, treatment-related discontinuation more than doubles going from nivolumab monotherapy to the combination of nivolumab and ipilimumab.

As a result, the authors undertook this OMNIVORE study, looking at whether a response-based approach to combination therapy could be employed. To do so, they included patients with advanced renal cell carcinoma of any histology.  Patients were allowed to have prior therapies, as long as these did not include PD-1 or CTLA-4 pathway inhibitors. Patients must have had measurable disease per RECIST version 1.1 criteria, a good performance status, ECOG 0 TO 2, as well as adequate end-organ function.

This was an open-label phase II adaptive trial. In designing this, all patients received induction nivolumab 240mg every 2 weeks initially and then 480mg every 4 weeks as the trial was amended, and then subsequent arm allocation was based on their response within the first 6 months. In arm A, among patients who had a complete or partial response, patients then went on to observation and cease systemic therapy, with nivolumab restarted when the disease progressed. In contrast, in arm B, which encompassed those with stable disease or progressive disease, patients continued nivolumab, as well as had the addition of ipilimumab. Patients were assessed during this induction phase with imaging at 8, 16, and 24 weeks. And then subsequently, if they met the criteria for arm A, they were imaged every 8 weeks. In arm B, they were imaged after the first 12 weeks, and then every 8 weeks.

The primary endpoints in arm A were the proportion of patients who had a durable complete or partial response at 1 year, following the cessation of nivolumab. In arm B, the authors assessed the proportion of patients who converted to a partial or complete response after the addition of ipilimumab. Secondarily, the authors assessed overall survival, the treatment-free interval, the duration of disease control, progression-free survival, and toxicity. This is a flow diagram outlining what we have just discussed, again, with evidence of an initial induction period, and then subsequent stratification on the basis of the initial response.

The authors planned to accrue 83 patients in total based on a number of assumptions. First, they assume that of these 83 patients, 23 patients would have a confirmed partial or complete response and can be allocated to arm A. This gives it the ability to have a 94% power to detect a durable partial or complete response of 35% and distinguish this from 10% using a one-sided alpha of 0.07. They further assumed that 57 patients would have stable or progressive disease, and would be allocated to arm B. Thus, this provided a 92% power for a true PR/CR conversion rate of 20%, compared to an assumed 5%, with the one-sided alpha of 0.05. Finally, they assumed that 3 patients would be withdrawing or ineligible from the trial.

The approach with an adaptive use of immunotherapy will be deemed effective if 5 or more patients in arm A had persistently present partial response or complete response at 1 year following the cessation of nivolumab monotherapy, or if 6 or more patients in arm B had converted with the addition of ipilimumab. The authors use Kaplan-Meier analyses to assess their time to event data. On that, I will pass it over to Dr. Klaassen, who will walk us through the results of this trial.

Zachary Klaassen: Thanks, Chris, for that great introduction of the OMNIVORE trial. You can see here that 85 patients were enrolled, and 83 received nivolumab induction therapy. Ultimately, 69 patients underwent arm allocation, including arm A and am B, as you can see, outlined here. I'll take your attention to the bottom of this slide, and you can see that the majority of patients were off treatment by the conclusion.

This is a baseline characteristics table. You can see here that the total number of patients had a median age of 61 years, the majority of which were male, at 81.2%, the majority of which were Caucasian, at 90%. 96% of patients had clear cell histology, and only 8% of patients had sarcomatoid differentiation. 14% of patients had rhabdoid differentiation, and the stage of diagnosis was M1 in 24% of patients, and M0 in 25.3% of patients. Most of these patients did have good performance status, at 66% ECOG 0 and 32% ECOG 1. The most common IMDC risk group was an intermediate risk, at 54.2%. And 86.7% of patients had prior nephrectomy. The majority of patients had no prior lines of therapy, at 50.6%. However, 37.3% of patients had one prior line of therapy.

This is the waterfall plot of a maximum percent decline in target lesion during induction nivolumab. The blue group is the treatment-naive group and the red group is the previously treated group. You can see that there was a majority of patients that did not have any benefit from this, with an objective response rate within 6 months of nivolumab induction of only 14% and a 95% confidence interval of 9% to 22%.

This is a swimmer plot of arm A treatment and outcomes. The blue lines are nivolumab monotherapy, the red lines are observation, and the green lines are nivolumab plus ipilimumab. You can see here that the majority of patients will derive a response, and some will remain on observation.  You can see here in the top three, but several of these patients will have an intensification of treatment after their initial nivolumab. So it is important to realize that there is a small subset that may derive benefit from nivolumab plus observation, but the majority will need subsequent treatment and may progress over time.

This is the results of table arm B for treatment response. It's basically a bit of a dismal table. You can see the complete response rate is 0% for these patients that had the addition of ipilimumab. There was only 6% of patients that had a partial response. Stable disease was 46% of patients. 40% of patients had progressive disease. So, this table, in summary, shows that ipilimumab addition to nivolumab in these patients was not beneficial.

This is the Kaplan-Meier curve for progression-free survival from ipilimumab initiation in arm B. We see here a median progression-free survival of 4.7 months and a 95% confidence interval of 2.7 to 8.3 months. This is the result of the overall survival of the total population. The median overall survival was not reached. However, looking at the 18-month overall survival rate, this was 79%, with a 95% confidence interval of 67% to 87%.

As Chris mentioned, the addition of ipilimumab with nivolumab does result in a high degree of adverse events. This is a table looking at maximum grade by toxicity type for treatment-related adverse events from nivolumab induction. At the top is the total number of events, 167, and you can see on the far right of this table, the percentage of adverse events broken down specifically. You see that 31% had fatigue, 20% had a rash, 13%, pruritus, 10%, ALT increase, and 10% diarrhea.

So, several discussion points from the OMNIVORE trial. This trial, unfortunately, did not generate sufficient evidence to overturn the approach of combination nivolumab plus ipilimumab, as opposed to sequential immune checkpoint blockade. This trial should be taken into context with two other adaptive studies that investigated nivolumab monotherapy followed by ipilimumab. First was the TITAN RCC trial, which was a phase 2 trial of 207 patients, with response to induction nivolumab of 28.7% in the treatment-naive and 18.2% in the previously treated, with a low complete response rate of 2.9% and a conversion rate to the partial or complete response of 10%. The second trial is the HCRN-GU16-260 trial, which had 123 patients, and response to induction to nivolumab was 31.7% and the overall complete response rate was also low at 5.7% and a partial response conversion rate of 13.3%.

This table is a summary of these three trials, the TITAN RCC, OMNIVORE, and the HCRN-GU16-260 trial. I'll direct your attention to the very bottom line, looking at the objective response rate. You can see here that the complete response rate for TITAN was 2.7%, the complete response rates for OMNIVORE and HCRN-GU16-260 was 0%. So, collectively, based on the data presented in this trial of OMNIVORE, as well as the previous two trials, salvage ipilimumab results in a low complete response and partial response complete response conversion rates.

in conclusion, OMNIVORE used a response adaptive design to assess this sequential addition of two doses of ipilimumab to nivolumab non-responders and discontinuation of nivolumab in responders. Nivolumab followed by response-based addition of two cycles of ipilimumab resulted in a lack of complete responses and a low partial to complete response conversion rate. Early nivolumab discontinuation in the absence of toxicity results in a durable response in a small subset of patients, so it's important to develop biomarkers to see if we can predict who will respond to nivolumab discontinuation. Ultimately, there is no evidence to support a response-based adaptive strategy of nivolumab plus ipilimumab, thus, upfront dual checkpoint blockade should be given to all eligible patients. Thank you very much for your attention to this UroToday Journal Club discussing the recently published OMNIVORE trial.
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