Examining Frontline Immune Checkpoint Inhibitor Combinations in Advanced RCC With Laurence Albigès, MD, PhD

Promising results from frontline combination immunotherapy trials for patients with advanced renal cell carcinoma (RCC) read out at the 2022 Genitourinary Cancers Symposium, sparking excitement within the field, according to Laurence Albigès, MD, PhD.

In an interview with CancerNetwork® during Kidney Cancer Awareness Month, she highlighted key findings from the phase 3 CheckMate 214 trial (NCT02231749), assessing nivolumab (Opdivo) and ipilimumab (Yervoy) as first-line treatment for previously untreated advanced or metastatic renal cell carcinoma (RCC), as well as the phase 3 CheckMate 9ER trial (NCT03141177), examining first-line cabozantinib (Cabometyx) and nivolumab in previously untreated advanced or metastatic RCC.^1,2 Additionally, she highlighted what she hopes to see emerge from future research efforts.

“The first-line landscape has evolved over time greatly and we now have a standard of care combination approach for our patients with clear cell RCC as frontline,” Albigès, a medical oncologist and head of the Genitourinary Unit at Gustave Roussy Institute, Villejuif, stated. “What we see is that we are impacting OS in our patients. These trials have changed the landscape of the expected OS benefit for our patients. We moved from about a median of 24 months to now 49 months, if we think about nivolumab plus ipilimumab. We have greatly increased the overall survival of our patients. This is impacting our treatment strategy in all our countries where we do have access to different regimens. We now need to tailor a bit more to define what is the combination that is most appropriate for 1 patient.”

Be sure to check out additional conversations with other key opinion leaders during Kidney Cancer Awareness month, such as Chung-Han Lee, MD, who spoke about other promising RCC combinations on the horizon.

CancerNetwork®: Could you start off by telling me about the patient population included in the CheckMate 214 trial?

Laurence Albigès, MD, PhD: The CheckMate 214 trial looked at patients with RCC who had metastatic disease that required first-line treatment. These patients can have any disease progression, either locally or at a metastatic level, and were not eligible for surgery but required systemic treatment. What is important in this trial is that the focus for the analysis is on the IMDC, or intermediate and poor [risk] patient population. These are patient who had at least 1 poor prognosis feature among 6 criteria that compose the IMDC classification. Overall, the [intent-to-treat] population in this trial also enrolled patients with good-risk disease. Nevertheless, the primary end point analysis was in the intermediate- or poor-risk population, which broadly accounted for 80% of our patient population.

What were some of the key takeaways from the trial?

CheckMate 214 was first reported in 2017. The key message is that for the first time, we have challenged the use of single agent VEGF targeting strategy, namely sunitinib [Sutent] here as the comparator arm with a combination of 2 immune checkpoint inhibitors, nivolumab plus ipilimumab. We do know that in RCC, VEGF targeting is very important, but this trial was very innovative because it was about having a strong and potent immune checkpoint inhibitor combination as a frontline strategy.

The key finding is that this trial demonstrated an overall survival [OS] benefit in favor of nivolumab plus ipilimumab. This benefit in terms of OS has been reported with a minimum follow up of 17 months but also is sustained over time. We had 30 months of follow up, 42 months of follow up, [and] even now 60 months of follow up with a very consistent hazard ratio of 0.68, clearly favoring the doublet immune checkpoint regimen over single agent sunitinib.

Is there anything else that your colleagues should just take away from the trial?

The takeaway beyond the OS benefit is about the likelihood to achieve about a 10% to 12% of complete response in our patients. It is also about sustained benefit over time, as I mentioned, with longer follow up. We do know that for some of these patients treatment-wise after discontinuation, they [maintained a] great response. It's really the long-term benefit that is a key message. In terms of safety, our colleagues are usually very familiar with the fact that we need to closely monitor those patients, especially in the first 6 months when we're [administering] the doublet part of this regimen, nivolumab plus ipilimumab. This is where immune-related toxicity may occur. Ultimately, I want to comment on the quality of life that has been reported with this regimen. In these patients, despite the risk of immune-mediated toxicity, we did see a great increase in terms of quality of life for our patients.

Pivoting to speak briefly about CheckMate 9ER, did you have any key takeaways from that study?

The CheckMate 9ER [regimen] is a strategy combining a potent VEGF Tyrosine kinase inhibitor, namely cabozantinib, with an immune checkpoint, nivolumab. This dual approach has been developed because of different trials and it has demonstrated across many trials with different combinations an OS benefit over single agent sunitinib. What is important with the CheckMate 9ER study is that we now have seen the final OS analysis with more than 25 months of minimum follow up and the median is around 32 months follow up.

What this final analysis shows us is [a continued] OS benefit with a hazard ratio of 0.70 over sunitinib [and] a progression-free survival [PFS] that is clear cut against sunitinib, meaning that we have a 2-fold longer PFS from 8.3 months to 16.6 months with cabozantinib plus nivolumab and a great benefit in terms of response rate. It's clearly a combination that is able to induce tumor shrinkage and long-term PFS benefit, as well as OS benefit.

Is there any emerging research in the RCC space that you anticipate will have good potential for clinical impact?

RCC is not always the same, including in clear cell RCC, and therefore, we need to isolate different patient populations so that we make the most of the regimens that are available. There has been a lot of work, [such as] genomic analysis and transcriptomic analysis based on clinical trial datasets that have identified a subset of patients, some of them being more VEGF-driven, some of them seem more [suited] to an immune strategy. Therefore, the way to go [regarding] emerging research is our ability to integrate such classification in our clinical trial development, so that we make sure that we will define the best strategy within 1 patient.

Are there any ongoing trials right now that you're looking forward to seeing the results of?

There are at least 2 fields that I'm looking forward to seeing more data in. The first one is the adjuvant space, [specifically] in patients who have had surgery for localized RCC. But for a patient who is considered at high risk of recurrence according to different scales that we're using, do we have an interest in using adjuvant immune checkpoint? There has been 1 clinical trial that has already reported in this field that is positive for disease-free survival benefit against placebo. There are other trials that we are waiting for that will reinforce for our patients the need for this adjuvant strategy in a highly selected population.

The second set of trials that I'm looking forward to are the combination trials. We don't know to date what is the [optimal] strategy for a patient who has [progressed on a] first-line combination regimen? What is the best second-line agent or what is the best strategy? Do we need a sustained PD-1/PD-L1 inhibition, for instance? These kinds of trials we are looking forward to and hopefully we'll have results in the coming months and years.

Are there any trials in particular that you think the RCC field should be aware of?

As a physician, it's important that we refer patients with non–clear cell RCC to dedicated clinical trials. Therefore, it's important to be aware on where I can refer a patient if I see [someone] who has not clear cell RCC but papillary RCC or chromophobe RCC who has metastatic disease, and I would like to refer them for a specific trial. That is clearly something that is important and it’s an unmet need for patients with RCC.

References

1. Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and safety of nivolumab plus ipilimumab (N+I) versus sunitinib (S) for first-line treatment of patients with advanced sarcomatoid renal cell carcinoma (sRCC) in the phase 3 CheckMate 214 trial with extended 5-year minimum follow-up. J Clin Oncol. 2022;40(suppl 6):352. doi:10.1200/JCO.2022.40.6_suppl.352
2. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: Nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(suppl 6):352. doi:10.1200/JCO.2022.40.6_suppl.352

For additional interviews with leaders in the treatment of pancreatic cancer, see other CancerNetwork® interviews conducted for pancreatic cancer awareness month:

RCC Paradigm Continues Moving Forward With New Combination Regimens on the Horizon