Refining Combination Strategies in Metastatic RCC - Episode 5

Implications for Treating Metastatic RCC With TKI/I-O Regimens Upfront

March 17, 2021
Toni Choueiri, MD

,
Robert J. Motzer, MD

Recommendations regarding how to use novel combinations such as lenvatinib and everolimus, or lenvatinib plus pembrolizumab as frontline therapy for metastatic renal cell carcinoma.

Robert J. Motzer, MD: We at Memorial Sloan Kettering Cancer Center [MSKCC] are the primary center, and I was the principal investigator for the initial trial of lenvatinib/everolimus compared to lenvatinib monotherapy compared to everolimus, that resulted in regulatory approval for lenvatinib plus everolimus in second-line therapy for RCC [renal cell carcinoma]. I have had considerable experience with that particular regimen, and then certainly when lenvatinib/pembrolizumab was proposed as a trial, we were on board and were one of the initial centers that participated in that. This was a study that was done across different malignancies, including endometrial cancer. Our PI [principal investigator] at the site, Vicky Makker, [MD,] was very much involved in the development of the combination for endometrial cancer as well.

In RCC we led the accrual for that particular regimen. It’s a single-arm regimen. It was initially dose-finding and then expanded in different cohorts. The total number of patients treated on that was over 140, and I treated 20 or 30 patients on that program. MSKCC was also the lead center for the CLEAR phase 3 trial. In that study, we accrued close to 40 patients. I’ve had considerable experience with the lenvatinib/pembrolizumab regimen, and I have been impressed with that regimen with regard to its efficacy.

I do think overall it’s a generally well-tolerated regimen, and the key is to start out high with the lenvatinib, and then as toxicities or adverse events are seen, individualize treatment to that patient by dose reduction of the lenvatinib. More than half of the patients do get dose reductions of lenvatinib, and when looking at the long term with that program, many of the patients are being maintained on a dose of lenvatinib at 10 mg. That’s a very comfortable dose for long-term treatment. The high dose early on may be important for the extreme efficacy that’s been seen with the regimen. It’s an exceptionally good regimen. The efficacy is quite remarkable. I’m hoping that soon it will be a treatment program we can offer our patients.

Toni Choueiri, MD: We are blessed now with 4 combinations that have an OS [overall survival] benefit: [nivolumab/ipilimumab], [pembrolizumab/axitinib], [pembrolizumab/lenvatinib], and [cabozantinib/nivolumab]. [Pembrolizumab/lenvatinib] is not approved at this time, but this regimen is likely to be approved at some point. They all have an overall survival benefit. It’s going to be a bit hard, and it is going to be personal preference. You’ll have to follow the label, [nivolumab/ipilimumab] is for intermediate- and poor-risk disease.

The one advantage is once you’re done with the 3-month combination and you’re on [nivolumab] maintenance, there are no TKI [tyrosine kinase inhibitor] [adverse] effects, and you have a data set that has been updated up to 4 years showing a hazard ratio 0.6. Now the PD [MV1] rate is around 20%, and the response rate is 40%. If you need an immediate response, if you have a significant disease burden, you could respond very well, this is lower than all the VEGF/IO [immunotherapy] combinations that posted anywhere between 55% and 70% response rate with a low rate of PD. The second thing to look at with the VEGF/TKI combos that have an OS benefit—[cabozantinib/nivolumab, pembrolizumab/lenvatinib and pembrolizumab/axitinib]—are the quality-of-life data.

The patient-reported outcome is the patient’s voice. And with what I mentioned about how the CTCAE [Common Terminology Criteria for Adverse Events] grading and toxicity reporting has many problems now, these were not devised for immunotherapy and TKIs. We have to dig more into the patient-reported outcomes to guide ours. To that extent, we have seen patient-reported outcomes with [cabozantinib/nivolumab], extensively so far, presented [at the Genitourinary Cancers Symposium 2021], that showed superiority over sunitinib. We have not seen that with the [pembrolizumab/axitinib] combination. It was not inferior to sunitinib, but there isn’t any metric that was superior, knowing the timing of that questionnaire was usually the same.

We haven’t seen any with [pembrolizumab/lenvatinib]. The other thing is not to forget, despite having combinations, that clinical trials are ongoing with 3 drugs versus 2 drugs. If we want to increase those responses and make them durable, one strategy is what is the 1 drug for this 1 patient, that concept of the biomarker. We haven’t had complete luck now, so perhaps we should revert back to many years ago and give the appropriate patients, say the intermediate and poor risk, a triple combination. These trials are ongoing.

I have experience with [pembrolizumab/axitinib], having co-led the phase 1 study with [Michael] Atkins, [MD]. I have experience with [pembrolizumab/lenvatinib] from the phase 3. I also have experience with [cabozantinib/nivolumab] from CheckMate 9ER. What we have done with our nursing staff and colleagues, is to be able to know the day-to-day management of these TKIs. That’s very important. The team here, at Dana-Farber [Cancer Institute], has done a great job, our nursing team and our research team, to manage the right dosage of the TKI to achieve the maximal exposure tolerated by the patient.

Transcript edited for clarity.