Combination Therapies to Overcome Resistance in mRCC

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Ulka Vaishampayan, MD: What combinations may be useful to overcome the resistance that is acquired, or can be used to treat patients with up-front refractory disease? Either to I/O [immuno-oncology] therapy or to a combination of anti-VEGF and I/O therapy?

Lenvatinib and pembrolizumab is a second-line therapy that was presented at GU ASCO [Genitourinary Cancers Symposium]. This regimen showed a fairly decent response rate in this setting. Here we repeat with I/O, along with lenvatinib, which is a multitargeted tyrosine kinase inhibitor [TKI] with anti-VEGF activity as well as FGFR inhibition activity.

That is definitely a regimen to be following, and there is a chance that the same regimen is also being tested in the frontline setting. So more to come. Stay tuned.

The other interesting regimen is a combination of cabozantinib with atezolizumab, a PD-L1 [programmed death-ligand 1] inhibitor. This combination—of cabozantinib with I/O—has shown remarkable efficacy. The remarkable efficacy shown has predominantly been in the frontline setting, but now this is also being tested in the second-line, randomized setting—cabozantinib plus or minus atezolizumab.

The other types of agents that are being looked at, of course, include novel targets, such as glutaminase inhibitors. CB-839 is currently in clinical trials. A clinical trial for the second-line therapy option of cabozantinib plus or minus CB-839 in advanced kidney cancer has completed. The results are awaited at present time, but preliminary data do show that there is efficacy. As was seen in the ENTRATA trial with everolimus plus or minus CB-839, the combination had an improved progression-free survival.

There is more to come on these therapies for the second- and third-line settings. Novel targets are being explored, and repeating treatment with I/O-based regimens with combinations with VEGF TKIs are also being explored.

Tian Zhang, MD: Ulka, that was a great summary, and I really do hope that these combinations will be more active in the second- and third-line settings. As we see frontline combinations—axitinib-based with pembrolizumab or with avelumab—hopefully there will be other broadening out of the targets with lenvatinib and FGFR-directed therapies, or with cabozantinib and MET and AXL. These may result in other immunomodulatory behaviors and may be more synergistic with immunotherapies in the early refractory setting in either the second- or third-line settings, and I’m very hopeful about both of these trials.

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