The choice between ICI plus ICI therapy or ICI plus TKI therapies should be individualized; ipilimumab plus nivolumab (CheckMate 214) has the longest follow-up and perhaps the most evidence for durable responses in a subset of patients. The ICI plus TKI therapies, including pembrolizumab plus axitinib (KEYNOTE–426), avelumab plus axitinib (JAVELIN Renal 101), pembrolizumab plus lenvatinib (CLEAR), and nivolumab plus cabozantinib (CheckMate 9ER), have high response rates (and low primary progressive disease rates) and perhaps have the most robust evidence for use in those patients with rapidly progressing disease. Although we cannot directly compare these therapies due to different patient populations in each trial, these are clear and notable trends in the different regimen. We introduced these interesting trends in our manuscript from the point of view of durability of response, need for immediate response, and toxicity in this review.
We also discussed adjuvant therapy using ICI. Specifically, we can use pembrolizumab in patients with clear cell RCC with high risk for recurrence after nephrectomy based on a positive adjuvant ICI trial (KEYNOTE–564). On the other hand, there are two negative adjuvant ICI trials (CheckMate 914 and ImMotion010) and one negative phase III perioperative ICI trial (PROSPER RCC). We note the difference in trials (higher toxicity and treatment discontinuation in CheckMate 914; use of an anti-PD-L1 in ImMotion010; the lower risk population, including of “non-clear cell” RCC in PROSPER), and we therefore highlighted that we have to decide to proceed with this adjuvant pembrolizumab therapy should be made jointly with the patient after thorough discussion of the risks and benefits.
Finally, we outlined the potential benefit of “triplet” regimens – cabozantinib, Ipilimumab and nivolumab (COSMIC–313), pembrolizumab, lenvatinib and belzutifan (MK–6482–012), and pembrolizumab, lenvatinib, and quavonlimab (MK–6482–012). We have to pay attention to whether “triplet” regimens can reduce the risk of rapid progression in ICI plus ICI therapy within an acceptable adverse event rate, and importantly, whether they increase the percentage of patients on the “flat part of the curve” (i.e. those with longer-term durable survival). Other adaptive approaches, such as the strategy in PDIGREE, should also be followed closely. In the future, we hope the development of a new generation of immunotherapies targeting novel immune checkpoints, inhibiting the myeloid compartment, and antigen-specific immune targeting therapies for advanced RCC.
Written by: Soki Kashima,1 David A. Braun2
- Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA; Department of Urology, Akita University, Graduate School of Medicine, Akita, Japan.
- Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
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