TKI/Immunotherapy Combinations Expand RCC Treatment Options

Rohit Kumar, MD, discusses the benefits of TKI/immunotherapy doublets in renal cell carcinoma, unmet needs regarding future research with triplet therapies in the frontline setting, and how hypoxia inducible factor inhibitors may play a role in the treatment of patients who have progressed on prior TKI/immunotherapy combinations.

Rohit Kumar, MD

Rohit Kumar, MD

Triplet regimens building off established combinations with TKIs and immunotherapies may provide additional benefits as first-line therapy for certain patient subgroups with metastatic renal cell carcinoma (RCC), according to Rohit Kumar, MD.

“The addition of immunotherapy to TKIs or to other immunotherapies has completely changed the RCC landscape,” Kumar said in an interview with OncLive®.

In the interview, Kumar discussed the benefits of TKI/immunotherapy doublets in RCC, unmet needs regarding future research with triplet therapies in the frontline setting, and how hypoxia inducible factor (HIF) inhibitors may play a role in the treatment of patients who have progressed on prior TKI/immunotherapy combinations.

Doublets comprised of TKIs plus immunotherapy agents have become the frontline standard of care in patients with advanced RCC. For example, the phase 3 CLEAR trial (NCT02811861) with lenvatinib (Lenvima) plus pembrolizumab (Keytruda) showed a median progression-free survival (PFS) of 23.9 months with the combination vs 9.2 months with sunitinib (Sutent) monotherapy in patients with advanced RCC.1

Regarding triplet therapy, the phase 3 COSMIC-313 trial (NCT03937219) is exploring the combination of 2 immunotherapy agents, nivolumab (Opdivo) and ipilimumab (Yervoy), plus cabozantinib (Cabometyx), a TKI, in patients with previously untreated advanced or metastatic RCC. Treatment with the triplet led to a median PFS that was not yet reached vs 11.3 months with nivolumab plus ipilimumab, meeting the trial’s primary end point.2 Kumar discussed these findings in the context of previously reported data with immunotherapy doublets in this population and emphasized the need for overall survival (OS) data to clarify the clinical implications of this combination.

Kumar is an assistant professor in the Department of Medicine at the University of Louisville in Kentucky.

OncLive®: What does the frontline RCC treatment landscape look like, and where is it headed?

Kumar: Clear cell RCC [represents] about 80% of kidney cancers. For decades, the treatment has been TKIs and immunotherapy, and now we’re moving into doublets with immunotherapy and TKIs for frontline treatment. [Additionally, the question surrounding] triplet options is: Are we ready to adopt them, or do we need more time to see how they pan out?

How have immunotherapy agents influenced the RCC treatment paradigm?

TKIs have always been an option for RCC. The addition of immunotherapy has changed the landscape. Even in stage IV cancers, the PFS [data are] in years and OS with the immunotherapy doublets is up to 5 years. If a patient with stage IV cancer is living 5 years [after treatment], we are essentially talking about their cure.

What is the potential role of up-front triplet therapy in this population?

Doublets are the standard now. Ipilimumab plus nivolumab has already been approved [and has] a median follow-up of 5 years. That’s a well-established option for patients with poor- or intermediate-risk RCC.

TKIs plus immunotherapy have also been established in multiple trials. The 3 National Comprehensive Cancer Network [NCCN]-preferred TKI/immunotherapy combinations are axitinib [Inlyta] plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab. These are well-established, approved drugs.

Since there are immunotherapy/immunotherapy combinations and TKI/immunotherapy combinations, the question became: Can we combine 2 immunotherapies and add a TKI? The data [from COSMIC-313] are not mature, however, the response rate from adding a TKI to the immunotherapy combination was not impressive; it was close to what we’ve seen with just an immunotherapy/immunotherapy combination. However, the trial met its primary end point of PFS.

[We have to] watch for the OS and see if there’s an OS benefit, because whenever we use doublets or triplets, we are also adding adverse effects [AEs]. Are the AEs worth it? The OS data will tell us. If there is an OS benefit, I would like to see if there’s a high-risk subgroup that we should watch out for [when using] this triplet therapy. [It’ll be important to] watch for the role of triplet therapy in the near future.

Besides TKIs plus immunotherapy, other novel agents like HIF inhibitors have been studied in combination with immunotherapy. Those are other novel agents we should watch.

What unmet needs in RCC would you like to see addressed in the frontline setting?

In clear cell RCC, we are getting good [responses]. Even in stage IV disease, the PFS is [measured] in years. Post-TKI and immunotherapy combinations are where the unmet need is. In the frontline setting, immunotherapy/immunotherapy combinations had an 18% primary progression rate, meaning patients are progressing while they’re getting therapy. A subgroup of patients doesn’t respond to immunotherapy.

Ongoing trials are investigating genetics and mutation genomics to figure out: Who are these 18% of high-risk patients who don’t respond to immunotherapy? Can we predict this? Can we use triplet therapy there? Can we use a novel agent there?

What is your main message for colleagues regarding doublets and triplets in RCC?

The improvements we have made over the past decades with this combination are now standard of care that all patients should be offered. With so many options, we also have a dilemma. What is the right option? What should we choose? [I hope the information I discussed] gives an idea of how to choose between all the treatment options [and decide] which will be the right fit for the patient.

What ongoing RCC research at the University of Louisville would you like to highlight?

There’s an unmet need after progression on immunotherapy, or primary progression. We have some phase 1 trials investigating HIF inhibitors. There’s already an FDA-approved drug, belzutifan [Welireg], for patients who have VHL-associated RCC, and HIF plays an important role in RCC outside of germline VHL mutations. The NCCN [recommends the use of] belzutifan in all-comers.

We have a novel agent, a HIF inhibitor, that is more potent than belzutifan. We are starting a phase 1/2 trial with that to see if patients who progress on TKIs and immunotherapy respond to it.


  1. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716
  2. Exelixis announces detailed results from phase 3 COSMIC-313 pivotal trial in patients with previously untreated advanced kidney cancer at ESMO 2022. News release. Exelixis. September 7, 2022. Accessed February 8, 2023.
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