Chung-Han Lee, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discusses the final results of the phase 2 cohort of a phase 1/2 trial (NCT02501096) evaluating lenvatinib (Lenvima) plus pembrolizumab (Keytruda) in patients with pretreated metastatic clear cell renal cell carcinoma (mRCC).

The trial enrolled patients who had progressive disease after treatment with a PD-1/PD-L1-containing therapy. The results, which were presented at the 2023 Kidney Cancer Research Summit, showed that with extended follow-up of 24 months, the combination elicited comparable activity in the treatment-naïve cohort as what has been seen in those enrolled in the pivotal phase 3 CLEAR trial, Lee says. Notably, a subgroup of patients with immune checkpoint inhibitor–pretreated disease also derived durable responses, Lee says.

These results stand in stark contrast to what was reported in the phase 3 CONTACT-03 trial (NCT04338269), which showed that the addition of atezolizumab (Tecentriq) to cabozantinib (Cabometyx) following progression of a PD-1/PD-L1 inhibitor did not improve progression-free survival or overall survival compared with cabozantinib alone in patients with mRCC.

The results from this trial suggest that continued use of a PD-L1 inhibitor in combination with cabozantinib does not have a role in immunotherapy-pretreated RCC, Lee explains. However, results from the phase 2 portion of the aforementioned trial suggest that PD-1 inhibition in combination with a different VEGF TKI, in this case, lenvatinib, may still be useful, Lee explains. Additionally, it remains unknown whether the addition of pembrolizumab provides added activity given the limitations of the trial design, Lee concludes.

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Chung-Han Lee, MD, PhD, discusses the final results of the phase 2 cohort of a phase 1/2 trial evaluating lenvatinib plus pembrolizumab in patients with pretreated metastatic clear cell renal cell carcinoma.

Dr Lee on Extended Follow-Up With Pembrolizumab and Lenvatinib in Pretreated mRCC 

Chung-Han Lee, MD, PhD, a medical oncologist at theMemorial Sloan Kettering Cancer Center, discusses the efficacy of combining immunotherapy with TKIs to treat patients with metastatic renal cell carcinoma (mRCC).

Currently, there is a lot of interest in evaluating some of the approaches that are used in the first-line space, in later lines of treatment. Certainly, many different agents are being examined in different combinations.For example, investigators have examined the role of immune checkpoint inhibitors in combination in this space, such as the combination of nivolumab (Opdivo)and ipilimumab (Yervoy) post progression on single-agent PD-1 inhibitor. Another research focus is determining whether VEGF immunotherapy combinations can be effective after progression on an immune checkpoint inhibitor, adds Lee.

Right now, the data on these TKI/immunotherapy combinations following progression on checkpoint inhibitors are very limited. Prospective data are only available for the combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda). Based on an initial analysis, the therapy appears to be an active regimen, says Lee. While the combination of lenvatinib plus pembrolizumab is not yet FDA approved, the initialresults are very encouraging, says Lee, who is hopeful that the regimen will be added to the cadre of medications that are available for patients with metastatic disease.

Chung-Han Lee, MD, PhD, discusses the efficacy of combining immunotherapy with TKIs to treat patients with metastatic renal cell carcinoma.

Dr. Lee on the Combination of Immunotherapy and TKIs in mRCC

Chung-Han Lee, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the potential for combining TKIs with immunotherapy in patients with metastatic renal cell carcinoma (mRCC) who have progressed on checkpoint inhibitors.

Historically, single-agent TKIs have been used for the treatment of patients with mRCC, says Lee. However, the introduction of checkpoint inhibitors has added to the armamentarium.

FDA-approved checkpoint inhibitor combinations include nivolumab (Opdivo)/ipilimumab (Yervoy), axitinib (Inlyta)/avelumab (Bavencio), and axitinib/pembrolizumab (Keytruda), explains Lee.

Although these combinations can lead to favorable outcomes, some patients will progress, says Lee.

As such, researchers are evaluating the combination of the TKI lenvatinib (Lenvima) with pembrolizumab as a potential salvage treatment for patients who progress on checkpoint inhibitors, concludes Lee.

Chung-Han Lee, MD, PhD, discusses the potential for combining TKIs with immunotherapy in patients with metastatic renal cell carcinoma who have progressed on prior checkpoint inhibitors.

Dr. Lee on Combining TKIs With Immunotherapy in mRCC

Chung-Han (Joe) Lee, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center, discusses second-line treatment options in renal cell carcinoma (RCC).

Historically, in the second-line setting, TKIs have been used after treatment with other TKIs, says Lee. In addition to cabozantinib (Cabometyx), which was approved based on data from the phase 3 METEOR trial, the use of axitinib has also been considered. Axitinib (Inlyta) was also examined in a randomized trial that showed benefit in this space, says Lee. Since 2005, there was some interest in examining different combination therapies in RCC.

The combination of lenvatinib (Lenvima) plus everolimus (Afinitor) was approved following results from a randomized phase 2 trial, which compared that doublet regimen with each agent alone. The results with the combination, in terms of improvements in objective response rates, progression-free survival, and overall survival, were outstanding, concludes Lee.

Chung-Han Lee, MD, PhD, discusses second-line treatment options in renal cell carcinoma.


Dr. Lee on Second-Line Treatment Options in RCC

Chung-Han Lee, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses treatment options for patients with relapsed/refractory metastatic renal cell carcinoma (mRCC).

Currently, the treatment landscape of mRCC is made up of 3 main classes of agents, says Lee.

TKIs and monoclonal antibodies have antiangiogenic effects, says Lee. Bevacizumab (Avastin) is an approved monoclonal antibody with clinical utility.

mTOR-targeted agents are another class of agents that alter the metabolism of the cancer, explains Lee.

While immune checkpoint inhibitors have demonstrated efficacy in the frontline setting, they may be utilized in the relapsed/refractory setting for patients who did not previously receive a checkpoint inhibitor, concludes Lee.

Chung-Han Lee, MD, PhD, discusses treatment options for patients with metastatic renal cell carcinoma. 


Dr. Lee on Treatment Options mRCC

Chung-Han Lee, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the results of the phase II ENTRATA trial in advanced renal cell carcinoma (RCC).

Data presented at the 2019 ESMO Congress indicated that the addition of the glutaminase inhibitor telaglenastat to everolimus extended progression-free survival versus everolimus alone in patients with heavily pretreated advanced RCC, meeting the prespecified endpoint of the ENTRATA trial. In the trial, the median progression-free survival was 3.8 months in the combination arm versus 1.9 months in the monotherapy arm (HR, 0.64; 95% CI, 0.34-1.20; one-sided 

These data demonstrate proof-of-concept for telaglenastat and support the use of glutaminase inhibition as a potential treatment strategy in advanced RCC, says Lee. The role of glutaminase inhibition is being further evaluated in the ongoing phase II CANTATA study, in which patients with advanced or metastatic RCC are being randomized to either telaglenastat in combination with cabozantinib (Cabometyx) or placebo plus cabozantinib.

Chung-Han Lee, MD, PhD

Articles

Dr Lee on Extended Follow-Up With Pembrolizumab and Lenvatinib in Pretreated mRCC

Dr. Lee on the Combination of Immunotherapy and TKIs in mRCC

Dr. Lee on Combining TKIs With Immunotherapy in mRCC

Dr. Lee on Second-Line Treatment Options in RCC

Dr. Lee on Treatment Options mRCC

Dr. Lee on the Results of the ENTRATA Trial in Advanced RCC