Scott Tykodi, MD, PhD, is an associate professor in the Clinical Research Division and an affiliate investigator in the Translational Science and Therapeutics Division at Fred Hutchinson Cancer Center.

Dr Tykodi on the Current Limitations of Cabozantinib-Based Triplets in Advanced RCC

"The narrative [with triplet regimens] is that there are too many [adverse] effects. Patients can’t tolerate the therapy, and too many patients are stopping treatment. So you really aren’t delivering the triplet therapy as intended to enough patients to see benefit. This is the fear going forward [with] other attempts to build on top of the doublets that we have."

Scott Tykodi, MD, PhD, an associate professor in the Clinical Research Division and an affiliate investigator in the Translational Science and Therapeutics Division at Fred Hutchinson Cancer Center; as well as an associate professor in the Division of Hematology and Oncology at the University of Washington School of Medicine, discussed the clinical efficacy and potential role for cabozantinib (Cabometyx) plus checkpoint inhibition for patients with favorable-risk advanced renal cell carcinoma (RCC), as well as the challenges posed by the increased toxicities associated with such triplet regimens.

Enthusiasm for triplet regimens including cabozantinib, such as the combination studied in the phase 3 COSMIC-313 trial (NCT03937219), has been tempered by tolerability concerns, Tykodi began. The prevailing interpretation of results from COSMIC-313 has been that, despite the biologic rationale, the addition of cabozantinib to nivolumab (Opdivo) plus ipilimumab (Yervoy) did not confer substantial benefit over nivolumab plus ipilimumab alone, he stated. Many patients in the trial experienced significant toxicities, leading to early discontinuation or inability to maintain full-dose treatment, which limited the regimen’s effectiveness in practice, Tykodi said.

This challenge of achieving the intended therapeutic intensity and maintaining tolerability with existing triplet regimens raises broader concerns about the feasibility of future triplet regimens incorporating TKIs, he explained. As such, the field’s attention has turned to ongoing trials evaluating alternative combinations that may be more tolerable. Tykodi highlighted the pending results of the 3-arm, phase 3 LITESPARK-012 study (NCT04736706) evaluating belzutifan (Welireg) in combination with lenvatinib (Lenvima) and pembrolizumab (Keytruda), which may offer a more favorable safety profile compared with TKIs, given belzutifan’s relatively mild toxicity spectrum. He also referenced another study arm that includes a low-dose CTLA-4 inhibitor with lenvatinib and pembrolizumab, designed to test whether modified dosing can improve tolerability without sacrificing efficacy.

Although COSMIC-313 represented a scientifically sound effort to enhance outcomes in favorable-risk RCC, the results underscore the challenges of balancing efficacy and toxicity in multi-agent regimens, Tykodi concluded. He expressed interest in seeing whether emerging strategies can improve on this balance in subsequent triplet trials.

Videos

Scott Tykodi, MD, PhD, discusses the challenges with developing effective, less toxic triplet regimens for patients with advanced RCC.


Scott Tykodi, MD, PhD

One of the most provocative of pieces of data now is the long-term follow-up report [where we can] look at the duration of response of the responding patients and [at] how long responding patients maintained that response."

Scott Tykodi, MD, PhD, an associate professor in the Clinical Research Division and an affiliate investigator in the Translational Science and Therapeutics Division at Fred Hutchinson Cancer Center, as well as an associate professor in the Division of Hematology and Oncology at the University of Washington School of Medicine, discussed updated long-term findings from the phase 3 CheckMate 214 trial (NCT02231749) and their implications for the use of frontline nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with favorable-risk advanced renal cell carcinoma (RCC).

Although early data from CheckMate 214 initially suggested inferior outcomes for the dual immune checkpoint blockade compared with sunitinib (Sutent) in the subgroup of patients with favorable-risk disease, extended follow-up has demonstrated a more nuanced picture, Tykodi explained. Although objective response rates with the immune-onologoy (IO)–based combination remain lower compared with TKIs and IO/TKI combinations, the durability of response (DOR) with the IO/IO combination was vastly superior to sunitinib in CheckMate 214, he continued.

These findings are clinically meaningful, particularly when weighing initial tumor response against the potential for long-term disease control, Tykodi said. In favorable-risk patients—who often present with indolent, low-volume, and asymptomatic disease—nivolumab plus ipilimumab offers a compelling option for those seeking the possibility of prolonged remission with the potential for treatment-free intervals. Although complete radiographic responses are uncommon, many patients exhibit prolonged disease stability, suggesting an underlying state of immune-mediated tumor control or dormancy.

Despite these benefits, Tykodi acknowledged the limitations of imaging and the current challenges in predicting which patients will derive long-term benefit from an IO/IO combination. He emphasized the importance of close monitoring, as relapses can occur even after extended periods of apparent disease quiescence. Nevertheless, the prolonged durability of response observed with IO/IO comhination therapy underscores its potential value in select favorable-risk patients with advanced RCC, particularly those prioritizing long-term outcomes over rapid tumor shrinkage, Tykodi concluded.

Scott Tykodi, MD, PhD, discusses data from CheckMate 214 for nivolumab plus ipilimumab vs sunitinib in favorable-risk advanced RCC.


Dr Tykodi on Long-Term Outcomes for Nivolumab Plus Ipilimumab in Favorable-Risk Advanced RCC

Dr Tarantino on Considerations Around the Frontline Treatment of Metastatic HER2+ Breast Cancer

"The phenotype of the patient, how much disease they have, and how symptomatic they are [will] influence [treatment] choices."

Scott Tykodi, MD, PhD, an associate professor in the Clinical Research Division and an affiliate investigator in the Translational Science and Therapeutics Division at Fred Hutchinson Cancer Center, as well as an associate professor in the Division of Hematology and Oncology University at Washington School of Medicine, discussed key clinical considerations that inform selection between dual immuno-oncology (IO) combinations (IO/IO) vs combinations featuring IO plus a TKI (IO/TKI) in the frontline treatment of advanced clear cell renal cell carcinoma (RCC).

Patient phenotype, disease burden, and symptomatology are critical in guiding treatment strategy, Tykodi explained. The National Comprehensive Cancer Network Guidelines currently list the IO/IO combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) as a preferred regimen for patients with favorable- or poor/intermediate–risk disease; however, only the poor/intermediate–risk recommendation is listed as category 1. Regarding IO/TKI combinations, axitinib (Inlyta) plus pembrolizumab (Keytruda), cabozantinib (Cabometyx) plus nivolumab, and lenvatinib (Lenvima) plus pembrolizumab all have category 1 recommendations as preferred regimens, regardless of risk. Notably, cabozantinib monotherapy is also a preferred regimen in patients with poor/intermediate–risk disease.

Iniitally, data from the phase 3 CheckMate 214 trial (NCT02231749) initially indicated poorer outcomes for nivolumab plus ipilimumab in favorable-risk patients compared with sunitinib (Sutent) monotherapy, Tykodi said. As a result, use of this IO/IO combination in this population has traditionally been limited, he added; however, longer-term follow-up from the study has demonstrated a potential overall survival (OS) advantage with nivolumab plus ipilimumab in patients with favorable-risk disease, prompting updates to clinical guidelines.

Despite this, most clinicians remain cautious when using IO/IO combinations in patients with favorable. These individuals often present with small-volume, asymptomatic, and indolent disease—such as isolated pulmonary metastases years after nephrectomy, Tykodi said. In such cases, clinicians may favor nivolumab plus ipilimumab to maximize long-term disease control and potentially induce durable responses, accepting the lower initial response rate in exchange for the possibility of prolonged OS. For these patients, the availability of subsequent lines of therapy is a critical safety net should progression occur.

In contrast, patients with high-volume or symptomatic disease at diagnosis are more appropriately treated with IO/TKI combinations, Tykodi elaborated. These regimens are associated with higher initial overall response rates, improved disease control, and lower incidence of primary refractory disease. They provide more immediate tumor shrinkage and symptomatic relief, which is particularly important in patients with rapidly progressive or symptomatic disease, he said.

Tykodi emphasized the value of tailoring therapy based on clinical presentation, with the flexibility to sequence agents based on initial response and emerging therapeutic options.

Scott Tykodi, MD, PhD, discusses key clinical considerations that informing selection between IO/IO and IO/TKI combinations in advanced renal cell carcinoma.

Dr Tykodi on the Selection Between IO/IO and IO/TKI Combinations in Frontline Advanced Clear Cell RCC

Scott S. Tykodi, MD, PhD, a physician with the Seattle Cancer Care Alliance, an associate professor within the Division of Medical Oncology at the University of Washington, and an associate professor of the Clinical Research Division, Fred Hutchinson Cancer Research Center, provides background to the phase 2 KEYNOTE-427 trial with pembrolizumab (Keytruda) in renal cell carcinoma (RCC).

KEYNOTE-427 is a single-arm frontline study of pembrolizumab monotherapy for advanced RCC,says Tykodi. Cohort A included patients with a clear-cell histology only, while cohort B included patients with non–clear cell disease, says Tykodi. Cohort A enrolled a total of 110 patients. The clinical outcomes have been presented previously and showed an objective response rate of 36%, which included 3 complete responses and a median progression-free survival of 7.1 months.

These are interesting data because this was the first study looking at monotherapy with an anti–PD-1 agent in kidney cancer, notes Tykodi. These results indicate that pembrolizumab is a highly effective drug, but it’simportant to recognize that the current FDA-approved frontline regimens are all doublets, such as PD-1 plus CTLA-4 blockade or PD-1/PD-L1 with a VEGF TKI. 

Now, investigators have taken the data set with well-established clinical end points, dug a bit deeper, and looked for biomarkers that might identify which patients are most likely to respond to treatment, explains Tykodi.This was a popular topic at the 

, and many similar attempts to look at the large clinical databases for biomarker discovery were made, notes Tykodi.

One of the techniques was taking the tumor tissue, conducting RNA sequencing, then clustering the gene expression into coherent pathways, and looking to see whether there is a signature of a biological pathway that is associated with the outcomes data, concludes Tykodi.

Scott S. Tykodi, MD, PhD, provides background to the phase 2 KEYNOTE-427 trial with pembrolizumab in renal cell carcinoma.

Dr. Tykodi on the KEYNOTE-427 Trial With Pembrolizumab in RCC

Scott S. Tykodi, MD, PhD, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, Clinical Research Division, University of Washington, Fred Hutchinson Cancer Research Center, discusses the clinical implications of the phase 2 KEYNOTE-427 trial in advanced renal cell carcinoma (RCC). 

, findings from the study showed promising antitumor activity with pembrolizumab (Keytruda) monotherapy as first-line therapy in patients with advanced RCC. 

These data represent a potential option for frail patients with advanced RCC who are ineligible to receive doublet therapy but may benefit from PD-1/PD-L1 inhibitors, explains Tykodi.

Pembrolizumab monotherapy has been evaluated in the adjuvant setting for patients with RCC following nephrectomy in the phase 3 KEYNOTE-564 trial. 

Although pembrolizumab monotherapy is not expected to receive an indication in the frontline setting in advanced RCC, it is approved in combination with axitinib (Inlyta) in this setting, Tykodi concludes.

Scott S. Tykodi, MD, PhD, discusses the clinical implications of the phase 2 KEYNOTE-427 trial in advanced renal cell carcinoma.  



Dr. Tykodi on the Clinical Implications of the KEYNOTE-427 Trial in Advanced RCC 

Scott S. Tykodi, MD, PhD, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, Clinical Research Division, University of Washington, Fred Hutchinson Cancer Research Center, discusses the efficacy of dual checkpoint blockade in renal cell carcinoma (RCC).

Most large studies evaluating dual checkpoint inhibitor blockade are fairly immature, explains Tykodi.

Currently, the phase 3 CheckMate-214 trial of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) has the longest follow-up, says Tykodi. At 42 months, median overall survival was 47 months with the combination versus 26.6 months with sunitinib (Sutent) in patients with intermediate- and poor-risk advanced RCC.

Compared to other available treatments in this setting including TKIs and cytokine therapies, checkpoint inhibitors appear to show promising clinical activity in this patient population, concludes Tykodi.

Scott S. Tykodi, MD, PhD, discusses the efficacy of dual checkpoint blockade in renal cell carcinoma.



Scott S. Tykodi, MD, PhD

Articles

Dr Tykodi on the Current Limitations of Cabozantinib-Based Triplets in Advanced RCC

Dr Tykodi on Long-Term Outcomes for Nivolumab Plus Ipilimumab in Favorable-Risk Advanced RCC

Dr Tykodi on the Selection Between IO/IO and IO/TKI Combinations in Frontline Advanced Clear Cell RCC

Dr. Tykodi on the KEYNOTE-427 Trial With Pembrolizumab in RCC

Dr. Tykodi on the Clinical Implications of the KEYNOTE-427 Trial in Advanced RCC

Dr. Tykodi on the Efficacy of Dual Checkpoint Blockade in RCC