Michael R. Harrison, MD, associate professor of medicine, member, Duke Cancer Institute, discusses several ongoing or upcoming studies that may change the treatment paradigm in renal cell carcinoma (RCC).

Clarifying the best use of dual immunotherapy vs immunotherapy and tyrosine kinase inhibitor (TKI) combinations in the frontline setting is an area of high interest in RCC, Harrison begins.

Several ongoing studies aim to maximize responses with existing immuno-oncology (IO)–based doublets by exploring the use of triplet regimens in the frontline setting, he states.

The phase 3 COSMIC-313 trial (NCT03937219) was the first trial comparing a triplet combination with a standard IO doublet in frontline RCC. Initial findings were presented at the 2022 ESMO Congress, Harrison says. In the trial, the addition of cabozantinib (Cabometyx) to nivolumab (Opdivo) and ipilimumab (Yervoy) was compared with nivolumab and ipilimumab in patients with intermediate- or poor-risk advanced or metastatic RCC. Results demonstrated that the trial met its primary end point of improved progression-free survival. Investigators also reporteddecreased progressive disease as best response with the triplet, he details. However, no significant overall survival benefit was observed for the triplet regimen, and longer-follow up data are necessary to clarify the exact role of this therapy.

Other studies in this space may help contextualize results from COSMIC-313 and are set to present their own initial data in the next few years, Harrison continues. These include the phase 3 PDIGREE study (NCT03793166), which attempts to determine the optimal sequencing of therapies in RCC. The unique trial design allows patients who progress on the initial treatment of ipilimumab and nivolumab to switch to cabozantinib at week 12, while those achieving complete responses will continue with standard-of-care nivolumab monotherapy. Individuals with stable disease or partial responses will be randomly assigned to either group. Although this study is not directly comparable to COSMIC-313, it may provide more data on the best use of these combinations, Harrison concludes.

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Michael R. Harrison, MD, discusses several ongoing or upcoming studies that may change the treatment paradigm in renal cell carcinoma.

Dr. Harrison on the Investigation of Combination Strategies in Frontline RCC

Michael R. Harrison, MD, associate professor of medicine, member, Duke Cancer Institute, discusses common toxicities associated with immuno-oncology (IO)–based combinations and their effects on treatment selection in renal cell carcinoma (RCC).

Several key clinical trials in RCC can guide the selection of immunotherapy-based combinations in RCC, Harrison begins. These include the phase 3 CheckMate-9ER study (NCT03141177) of cabozantinib (Cabometyx) in combination with nivolumab (Opdivo), the phase 3 CLEAR study (NCT02811861) of lenvatinib (Lenvima) plus pembrolizumab (Keytruda), the phase 3 CheckMate-214 study (NCT02231749) of ipilimumab (Yervoy) plus nivolumab, and the phase 3 KEYNOTE-426 study (NCT02853331) of axitinib (Inlyta) combined with pembrolizumab.

Cross-analysis of patient characteristics, adverse effects (AEs), and efficacy in these trials is necessary to understand which patients may benefit from certain IO-based regimens, Harrison states.

In terms of patient characteristics, the proportion of favorable- vs poor-risk patients differed amongst these trials, he says. Factors affecting at-risk status include sarcomatoid features, prior nephrectomy, and liver metastasis. Moreover, high rates of dose reduction were observed with the use of cabozantinib and lenvatinib in the CheckMate-9ER and CLEAR trials. The immunotherapy component was stopped after 24 months of treatment in all trials, although some patients in CheckMate-214 were able to continue treatment for a longer period.

Although commonly experienced treatment-related AEs (TRAEs) should be factored into treatment selection, long-term TRAEs are difficult to decisively measure across trials, Harrison explains. Therefore, the selection of IO-based regimens should be guided by patient-reported quality of life (QOL) and an individual experience of toxicities, he emphasizes. QOL data from CheckMate-9ER are persuasive and show that patients receiving cabozantinib plus nivolumab have better QOLcompared with those receiving sunitinib (Sutent). This outcome was not observed with the other IO-TKI combinations, Harrison concludes.

Michael R. Harrison, MD, discusses common toxicities associated with immuno-oncology–based combinations and their effects on treatment selection in renal cell carcinoma. 
 

Dr. Harrison on the Effect of IO-Related Toxicities on Treatment Selection in RCC  

Michael R. Harrison, MD, assistant professor of medicine, Duke Cancer Institute, discusses choosing frontline treatment for patients with renal cell carcinoma (RCC).

Considering the data with cabozantinib (Cabometyx) versus ipilimumab (Yervoy) and nivolumab (Opdivo), the field is changing so rapidly. There is going to be data of those combinations with checkpoint inhibitors and anti-VEGF agents, but the future lies in other combinations, explains Harrison.

According to Harrison, axitinib (Inlyta) would also be reasonable since it has a second-line approval and is being investigated in clinical trials.

Michael R. Harrison, MD, assistant professor of medicine, Duke Cancer Institute, discusses choosing frontline treatment for patients with renal cell carcinoma (RCC). 

Dr. Harrison on Choosing Frontline Treatment for RCC

Michael R. Harrison, MD, assistant professor of medicine, Duke Cancer Institute, discusses the possibility of nivolumab (Opdivo) plus ipilimumab (Yervoy) becoming the new interleukin-2 (IL-2).

The phase III CheckMate-214 trial examined how nivolumab combined with ipilimumab compared with sunitinib (Sutent) for intermediate- and poor- risk population patients with untreated advanced or metastatic renal cell carcinoma.

Prior to the study, oncologists thought nivolumab plus ipilimumab would become the new high dose IL-2. The study results indicated that the favorable-risk subgroup, about 250 to 300 patients, had a better response rate and progression-free survival rate with sunitinib compared with nivolumab plus ipilimumab. However, there were opposite results for the intermediate- and poor-risk cohort.

There are not enough data currently to explain these results, says Harrison. Consequently, oncologists will likely continue to defer systematic therapy, sunitinib, or high dose IL-2 for the favorable-risk patient population.

Michael R. Harrison, MD

Articles

Dr. Harrison on the Investigation of Combination Strategies in Frontline RCC

Dr. Harrison on the Effect of IO-Related Toxicities on Treatment Selection in RCC

Dr. Harrison on Choosing Frontline Treatment for RCC

Dr. Harrison on the Possibility of Nivolumab Plus Ipilimumab Becoming the New IL-2