Che-Kai Tsao, MD, associate professor of medicine, hematology and medical oncology, the Icahn School of Medicine at Mount Sinai, discusses key updates from the phase 3 CheckMate 9ER trial (NCT03141177), and how these data clarify the role of nivolumab (Opdivo) plus cabozantinib (Cabometyx) as a new standard of care (SOC) in renal cell carcinoma (RCC).

The randomized CheckMate 9ER trial randomly assigned previously untreated patients with advanced or metastatic RCC to recieve nivolumab and cabozantinib vs sunitinib (Sutent), Tsao begins. Prior data from this trial demonstrated that the combination led to an improvement in both progression-free survival (PFS) and overall survival (OS), he states.

Updated findings from this trial were presented at the 2023 Genitourinary Cancers Symposium, Tsao continues. At a minimum of 33 months follow-up, patients in the overall population who received the nivolumab and cabozantinib doublet continued to demonstrate a strong PFS and OS benefit vs those given sunitinib, Tsao reports. Hazard ratios for the doublet were 1.07 in the favorable-risk group, 0.75 in the intermediate-risk group, 0.46 in the poor risk group, and 0.65 in the intermediate-/poor-risk group, respectively.

When patients were analyzed according to risk status, those in the favorable risk group may not have achieved the degree of OS benefit expected, Tsao notes. Additionally, median OS in the combination arm of the favorable risk subgroup was not reached, while median OS in the control arm was 47.6 months, Tsao adds. In the overall population, median OS improved by 11.8 months with the doublet.

Additional efficacy results showed that the overall response rate (ORR) continued to benefit with the combination across subgroups. In the favorable risk group, the ORR was 66% with the doublet vs 44% with sunitinib. These ORRs were comprised of 14% and 11% complete responses, respectively. Moreover, an exploratory post-hoc analysis of this trial showed that patients experienced a PFS and OS benefit with the regimen independent of PD-L1 and c-MET tumor status.

Based on results from CheckMate 9ER, the combination of 

nivolumab and cabozantinib was approved by the FDA

 for for the treatment of this patient population in January 2021. Ultimately, these updated data confirm the long-term efficacy of nivolumab plus cabozantinib and support its new role as a SOC in the frontline setting for metastatic RCC, Tsao concludes.

Videos

Che-Kai Tsao, MD, discusses key updates from the phase 3 CheckMate 9ER trial, and how these data clarify the role of nivolumab plus cabozantinib as a new standard of care in renal cell carcinoma. 


Dr Tsao on the Role of Nivolumab Plus Cabozantinib in Advanced RCC

Che-Kai Tsao, MD, associate professor of medicine, Hematology and Medical Oncology, the Icahn School of Medicine at Mount Sinai, discusses the investigation of cabozantinib (Cabometyx) in combination with nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with renal cell carcinoma (RCC).

The phase 3 COSMIC-313 trial (NCT03937219) was a multicenter, randomized, double-blinded, placebo-controlled trial that evaluated cabozantinib or placebo plus nivolumab and ipilimumab in previously untreated patients with advanced or metastatic RCC. The study accrued patients who had intermediate- or poor-risk advanced RCC, Tsao says, adding that the majority of patients had intermediate-risk disease.

Data presented at the 2023 Genitourinary Cancers Symposium showed that the triplet elicited a progression-free survival (PFS) benefit over the doublet plus placebo. In the intent-to-treat population, the median PFS was 16.9 months (95% CI, 11.5–not estimable [NE]) for the cabozantinib group vs 11.3 months (95% CI, 7.7-14.0) for the placebo group (HR, 0.74; 95% CI, 0.58-0.94). However, the overall survival (OS) results were not yet mature, Tsao says.

The overall response rates (ORRs) were below 50% for both the intermediate- and poor-risk populations, which was disappointing, Tsao says. For the intermediate-risk subgroup, the cabozantinib regimen produced an ORR of 45%, compared with 36% for the placebo regimen. For the poor-risk subgroup, the ORRs were 36% and 38% for the cabozantinib and placebo arms, respectively.

Tsao also explains that a notable proportion of patients were not able to complete the 4 cycles of nivolumab and ipilimumab, despite this specific portion of treatment being important. It remains to be seen if the triplet combination of cabozantinib, nivolumab, and ipilimumab will eventually be approved by the FDA for first-line use, Tsao says. Additionally, in a recent presentation, Thomas Powles, MD, of Barts Cancer Centre, presented data from a subgroup analysis that showed patients who have benefited the most from treatment are those with intermediate high-risk disease. Therefore, investigators will aim to better understand which patients could benefit most from this triplet approach, Tsao concludes.

Che-Kai Tsao, MD, discusses the investigation of cabozantinib in combination with nivolumab and ipilimumab in patients with renal cell carcinoma.

Dr Tsao on the Investigation of Cabozantinib With Nivolumab and Ipilimumab in RCC

Che-Kai Tsao, MD, associate professor of medicine, Hematology and Medical Oncology, the Icahn School of Medicine at Mount Sinai, discusses first-line treatment approaches for patients with clear cell renal cell carcinoma (RCC).

The accelerated development of treatment options across different settings has provided novel agents and regimens for patients with RCC, Tsao begins. Specifically, regarding first-line options for patients with clear cell RCC, the emergence of different combination therapies has improved upon prior single-agent treatment patterns, he adds. The immunotherapy-based combination era has increased disease control for these patients, allowing them to experience improved survival, Tsao notes.

Combination therapies currently improved by the FDA in the frontline setting, such nivolumab (Opdivo) plus ipilimumab (Yervoy), lenvatinib (Lenvima) plus pembrolizumab (Keytruda), and nivolumab plus cabozantinib (Cabometyx), have provided a forward shift in the landscape for clear cell RCC, Tsao says.

Despite the availability of different combination options in the frontline setting, there is still not one-size-fits-all treatment approach for these patients, he notes, adding that there are not great biomarkers currently available to drive treatment decisions for these patients. However, it remains vital to focus on a personalized treatment approach, Tsao says. Patient factors, such as their goals of care and other components, could help inform frontline treatment decisions for patients with clear cell RCC, Tsao says.

From a disease perspective, risk, tumor location, symptoms, and genomics should also be used to recommend treatments for individual patients, Tsao expands. Reviewing treatment options with each patient is vital to provide the best personalized care, Tsao concludes.

Che-Kai Tsao, MD, discusses first-line treatment approaches for patients with clear cell renal cell carcinoma.


Dr Tsao on First-line Treatment Approaches in Clear Cell RCC

Che-Kai Tsao, MD, medical director of the Ruttenberg Treatment Center at the Tisch Cancer Institute of Mount Sinai Hospital and an associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, shares strategies to improve outcomes in renal cell carcinoma (RCC).

Overall, 3 areas should be considered when attempting to improve outcomes for patients with regional disease, says Tsao. First, it is important to determine the disease can be better characterized. Developing an understanding of who to treat and who not to treat is also necessary. Some of the strategies to do this can include better imaging and, potentially, the use of biomarkers, which is not currently a standard; that is still an area of active investigation. Some of the prediction models that currently exist might also be used to understand which patients recur or not.

The second strategy would be to consider whether better surgery could be performed, adds Tsao. Now, routine lymph node dissection in patients with regional disease is not considered a standard. However, studies show that by performing a lymph node dissection, one can better understand whether patients truly have disease in their lymph nodes; that information could help determine who is at a higher risk for recurrence.

Third, it has to do with effective systemic therapy, says Tsao. The treatment landscape is changing and many exciting combination therapies have emerged, both in immunotherapy as well as targeted therapy, concludes Tsao.

Che-Kai Tsao, MD, shares strategies to improve outcomes in renal cell carcinoma.

Dr. Tsao on Improving Outcomes in RCC

Overall, 3 areas should be considered when attempting to improveoutcomes for patients with regional disease, says Tsao. First, it is important to determine the disease can be better characterized.Developing an understanding of who to treat and who not to treat is also necessary. Some of the strategies to do this can include better imaging and, potentially, the use of biomarkers, which is not currently a standard; that is still an area of active investigation. Some of the prediction models that currently exist might also be used to understand which patients recur or not.

The second strategy would be to consider whether better surgery could be performed, adds Tsao. Now, routine lymph node dissection in patients with regional disease is not considered a standard. However, studies show that by performing a lymph node dissection, one can better understand whether patients truly have disease in their lymph nodes; that information could help determine who is at a higher risk for recurrence.

Third, it has to do with effective systemic therapy, says Tsao. The treatment landscape is changing and many exciting combination therapies have emerged, both in immunotherapy as well as targeted therapy, concludes Tsao.

Che-Kai Tsao, MD, an associate professor at Mount Sinai Health, discusses the rationale behind staging disease, especially in the context of when patients are diagnosed with renal cell carcinoma (RCC).

Generally staging serves to characterize the extent of the disease and is performed in all types of cancers, explains Tsao. In solid tumors, such as RCC, the extent of the disease is related to whether patients can be cured with surgery or other modalities without recurrence.

It is important to determine a patient’s diagnosis upfront in earlier stages of the disease when there is a better chance of curing those patients, ultimately providing better outcomes, says Tsao. The majority of metastatic patients with RCC will not be cured and the outcomes will not be as good as those with early-stage disease, concludes Tsao.

Che-Kai Tsao, MD, discusses the rationale behind staging disease, especially in the context of when patients are diagnosed with renal cell carcinoma.

Che-Kai Tsao, MD

Articles

Dr Tsao on the Role of Nivolumab Plus Cabozantinib in Advanced RCC

Dr Tsao on the Investigation of Cabozantinib With Nivolumab and Ipilimumab in RCC

Dr Tsao on First-line Treatment Approaches in Clear Cell RCC

Dr. Tsao on Improving Outcomes in RCC

Dr. Tsao on Improving Outcomes in RCC

Dr. Tsao on Rationale for Staging Renal Cell Carcinoma