Recap: Combination Therapy Shows Promise in Renal Cell Carcinoma

In a recent Between the Lines episode, Toni Choueiri, MD, and Rohit Gosain, MD, reviewed results from the phase 3 CheckMate 9ER trial (NCT03141177), which was presented at the 2023 Genitourinary Cancers Symposium.¹

Choueiri, director of the Lank Center for Genitourinary Oncology and medical director of international strategic initiatives at Dana-Farber Cancer Institute, as well as the Jerome and Nancy Kohlberg chair and professor of Medicine at Harvard Medical School in Boston, Massachusetts; and Gosain, a medical oncologist from the University of Pittsburgh Medical Center in Pennsylvania, reviewed the clinical impact of this trial.

The clinicians discussed how dosing regimens may affect certain patient populations and how the future of medicine has changed since they began practicing.

Overview of RCC

To begin the discussion, Choueiri, an academic oncologist, mentioned that, of the patients he sees, 70% have renal cell carcinoma (RCC) in his practice compared with Gosain, a community oncologist, who sees about 20% to 25%.

In regard to treatment, Gosain said he no longer needs to use single-agent tyrosine kinase inhibitors (TKIs) because of all the recent advances in the space. When reviewing the current standard of care in RCC, Choueiri said, “VEGF inhibitor plus immune checkpoint inhibitor vs double immune checkpoint inhibitors is the standard most of the time.”

CheckMate 9ER Trial

Currently, 1 standard first-line treatment is nivolumab (Opdivo) plus cabozantinib (Cabometyx). This combination was analyzed vs sunitinib (Sutent) in the CheckMate 9ER trial.

A total of 651 patients were randomly assigned 1:1 to receive 240 mg of nivolumab intravenously every 2 weeks plus 40 mg of cabozantinib orally once every day, or 50 mg of sunitinib once a day using a 4-weeks-on, 2-weeks-off schedule. The primary end point was progression-free survival (PFS), and secondary end points were overall survival (OS), overall response rate (ORR), and safety.

At the median follow-up of 44.0 months, the median PFS in the intent-to-treat (ITT) arm was 16.6 months (95% CI, 12.8-19.8) in the combination arm vs 8.4 months (95% CI, 7.0-9.7) in the sunitinib arm (HR, 0.58; 95% CI, 0.48-0.71). Additionally, at 18 months, the PFS rate was 47.7% vs 27.0%, and 21.0% vs 11.6% at 36 months in each respective cohort.

The OS was 49.5 months (95% CI, 40.3-not evaluable) with nivolumab plus cabozantinib vs 35.5 months (95% CI, 29.2-42.3) with sunitinib (HR, 0.70; 95% CI, 0.56-0.87). The OS rate at 18 months was 79.0% vs 68.8%, and 58.7% vs 49.5% at 36 months in each respective cohort.

In the combination arm, the ORR was 55.7% (95% CI, 50.1%-61.2%) vs 28.4% (95% CI, 23.5%-33.6%) in the sunitinib arm (odds ratio, 3.3; 95% CI, 2.4-4.6).

Grade 3 or higher adverse effects (AEs) were observed in 67% of patients in the combination arm vs 55% in the sunitinib arm. The most frequent AEs included hypertension (13% vs 13%, respectively), palmar-plantar erythrodysesthesia (8% vs 8%), and diarrhea (7% vs 5%).

The trial also analyzed subgroups based on the International Metastatic RCC Database Consortium (IMDC) and included patient populations of intermediate-/poor- and favorable-risk disease groups.

Analyzing Trial Results in the Real World

Both experts commented on baseline characteristics of the disease, based on what they see in practice and those who were enrolled in the trial. “In the trial, the patients had to have had good performance status. One thing we would like [to see] is, once the community and those that deal with this regimen [in everyday practice] accumulate more data, the efficacy of that regimen in other potential patient [populations] that weren’t included in the clinical trial,” said Choueiri.

PFS for the favorable-risk population was 21.4 months (95% CI, 13.1-24.8) with nivolumab plus cabozantinib vs 13.9 months (95% CI, 9.6-18.5) with sunitinib (HR, 0.75; 0.50-1.13). While the combination still demonstrated superiority, Choueiri commented that these results showed him more on what sunitinib did in terms of the favorable-risk group, improving PFS from 8.4 months in the overall ITT group to 13.9 months.

“Given the aggressiveness of the underlying tumor, one would expect the combination [to do better. However,] we’ve seen multiple studies [whose data have also demonstrated improved PFS in certain risk-stratified groups with] cabozantinib, which is itself a strong TKI and tends to do well, [as well as with] sunitinib, axitinib [Inlyta], or even cabozantinib. They stand just about the same,” Gosain agreed.

Choueiri and Gosain also spoke about the rate of progressive disease. In the ITT population it was 6.2% in the combination arm vs 13.7% in the sunitinib arm. For those segmented by IMDC risk group, the rates were substantially lower. With these rates of progressive disease, patients are presenting almost in “visceral crisis,” noted Choueiri.

Dosing Options

Gosain asked Choueiri how he typically starts a treatment regimen for patients who are being treated in the inpatient setting, namely, whether cabozantinib is initiated and whether or not nivolumab is administered upon discharge. Choueiri explained that he will do either depending on the patient and how they present. In the trial, Choueiri was surprised by the rates of treatment discontinuation, specifically because of toxicity.

For older patients, Choueiri will typically start the treatment combination at 20 mg and if they can tolerate it, he will go up to 40 mg. In the study, most patients tolerated treatment and AEs were grade 1/2.

“With the dose reduction, [AEs] can easily be managed, especially out in the community. We are used to immunotherapy-related AEs with nivolumab, [especially after using it in] bladder cancer. These are all very manageable AEs,” said Gosain.

In the trial, most AEs were immune-mediated because of the use of nivolumab. One concern was how to mediate diarrhea, especially when it is suspected to have arisen from immune-related colitis. In Choueiri’s practice, he will typically hold the cabozantinib, and if the diarrhea does not resolve, he will order an inpatient scope or a colonoscopy to determine the cause.

Moving Forward

Both doctors emphasized the improved survival data shown for this patient population. “About 5 years ago, we would never think that we would be talking about these things [like extensive] survival data,” said Gosain.

“The median survival when I started training was 1, 2, 3 years. Now we’re seeing 5 years and hopefully, some patients are cured. We have to continue by looking at the right patient population with biomarkers, whether they’re adding 3 or 4 drugs, finding better drugs, or just getting smarter or lucky,” concluded Choueiri.

Reference

1. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl 6):603. doi:10.1200/JCO.2023.41.6_suppl.603