Immune checkpoint combination improves overall survival for mRCC

By John Murphy, MDLinx
Published September 16, 2017

Key Takeaways

In patients with previously untreated advanced or metastatic renal cell carcinoma (mRCC), combination immunotherapy with nivolumab plus ipilimumab showed 32% greater overall survival (OS), as well as prolonged progression-free survival (PFS) and a greater objective response rate (ORR), than current standard therapy, according to phase 3 clinical trial results from the CheckMate-214 study presented recently at the 2017 Congress of the European Society for Medical Oncology (ESMO) in Madrid, Spain.

The investigators reported that the combination immunotherapy provided greater benefit in intermediate- and poor-risk patients with advanced or metastatic RCC—who comprised about 75% of the intent-to-treat population—and the therapy was particularly beneficial for those with higher levels of PD-L1 expression at baseline. However, sunitinib showed greater ORR and PFS in patients with good-risk advanced or metastatic disease.

“These results support the use of nivolumab and ipilimumab as a new first-line standard of care option for patients with advanced RCC,” said presenter and study co-leader Bernard Escudier, MD, Chairman of the Renal Cancer Unit at Institut Gustave Roussy, in Villejuif, France. “These results for the combination of nivolumab and ipilimumab are very encouraging in patients with first-line mRCC who have a very poor prognosis.”

“This is a very important result for kidney cancer patients,” said study co-leader Hans J. Hammers, MD, PhD, Associate Professor of Internal Medicine and co-leader of the Kidney Cancer Research Program at University of Texas (UT) Southwestern Medical Center in Dallas, TX. “The data are very clear: Dual immune checkpoint inhibition with nivolumab and ipilimumab is superior to the standard of care drug, sunitinib.”

For this trial, investigators recruited about 1,100 adult patients with measurable clear-cell metastatic RCC. Half of the patients received combination therapy with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks. Patients in the other group received sunitinib 50 mg once daily in six-week cycles of four weeks on and two weeks off.

After nearly 18 months of follow-up, CheckMate-214 showed the following results:

Overall survival: Median OS wasn’t reached with nivolumab/ipilimumab compared with median OS of 32.9 months with sunitinib—a 32% reduction in the risk of death. In intermediate- and poor-risk patients in particular, median OS wasn’t reached in the nivolumab and ipilimumab group and was 26.0 months in the sunitinib group—a 37% reduction in the risk of death. However, in patients with favorable risk, the combination treatment showed no benefit over sunitinib.

Objective response rate: In intermediate- and poor-risk patients, ORR was 41.6% with the nivolumab/ipilimumab combination compared with 26.5% with sunitinib. In intermediate- and poor-risk patients with higher (≥1%) PD-L1 expression at baseline, ORR with the nivolumab/ipilimumab combination was 58% compared with 25% for sunitinib. In favorable-risk patients, ORR was better with sunitinib—52% versus 29% with nivolumab/ipilimumab.

Progression-free survival: In intermediate- and poor-risk patients, median PFS was 11.6 months with nivolumab/ipilimumab compared with 8.4 months with sunitinib (hazard ratio [HR] 0.82). In intermediate- and poor-risk patients with higher (≥1%) PD-L1 expression at baseline, median PFS with the combination was 22.8 months versus 5.9 months with sunitinib (HR 0.48). In favorable-risk patients, median PFS was greater with sunitinib—25.1 months compared with 15.3 months with nivolumab/ipilimumab (HR 2.17).

When patients at any risk were grouped altogether, investigators found no significant difference in ORR or PFS between the two treatments.

Complete response: CR occurred in 9.4% of intermediate- and poor-risk patients on combination therapy compared with 1.2% of similar patients on sunitinib.

Adverse events: A total of 54% of patients in the nivolumab/ipilimumab cohort had a grade 3 to 4 AE, while 63% of patients in the sunitinib group had a grade 3 to 5 AE. Some 22% of combination patients discontinued treatment due to an AE, compared with 12% of sunitinib patients.

The investigators concluded that the results from this trial support the use of combined nivolumab plus ipilimumab as a potential first-line treatment for patients with intermediate/poor risk metastatic RCC, particularly those patients who have higher (≥1%) tumor PD-L1 expression. The trial doesn’t support use of nivolumab/ipilimumab in good-risk patients, though.

“I believe this combination immunotherapy will be the new standard of care for previously untreated kidney cancer patients, especially for those with intermediate and poor risk disease,” Dr. Hammers said. “The efficacy data are remarkable and place immunotherapy front and center for treatment of our patients.”

Immunotherapy with nivolumab and ipilimumab is already FDA-approved for treating melanoma and is currently being investigated for other cancers.

Manuela Schmidinger, MD, Associate Professor of Medicine and Director of Renal Cell Carcinoma Program at Medical University of Vienna, in Vienna, Austria, commented on the results presented at ESMO. “Nivolumab plus ipilimumab induces a high rate of objective responses,” she said. “The quality of the response is highlighted by the rate of complete remissions, the duration of response, and its translation into OS benefit.”

First-line treatment with immune checkpoint inhibitors is a new standard of care with massive impact, Dr. Schmidinger said. However, she added, it’s not yet “the final picture.”

“Once we will be able to properly address the biology of a patient’s individual tumor, we may pick out the best individual treatment among various first-line options,” Dr. Schmidinger said. “Furthermore, multiple combinations are currently under investigation in phase 3 trials, [and] some of these combinations will most likely be included in the standard of care.”

This trial was sponsored by Bristol-Myers Squibb and Ono Pharmaceutical Co. Ltd.

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