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Immunotherapy combination ‘new standard of care’ in metastatic renal cell carcinoma
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MIAMI — The combination of ipilimumab and nivolumab is an effective standard frontline treatment of patients with metastatic renal cell carcinoma, according to results from the Checkmate-214 trial presented at the International Kidney Cancer Symposium.
“Ipilimumab-nivolumab is a standard of care in frontline metastatic renal cell carcinoma patients, in part because of the higher complete and partial response rates with durability, which achieves the goal of what we are trying to do cure and control the disease over the long term,” Brian I. Rini, MD, from the department of solid tumor oncology at Cleveland Clinic Taussig Cancer Center and a HemOnc Today Editorial Board Member, said during his presentation.
As HemOnc Today previously reported, researchers presented data from this trial at the European Society for Medical Oncology Congress.
The randomized, open-label phase 3 Checkmate-214 study evaluated the safety and efficacy of nivolumab (Opdivo, Bristol-Myers Squibb) in combination with ipilimumab (Yervoy, Bristol-Myers Squibb) compared with sunitinib (Sutent, Pfizer) in 1,096 adults with measurable clear-cell metastatic renal cell carcinoma and a Karnofsky performance score of 70 or greater.
The researchers randomly assigned patients 1:1 to receive the combination or sunitinib until progression or unacceptable toxicity.
Patients in the combination arm (n = 550) received 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks for four doses, followed by 3 mg/kg nivolumab every 2 weeks. Patients assigned sunitinib (n = 546) received 50 mg once daily for 4 weeks and 2 weeks off in 6-week cycles.
Overall response rate, PFS and OS in patients with intermediate- and poor-risk disease which included 425 patients assigned the combination and 422 assigned sunitinib served as co-primary endpoints.
More patients assigned the combination demonstrated an overall response (42%; 95% CI, 37-47) than patients assigned sunitinib (27%; 95% CI, 22-31).
In addition, more patients who received the combination arm achieved complete response (9% vs. 1%) or partial response (32% vs. 25%), which will be significant and durable, Rini noted.
“We don’t really talk in kidney cancer about very good partial responses or some of the other terms that are often used in other malignancies. But, certainly in my clinical experience, some of these partial responses will be significant,” Rini said. “This means they will be deep and durable, with 80% to 90% tumor shrinkage and minor residual abnormalities. One of the things we will need to do with this dataset is look into how many of these partial responses are deep and durable. And, how do we predict that?”
Patients assigned the combination also demonstrated significantly longer median PFS (11.6 months vs. 8.4 months; HR = 0.82; P = .0331).
Median OS was not reached (95% CI, 28.3 to not reached) in the combination arm compared with 26 months (95% CI, 22.1 to nonevaluable) in the sunitinib arm (HR = 0.63; 99.8% CI, 0.44-0.89; P = .00003).
Researchers also evaluated ORR, PFS and OS in all patients, regardless of risk, as co-secondary endpoints.
A small ORR advantage occurred among patients who received the combination regimen (39%; 95% CI, 35-43) compared with sunitinib (32%; 95% CI, 28-38; P = .019).
However, median PFS was nearly identical (12.4 months vs. 12.3 months; HR = 0.98; 99.1% CI, 0.79-1.23).
OS was not reached in the combination arm compared with 32.9 months in the sunitinib arm (HR = 0.68; 99.8% CI, 0.49-0.95).
The researchers also evaluated antitumor activity by tumor PD-L1 expression level.
Greater benefit occurred among intermediate- and poor-risk patients with PD-L1 levels of at least 1% at baseline in terms of ORR (58% vs. 22%) and median PFS (22.8 months vs. 5.9 months; HR = 0.48; 95% CI, 0.28-0.82).
“The response rate, and especially the complete response rate, is enhanced in PD-L1-positive patients,” Rini said. “Although, importantly, PD-L1-negative patients still have complete responses, which is the distinguishing feature of this regimen.”
Drug-related adverse events occurred among 93% of patients in the nivolumab-ipilimumab cohort and 97% of patients assigned sunitinib. Fifty-four percent of patients assigned the combination experienced a grade 3 to grade 4 adverse event, and 63% of the sunitinib arm experienced a grade 3 to grade 5 event.
Of note, discontinuation due to toxicity occurred among 22% of patients assigned the combination and 12% assigned sunitinib.
“In this case, that is not really a bad thing,” Rini said. “Development of toxicity is probably one sensitivity marker of development of an effective antitumor T-cell response. ... Coming off from toxicity after induction is not a bad thing. In fact, it is probably a good thing, and patients will do well for a while after that.” by Kristie L. Kahl
Reference:
Rini B. IO is the new standard of care for all mRCC patients. Presented at: International Kidney Cancer Symposium; Nov. 3-4, 2017; Miami.
Disclosure: Rini reports consultant roles with Accelion, Novartis and Pfizer; and research funding from Bristol-Myers Squibb, Immatics, Peleton and Pfizer; and expenses from Pfizer.