PracticeUpdate Oncology May 2019

EDITOR’S PICKS 16

Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma Journal of Clinical Oncology Take-home message • The authors of this phase IIIb/IV study compared the safety profile of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) and nivolumab 1 mg/kg plus ipili- mumab 3 mg/kg (NIVO1+IPI3) in 360 patients with previously untreated unresectable stage III or IV melanoma. After 12 months of follow-up, the rate of treatment-related grade 3–5 adverse events was 34% with NIVO3+IPI1 versus 48% with NIVO1+IPI3 (P = .006). Descriptive analysis showed no significant difference between the two groups for any efficacy outcomes, although the median overall survival was not reached. • The study met its primary endpoint, showing that NIVO3+IPI1 is associated with a significantly lower incidence of treatment-related grade 3–5 adverse events compared with NIVO1+IPI3. There did not appear to be any meaningful differences between the groups for any efficacy outcomes, but longer follow-up may be nec- essary to confirm this. Jeffrey M. Wiisanen MD

COMMENT By Ari VanderWalde MD, MPH, FACP T he combination of the PD-1 inhibitor nivolumab with the CTLA-4 inhibi- tor ipilimumab has been found to be a highly effective regimen as compared with ipilimumab alone in important studies in melanoma (CheckMate 067, Check- Mate 069). 1,2 Although no formally powered comparison has been made between com- bination therapy and single-agent PD-1 therapy, response rates and overall survival appear to be numerically higher in patients who have received ipilimumab + nivolumab as compared with nivolumab alone. How- ever, this potentially slight increase in efficacy comes at a substantial increase in toxicity. Single-agent PD-1 therapy has led to a grade 3/4 toxicity rate of approximately 15% in large studies, whereas ipilimumab + nivolumab combined has been associ- ated with grade 3/4 toxicity rates of up to 55%. As such, both single-agent PD-1 or PD-1 + CTLA-4 remain an acceptable first- line treatment in patients with metastatic melanoma, without a clear winner. Given that one of the major barriers to combination therapy is the increase in toxicity, the investigators of the Check- Mate 511 study explored different doses of combination immunotherapy in an attempt to determine whether a change in dosing could mitigate the toxicity seen with conventional dosing of ipilimumab + nivolumab. In the pivotal study of combina- tion therapy, ipilimumab was given at the dose of 3 mg/kg for four doses, whereas nivolumab was given at the relatively low dose of 1 mg/kg during this time, and fol- lowing the four doses of ipilimumab, was increased to 3 mg/kg. The likely reason for this dosing schema was not due to the assumption of increased efficacy, but rather because, prior to the pivotal study, the only approved front-line regimen to treat mel- anoma was ipilimumab 3 mg/kg, and the authors may not have felt comfortable giv- ing potentially subtherapeutic doses of the standard therapy in the combination arm. In non-melanoma cancers (such as lung, kidney, and others), where ipilimumab had not been approved as a single agent prior to combination studies, lower doses of ipilimumab (1 mg/kg) have been used in combination with standard doses of nivolumab with reasonable efficacy. In the CheckMate 511 study, investigators randomized patients in a 1:1 fashion to standard-dose ipilimumab/nivolumab (ipi 3 mg/kg, nivo 1 mg/kg) or low-dose ipili- mumab combined with nivolumab given at

Abstract PURPOSE Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) is approved for first-line treatment of patients with advanced melanoma in several countries. We conducted a phase IIIb/IV study (CheckMate 511) to determine if nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) improves the safety profile of the combination. PATIENTS AND METHODS Patients (N = 360) age 18 years or older with previously untreated, unre- sectable stage III or IV melanoma were randomly assigned 1:1 to NIVO3+IPI1 or NIVO1+IPI3 once every 3 weeks for four doses. After 6 weeks, all patients received NIVO 480 mg once every 4 weeks until disease progression or unac- ceptable toxicity. The primary end point was a comparison of the incidence of treatment-re- lated grade 3 to 5 adverse events (AEs) between groups. Secondary end points included descrip- tive analyses of objective response rate, progression-free survival, and overall survival. The study was not designed to formally demon- strate noninferiority of NIVO3+IPI1 to NIVO1+IPI3 for efficacy end points. RESULTS At a minimum follow-up of 12 months, incidence of treatment-related grade 3 to 5 AEs was 34% with NIVO3+IPI1 versus 48% with NIVO1+IPI3 ( P = .006). In descriptive analy- ses, objective response rate was 45.6% in the NIVO3+IPI1 group and 50.6% in the NIVO1+IPI3 group, with complete responses in 15.0% and 13.5% of patients, respectively. Median pro- gression-free survival was 9.9 months in the NIVO3+IPI1 group and 8.9 months in the NIVO1+IPI3 group. Median overall survival was not reached in either group.

CONCLUSION The CheckMate 511 study met its primary end point, demonstrating a significantly lower incidence of treatment-related grade 3-5 AEs with NIVO3+IPI1 versus NIVO1+IPI3. Descriptive analyses showed that there were no meaningful differences between the groups for any efficacy end point, although longer fol- low up may help to better characterize efficacy outcomes. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol 2019 Feb 27;[EPub Ahead of Print], C Lebbé, N Meyer, L Mortier, et al. www.practiceupdate.com/c/80430 de-escalation strategies can truly maintain efficacy while reducing toxicity. " " The decision of whether to use PD-1 alone or in combination should not be influenced by this study. We must hope for further, better-designed trials to clarify whether

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