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Select GI AEs Managed in Studies of Nivolumab, Ipilimumab in Melanoma in Pooled Post-Hoc Analysis

Darcy Lewis
Published Online: 1:46 PM, Mon June 5, 2017

Jeffrey S. Weber, MD, PhD

Nivolumab (Opdivo) plus ipilimumab (Yervoy) or ipilimumab alone are associated with a high incidence of gastrointestinal (GI) toxicity, but most adverse events (AEs) are effectively managed using immunomodulators, which do not appear to inhibit tumor response. Additionally, nivolumab plus ipilimumab significantly improved overall survival (OS) and objective response rate (ORR) versus ipilimumab alone in patients with untreated advanced melanoma. These findings, which were drawn from a post-hoc analysis of pooled data from the CheckMate-069 and CheckMate-067 studies, were presented during the 2017 ASCO Annual Meeting.1
CheckMate-069 is a phase II trial and the first randomized study to evaluate the nivolumab and ipilimumab doublet regimen in treatment-naïve patients with advanced melanoma. In this trial, the combined regimen demonstrated a 2-year OS rate of 69% compared with 53% for ipilimumab alone (HR, 0.58; 95% CI, 0.31-1.08) in patients with BRAF wild-type advanced melanoma.2
The phase III trial CheckMate-067 is the second randomized trial to show clinical benefit of the nivolumab plus ipilimumab regimen in previously untreated advanced melanoma. Median progression-free survival (PFS) was 11.5 months for the combined regimen and 6.9 months for nivolumab monotherapy versus 2.9 months for ipilimumab monotherapy.3
“The pooled analysis showed that nivolumab plus ipilimumab significantly improved OS and ORR versus ipilimumab alone in patients with untreated advanced melanoma, but is associated with a higher incidence of select GI immune-related AEs. But the majority of high-grade events were manageable and resolved with the use of immunomodulators within 3 to 4 weeks,” said lead investigator Jeffrey S. Weber, MD, PhD, deputy director of the Perlmutter Cancer Center at NYU Langone Medical Center. “Close communication between patients and the clinical team and prompt initiation of immunomodulators based on the severity of select GI immune-related AEs are key to optimizing patient outcomes.”
Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles, followed by nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, or ipilimumab 3 mg/kg with placebo every 3 weeks for 4 cycles, followed by placebo every 2 weeks. The total numbers of patients treated with the combined regimen or ipilimumab monotherapy were 407 and 357, respectively, of which only patients with select GI immune-related AEs were analyzed.
In the combined treatment arm, 195 patients (47.9%) experienced GI AEs of any type or severity, compared with 132 (37.0%) in the monotherapy arm. The grade 3/4 GI AE breakdown was as follows: 75 patients (18.4%) in the combined group versus 42 (11.8%) in the ipilimumab group. Diarrhea was the most common GI AE, with 39 patients (9.6%) in the combined arm versus 24 patients (6.7%) experiencing grade 3/4 diarrhea. There were no grade 5 treatment-related select GI immune-related AEs.
Corticosteroids were widely used to manage select GI immune-related AEs in patients in both treatment arms. Among the 67 patients in the combined arm who developed grade 3/4 GI AEs, 61 (91.0%) of them were treated with corticosteroids and 21 patients (31.1%) received infliximab. In the monotherapy arm, all 41 patients with grade 3/4 AEs received corticosteroids and 14 patients (34.1%) were treated with infliximab.
Almost all select GI immune-related AEs resolved with the use of immunomodulators in patients treated with the combined regimen (94% to 97%) or monotherapy (79% to 92%) with a median time to resolution of 3.0 to 4.5 weeks and 2.4 to 7.8 weeks, respectively. In the combined therapy group, 183 patients (94.8%) had complete resolution of any grade select GI immune-related AEs. Of the 84 and 66 patients with grade 2 or 3 select GI immune-related AEs, 61 (73%) and 33 (50%), respectively, were retreated with study drug following resolution.
The best overall responses in all treated patients and patients with any grade select GI immune-related AEs, managed with corticosteroids alone or corticosteroids plus infliximab, are as follows: the ORR in the combined arm was 58.2% (95% CI 53.3-63.1) and 18.2% (95% CI 14.3-22.6) in the monotherapy arm; among the patients who had any grade of select GI immune-related AEs, ORR was 63.1% (95% CI 55.9-69.9) in the combined arm and 18.9% (95% CI 12.6-26.7) in the monotherapy arm.
In patients who received corticosteroidal treatment for GI AEs, the ORR was 62.5% (95% CI 50.3-73.6) in the combined arm and 25.0% (95% CI, 13.2-40.3) among monotherapy patients. In patients whose GI AEs were treated with corticosteroids plus infliximab, the ORR was consistent with the other groups: 54.5% (95% CI, 32.2-75.6) in the combined group and 25.0% (95% CI, 7.3-52.4) in the ipilimumab-only group.
The median duration of response was not reached in patients with any grade select GI immune-related AEs, including those managed with corticosteroids.
At 2 years, the OS rate among all treated patients was 64% in the combined arm and 46% in the monotherapy arm (HR, 0.58; 95% CI, 0.47-0.71). In patients with GI AEs, OS was 71% for doublet therapy compared with 50% in the ipilimumab group (HR, 0.44; 95% CI, 0.32-0.61). In patients who were treated with high-dose corticosteroids, the OS rate was 69% in the combined arm compared with 50% in the ipilimumab group (HR, 0.44; 95% CI, 0.26-0.77).
According to Weber, future research is required to prospectively examine the earlier use of immunomodulators such as infliximab in managing refractory grade 3/4 select GI immune-related AEs.
  1. Weber JS, Larkin JMG, Schadendorf D, et al. Management of gastrointestinal (GI) toxicity associated with nivolumab (NIVO) plus ipilimumab (IPI) or IPI alone in phase II and phase III trials in advanced melanoma (MEL). J Clin Oncol. 35, 2017 (suppl; abstr 9523).
  2. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-2017. doi: 10.1056/NEJMoa1414428.
  3. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. New Engl J Med. 2015;373:23-34. doi: 10.1056/NEJMoa1504030.

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