Nivolumab/Ipilimumab Combination Active in Advanced NSCLC

Naiyer A. Rizvi, MD

A chemotherapy-free regimen of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated activity as a first-line therapy for patients with advanced non—small cell lung cancer (NSCLC), according to a preliminary clinical trial presented at the 2015 World Conference on Lung Cancer.

Four different regimens of the PD-1 inhibitor nivolumab and the anti-CTLA-4 antibody ipilimumab led to response rates of 13% to 39% in 148 patients with no prior exposure to systemic therapy. The combination produced responses that were both deep and durable with a low rate of treatment-emergent grade 3/4 adverse events (AEs) leading to discontinuation.

“Clinical activity was observed regardless of tumor PD-L1 expression,” said lead investigator Naiyer A. Rizvi, MD, director of Thoracic Oncology and Immunotherapeutics at Columbia University Medical Center. “We have preliminary evidence of greater activity in tumors that have 1% or greater PD-L1 expression. The median disease control rate [response plus stable disease] was not reached in any arm, regardless of PD-L1 expression.”

The lung cancer clinical development program for nivolumab includes the CheckMate-012 Trial, which is evaluating nivolumab in previously untreated stage IIIB/IV NSCLC as monotherapy and in various combinations with cytotoxic and targeted therapies.

Investigators in CheckMate-012 evaluated four administration/dosing schedules for the combination of nivolumab and ipilimumab. In arm A, both agents were administered at a dose of 1 mg/kg every 3 weeks (Q3W, N = 31). In arm B nivolumab was administered at 1 mg/kg every 2 weeks (Q2W) plus ipilimumab 1 mg/kg every 6 weeks (Q6W; N = 40). Arm C and D dosed nivolumab at 3 mg/kg Q2W and ipilimumab 1 mg/kg every 12 weeks (Q12W; N=38) or Q6W (N = 39).

Across the four groups, the patient cohorts had a median age of 62 to 68, stage IV disease in more than 90% of cases, nonsquamous histology in more than 80%, and ECOG 0-1 performance status.

All four regimens demonstrated activity, with the arms containing nivolumab at 3 mg/kg showing the best objective response rate (ORR). In arm C, the ORR was 39% and in arm D the ORR was 31%. The ORRs were 25% and 13%, in arm B and arm A, respectively.

Median PFS ranged from 4.9 months in arm B to 10.6 months in arm A. Median PFS was 8 months in arm C and 8.3 months in arm D. The 24-week PFS was 55% in arm A, 63% in arm C, and not yet reached in the other two groups. Median overall survival was not yet reached in all four arms (follow-up range, 6.2-16.6 months).

In those with ≥1 PD-L1 expression by IHC (n = 77; 68%) the ORR was 8%, 24%, 48%, and 48% in arms A, B, C, and D, respectively. Median PFS across each arm were 11.5 weeks, 21.1 weeks, 34.6 weeks, and not reached and the 24-week PFS rates were 42%, 40%, 74%, and 65%, respectively.

Treatment-emergent grade 3/4 adverse AEs occurred in 28% to 35% of patients in each group but led to discontinuation in just 3% to 10% of cases. All grade treatment-related AEs occurred in 77%, 73%, 74%, and 69% of patients in groups A, B, C, and D, respectively. The safety profile was consistent with previous studies of the combination, and the discontinuation rate associated with AEs was similar to rates observed with nivolumab alone.

The only grade 3/4 adverse events that occurred in as many as 10% of patients were hepatic in arm B (10%) and skin-related in arm C and D (13%). Grade 3/4 pulmonary AEs occurred in no more than 3% of patients in any of the groups. There were no treatment-related deaths in the trial.

The rationale for evaluating nivolumab and ipilimumab includes the observation that both agents enhance T-cell antitumor activity through different but complementary mechanisms, said Rizvi. Preclinical studies have suggested the combination has synergistic activity as compared with either agent alone, observations that were supported in clinical trials of the combination in advanced melanoma.

“Clinical results from Opdivo+Yervoy have already been reported in previously untreated metastatic melanoma, showing the potential of dual immune checkpoint blockade targeting both PD-1 and CTLA-4,” Rizvi said in a statement. “The preliminary results from this trial in advanced non-small cell lung cancer similarly push the envelope of benefit with an immunotherapy combination strategy in the first-line treatment of advanced non-small cell lung cancer which warrants further studies.”

An ongoing phase III trial is comparing nivolumab alone or in combination with ipilimumab versus platinum-based chemotherapy in patients with advanced NSCLC and no prior exposure to chemotherapy. In two phase III trials, single-agent nivolumab led to improved overall survival compared with docetaxel in patients with previously treated, advanced NSCLC, regardless of histology.

In addition to indications in melanoma, Nivolumab has an FDA approval for the treatment of patients with metastatic squamous-cell NSCLC that progressed on or after treatment with platinum-based chemotherapy. Additionally, an application for the drug in previously-treated patients with metastatic nonsquamous cell NSCLC was granted a priority review by the FDA, with a decision deadline of January 2, 2016.

Rizvi NA, Gettinger SN, Goldman MD, et al. Safety and Efficacy of First-Line Nivolumab (NIVO; Anti-Programmed Death-1 [PD-1]) and Ipilimumab in Non-Small Cell Lung Cancer (NSCLC). Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 786.

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