Nivolumab/Ipilimumab Frontline Response Nears 60% in PD-L1+ NSCLC

Matthew D. Hellmann, MD

Upfront treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated an objective response rate (ORR) of 57% in patients with PD-L1-positive advanced non—small cell lung cancer (NSCLC), according to updated pooled findings from the phase Ib CheckMate-012 study presented at the 2016 ASCO Annual Meeting.

In the 3-arm study, patients received nivolumab alone or in combination with ipilimumab every 6 weeks (Q6W) or every 12 weeks (Q12W). Across the full population, which was not selected based on PD-L1 expression, single-agent nivolumab had an ORR of 23%. In the combination arms, the ORRs were 47% and 39%, in the Q12W and Q6W arms, respectively.

For the PD-L1 assessment, data were combined from the two combination arms. The 57% ORR was found in those with ≥1% PD-L1 expression on cells. In those with ≥50% PD-L1 expression, the ORR was 92%. In patients who tested PD-L1-negative, the ORR with the combination regimen was 15%.

"Nivolumab plus ipilimumab has promising activity, with response rates ranging from 39% to 47%. Median duration of response was not yet reached," said lead investigator Matthew D. Hellmann, MD, Memorial Sloan Kettering Cancer Center. "Efficacy with nivolumab plus ipilimumab is enhanced with increasing PD-L1 expression."

In the study, patients were randomized to receive nivolumab at 3 mg/kg every 2 weeks alone (n = 52) or at the same schedule in combination with ipilimumab Q6W (n = 39) or Q12W (n = 38). The primary endpoints of the study were ORR and 24-week progression-free survival (PFS). Secondary endpoints included overall survival (OS) and efficacy by PD-L1 expression.

In the Q12W and Q6W arms, the median PFS were 8.1 and 3.9 months, respectively. In the single-agent nivolumab group, the median PFS was 3.6 months. The 1-year OS rate was not reached in the Q12W arm, and was 69% and 73% in the Q6W and single-agent arms, respectively.

In those with ≥1% PD-L1 expression, median PFS were 8.1 and 10.6 months, in the Q12W and Q6W arms, respectively. With single-agent nivolumab, median PFS was 3.5 months. The 1-year OS rates were 90%, 83%, and 79% and ORRs were 57%, 57%, and 28%, for the Q12W, Q6W, and monotherapy arms, respectively.

In the pooled analysis, responses to frontline nivolumab and ipilimumab varied based on smoking and EGFR mutation status. The ORR in never smokers treated with the combination (n = 11) was 27% compared with 46% in current or former smokers (n = 65). A similar trend was seen for single-agent nivolumab, at 9% and 27%, in never (n = 11) and current/former smokers (n = 41), respectively.

For those with EGFR-mutant NSCLC in the combination arm (n = 8), the ORR reached 50%. In EGFR wild-type tumors (n = 54), the ORR was 41%. For single-agent nivolumab, ORRs were 14% and 30%, in EGFR mutated (n = 7) and wild-type tumors (n = 30), respectively.

"These results must be interpreted with caution," warned Hellman. "Of these 4 responders in the EGFR mutant group, 1 did not have classical exon 19 deletion or L858R EGFR activating mutations, 3 were former/current smokers, and 3 had high PD-L1 expression levels."

All-grade adverse events (AEs) were similar across each arm, occurring in 82%, 72%, and 71% of those in the Q12W, Q6W, and monotherapy arms, respectively. Grade 3/4 AEs were higher in the combination arms, at 37% and 33% for the Q12W and Q6W schedules of ipilimumab, respectively. In the single-agent arm, grade 3/4 AEs were experienced by 19% of patients. Grade 3/4 AEs led to treatment discontinuation for 5%, 8%, and 10% of those in the Q12W, Q6W, and single-agent arms, respectively.

“The results from this study provide important insight into the combination immunotherapy with nivolumab and ipilimumab, and supports the potential for this combination as a first-line treatment option for patients with advanced NSCLC,” Hellmann said in a press release. “We look forward to additional research of this combination in the first-line setting of patients with non-small cell lung cancer.”

Frontline treatment with the combination continues to be assessed in the phase III CheckMate-227 trial. For this 4-arm study, platinum-doublet chemotherapy is being compared with nivolumab alone or in combination with ipilimumab at 1 mg/kg Q6W or platinum-doublet chemotherapy. The primary endpoint is OS, and the study plans to enroll 1980 patients. The estimated primary completion date is January 2018 (NCT02477826).

Hellmann MD, Gettinger SN, Goldman JW, et al. CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol. 2016;34 (suppl; abstr 3001).

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