Nivolumab/Ipilimumab Combination Active in Recurrent SCLC

Scott J. Antonia, MD, PhD

Treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated a median overall survival (OS) of 7.7 months and a 1-year OS rate of 43% for patients with recurrent small cell lung cancer (SCLC), according to findings from CheckMate-032 study presented at the 2016 ASCO Annual Meeting and published in Lancet Oncology.^1,2

The addition of ipilimumab to nivolumab doubled response rates for patients with recurrent SCLC compared with single-agent nivolumab. Moreover, durable responses were observed regardless of platinum sensitivity, with responses seen across all treatment arms for those with platinum-refractory disease. Responses in the study were similar to those seen in patients with non—small cell lung cancer, observed lead investigator Scott J. Antonia, MD, PhD.

"There were responses—monotherapy produces responses 10% of the time and there was a doubling in response rate with the combination therapy. The early survival results are encouraging," said Antonia, department chair of the Thoracic Oncology Department at the H. Lee Moffitt Cancer Center and Research Institute. "The safety profile of these drugs is similar to what we've seen in other diseases, and only 10% of patients come off treatment because of toxicity."

The CheckMate-032 trial randomized 216 patients with progressive SCLC following ≥1 prior line of therapy to receive single-agent nivolumab or the combination of nivolumab and ipilimumab at one of two doses. The primary endpoint of the study was objective response rate (ORR). Secondary outcome measures focused on OS, progression-free survival (PFS), duration of response (DOR), and the occurrence of treatment-related adverse events (AEs) leading to treatment discontinuation.

In the monotherapy arm, 98 patients received nivolumab at 3 mg/kg every 2 weeks. In the combination arms, patients received nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks (N1/I3; n = 61) or nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks (N3/I1; n = 54). After 4 cycles, those in the combination arm went on to receive nivolumab monotherapy at 3 mg/kg every 2 weeks.

In the single-agent arm, the median age was 63 years and 9% were ≥75 years. Thirty-one percent had platinum-resistant SCLC, and the majority had received 2-3 prior lines of therapy (56%). In the N1/I3 and N3/I1 arms, the median ages were 66 and 61 years and 11% and 0% were ≥75 years, respectively. Thirty-eight percent and 52% of patients had received 2 to 3 prior regimens and 38% and 39% were platinum-resistant, for the N1/I3 and N3/I1 arms, respectively.

The median OS in the monotherapy arm was 4.4 months (95% CI, 3·0-9·3) and the 1-year OS rate was 33% (95% CI, 22-45). In the N3/I1 group, the median OS was 6.0 months (95% CI, 3.6-11.0) and the 1-year OS rate was 35% (95% CI, 22-48). In the N1/I3 arm, median OS was 7.7 months (95% CI, 3.6-18.0) and the 1-year OS was 43% (95% CI, 30-56).

"This is a relatively few number of patients, but it appears that there is a tail in the survival curve that is keeping up with follow up, which is the most important aspect of immunotherapy," said Antonia.

The median PFS was 1.4 months in the single-agent nivolumab arm (95% CI, 1.4-1.9). In the combination groups, the median PFS were 1.4 months (95% CI, 1.3-2.2) and 2.6 months (95% CI, 1.4-4.1), in the N3/I1 and N1/I3 arms, respectively. At the March 24, 2016, data cutoff, the 1-year PFS rate was 11% (95% CI, 5-19) with single-agent nivolumab. In the N1/I3 group, the 1-year PFS was 19% (95% CI, 9-32). The 1-year PFS rate was not reached in the N3/I1 group.

The ORR in the single-agent nivolumab arm was 10% (95% CI, 5-18), and the ORRs were 23% (95% CI, 13-36) and 19% (95% CI, 9-31) in the N1/I3 and N3/I1 arms, respectively. Responses generally consisted of partial responses, with 1 complete response seen in the N1/I3 arm. Stable disease rates were 22%, 21%, and 17%, in the single-agent, N1/I3, and N3/I1 arms, respectively. Across arms, both platinum-sensitive and -resistant patients responded to treatment.

The median DOR was not yet reached with single-agent nivolumab. In the N3/I1 group, the median DOR was 4.4 months (95% CI, 3.7-not reached). In the N1/I3 group, the median DOR was 7.7 months (95% CI, 4.0-not reached).

Overall, 69% of patients were evaluable for PD-L1 expression at baseline, with 17% expressing the ligand on ≥1% of cells. Responses were seen regardless of PD-L1 expression. Sixteen patients experienced a DOR of more than 6 months, 50% of which were in the N1/I3 group.

AEs were more common in the combination arms versus the single-agent. All-grade AEs were experienced by 53% of those in the monotherapy arm, with a grade 3/4 AE rate of 13%. In the N3/I1 and N1/I3 arms, 74% and 79% of patients experienced AEs of any grade, respectively. Grade 3/4 AEs occurred in 19% and 30% of patients, in the N3/I1 and N1/I3 groups, respectively.

"The toxicity we saw is reminiscent of what we're seeing with these drugs in other diseases. About half of patients treated with nivolumab monotherapy had some sort of immune-mediated adverse event," said Antonia. "Toxicity was definitely greater in the combination arms, with about three quarters of patients having some sort of toxicity. Despite this toxicity, patients decided to stay on treatment. Only about 10% of patients came of treatment."

AEs led to treatment discontinuation for 6%, 7%, and 11% of patients in the monotherapy, N3/I1, and N1/I3 arms, respectively. Two treatment-related deaths occurred in the N1/I3 arm from myasthenia gravis and renal failure and 1 death was seen in the N3/I1 arm from pneumonitis. Treatment-related limbic encephalitis occurred in 2 patients and resolved in 1.

"Small cell lung cancer has been a very suborn disease, not for lack of trying. There really has only been trivial progress made in the past 30 to 40 years," said Antonia. "With this data, it looks like it is quite hopeful that there might be a significant change in this disease, with the addition of immunotherapy.”

A randomized expansion arm of the CheckMate-032 study is enrolling 250 patients to receive nivolumab alone or the N1/I3 combination. Additionally, two phase III studies are assessing nivolumab and ipilimumab as treatments for patients with SCLC.

In the phase III CheckMate-331 study, nivolumab is being compared with standard chemotherapy for patients with relapsed SCLC. This study plans to enroll 480 patients with the primary completion date of July 2017 (NCT02481830).

In the 3-arm phase III CheckMate-451 trial, patients will receive placebo, nivolumab alone, or nivolumab at 1 mg/kg combined with ipilimumab at 3 mg/kg as maintenance therapy following platinum-based frontline therapy for patients with extensive-stage SCLC. The study plans to enroll 810 patients, with an estimated completion date of April 2018 (NCT02538666).

1. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Checkmate 032: Nivolumab (N) alone or in combination with ipilimumab (I) for the treatment of recurrent small cell lung cancer (SCLC). J Clin Oncol. 2016;34 (suppl; abstr 100).
2. Antonia SJ, Lopez-Martin JA, Bendell JC, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial [published online June 4, 2016]. Lancet Oncol. DOI: 10.1016/S1470-2045(16)30098-5.

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