Prolonged PFS From Addition of Ipilimumab to Nivolumab in Advanced NSCLC

Scott Gettinger, MD

Findings from an efficacy update of patients participating in a study in the CheckMate series revealed that first-line nivolumab (Opdivo) demonstrated activity in advanced non—small cell lung cancer (NSCLC), and the addition of ipilimumab (Yervoy) resulted in enhanced activity, specifically in prolonged progression-free survival (PFS) and higher objective response rates (ORR), investigators reported at the 17th World Lung Cancer Conference, the Annual Meeting of the International Association for the Study of Lung Cancer (IASLC) in Vienna.

With a median follow-up of 22 months for nivolumab monotherapy and 16 months for the combination cohorts, the confirmed ORR with nivolumab monotherapy was 23% and the median duration of response (DoR) was not reached.

In contrast, the confirmed ORR in the first-line combined nivolumab plus ipilimumab cohorts was 43%.

This activity was enhanced as PD-L1 expression levels in the tumor increased. The ORR in patients with <1% PD-L1 expression was 16% versus 21%, and 26% versus 57% in patients with PD-L1 expression &ge;1% in the monotherapy versus pooled combination arms, respectively. In patients with PD-L1 expression of 50% or greater the ORR rose to 50% versus 92% with monotherapy versus combination treatment.

Lead author Scott Gettinger MD, Yale Cancer Center, presented data from the CheckMate 012 phase I trial comparing nivolumab monotherapy administered at 3 mg/kg every 2 weeks in 52 patients versus nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 12 weeks in 38 patients or the same doses of the combination but with ipilimumab administered every 6 weeks in 39 patients, all as first-line treatment in advanced NSCLC. The patients had stage IIIB/IV NSCLC of any histology and ECOG PS 0 or 1.

Nivolumab is a PD-1 immune checkpoint inhibitor that enhances T-cell antitumor activity. &ldquo;It is thought that the CTLA-4 inhibitor, ipilimumab, works by priming the immune system by inducing tumor infiltration of effector T cells, while depleting the number of myeloid-derived suppressor cells and suppressive regulatory T cells within the tumor microenvironment,&rdquo; explained Gettinger.

The combination of nivolumab plus ipilimumab has been approved for the treatment of melanoma by the FDA, and nivolumab monotherapy has been approved by the FDA for adults with locally advanced NSCLC progressing after platinum-doublet chemotherapy.

&ldquo;Efficacy with nivolumab plus ipilimumab was enhanced with increasing tumor PD-L1 expression, but was also observed in patients with <1% PD-L1, he noted.

PFS was doubled with the addition of ipilimumab to nivolumab. Median PFS by tumor PD-L1 expression (overall population versus PD-L1 expression >1% versus PD-L1 &ge;50%) in the monotherapy arm was 3.6 months versus 3.5 months versus 8.3 months compared to 8.0, versus 12.7 versus not reached in the combination arms, respectively.

When efficacy was compared between monotherapy and each of the combination arms in patients with expression &ge;1%, median PFS was greatest in the nivolumab every 2 weeks, ipilimumab every 6 weeks interval cohort, leading the investigators to take this regimen forward in future trials. Median PFS in this setting was 3.5 versus 10.4 versus 13.2 weeks, in patients receiving monotherapy, ipilimumab every 12 weeks and ipilimumab every 6 weeks, respectively. Median 1-year OS rates showed a similar pattern; median OS was 69% with monotherapy, 91% with combined ipilimumab given every 6 weeks, and 83% with combined ipilimumab given every 12 weeks.

The safety summary of first-line nivolumab with and without ipilimumab showed there were no treatment related deaths. &ldquo;After an additional 6 months of follow-up in the combination cohorts, rates of treatment-related adverse events with nivolumab plus ipilimumab remained similar to those previously reported,&rdquo; according to Gettinger.

&ldquo;The regimen of nivolumab at 3mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks is being evaluated in the phase 3 CheckMate 227 trial,&rdquo; said Gettinger. CheckMate-227 will test the combination at these doses and intervals against nivolumab monotherapy and chemotherapy in patients with PD-L1 expression below and above 1% in patients with stage IV or recurrent NSCLC who will be stratified by squamous versus non-squamous histology prior to randomization.

Reference:

First-line nivolumab monotherapy and nivolumab plus ipilimumab in patients with advanced NSCLC: long-term outcomes from CheckMate 012. Presented at: International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer (WCLC) in Vienna, Austria.