Higher Cytokine Levels Improve Nivolumab Efficacy in Squamous NSCLC

Suresh S. Ramalingam, MD

Efficacy and safety remained strong at 2 years following treatment with nivolumab in previously treated patients with advanced, refractory, squamous non-small—cell lung cancer (NSCLC), according to updated results from the CheckMate 063 and CheckMate 017 trials presented at the 2016 European Lung Cancer Conference, and an exploratory analysis also signaled an association between baseline serum cytokine levels and the immunotherapy’s efficacy.

With nivolumab, the 2-year overall survival (OS) rate in CheckMate 063 was 22% (95% CI, 15-30), and median OS was 8.1 months (95% CI, 6.1-10.9).

“Findings were consistent across the phase II CheckMate 063 trial of nivolumab and phase III CheckMate 017 trial of nivolumab versus docetaxel in patients with advanced platinum-refractory squamous NSCLC,” reported Suresh Ramalingam, MD, of the Winship Cancer Institute at Emory University.

Ramalingam also presented findings from a multivariate analysis of baseline levels of serum cytokines in patients participating in both trials. A SQ-cytoscore was generated, defined as “high” or “low” based on the median cutoff, and the association of the score to OS was assessed by Kaplan-Meyer analysis.

This analysis revealed a relationship between baseline serum cytokine levels and therapeutic efficacy. OS in 102 patients with high baseline cytoscores was nearly 3 times longer with nivolumab when compared with 120 patients who had low serum cytokine levels at baseline. Median OS was 15.6 versus 5.3 months in the high and low cytoscore groups, respectively (hazard ratio [HR] for OS, 0.48; 95% CI, 0.36-0.64; P <.0001).

Although an effect from baseline serum cytokine levels was observed among docetaxel-treated patients in CheckMate 017, median OS was longer with nivolumab versus docetaxel in both cytoscore groups. With docetaxel, 70 patients having high and 48 patients with low cytoscores showed median OS of 9.1 versus 4.9 months, respectively (HR, 0.39; 95% CI, 0.27-0.54; P <.0001). Difference in median OS in the high and low cytoscore groups (6.5 and 5.4 months, respectively) favored nivolumab over docetaxel.

Nivolumab had been administered in CheckMate 063 at 3 mg/kg every 2 weeks to 117 patients until progressive disease (PD) or unacceptable toxicity occurred. CheckMate 017 randomized 135 patients to receive nivolumab at the same dose and 137 patients to docetaxel at 75 mg/m² every 3 weeks until PD or discontinuation due to toxicity or other reasons.

The primary endpoints were overall response rate (ORR) by independent radiology committee (IRC; RECIST v1.1) in CheckMate 063 and OS in CheckMate 017. Treatment beyond PD was permitted in both studies.

In CheckMate 017, the 12- and 18- month OS was 42% and 28%, respectively, with nivolumab, compared with 24% and 13% with docetaxel. Median OS was 9.2 months (95% CI, 7.33-12.62) with nivolumab versus 6.0 months (95% CI, 5.29-7.39) with docetaxel (HR, 0.82; 95% CI, 0.48-0.81; P = .0004).

In CheckMate 063, the IRC-assessed ORR at 6 months was 12% (95% CI, 7-19), and median time to response (TTR) was 3.0 months (range, 1.7-4.0). The best overall response included 12 partial responses (PR), 29 patients achieved stable disease (SD), and 43 patients showed PD. Response was unable to be determined in 16 patients. Median duration of response was not reached (95% CI 2.8-6.9⁺) with 71% of patients showing an ongoing response. The 6-month PFS rate was 27% (95% CI, 18-36) and median PFS was 1.9 months (95% CI, 1.8-3.2).

“Patients with platinum-refractory, advanced squamous NSCLC had few treatment options until nivolumab was approved for treatment of patients with locally advanced or metastatic NSCLC after prior chemotherapy in both the United States and the European Union,” Ramalingam noted. “Nivolumab continues to demonstrate clinically meaningful efficacy in CheckMate 063.”

The 24-month efficacy update showed IRC-assessed ORR of 15% (95% CI, 9-22), with 29% of patients showing an ongoing response. Complete response was achieved by 2 patients, 13 showed PR, 30 had SD, and 45 patients experienced progression. The PFS rate was 9% (95% CI, 4%-15%) and median PFS was 2.0 months (95% CI, 1.8-3.2) Median TTR was 3.3 months (95% CI, 1.6-7.4) and median duration of response was 19 months (95% CI, 4.5+-27.5+). Ten patients were unevaluable for response.

It was noted that 4 patients were on nivolumab at the 24-month data cutoff, and 5 of 26 patients treated beyond PD showed a nonconventional pattern of benefit.

The CheckMate 063 safety update after 2 years was similar to that seen at 1 year; treatment-related adverse events (TRAEs) of any grade were reported in 75% of patients, with 12% leading to study discontinuation. Grade 3/4 TRAEs occurred in 18% of patients leading to study discontinuation in 10% of patients.

As of the December 2015 database lock, 82% of patients had died; of these deaths, 74% were due to disease progression, 2% from study drug toxicity and 7% of patients died due to other reasons.

“The safety profile of nivolumab is manageable and consistent with previous studies,” Ramalingam said.

Importantly, no treatment-related deaths occurred since the 6-month database lock, and no new grade 3 / 4 TRAEs have been reported since the database lock at one year.

“The results presented here today demonstrate that the SQ-cytoscore, derived from select serum cytokines at baseline, appears to be associated with better prognosis in patients with advance squamous NSCLC,“ concluded Ramalingam. “These preliminary SQ-cytoscore findings require prospective validation in future studies.”

Lena H, Rizvi NA, Wolf J, et al. Nivolumab in patients (pts) with advanced refractory squamous (SQ) non-small cell lung cancer (NSCLC): 2-year follow-up from CheckMate 063 and exploratory cytokine profiling analyses. Presented at: 2016 European Lung Cancer Conference; April 13-16, 2016; Geneva, Switzerland. Abstract 137O

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