Frontline Nivolumab Leads to Early, Durable Responses in NSCLC

Scott Gettinger, MD

One-third (30%) of chemotherapy-naïve non—small cell lung cancer (NSCLC) patients treated with nivolumab, an anti-PD-1 immune checkpoint antibody, responded to treatment in a phase I study presented at the 2014 ASCO Annual Meeting. Thirty-six percent of nonsquamous patients (four) and 22% of squamous patients (two) responded to the therapy. Of the twenty patients on the trial, two patients—one nonsquamous and one squamous—had a complete response.

“The study demonstrated a high response rate and excellent tolerability [to nivolumab],” said lead author Scott Gettinger, MD, associate professor of Clinical Oncology at the Yale Cancer Center.

“We are seeing excellent responses with the majority of the patients living beyond a year,” said Julie Brahmer, MD, another study author and a lung cancer clinician and associate professor of oncology at Johns Hopkins School of Medicine and the Sidney Kimmel Comprehensive Cancer Center. “This is amazing because I have these patients in my clinic and they are doing well.”

The overall median progression-free survival (PFS) reported was 36.1 weeks, with a median PFS of 47.3 and 15.1 weeks for patients with nonsquamous and squamous histologies, respectively. The median overall survival has not yet been reached. Durations of responses ranged from 23.7 weeks to a patient still on trial who has had a r esponse for more than 71.4 weeks. At the time of the analysis, four patients— three non—small cell and one small cell—w ere still receiving treatment.

Seventeen of the patients could be evaluated for PD-L1 tumor expression. Five of the 10 PD-L1—positive patients had a response to nivolumab, compared with zero of seven patients who did not express PD-L1. The median PFS for PD-L1–positive responders was 45.6 weeks.

Although all of the patients in this study who responded to the immunotherapy had PD-L1—positive tumors, this does not exclude the ability of other patients to respond to the treatment, which has been seen in other nivolumab lung cancer trials. “Researchers are currently working on using other methods to identify patients who are more likely to respond to these immune checkpoint therapies,” said Brahmer.

The median age of patients on the trial was 67.5 years and 95% of patients had stage IV disease. Half of the patients had an adenocarcinoma and 45% (nine patients) had small cell carcinoma.

Eighty-five percent (17) of patients experienced an adverse event. Seventy-six percent of these were either grade 1 or grade 2. The most common low-grade adverse events were fatigue (40%), nausea (20%), rash (20%), and diarrhea (15%).

Five treatment-related adverse events were reported in four patients including one case each of increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), hyperglycemia, rash, and cardiac failure. Two patients, one who experienced a grade 3/4 increased ALT and AST and another who had cardiac failure, discontinued therapy.

No cases of pneumonitis were reported in this small patient population trial. “Pneumonitis has been an infrequent manageable toxicity in patients treated with anti-PD1 antibodies,” said Gettinger. He noted that there are no clear characteristics that can currently identify patients who may be more predisposed to this type of adverse event. “Some of these patients are older patients and have comorbidities and they have tolerated this therapy quite well,” said Brahmer.

The adverse-event profile of these first-line patients is similar to that of postchemotherapy NSCLC patients who have been treated with several therapies for their advanced disease, according to Brahmer. Still, Brahmer cautions that too few patients have been treated to make a valid comparison.

“Anti-PD1 and anti—PD-L1 antibodies have shown encouraging activity in patients with pretreated advanced non–small cell lung cancer,” said Gettinger. “Durable responses with median durations of 17 months in one trial enrolling heavily pretreated NSCLC have been demonstrated. [What our study shows is that] nivolumab also has activity in patients who are chemotherapy naïve.”

Nivolumab is currently being compared with platinumbased chemotherapy, the current standard of care in NSCLC, in a recently started 500-patient phase III trial of chemotherapy- naïve NSCLC patients (NCT02041533).

Gettinger S, Shepherd FA, Antonia SJ, et al. First-line nivolumab (anti- PD-1; BMS-936558, ONO-4538) monotherapy in advanced NSCLC: safety, efficacy, and correlation of outcomes with PD-L1 status. J Clin Oncol. 2014;32:5s (suppl; abstr 8024).