On Saturday, May 30, two abstracts were presented during the Lung Cancer Oral Abstract Session reporting on PD-1 therapies for the treatment of patients with small cell lung cancer (SCLC). Discussant Roy S. Herbst, MD, PhD, of Yale School of Medicine, who reviewed the design and results of the two trials, said that immunotherapy with PD-1 agents shows activity in relapsed disease with “impressive responsive rates” and that randomized studies are clearly indicated.
The high-affinity, humanized monoclonal PD-1 antibody pembrolizumab (MK-3475) showed promising antitumor activity in the KEYNOTE-028 trial of patients with heavily pretreated, PD-L1–positive, extensive-stage SCLC. Patrick A. Ott, MD, PhD, of the Dana-Farber Cancer Institute, presented the preliminary safety and efficacy results (Abstract 7502).
Trial participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, one or more measurable lesions, PD-L1 positivity, and no autoimmune disease or interstitial lung disease. Patients received 10 mg/kg of intravenous pembrolizumab once every 2 weeks. Response was assessed every 8 weeks for the first 6 months, then every 12 weeks thereafter.
Dr. Ott said the favorable safety and toxicity profile was consistent with previous experience with pembrolizumab in other tumor types. The overall response rate (ORR) to pembrolizumab in antitumor activity was 35% (95% CI [15%, 59%]), and the responses appear durable, with six of seven ongoing at data cutoff. The median time to response was 8.6 weeks (range: 7.7-16.1 weeks); median duration of response was 29.1 weeks (range: 0.1-29.1 weeks). Five of seven patients who had a disease response had reduction in tumor size from baseline of 50% or more, he said.
Six of seven responses occurred after 8 weeks of initiating treatment, and one patient who had stable disease at 8 weeks then had a partial response at 16 weeks.
Treatment-related adverse events affecting two or more patients occurred in 14 patients; two patients had grade 3-5 adverse events, including one case of colitis that resulted in the patient’s death. One case of grade 2 autoimmune thyroiditis resulted in treatment interruption.
Dr. Scott J. Antonia
Nivolumab is the first and only PD-1 therapy that has demonstrated an overall survival (OS) benefit in patients with previously treated metastatic squamous non–small cell lung cancer, and it was approved by the U.S. Food and Drug Administration in 2015 for this indication.
The CheckMate 032 study included 128 patients with progressive disease after one or more lines of therapy, including a first-line platinum-based regimen, divided into four arms. One arm received 3 mg/kg of intravenous nivolumab every 2 weeks (40 patients), and two arms received 1 mg/kg of intravenous nivolu-mab in combination with either 1 mg/kg or 3 mg/kg of intravenous ipilimumab every 3 weeks for four cycles (3 patients and 47 patients, respectively). Data are not yet available from the fourth arm, which included 3 mg/kg of intravenous nivolumab plus 1 mg/kg of intravenous ipilimumab every 3 weeks for four cycles.
Fifteen percent of patients in the arm treated with nivolumab monotherapy had grade 3-4 adverse events; 34% had grade 3-4 adverse events in the arm treated with nivolumab plus the higher dose (3 mg/kg) of ipilimumab. Very few patients discontinued treatment because of treatment-related adverse events. One patient died from treatment-related causes (myasthenia gravis) in the combination arm receiving the higher dose of ipilimumab.
ORR was 18% with nivolumab monotherapy and 17% with nivolumab/ipilimumab. The disease control rate was 38% with monotherapy and 54% with combination therapy. The median OS was 4.4 months with monotherapy (95% CI [2.9, 9.4]) and 8.2 months with combination therapy (95% CI [3.7, not reached]).
The safety profiles of nivolumab monotherapy and nivolumab/ipilimumab are “consistent with what you see with other tumor types and were easily managed with established safety guidelines,” Dr. Antonia said, adding that attention must be paid to paraneoplastic syndromes. Three patients had limbic encephalitis; in two cases, this was resolved with immunosuppression.
The response rate and frequency of tumor reduction indicate an increased effect of the combination, and activity was observed in both platinum-sensitive and platinum-resistant/refractory disease. Responses occurred regardless of PD-L1 expression. “This was a preliminary analysis because not all of the tumors have been obtained and studied for PD-L1 expression. How this will all sort out in the end is not yet known,” Dr. Antonia said.
In his discussion of the trials, Dr. Herbst said that immunotherapy shows activity in relapsed disease with impressive response rates, given that the historical response for platinum-refractory disease is less than 10%.
Randomized trials are clearly indicated and it will be critical to obtain samples for correlative studies, including mutational studies (because of the high mutational burden in this disease) and T-cell analysis. “As always, biology will drive new combinations in this smoking-associated disease,” Dr. Herbst concluded.
Watch the session: Visit the ASCO Virtual Meeting website.