CHICAGO (FRONTLINE MEDICAL NEWS) – A combination of checkpoint inhibitors nivolumab plus ipilimumab produced superior objective response rates, progression-free survival, and overall survival, compared with nivolumab alone for previously treated patients with small cell lung cancer but at a cost of added toxicity, according to a phase I/II study presented at the annual meeting of the American Society of Clinical Oncology.

The observed responses were independent of tumor platinum sensitivity and programmed death-ligand 1 (PD-L1) expression.

Nivolumab as a single agent had activity, showing a 10% objective response rate, which was nearly the same whether the tumors were platinum sensitive or platinum resistant. However, the response rates were doubled for patients treated with combination therapy, reported Dr. Scott Antonia of the H. Lee Moffitt Cancer Center & Research Institute in Tampa.

The phase I/II Checkmate 032 enrolled 216 patients with progressive small cell lung cancer (SCLC) after one or more prior lines of therapy including a first-line platinum-based regimen. Patients were not selected based on PD-L1 expression in their tumors. They were assigned to treatment with nivolumab 3 mg/kg intravenously (IV) every 2 weeks (Niv3; n = 98), to nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV every 3 weeks for four cycles (Niv1/Ipi3; n = 61), or to nivolumab 3 mg/kg + ipilimumab 1 mg/kg IV every 3 weeks for four cycles (Niv3/Ipi1; n = 54). All patients then received nivolumab 3 mg/kg IV every 2 weeks.

The arms of the trial were well matched for age, sex, race, number of prior treatment regimens, smoking history, and tumor PD-L1 level of expression. “The interesting thing with small cell is that very few of the patients actually have tumors that express PD-L1,” Dr. Antonia said. “Only about a quarter of them express PD-L1, probably reflective of the fact that there are very few tumor-infiltrating lymphocytes generating gamma-interferon, and inducing this molecule.”

Combination therapy beats single agent

Nivolumab as a single agent had activity, showing a 10% objective response rate, which was nearly the same whether the tumors were platinum sensitive or platinum resistant. “The response rates were doubled when we treated the patients with combination therapy,” Dr. Antonia said, to 23% in the Niv1/Ipi3 arm and to 19% in the Niv3/Ipi1 arm. He said while it is still early to tell, the responses appear to have similar characteristics to what has been seen with non–small cell lung cancer, that is, even patients with bulky disease can have responses.

Only two complete responses occurred, and those were among the 61 patients in the Niv1/Ipi3 arm. All the rest of the responses were either partial or were stable disease. Most responses were rapid, occurring in the first 6-12 weeks. In many of the cases, responses were durable out past 1 year. A few rare cases of pseudoprogression were seen. “Responsiveness did not require PD-L1 expression. … The PD-L1–negative patients responded just as well as the PD-L1–positive patients,” Dr. Antonia said.

The greatest number of patients with tumor regression from baseline occurred in the Niv1/Ipi3 arm, contributing to the investigators’ decision to choose this combination to move forward into phase III trials. Again, while it is still early, the Niv1/Ipi3 combination produced the best overall survival, with a median of 7.7 months and a 1-year overall survival rate of 43%, with a median follow-up of 16.5 months.

Efficacy comes at a cost of toxicity

Toxicity of the treatments was consistent with what has been seen using these drugs with other cancers. Toxicity was greatest in the drug combination arms. For Niv3, 53% of patients had any grade of a treatment related adverse effect (AE). Grade 3/4 AEs affected 13%. For the arms combining nivolumab with ipilimumab, total AEs were in the 74%-79% range, with grade 3/4 AEs affecting 19%-30%. The most common AEs, largely grade 1/2, were fatigue, pruritus, and diarrhea, which were more prevalent when ipilimumab was used. Interestingly, with the higher dose of ipilimumab, 16% of patients experienced low-grade hypothyroidism, and 11% experienced low-grade hyperthyroidism. Treatment-related AEs leading to discontinuation occurred in 6% of the Niv3 arm, 18% of the Niv1/Ipi3 arm, and 13% of the Niv3/Ipi1 arm. Three treatment-related deaths occurred, all among the 115 patients in the combination arms. Dr. Antonia said even grade 3/4 immune-related AEs were well managed using established safety guidelines.

Trial results were simultaneously published in the Lancet Oncology (2016 Jun 3. pii: S1470-2045[16]30098-5. doi: 10.1016/S1470-2045[16]30098-5 ).

This study is being expanded to include more patients, and nivolumab alone and Niv1/Ipi3 are being tested earlier in the disease as front-line consolidation or maintenance therapy just after platinum-based therapy.

Discussant Dr. Jedd Wolchok of Memorial Sloan Kettering Cancer Center, New York, said people working in immunotherapy feel like they have been riding a wave over the past few years and have just washed up on a beach, wondering where to go from here. “I think combination therapies have really announced themselves as being the next step forward,” he said. Early studies with checkpoint inhibitors produced some strong and durable remissions, but for the most part, in only a minority of patients.

So investigators started to try checkpoint inhibitors with nonredundant targets, as Dr. Antonia’s study did. Nivolumab + ipilimumab has been tried in melanoma, but grade 3/4 toxicity was more prevalent than in this SCLC trial. Dr. Wolchok suggested maybe SCLC patients are more immunosuppressed and therefore do not react to the combination treatment as strongly. The toxicity was lower even than that seen in non-SCLC, “so even in diseases that occur at the same organ site, there is a different biology in the microenvironment that is leading to different tolerability, different degree of immune suppression,” he said.

He congratulated the Checkmate 032 investigators and sponsors for testing different doses and schedules “because this is not one-size-fits-all.” But he said more patients have to be studied. And remaining questions concern the nature of the response, that is, is the response deeper with the combination therapy, and balanced against the additional toxicity?

He noted that not all patients in Dr. Antonia’s study had fine needle aspirates, so their tumors could not be evaluated for PD-L1 expression. So it is still not entirely clear if a subset of patients could benefit the most, such as ones with higher expression.