Results of the START trial suggest that maintenance therapy with the investigational immunotherapy tecemotide (formerly known as L-BLP25) may have a role in the treatment of patients with unresectable stage III non–small cell lung cancer (NSCLC). Although there was no significant overall survival advantage for tecemotide in the main modified intent-to-treat analysis of the trial, a prespecified subgroup analysis showed a 10-month survival edge for maintenance therapy with tecemotide vs placebo in patients treated with concurrent chemoradiotherapy.
“Patients receiving concurrent [chemoradiotherapy] followed by maintenance immunotherapy represent a very large subgroup of 806 patients. We haven’t seen this type of clinically meaningful survival benefit with any other investigational therapies [in unresectable stage III NSCLC]. Nothing else has been as exciting,” said lead author Charles A. Butts, MD, a medical oncologist at Cross Cancer Institute, Edmonton, Canada. Dr. Butts believes that further study of tecemotide should go forward.
Tecemotide is an antigen-specific injectable peptide vaccine that targets MUC1, a mucinous glycoprotein that is overexpressed in lung cancer. Preliminary studies have established the safety of this therapy and shown promise in extending survival in patients with NSCLC, Dr. Butts said.
START (Stimulated Targeted Antigenic Responses To NSCLC) is a multicenter, randomized, double-blind, placebo-controlled, phase III study of patients with unresectable stage III NSCLC who have responded or had stable disease after at least two cycles of platinum-based chemotherapy plus radiation and had good performance status. (Drugs used with platinum were not prespecified.) Patients were stratified for stage IIIA and IIIB, complete response/partial response vs stable disease on chemoradiotherapy, concurrent vs sequential chemoradiotherapy, and geographic region.
Following chemoradiotherapy, eligible patients (ie, responding or with stable disease) were randomized to maintenance therapy with tecemotide vs placebo. Both groups received weekly injections for 8 consecutive weeks, followed by maintenance injections every 6 weeks until disease progression.
After the trial was initiated, with a planned enrollment of 1,322 patients, it was halted temporarily, triggered by a single case of fatal encephalitis in a phase II study of tecemotide in a patient with multiple myeloma. At the time of the clinical hold, 531 patients had received treatment and had treatment suspended for a median of 4 months. After additional safety monitoring, treatment was restarted.
The final sample size—excluding patients randomized within 6 months of the clinical hold—was 1,239 patients who were included in a modified intent-to-treat analysis. The safety population included 1,501 patients who received at least one dose of the study therapy.
“Patients within 6 months of randomization at the time of the clinical hold were thought to be the patients most likely to be impacted by interruption of their treatment,” said Dr. Butts. “The 6 months represents the eight weekly injections and two subsequent 6-weekly injections of tecemotide. It was felt that this duration was likely necessary to induce the immune response.”
“This was the largest trial ever reported in stage III NSCLC,” Dr. Butts told listeners.
Both arms were well balanced for demographic and disease characteristics. The largest group of patients received concurrent chemoradiotherapy (65%) as initial therapy; 35% received sequential chemoradiotherapy.
At a median follow-up of about 39 months, the study failed to meet the primary endpoint of overall survival. In a modified intent-to-treat analysis, median overall survival was 25.6 months for immunotherapy vs 22.3 months for placebo, demonstrating a nonsignificant trend favoring tecemotide. Time to disease progression (median, 10 vs 8.4 months for tecemotide and placebo, respectively) and time to symptomatic progression (median, 14.2 vs 11.4 months) were also not significantly different.
“When patients who were excluded from the primary analysis due to the clinical hold were analyzed, there was no treatment effect, suggesting that uninterrupted therapy is critical for efficacy,” Dr. Butts emphasized.
Prespecified subgroup analysis favored tecemotide, and this finding was most robust for concurrent vs sequential chemoradiotherapy, he continued. In the concurrent chemoradiotherapy patients (n = 806), median overall survival was 30.8 months for tecemotide recipients vs 20.6 months for placebo recipients (P = .016). No difference was seen between the two treatment arms in the group of patients treated with sequential chemoradiotherapy.
No safety signals emerged in this trial. No difference between the two treatment arms was found in frequent adverse events, grades 3 and 4 adverse events, or adverse events leading to death.
Dr. Butts speculated on the “million dollar question”: Why were results so much better in the concurrent chemoradiotherapy arm? “It may be explained by patient selection. Probably patients selected for sequential therapy are not treated with a curative intent,” he noted. ■
Disclosure: Dr. Butts has been a consultant or advisor for and has received honoraria from Merck KGaA and Merck Serono.
1. Butts CA, Socinski MA, Mitchell P, et al: START: A phase III study of L-BLP25 (tecemotide) cancer immunotherapy for unresectable stage III on-small cell lung cancer. 2013 ASCO Annual Meeting. Abstract 7500. Presented June 4, 2013.
Formal discussant Johan F. Vansteenkiste, MD, PhD, Professor of Internal Medicine at University Hospital KU, Leuven, Belgium, was also enthusiastic about the findings in the concurrent chemoradiotherapy arm, and believes that a confirmatory trial should be done.
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