Addition of TG4010 Vaccine to First-Line Chemotherapy Appears to Improve Progression-Free Survival in Advanced NSCLC
As reported in The Lancet Oncology by Quoix et al, the addition of immunotherapy with TG4010—the modified vaccinia Ankara expressing MUC1 and interleukin 2—to first-line chemotherapy improved progression-free survival in patients with advanced non–small cell lung cancer (NSCLC) in the phase IIb portion of a phase IIb/III trial. The trial is moving on to phase III evaluation.
Study Details
MUC1 is a tumor-associated antigen expressed by NSCLC and many other solid tumors. A previous study showed that activity of TG4010 with chemotherapy in NSCLC might be associated with baseline values of CD16, CD56, CD69 triple-positive activated lymphocytes (activated natural killer cells). Assessment of outcome according to levels of these triple-positive activated lymphocytes was a primary objective of the phase IIb portion of the trial.
In the double-blind study, 222 previously untreated patients with stage IV disease without a known activating EGFR mutation and with MUC1 expression in ≥ 50% of tumor cells from 45 sites in 9 countries were randomized between April 2012 and September 2014 to receive a platinum-based chemotherapy doublet with TG4010 given subcutaneously at 108 plaque-forming units (n = 111) or placebo (n = 111). Treatment was given from the start of chemotherapy every week for 6 weeks and then every 3 weeks up to disease progression or treatment discontinuation. Bevacizumab (Avastin) and maintenance pemetrexed (Keytruda) or erlotinib were permitted according to labeling. Randomization was stratified by baseline value of triple-positive activated lymphocytes (≤ or > the upper limit of normal [ULN]). The primary endpoint was progression-free survival. Triple-positive activated lymphocyte values were ≤ ULN in 77% of patients in both groups.
Progression-Free Survival
In the total population, median progression-free survival was 5.9 months (95% confidence interval [CI] = 5.4–6.7 months) in the TG4010 group vs 5.1 months (95% CI = 4.2–5.9 months) in the placebo group (hazard ratio [HR] = 0.74, P = .019). Hazard ratios for progression-free survival were 0.75 (95% CI = 0.54–1.03) in patients with triple-positive activated lymphocyte values ≤ ULN (meeting the predefined criterion for triple-positive activated lymphocyte validation) and 0.77 (95% CI = 0.42–1.40) in those with values > ULN (not meeting the predefined criterion). Progression-free survival was significantly prolonged with TG4010 treatment among the 147 patients with triple-positive activated lymphocyte values ≤ the 3rd quartile (HR = 0.66, P = .010), particularly among the 127 patients with nonsquamous tumors (HR = 0.59, P = .0033).
Among all 196 patients with nonsquamous tumors, the hazard ratio was 0.69 (P = .0093).
Adverse Events
Grade 1 or 2 injection-site reactions occurred in 33% of the TG4010 group vs 4% of the placebo group. No grade 3 or 4 or serious adverse events considered related to TG4010 alone were observed. The most common grade ≥ 3 adverse events were neutropenia (grade 3 in 26% vs 21%, grade 4 in 12% vs 10%), anemia (grade 3 in 11% vs 15%), and fatigue (grade 3 in 11% vs 12%, grade 5 in 1% vs 0%).
The investigators concluded: “TG4010 plus chemotherapy seems to improve progression-free survival relative to placebo plus chemotherapy. These data support the clinical value of the TrPAL [triple-positive activated lymphocytes] biomarker in this clinical setting; because the primary endpoint was met, the trial is to continue into the phase 3 part.”
The study was funded by Transgene, Avancées Diagnostiques pour de Nouvelles Approches Thérapeutiques, and OSEO.
Elisabeth Quoix, MD, of Les Hôpitaux Universitaires de Strasbourg, is the corresponding author of The Lancet Oncology article.
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