Vaccine Strategy for Biomarker in NSCLC Reaches Phase III Study

An emerging vaccine strategy, of TG4010 immunotherapy and first-line chemotherapy, that could target a potential new biomarker in patients with advanced non-small cell lung cancer (NSCLC) has successfully reached a phase III clinical trial, researchers noted.

Charles Butts, MD

An emerging vaccine strategy of TG4010 immunotherapy and first-line chemotherapy, that could target a potential new biomarker in patients with advanced non-small cell lung cancer (NSCLC), has successfully reached a phase III clinical trial, according to an article recently published in Lancet Oncology.1

In most recent data of the TIME trial, previously untreated patients with NSCLC tumors expressing the MUC-1 mutation experienced a median progression-free survival (PFS) of 5.9 months when they received the experimental vaccine in combination with standard first-line chemotherapy. This is in comparison to a PFS of 5.1 months in patients who received placebo plus standard chemotherapy (P =.019).

Because the trial successfully met its first endpoint, it will continue on to phase III. This portion of the trial will enroll 812 patients, according to Charles Butts, MD, professor of Oncology at the University of Alberta in Edmonton, Canada.

“The difference in median PFS of 0.8 months is not clinically meaningful, but the hazard ratio for progression-free survival was 0.66 for patients in the group with lower triple-positive activated lymphocytes (TrPAL) scores. This would be clinically meaningful,” explained Butts, who coauthored a comment on the trial, which appeared in the same issue of Lancet Oncology as the aforementioned article.2

Overall survival (OS) was also significantly better in those with nonsquamous histology, Butts wrote.

Therapeutic vaccine strategies, which have generated much excitement in the context of checkpoint inhibitor therapies such as nivolumab for the treatment of advanced melanoma, have not yet elicited benefit in patients with NSCLC. That may be because, unlike melanoma vaccines, they have not adequately addressed “immunosuppressive mechanisms employed by tumor cells to avoid T-cell recognition,” Butts explained.

“The success of the checkpoint inhibitors, which overcome negative or inhibitory signals on T cells, is proof of the importance of addressing tumor-induced immunosuppression,” he added.3

TrPAL Biomarker Meets Primary Endpoint

Lancet Oncology

In the phase II TIME trial, investigating TG4010 immunotherapy and first-line chemotherapy for advanced NSCLC, has found “encouraging results with improvements in outcomes and minimal toxicities. This vaccine strategy and the conditions of the phase III portion of the trial optimize the chance for successful T-cell stimulation,” wrote Butts.In the study, researchers put together a cohort 222 patients between April 2012 and September 2014. All patients in the study had newly-diagnosed stage IV NSCLC, and were randomized to either the novel vaccine, TG4010, combined with standard chemotherapy or placebo with standard chemotherapy. One requirement of the patients, ages 18 or older, was that they had to express the MUC1 mutation in at least half of their cancer cells and could not harbor an EGFR mutation, according to the article.

The vaccine, TG4010, is a modified vaccinia ankara expressing MUC-1 and interleukin-2. “MUC-1 provides the antigenic stimulus to induce a cellular response while the viral vector serves to potentiate the immune response. The role of interleukin-2 is to optimize presentation of antigen to T cells,” Butts wrote.

Additionally, the viral vector is designed to limit interleukin production to the injection site, which aids in reducing side effects, according to Butts.

The primary endpoint of phase IIb was the ability of a biomarker, consisting of CD16, CD56, CD69, and TrPAL, to predict improved PFS in patients who received the vaccine.

Although patients with reduced measurements of the biomarker did better, the same was not true of patients with higher quantities of TrPAL. The hazard ratio for PFS in patients with lower TrPAL measurements was 0.75 compared with 0.77 for those with high measurements of TrPAL.

“Previous studies suggested that the higher TrPAL patients actually did worse with vaccine and chemo versus chemo alone. This comparison suggests the high TrPAL patients are unlike to benefit from the vaccine, but don’t necessarily do worse,” explained Butts in an interview with OncLive.

Additionally, the researchers also conducted safety analyses in the intent-to-treat population. Grade 3 neutropenia was slightly higher in the vaccine group (26% vs 21%), as were injection-site reactions (33% vs 4%).


  1. Quoix E, Lena H, Losonczy G, et al. TG4010 immunotherapy and first-line chemotherapy for advanced non-small cell lung cancer (TIME): Results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial [published online December 22, 2015]. Lancet Oncology. doi: 10.1016/S1470-2045(15)00483-0.
  2. Butts C, Sangha R. TIME for a successful cancer vaccine in NSCLC? [published online December 22, 2015]. Lancet Oncology. doi:10.1016/S1470-2045(15)00554-9. Visited Jan. 15, 2016.
  3. Butts, C. TIME for a Successful Cancer Vaccine? Preliminary draft on file with the author.