Lung Cancer Vaccine Improves Progression-Free Survival

Janis C. Kelly

October 26, 2011

October 26, 2011 — A phase 2b study has found that adding TG4010, a new cancer vaccine, to standard platinum-based chemotherapy slows the progression of advanced nonsmall-cell-lung cancer (NSCLC), compared with chemotherapy alone. The study, by Elisabeth Quoix, MD, and colleagues, was published online October 22 in the Lancet Oncology.

Dr. Quoix, who is from Université de Strasbourg, France, told Medscape Medical News that the study was not designed to "show any difference in progression-free survival between the control arm and the experimental arm, but to demonstrate whether progression-free survival at 6 months was observed in more than 30% of patients. This end point was achieved and the study is positive.... In the coming [phase 3] study, there will be a proper comparison of progression-free survival between the experimental (chemotherapy + vaccine) and the control group (chemotherapy alone)."

TG4010 is a novel therapeutic vaccine designed to stimulate an immune response against the MUC1 protein, with the aim of activating the body's own immune system to attack and destroy cancer cells. The MUC1 protein is altered and produced in excess by tumor cells in advanced lung cancer and several other cancers. Around 60% of NSCLCs overexpress MUC1.

The phase 2b study was designed as a 1-stage trial with an inactivity cutoff of 30% and an activity cutoff of 50%. To reject the null hypothesis (that TG4010 has no effect), at least 40% of patients in the TG4010 group had to be progression-free at 6 months; this end point was met. TG4010 will now move forward in phase 3 trials. In March 2010, Transgene S.A. signed a billion-dollar licensing agreement with Novartis for the commercial development of TG4010 if it gets through phase 3 testing. Transgene S.A., the manufacturer of TG4010, funded the phase 2b study.

Improved on Chemotherapy

Dr. Quoix and colleagues enrolled 148 chemotherapy-naive patients with advanced MUC1-expressing NSCLC from 23 centers in France, Germany, Hungary, and Poland. Patients were assigned to either combination TG4010 plus cisplatin and gemcitabine (n = 74) or chemotherapy alone (n = 74; control group).

At 6 months, progression-free survival was 43% in the combination group and 35% in the control group (P = .307); the response rate was 41.9% and 28.4%, respectively (P = .082). The combination regimen was particularly effective for patients with normal numbers of activated natural killer (NK) cells (triple-positive CD16+CD56+CD69+ lymphocytes that can either stifle or intensify immune responses). In patients with normal activated NK levels at baseline, adding TG4010 to gemcitabine/cisplatin increased 6-month progression-free survival from 37.7% to 56.3% (P = .065), the response rate from 28.3% to 54.2% (P = .0008), and median overall survival from 11.3 to 17.1 months (P = .062).

Jean-Marc Limacher, MD, chief medical officer at Transgene S.A., explained that the primary objective of this study was to show that adding the vaccine to chemotherapy increased 6-month progression-free survival beyond the expected 30%. "With 43.2% of patients progression-free at 6 months, it is significantly different from 30% (P = .01), and therefore the study end point is achieved and the study outcome is positive. This was a phase 2, not a comparative phase 3, study, and the main role of the control arm was to ensure that there was no bias in recruitment. Having a control arm allows for additional exploratory comparisons between arms, but the study was not powered to observe significant differences between arms. The main conclusions for the whole study population are that the study achieved its primary end point based on 6-month progression-free survival and that the addition of the vaccine showed encouraging signs of improvement on other efficacy metrics," Dr. Limacher said.

Subgroup analyses showed that the vaccine improved 6-month progression-free survival, response rate, median time to progression, and overall survival in patients with normal levels of activated NK levels, generating the hypothesis that stratification for CD16/CD56/CD69 might be a useful biomarker in testing agents like TG4010. Dr. Limacher noted that since the suspected mechanism of the NK effect is not specific to TG4010, this parameter should be considered in clinical trials testing other cancer vaccines, especially those based on viral vectors. Dr. Limacher noted that frozen peripheral blood mononuclear cells retained from previous vaccine trials might should be checked for CD16/CD56/CD69 status, on the chance that potentially useful vaccines might have been missed because of this effect.

Dr. Limacher said that the phase 2b/phase 3 study will begin accrual in a few weeks and that the researchers expect to report data from the phase 2b part of that trial in 2013.

Tumor vaccine expert Angus G. Dalgleish, MD, from St. George's University in London, United Kingdom, reviewed the study for Medscape Medical News. "I have analyzed other therapeutic cancer vaccine trials for biomarkers and noted that the only thing that nonresponders have in common is anti-inflammatory markers. There is no one magic [biomarker]; the activated NK marker reported here is a unique observation." Dr. Dalgleish said. "What matters is that inflammatory phenotypes can drown out a vaccine response, and they need to be excluded, which is why I have a team working on the ideal combo of markers!"

The study was supported by Transgene S.A. Dr. Quoix reports having an advisory role for Transgene, Eli Lilly & Co., and Roche. Dr. Limacher is a Transgene S.A. employee. Dr. Dalgleish reports having an advisory role for Transgene S.A.

Lancet Oncol. Published online October 22, 2011. Abstract


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