Second Phase III flop for GSK's cancer vaccine
This article was originally published in Scrip
GlaxoSmithKline MAGE-A3 cancer vaccine has failed to meet two co-primary endpoints in a second Phase III trial.
The MAGRIT trial, in non-small cell lung cancer (NSCLC) patients, did not significantly extend disease-free survival (DFS) when compared to placebo in either the overall MAGE-A3 positive population (first co-primary endpoint) or in those MAGE-A3-positive patients who did not receive chemotherapy (second co-primary endpoint).
GSK said it remained blinded to the overall trial data from the analysis of the first two co-primary endpoints to allow for the unbiased generation of a mathematical model to assess the third co-primary endpoint.
MAGE-A3 failed to meet the one co-primary endpoint in another Phase III trial, DERMA, in melanoma patients last year (scripintelligence.com, 5 September 2013).
GSK is continuing the DERMA trial until a second co-primary endpoint is assessed. This endpoint, DFS in the gene signature positive sub-population, is designed to identify a subset of MAGE-A3 positive patients that may benefit from the treatment.
GSK will also continue the MAGRIT trial in order to assess a third co-primary endpoint. This endpoint is also designed to identify a subset of MAGE-A3 positive patients that may benefit from the treatment.
Data on the remaining endpoints from the DERMA and MAGRIT trials are expected in 2015.
"We are disappointed that the trial did not demonstrate a benefit for overall MAGE-A3 positive patient population, but we remain committed to the effort to identify a sub-population of NSCLC patients who may benefit from this investigational treatment," said Vincent Brichard, senior vice-president and head of immunotherapeutics, GSK Vaccines.
GSK's stock price was not unduly troubled by the news. However, the same could not be said for the US biotech Agenus whose QS-21 Stimulon adjuvant forms part of MAGE-A3 as a component of GSK's adjuvant system AS15. Its shares dropped 12% to $3.76 in pre-market trading (20 March).
'not a surprise'
"I'm not surprised that MAGE-A3 failed to meet the primary endpoints in the larger study population, because earlier Phase II data did not show a significant reduction in the risk of recurrence after surgery compared to placebo in the adjuvant setting," Datamonitor Healthcare analyst Michael Haydock told Scrip. "It's important to note that this news doesn't signal the end for MAGE-A3 yet. Its future now hangs on whether it is effective in patients possessing the pre-defined gene signature that is a predictor of response to MAGE-A3. If so, then the company will still seek approval of MAGE-A3 as an adjuvant for this smaller subgroup. Although this would limit the target population, the vaccine would likely see strong uptake in that particular niche."
Immatics Biotechnologies is a German cancer vaccine developer that recently raised a €34m in a series D financing round and signed a broad oncology deal with Roche for which it received $17m up front and potential milestones of more than $1bn (scripintelligence.com, 15 October 2013; 13 November 2013). Its CEO Paul Higham had this to say to Scrip about the latest news from GSK: "We are of course disappointed that GSK's MAGE-A3 failed to show benefit on the first two co-primary endpoints of this pivotal study. However, the field of immunotherapy has advanced very rapidly in recent years, as we saw at ASCO. The depth of understanding is increasing all the time and, in our view, it's becoming increasingly clear that targeting the right antigens is crucial for developing a successful immunotherapeutic approach, whether it is cancer vaccines, soluble T-cell receptors or monoclonal antibodies."
Immatics uses a multi-antigen approach for its cancer vaccines. Its lead product IMA901, which is in a Phase III trial, is a cancer vaccine made up of 10 different tumor-associated peptides (TUMAPs) that are over-expressed in the majority of renal cell carcinomas (RCC). "As is the nature of drug development, some immunotherapies will fail but ultimately we are, along with many others, optimistic the area will achieve its potential," said Mr Higham.
MAGRIT details
MAGRIT, a randomized, double-blind, placebo-controlled trial, is evaluating the efficacy and safety of MAGE-A3 in Stage IB, II and IIIA completely resected NSCLC patients whose tumors expressed the MAGE-A3 gene. Patients were given up to 13 intramuscular injections of either the MAGE-A3 immunotherapeutic or placebo over a period of 27 months.
MAGE-A3 is a tumor-specific antigen expressed in a variety of cancers but not in normal cells. In NSCLC, it is expressed in approximately one third of tumours in patients diagnosed with Stage IB-IIIA disease. The MAGRIT trial enrolled 2,312 MAGE-A3-positive patients across more than 400 sites in 34 countries worldwide.