MAGE-A3 trial miss points to finding the right patients

MAGE-A3 is, if not dead, very nearly so. GlaxoSmithKline’s cancer vaccine has missed two of its three primary endpoints, failing to prolong disease-free survival in either the overall population in the 2,200-patient Magrit study or in a subset of chemotherapy-naïve patients.

Glaxo is continuing the study in hope of identifying a group of patients that will benefit from the vaccine, but any effect will have to be pretty spectacular to permit the company to file. In any case, if the largest-ever trial of a cancer vaccine (see table) cannot find an overall signal, it is worth wondering whether bigger is always better.

Magrit: ceci n’est pas une win

All is not necessarily lost: the lack of any new therapies for non-small cell lung cancer might cause regulators to look favourably on MAGE-A3 if a population of responders can be identified. And the fact that Glaxo prespecified the responder hunt as the third study endpoint means accusations of data mining would be somewhat unjust.

The Magrit failure is not MAGE-A3’s first. The vaccine crashed out of a 1,349-patient study in melanoma six months ago (Glaxo’s cancer vaccine trips at first phase III hurdle, September 5, 2013). Here, too, Glaxo responded by drilling into subgroups in search of responders.

Results of the quests for responders in both trials are expected in 2015, Glaxo says.

As more cancer vaccine trials flare and fail it is becoming apparent that companies might do better by identifying those patients most likely to respond beforehand. “That’s one of the things that everyone’s looking much harder at nowadays,” Paul Higham, chief executive of the cancer vaccine developer Immatics, told EP Vantage. “It’s not always easy to identify up front who’s going to respond and who isn’t, but most of the late-stage studies, including ours, are looking really extensively at biomarkers.”

Still, EvaluatePharma’s Clinical Trials module lists seven cancer vaccine studies that have enrolled more than 1,000 patients. Many of these were initiated before the true importance of stratifying patients had come to light, and their sponsors could find that they end up with the same needle-in-a-haystack problem as Glaxo.

“Over the last 12-18 months we’ve seen a lot of new advances and new understanding, and it’s becoming clear that some of the approaches that are generating late-stage results were put in place before that understanding was there,” Mr Higham says.

Bigger and better? The 10 largest late-stage cancer vaccine trials
Company Project Indication Pharmacological Class Enrolment Trial name and ID
GlaxoSmithKline MAGE-A3 Non-small cell lung cancer Anti-MAGE-A3 vaccine 2,278 Magrit
Merck KGaA Tecemotide  Non-small cell lung cancer Anti-MUC1 vaccine 1,513 Start
GlaxoSmithKline MAGE-A3 Melanoma Anti-MAGE-A3 vaccine 1,351 Derma
Bavarian Nordic Prostvac Prostate cancer Anti-PSA vaccine 1,200 Prospect
PT Kalbe Farma, RECOMBIO,
Laboratorio Elea, CIMAB
Vaxira  Non-small cell lung cancer B-cell lymphoma vaccine 1,082 NCT01460472
CK Life Sciences POL-103A Melanoma Melanoma vaccine 1,059 Mavis
Transgene TG4010 Non-small cell lung cancer Anti-MUC1 vaccine 1,000 Time
NewLink Genetics HyperAcute Pancreas Pancreatic cancer Cancer vaccine 722 Impress
Galena Biopharma NeuVax Breast cancer Anti-HER2 (ErbB-2) vaccine 700 Present
Celldex Therapeutics CDX-110 Glioblastoma multiforme EGFr cancer vaccine 700 Act IV

Size doesn’t matter

Immatics has already made progress in identifying response biomarkers in phase II trials of its renal cell carcinoma vaccine, IMA901. A phase III study is now ongoing in 340 patients with the aim of validating the biomarkers, though this goal is secondary to proving the vaccine’s efficacy. The trial’s relatively small size is due principally to the nature of the indication – RCC is rarer than NSCLC and the patients die more quickly, Mr Higham says.

The Glaxo failure is a disappointment for other developers in this space, Mr Higham says. “I’m hoping that these results don’t cast a dark shadow over the rest of cancer immunotherapy.”

Cancer vaccines have been under development for over a decade, but the class has yet to see a true success. Pre-emptive patient selection could be the key to conducting a successful phase III trial.

Perhaps even a lung cancer vaccine could be trialled in 400 patients – if, of course, they are the right 400 patients.

To contact the writer of this story email Elizabeth Cairns in London at [email protected] or follow @LizEPVantage on Twitter

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