Following in the path of other cancer vaccines that have already lived up to low expectations, Stimuvax has been revived to try again. Merck KGaA (OTCPK:MKGAY) made the surprise announcement today that it would put the project, now called tecemotide, through another large phase III trial to try and replicate results that had emerged in a subgroup of the failed Start study.
That subgroup generated some intriguing data; at 800 patients strong investigators called it the largest clinical trial conducted in stage III non-small cell lung cancer patients in its own right, and the only one to demonstrate a significant survival benefit. A specific chemo-radiation regimen appears to have produced much stronger responses; Merck now needs to work out whether the presence of tecemotide contributed anything to the effect.
Start tested tecemotide (also known as L-BLP25) in a maintenance setting, enrolling patients with unresectable, locally advanced stage III NSCLC who had stable disease after at least two cycles of platinum-based chemo-radiotherapy. They were then treated with either tecemotide or a placebo, to see if the immunotherapy would prolong survival. Five-year survival for patients with lung cancer at this stage is 10-25%.
The trial was an unequivocal failure overall – median overall survival was 25.6 months for patients in the tecemotide group compared with 22.3 months for those on placebo (p=0.123).
However the initial chemo-radiotherapy given as standard of care in this setting can vary, and Merck had stratified patients getting two different regimens – those who received chemotherapy and radiation concurrently, or those who received them sequentially.
Patients who received the therapies concurrently seemed to respond much more strongly to tecemotide, living 10 months longer than those in the placebo group – a post-hoc analysis revealed a median overall survival of 30.8 months compared with the placebo group’s 20.6 months (p=0.016).
This subgroup represented a big proportion of the total recruited – of the 1,239 patients enrolled into the study, 806 had received concurrent chemo-radiotherapy.
Hence the decision to run Start2, which will look almost identical to Start1, but enroll only patients who have received the concurrent regimen. The FDA has agreed a Special Protocol Assessment for the study, and Merck says it has received advice from the European Medicines Agency.
Explaining the response
Merck does not why this subgroup seemed to respond much more strongly to tecemotide.
Although the project is a MUC-1 antigen-specific immunotherapy, the pivotal studies have not recruited or stratified patients based on their MUC-1 status. A spokesman for Merck could not confirm whether this would be different in Start2, saying only that the company would be seeking to understand the immunological response and look for potential predictive biomarkers.
Charles Butts, a clinical investigator for the Start trial who presented the study at Asco earlier this year, put forward a couple of possible explanations at the time.
While chemotherapy and radiotherapy have long been considered immunosuppressive, it is now thought that in certain cases, and depending on how they are given, they can be immune-potentiating. It has been hypothesised that some chemotherapies and radiation given together produce a more inflammatory or immunogenic type of cell death and therefore might be more susceptible to an immune-mediated response, although this remains to be proven.
Dr Butts also said patient selection might be a simpler explanation. Those who get selected for sequential chemo-radiotherapy are not really being treated with curative intent, he said. It is widely believed that immunotherapies are likely to work better in relatively healthier patients, and those are the patients being given concurrent chemo-radiation.
Start2, which will recruit 1,000 patients, will be a big enough trial to determine whether tecemotide can indeed add anything to this chemo-radiotherapy regimen. Currently, there are no further options once patients stop responding to this treatment. So should tecemotide manage to replicate the Start1 finding, a 10-month prolongation of life would be considered a big step forward, particularly as it does not appear to add any toxicity or tolerability issues.
Although the subgroup on which this decision is based was large, many will still consider this a risky basis for further study. Some investors thought it was a risk worth taking: shares in Oncothyreon (ONTY), which licensed the drug to Merck and saw its valuation more than halve on news of the Start failure, were trading 22% higher this morning at $2.19; Merck KGaA stock was little changed. But, in the meantime, tecemotide will struggle to shake off the stain of past failure.