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The Ups and Downs of the START Trial with Stimuvax Immunotherapy

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One of the highest profile clinical studies over the last few years has been the START trial of Stimuvax, also known as L-BLP-25 or tecemotide, an immunotherapy that looked promising in a randomized phase II trial that led to a subsequent phase III trial that administered Stimuvax or placebo after chemo and radiation for locally advanced (stage III) NSCLC, as described more in this post about STIMUVAX and the START trial from early 2007.

Over the next five years, the level of anticipation over the trial was remarkable.  Though oncologists specializing in lung cancer were hopeful about it, financial analysts and patient/caregiver communities became exceptionally focused on the trial, many people becoming essentially convinced it was a “can’t miss” trial long before the trial was completed.

Unfortunately, we received news at the beginning of this year that the START trial failed to meet its primary endpoint of significantly improving overall survival with Stimuvax.  Without any specific information of results beyond this, I did a video post to address the implications of the negative START trial, primarily noting that a negative trial for Stimuvax doesn’t mean that other immunotherapies aren’t promising and won’t work. 

At ASCO 2013, we actually saw the data from the trial, which led me to question whether these results should be boiled down to just being considered “positive” or “negative”, effective or useless.  Specifically, the trial showed a modest, 3.3 month longer median overall survival in the 829 recipients of Stimuvax compared to the 410 recipients of placebo (the randomization was 2:1 for the active treatment), but there was a whopping 10.2 month difference in favor of Stimuvax recipients when the analysis was limited to the 65% of patients on the trial who had previously received their chemo and radiation concurrently, as opposed to sequentially.

Survival in Entire Population, START Trial

Survival in Entire Population, START Trial

 

Survival in Concurrent CTRT Pts, START Trial

Survival in Concurrent CTRT Pts, START Trial

When these data were presented at the ASCO meeting, I noted that a 10.2 month difference in overall survival is rather remarkable, even if it was a subset analysis (806 patients) of a larger trial. That’s quite far from a complete strikeout. In fact, I found it very encouraging. However, when you look at the survival curves in the lower figure, you can appreciate that the curves just happen to separate hugely in the middle, then converge by 4 years out.

Unfortunately, this means that Stimuvax isn’t curing patients, which is what we really hoped might happen. Instead, a subset of patients may be doing better for a few months, but it’s not converting more potentially curable patients from “not cured” to “cured”.

Word on the street is that Merck KGA, the company developing Stimuvax, or tecemotide, is planning a START trial redux that only enrolls patients who received concurrent chemo/radiation. We don’t know why the results seem to be different and more favorable in these patients, but this is the preferred and more curative treatment approach, so there may be some significant difference by which the locally advanced NSCLC patients who are good candidates for concurrent chemo/radiation truly benefit from this immunotherapy. However, even if a subsequent trial shows a survival difference, it will be important to clarify whether this therapy is actually curing patients who wouldn’t otherwise be cured or “merely” prolonging survival for several months. The latter is still a helpful development, but it’s not as valuable as curing more patients with lung cancer.


4 Responses to The Ups and Downs of the START Trial with Stimuvax Immunotherapy

  • ssflxl says:

    Dr. West

    Thanks for this info. I agree with your comment/thinking. Nowadays, we need to get away from the black and white since there is a lot of gray out there. I thought there was some talk of redefining endpoints for immunotherapy as it is quite different from the standard chemo. Even if it’s not the cure that everyone hoped for, it is still another tool available for us with this treacherous cancer. This may be useful if the side effect is much easier than the routine chemo.

    thanks so much

    ssflxl

  • mikey says:

    The number of patients out to 4 and 5 yrs is small. The trial started in early 2007 with ~100 pts enrolled by late 2008. The data presented appears to be from analysis done mid-last year.

    The number of placebo to BLP25 patients out at 4 and 5 years looks rather small.

    Is it possible that the data out 3+ yrs is not mature and that it is difficult to make a conclusion on the long-term effects? In addition, the trial was interrupted by a hold where quite a large number of patients missed continuously therapy with BLP25. Could this hold have impacted the survival?

  • Dr West says:

    I think those are both fair points. However, I think the key point from START is that the results aren’t sufficient to get it approved, but they are promising enough to warrant a subsequent trial, ideally one that gives the exact same treatment, including the immunostimulants given along with Stimuvax, to both arms (I believe that in START, only the Stimuvax arm received the immunostimulant also known as “adjuvant”, a different meaning for the same term we use for “post-operative” therapy, but signifying “helper” in both cases), except for placebo substitution for Stimuvax.

    The issues you note could modify what our level of enthusiasm or optimism should be about this trial, but I think in the end, it’s definitely not enough to adopt the approach, but it’s favorable enough to warrant further study.

    -Dr. West

  • hopey5000 says:

    Good analysis Dr. West. Many of the studies focus on subsets of patients. The initial studies on Iressa were unimpressive until the subset of EGFR positive patients were separated. One is concerned that companies periodically try to generalize studies to provide a larger market for their product, instead of limiting the results to the subset who truly benefit.

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