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Dr. Jack West -The Immunotherapy Stimuvax on the START Trial


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The Immunotherapy Stimuvax on the START Trial: An Encouraging Signal from a “Negative” Trial

July 5th, 2013 - by Dr. Jack West

The START trial of the immunotherapy Stimuvax, which is also know as tecemotide or L-BLP-25, initially looked very favorable in a randomized phase II trial conducted several years ago. This early effort led to a subsequent phase III trial, conducted over the past few years, that administered Stimuvax or placebo on multiple occasions over two years after chemo and radiation for locally advanced (stage III) NSCLC. For more details on the background and the phase III START trial, check out this post on Stimuvax from the GRACE website in early 2007.

Since that time, the degree of anticipation around this drug and trial has been somewhat between hopeful and frenzied. Though oncologists specializing in lung cancer were guardedly optimistic about it, financial analysts and patient/caregiver communities sometimes became, in my view, irrationally exuberant about it, with some zealots of immunotherapy becoming convinced it was a “can’t miss” treatment long before the work had been completed.

Unfortunately, several months ago we learned that the START trial did not actually meet its primary endpoint of significantly improving overall survival with Stimuvax vs. placebo. Though I had no specific data and just this headline to go on, I felt that the key implication of what little we knew so far was that I wouldn’t “throw out the baby with the bathwater” and presume that all other immunotherapy-based work in lung cancer would follow the same fate.

It wasn’t until ASCO 2013, in early June, that we actually saw data from the trial, which made me conclude that a declaration of the trial as being simply “negative” didn’t do justice to the complexity of the results. Specifically, the START trial showed a modest, statistically non-significant 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). However, when looking at just the 65% of patients who had received their prior chemo and radiation concurrent (as is preferred for maximal opportunity for cure when patients can tolerate this more challenging approach than chemo and radiation delivered sequentially), the median overall survival was a striking 10.2 months longer in recipients of Stimuvax vs. placebo. See the figures below for details (you can click on them to enlarge).

Survival in Entire Population, START Trial

(To see the detailed graph, please click on the following link)

http://cancergrace.org/lung/files/2013/ ... -trial.jpg

Survival in Concurrent CTRT Pts, START Trial

(To see the detailed graph, please click on the following link)

http://cancergrace.org/lung/files/2013/ ... -trial.jpg

As these results were being conveyed, I considered the difference in overall survival in this large subset of patients on the trial to be rather remarkable — far from a complete strikeout. In fact, I found that 10.2 month difference in a subgroup comprised of 806 patients to be quite encouraging. That said , looking at the survival curves in the lower figure, it’s important to not that the curves happen to separate hugely in the middle (right where the median overall survival is measured, then converge again.

Unfortunately, this means that Stimuvax isn’t curing patients, which was our hope for potentially curable patients with locally advanced NSCLC. Instead, it seems more likely that 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”.

My understanding 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.

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