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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Picoplatin for SCLC: Review of Data Presented at ASCO
Sun, 09/05/2010 - 10:07
Author
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

Here is the discussion about the study of picoplatin vs. placebo for relapsed SCLC, from the post-ASCO review that I did with Dr. Pennell. Unfortunately, this work was an overall disappointment, not quite beating placebo in a setting for which we already have a more active alternative. Here's the transcript and figures from that portion of the discussion.

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Dr. West: So we'll turn to the SPEAR trial. This is a small-cell study with picoplatin which has been one that has been on the radar for small cell for several years at this point. And this is a randomized trial, a 2 to 1 randomization, of patients who had previously received chemotherapy for extensive small-cell lung cancer, and this was for patients who had relapsed within six month,s with the thought being that the patients who actually progressed beyond six months would often get their prior chemo instead.

spear-trial-schema (click on image to enlarge)

So patients were randomized to picoplatin with supportive care or one third of patients getting supportive care alone, and the trial looked primarily at overall survival.

There was overall just a 4% response rate, most of those being partial responses, but there's more information in the waterfall plot as shown here -- on this, any bars that are falling down or directed downward below the horizontal line represent tumor shrinkage.

spear-trial-waterfall-plot-of-response

There were certainly some patients who were demonstrating tumor shrinkage that did not meet the criteria because of confirmatory scans or other criteria for an objective response. Nevertheless, the official response rate is 4%, with another 44% showing stable disease.

But the key endpoint was overall survival. So the curve on the right is the overall survival curve, which was not statistically significant and did show a slight increase. On that plot, the curve on top is with picoplatin, but it was not enough of a difference to achieve statistical significance with a P value of 0.08.

spear-trial-efficacy-curves

The progression--free survival which is actually shown on the left here was significant with a P value of about 0.03. In absolute terms, it wasn't a major difference, really just a matter of weeks, 6.6 weeks with supportive care versus 9 weeks with picoplatin.

Now, the authors or the presenters did look retrospectively at a couple of subsets and made the point that many of the patients did end up getting additional treatment afterwards: this was disproportionately patients who were randomized to supportive care alone, 42 % of whom got additional treatment compared with 28% of the patients on picoplatin getting additional treatment. And when you removed the patients who had received any additional chemotherapy, there was actually a statistically significant improvement in overall survival, and that's shown in set of curves on the left. That still in absolute terms amounts to about four weeks of a median survival difference.

spear-trial-with-retrospective-subset-analyses

They also looked at relapse within 45 days and saw the same kind of thing in a matter of weeks, but this unplanned subset analysis achieving statistical significance.

So, before we move on, what can we say about this? The trial was negative for what it was seeking to detect, which was an overall survival improvement against supportive care alone. There were certainly some grains of positivity that there is some activity to the drug. It did have some tumor shrinkage and there was some evidence, at least subsets of patients, of an improvement in overall survival. But I would have to say there was not a great deal of enthusiasm for this approach or this agent because the bar was rather low and in some people's mind, unacceptably low, in that we do have an established second-line therapy in topotecan which has been compared to supportive care and shown to confer a survival benefit in that setting. And the point has been made by other investigators that this in itself was questionable about comparing to supportive care, because we should no longer be doing that. And so even if there is some element of activity here, it's very questionable whether this represents anything better than what is already available.

Now, picoplatin is a platinum drug which has some at least theoretical and pre-clinical suggestion that it could reverse resistance to prior platinum exposure, but that really was not seen in any great way on this study. So overall it was marginally positive, but the overall consensus was that this was not impressive enough to necessarily merit being expanded into another study. Nate, do you have any additional thoughts on it?

Dr. Pennell: I think that it's incredibly disappointing that this was the most exciting presentation for small-cell lung cancer this year. There really is a dearth of anything promising that's come out in small cell over too long a time, and this certainly had some promise, but I have really nothing good to say about the results of this trial. It had an incredibly low bar to cross, as you said, going up against best supportive care, and especially since many of these patients are what we would consider to be chemotherapy-sensitive relapsed patients, who had relapse greater than 90 days after their initial chemotherapy, and approved drugs like topotecan might have response rates in the >20% range and a clear survival benefit compared to best supportive care in previous trials, and this couldn't even do that.

Putting aside for a minute the question of whether it was ethical to even put someone in best supportive care when you've got a drug that shows a proven survival benefit, I think this is just about as negative as it gets. So I wouldn't be too enthusiastic about testing this drug any further, at least not in the second-line setting like this. Maybe in first line as an alternative to other platinum drugs, it might be worth testing, but I'm not sure I would be enthusiastic about trying to put it up head-to-head against topotecan, which would be the only other real logical second-line trial to do.

Dr. West: Yeah, which is really the main question that we're facing: is this better than what we already have?

Dr. Pennell: Right.

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