Though there are many presentations to discuss in the wake of ASCO, we'll need to pace ourselves on these. I and some of the other faculty members will offer thoughts on some of these in the coming weeks, and we also have our upcoming post-ASCO review on June 23rd (click here to learn more and sign up for this free online program).

Today we saw the results of a couple of long-awaited trials of treatment approaches that represented a couple of the more promising concepts for moving forward in our treatment of extensive SCLC, and I'll cover the first of these today (though only with the benefit of my notes, rather than as many details as I'd like, so these comments are subject to revision and added details later). Amrubicin has been the subject of some prior discussion here, but that discussion focused on smaller, phase II trials; we've needed the results of a randomized phase III trial that directly compares the chemo agent amrubicin as a single agent to our current standard for Hycamtin (topotecan). The ACT-1 trial in enrolled 637 patients with extensive disease SCLC who had all received first line therapy and then relapsed -- the trial included patients who had a "sensitive" relapse, 3 or more months after prior chemo had ended, as well as "resistant" relapse, which is marked by progression within 3 months of prior chemo ending (pretty evenly split at nearly 50/50 on the trial). Patients were randomized 2:1 to either amrubicin at 40 mg/m2 IV on days 1-3 of a 21 day cycle, or topotecan at 1.5 mg/m2 IV days 1-5 of a 21 day cycle.

One of the many challenges of topotecan is that the FDA-approved dose and schedule is very difficult for us to actually deliver, so it wasn't surprising to see that fewer patients on amrubicin required a dose reduction, and that the "dose intensity", the proportion of drug actually delivered vs. reduced due to dose reductions, was higher with amrubicn (93% vs. 87%). At the same time, severe drops in the blood counts, especially anemia and low platelet counts (thrombocytopenia), were less common with amrubicin. But the crux of the presentation was efficacy, which was frankly disappointing in light of the very promising leads we'd seen with amrubicin: the median overall survival (OS) was 7.5 months with amrubicin vs. 7.8 months with topotecan, while median PFS was also very comparable between the two arms (4.1 vs. 4.0 months). Because the trial was looking for a significant survival benefit, this is considered a negative trial, but I think there were some encouraging findings that would still lead me to welcome the opportunity to use this agent in SCLC.

Specifically, though we don't have the curves to show right now, the OS and PFS curves show that further out in time, the curves do separate and favor the arm that received amrubicin -- for instance 18 month OS was 16 vs. 9%, and there were a few patients who went out to a year or more on amrubicin without progression, compared with essentially none on the topotecan arm. The response rate with amrubicin was also significantly higher than with topotecan (31% vs. 17%, p = 0.0002). And along with the significantly lower incidence of some side effects with amrubicin (related to blood counts and need for red blood cell transfusions), the amrubicin recipients had less symptom worsening than the topotecan arm -- though it's not clear whether this is really because of better control of the cancer-related symptoms with amrubicin or less significant cumulative side effects with amrubicin. I don't think it matters though, if people feel a little better and do as well or better with the new agent.

So in summary, while disappointed with the lack of a progression-free survival or overall survival benefit, I was more favorably inclined toward amrubicin than I thought I'd be, going into the presentation. Dr. Bonnie Glisson, a SCLC expert at MD Anderson who has the dubious honor of providing the commentary on the negative trials on SCLC just about every year, made the point that topotecan was approved for 2nd line treatment of SCLC on the basis not of improved efficacy compared with an older regimen called CAV, but rather because it was associated with better quality of life/symptom profile with the same survival. I reflected as well that Alimta (pemetrexed) was approved as second line treatment for advanced NSCLC not based on superiority compared with Taxotere (docetaxel), but rather identical efficacy and what was actually a rather minimal improvement in side effects (primarily blood related, rather than symptom-related). In fact, most patients and caregivers do seem to find Alimta notably more manageable/less unpleasant than Taxotere, I'd say, but when you go back and look at the head to head comparison, it doesn't show real differences in side effects other than those related to blood counts and need for transfusions. And yet, Alimta was not only approved by the FDA but became the clearly favored choice for second line therapy (at least for patients with non-squamous NSCLC -- the finding that Alimta is only active in patients with non-squamous NSCLC was clarified in the years after this trial was reported).

There are definitely some important differences -- most notably, that the Alimta vs. Taxotere trial was specifically designed as a non-inferiority trial that was statistically "positive", while the amrubicin trial was looking for a significant benefit but failed to achieve that and is therefore, technically "negative". But at the end of the day, we have a drug that has activity at least as good as one that is far from beloved as our leading option for relapsed SCLC, with several hints of modest superiority, a (modestly) more favorable side effect profile, slightly better quality of life measurements, and is given over 3 instead of 5 days in the infusion center every three-week cycle. It makes me want to feel a little more charitably disposed towards amrubicin: overall, I'd prefer to use it for my own patients over topotecan if I had the choice.

But Dr. Glisson also concluded that these results wouldn't likely be enough to lead to an FDA approval. I believe she's right, so for now, that option isn't available to me or my relapsed SCLC patients.