The PointBreak Trial: Boiling results down to four key point

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The PointBreak Trial: Boiling results down to four key points.

September 8th, 2012 - by Dr. Jack West

http://blog.lungevity.org/2012/09/08/pointbreak/

This year at the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology that’s just ending, one bit of new information was the presentation of the long-awaited PointBreak study. Specifically, the trial pitted Alimta (pemetrexed)-based first line and maintenance chemo against the well-established standard first line and maintenance therapy regimen. It randomized 939 first line advanced non-squamous NSCLC patients either 4 cycles of the “Patel regimen” of carboplatin/Alimta/Avastin (bevacizumab) followed by maintenance Alimta/Avastin (as studied in the early study, led by Dr. Jyoti Patel, that piloted the combination) or 4 cycles of the “Sandler regimen” from the ECOG 4599 trial that established the superior survival for this strategy over chemo alone, of carbo/Taxol (paclitaxel)/Avastin followed by maintenance Avastin.

The primary objective of the trial was to demonstrate significant superiority in terms of overall survival (OS) for the Patel regimen with Alimta compared with the Sandler regimen with Taxol. While the trial failed in that regard, it did provide what I would consider to be four valuable conclusions.

1) Patients did marginally better on the Patel regimen while they were receiving first line therapy. I don’t want to overstate it, because the differences are truly minimal, but as you can see from the curves below, the progression-free survival (PFS) is a little better for the Alimta-based regimen. Admittedly, however, with a median PFS difference of two weeks (6.0 vs. 5.6 months, hazard ratio 0.83) and really no difference in objective response rate (34% vs. 33%), I wouldn’t go so far as to call this a clinically significant difference.

2) Overall survival was completely overlapping between the two regimens. As shown in the figure below, the OS curves for the two arms travel together and just cross over each other multiple times. One may beat the other numerically at a single point in time, but the only trend is that they really travel together.

3) Despite the widely held perspective that the Alimta-based chemo combination is especially well-tolerated, the side effect profiles of the two regimens also didn’t demonstrate a clear winner. In my mind, even without showing a significant survival difference, I would say that the Alimta arm could have demonstrated some superiority for showing equivalent efficacy with notably lower side effects. That didn’t happen. As expected, there was more neuropathy and hair loss with Taxol, but the Alimta arm showed a little more of a drop in blood counts with Alimta. Overall, even the side effect profiles appeared more similar than different and failed to declare a “secondary winner”

4) You can make the argument that the Alimta/Avastin combination was superior to Avastin alone in the maintenance therapy component of the trial. In keeping with the results from the AVAPERL trial that revealed significantly superior PFS (and OS not reported out yet) for maintenance Alimta/Avastin vs. Avastin alone after first line cisplatin/Alimta/Avastin, both PFS and OS are longer (by 1.7 and 2.0 months, respectively) when restricting our review of results only to the 63% of patients who went on to maintenance therapy (the others dropping off because of progression, prohibitive side effects, or other complications), as shown in the figures below. This was a pre-specified question that the investigators wanted to address, though it wasn’t the main question of the trial. In real life, when we’re making recommendations about what treatment to start with, we can’t know which patients will do well through first line chemo and which ones won’t.

Despite the difference in efficacy of maintenance therapy, at the end of the day, there wasn’t a significant difference in overall survival when you add in the patients who dropped off before maintenance. And then, there is an equalizing effect from post-trial subsequent therapies, though less than 2/3 of patients received further therapy, when these are patients we’d have really generally hoped and expected should have received further treatment (in trial after trial, we consistently see fewer patients received with second line and later systemic therapy than oncologists believe they’re treating). Patients assigned to the Alimta arm were significantly more likely to get Taxotere (docetaxel) afterward, and patients assigned to the Taxol arm were significantly more likely to get Alimta afterward (as you’d expect).

So what does it all mean, at the end of the day? Over the past few years, many lung cancer experts (including this one) have tended to favor carbo/Alimta/Avastin over the established ECOG 4599 trial regimen because we felt it was extremely likely to be at least as good if not significantly better than the carbo/Taxol/Avastin regimen. Indeed, it was just as good, but the PointBreak trial disabuses us of the notion that it might be significantly better, even with the advantage of giving what truly appears to be a more effective maintenance therapy with the Alimta/Avastin combination. At the same time, many of us who treat lung cancer patients every time might have estimated that there would be significant advantage in terms of side effects for the Alimta regimen compared with the Taxol regimen. The actual evidence doesn’t support that conclusion either.

With the dust settling now, I’d say that the PointBreak trial leaves us with the idea that it’s appropriate to continue to do exactly what you’ve been inclined to do. Some people will value the Alimta regimen because of the much lower risk of neuropathy and hair loss, while others will favor Taxol as being well established, considerably less expensive, and achieving results completely comparable to the carbo/Alimta/Avastin regimen overall. You can make a good argument that for patients who get as far as the maintenance portion, patients are better served by the Alimta/Avastin combination than Avastin alone, and that remains my preference, though we can also look forward to getting a more direct test of maintenance therapy strategies from the ongoing important ECOG 5508 trial.

I think a leading question now is whether insurers will use the results to justify refusing to pay for the more expensive Patel regimen when the evidence indicates that patients can experience the same survival with the less expensive Sandler regimen. We’ll have to see how our pre-authorizations change in the next few months.

Do these results lead you to feel comfortable with either regimen, or do you clearly favor one? If you had to pay more to receive the Alimta-based regimen, would you accept a significant co-payment to cover the difference?