GRACE :: Lung Cancer

PFS vs. pfs: Why Progression-Free Survival Remains Controversial in Lung Cancer

Last year, an article came out in the Journal of Clinical Oncology that noted a gradual shift away from the “hard endpoint” of overall survival (OS) for lung cancer trials toward progression-free survival (PFS), a “softer endpoint” that is much more subject to interpretation.  The analysis also noted that many of the trials that were technically negative for the primary endpoint, the prospectively defined emphasis of the trial, were written up as if they were positive, highlighting a secondary endpoint that looked favorable, or a subset of patients who demonstrated a more favorable result than was seen in the overall trial population.

The accompanying editorial implied that this shift represented a regrettable relaxing of appropriate standards, but I actually didn’t and don’t see it that way.  First, we’ve seen that some trials haven’t reported on survival because patients were responding and continuing without progression for so long that it was self-obvious that survival was improving.  For instance, the US FDA approved XALKORI (crizotinib) back in August, 2011 for ALK rearrangement-positive patients, based on the terrific results in a single-arm, phase I/II trial that showed that nearly two thirds of patients had significant tumor shrinkage and that the median PFS was in the range of 8-10 months. Both of these results were about twice what we would expect from standard chemotherapy regimens.  It wasn’t until several years later that we saw the definitive evidence that XALKORI was superior to chemotherapy in terms of OS. How many ALK-positive patients would have been denied this clearly beneficial therapy over the additional 3 years just so that we could run a randomized trial that is the equivalent of running a trial to confirm the value of parachutes for people falling out of an airplane (technical term — “gravitationally challenged”)?  Most of the lung cancer community rightly considered XALKORI the clear standard of care in the first line setting without waiting for the subsequent trial to prove a survival benefit, because the conclusion was already self-evident based on a profound PFS benefit.  The FDA has actually just put out a new document noting that they will continue to consider approving drugs for lung cancer based on secondary endpoints like PFS.

Back in 2000-2005, there was much more reason to question the value of PFS as an independent and predictive endpoint.  Before trials with targeted therapies, the magnitude of PFS differences that you’d see between two arms of a trial was usually only up to 1.5-2 months. If that isn’t accommodated by at least as much of an improvement in OS, it’s hard to get excited about that. Yes, patients can argue that a few extra weeks before being told that their scan looks worse is valuable, and while that’s justifiable for drugs that don’t cost $5000-10,000/month or more, it’s fair for society to expect much more compelling value for cancer drugs when everyone ends up sharing the cost burden by paying taxes or rising insurance premiums.  On the other hand, I have firmly believe that seeing a PFS of more than 6 months in a randomized trial of Tarceva (erlotinib) with or without Avastin (bevacizumab) in favor of the combination is very clinically meaningful and predicts for a high probability of a survival benefit with additional follow up.   Imagine having two homes for sale that are next door to each other, very comparable, but one is in a color you clearly prefer and one is a less preferred color. Does color matter? Yes, and if they cost the same, you should jump at this minor factor. But if the home in your preferred color costs 25% more, it’s absolutely not worth it. It’s a very minor factor. On the other hand, if the color of the home also correlated with something that really matters, such as if the home in the color you prefer was also bigger and much nicer, it’s clearly worth paying the 25% premium.  

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The Immunotherapy Cola Wars

It’s been a big week for immunotherapy for lung cancer. Right on the heels of a press release that the PD-1 inhibitor Opdivo (nivolumab) significantly improved survival for patients with advanced non-squamous NSCLC, my friend Dr. Garon from UCLA presented results at the American Association for Cancer Research conference with another PD-1 inhibitor, Keytruda (pembrolizumab). These results are from phase I trial of this agent given at different doses and schedules to patients with advanced NSCLC, either squamous or non-squamous, most but not all patients having received prior chemotherapy, coincident with the online publication of the results in the New England Journal of Medicine.  Taken together, the entire population demonstrated an objective response rate of 19.4% and median overall survival (OS) of 12 months, median progression-free survival (PFS) of 3.7 months. These numbers are not especially impressive, though the median duration of response (DOR) in responders was a little over a year (12.4 months). 

What was most impressive here were the results in a subset of a little more than a third of the patients with tissue testing that showed a high proportion of the protein PD-L1, which is a key mediator of immune system activation vs. suppression. In that subpopulation with at least 50% of their tumor cells staining for PD-L1, the response rate was 45.2%, compared with 16.5% for patients with lower but detectable PD-L1 expression (on 1-49% of tumor cells) and 10.7% for patients <1% of tumor cells positive for PD-L1 expression. OS and PFS also appear to be higher for the high PD-L1 expression subgroup. 

These are very encouraging results, to be sure. But as we are now clearly entering an era where we have multiple immunotherapies for overlapping clinical settings, it’s time to ask whether these agents really provide meaningful differences if given to the same patients, or are the differences truly marketing differences of segmenting markets for remarkably similar treatments. Are we really just seeing results for Coke and Pepsi, perhaps with a newly created “Pepsi Generation”? 

Soda choices


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Immunotherapy Opdivo (Nivolumab) Non-Squamous NSCLC Trial Stopped, Reported as Positive

In January, 2015, the CheckMate 017 trial of the immune checkpoint inhibitor Opdivo (nivolumab) versus the standard chemo agent Taxotere (docetaxel) as second line therapy for patients with advanced squamous NSCLC was reported in a press release to be positive for a significant improvement in overall survival. No further details were offered at that time, but additional data were submitted to the FDA just days before the FDA approved Opdivo on March 4, 2015 and made it commercially available for these patients (with the FDA deserving credit for seemingly waiting in a conference room to go through an immediate approval process once the full data was supplied). We have since learned that Opdivo was associated with a significant, 3.2 month improvement in median overall survival, 9.2 vs. 6.0 months, but additional data await presentation at the annual ASCO meeting in Chicago in late May/early June.

Bristol-Myers-Squibb  (BMS) ran a parallel trial called CheckMate 057, also directly comparing Opdivo to docetaxel as second line therapy for patients with non-squamous NSCLC, which comprises about 75-80% of NSCLC patients in North America.  That trial completed enrollment around the same time as the squamous trial, but no results were forthcoming until this week, when a press release from BMS noted that an interim data review from this trial has demonstrated a significant survival benefit again for Opdivo — with no additional data offered yet. 

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Lung Cancer Immunotherapy Q&A

Immunotherapy Forum Video #26: Drs. Jared Weiss and Matthew Hellmann answer questions from the audience following their presentations on immunotherapy for lung cancer. Moderated by Dr. Jack West.

Benjamin Levy, MD, Hails 2015 as the Year of Lung Cancer Clinical Trials

Thoracic oncologist Dr. Ben Levy highlights what he believes was the biggest news for lung cancer patients in 2014 as well as his take on exciting clinical trials taking place in lung cancer in 2015.

Download a transcript of the video


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