PD-1 antibodies a ‘big leap forward’ for NSCLC
The 3-month median difference in OS seen in the trial by Paz-Ares and colleagues is outstanding.
Since docetaxel was approved in 1999, there has been essentially nothing, either alone or in combination, that has been able to beat it. Ramucirumab (Cyramza, Eli Lilly) was recently approved, but in combination with docetaxel.
This represents a big leap forward. Those of us who participated on these clinical trials like CheckMate 057 have patients who are still in remission 3 years later. They are doing regular activities, and their lives are no longer defined by the label of lung cancer. The cancer is really a minor component of their lives. They are not just surviving — they are living.
Benjamin C. Creelan
Importantly, these results were positive in the overall population. My expectation is that the drug would be FDA approved for the overall population, regardless of PD-L1 status. It is true that in this non-squamous population, we see a dramatic difference in outcomes with the PD-L1–positive patients. Even just using a 1% cutoff — one of the lowest thresholds used for most companies — demonstrated benefit with nivolumab. In contrast, for squamous lung cancer, PD-L1 expression was completely irrelevant. The survival benefit was seen in both PD-L1–negative and PD-L1–positive squamous patients regardless of the cutoff point.
So regarding CheckMate 057 and the PD-L1 question, let’s look into the purported clinical utility of that biomarker in more detail. What are the important components of a good biomarker?
First, you want a biomarker if it will spare patients treatments that are not going to work when other effective treatment is available. Does this biomarker do that? No. There are PD-L1–negative patients who still respond. Even with a less than 1% cutoff, there are some patients who respond.
Second, you want a biomarker if it is also going to spare patients toxicity from a drug that might not work. In this case, what do I have to offer that is so much better than nivolumab in the second-line setting?
Frankly, the outcomes with docetaxel have been pretty dismal for long-term durable responses. We know that the OS for patients in the squamous population with docetaxel was 22% at 1 year, and that might be a little higher in the non-squamous population, but you are still talking about a median survival of less than half a year. If I have a drug that can increase that — or come close with less toxicity — I am going to use it.
Would I not treat a patient who is PD-L1 negative? I would still have a discussion with them, and I would still give the drug if the patient wanted it. I find patients usually are the ones pushing us to do those treatments. If I am a patient and I know there is a 10% to 12% response rate with this drug since I’m PD-L1 negative, I’m guessing a lot of patients are going to go for it. Most people would rather go for a smaller chance of a long-term durable remission with fewer side effects and better quality of life than going with our traditional options.
Let’s also remember that a PD-L1 result must always be viewed with skepticism due to the intrinsic nature of lung cancer. One: It gives a score, not a yes/no answer. Two: PD-L1 is an inducible biomarker that changes over time. Three: There is high variability about where in the tumor you test PD-L1.
One interesting aspect of these trials — a current unanswered question — is that both trials continued treatment with nivolumab every 2 weeks indefinitely for as long as it was working. What we don’t know is whether stopping the treatment and allowing the immune system to continue its vigilance would work. We do have a clinical phase 3 trial, CheckMate 153, comparing 1 year of treatment vs. continuation in patients, but that trial may end up being somewhat underpowered to answer that question. In the long run, it may be handled at the physician’s discretion.
Cost aside, and as long as the patients are in agreement, I would keep giving the drug as long as it is working. There have been patients from the original phase 1 trial — the CheckMate 003 trial, in which the drug was stopped at 2 years — who progressed, were retreated and had a response again. That suggests a benefit to continuing the drug, at least anecdotally.
Brahmer J, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1504627.
Paz-Ares LG, et al. Abstract LBA109.
Spigel DL, et al. Abstract 8009.
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Benjamin C. Creelan, MD, is a medical oncologist at Moffitt Cancer Center. He can be reached at email@example.com.
Disclosure: Creelan reports speakers fees from Bristol-Myers Squibb. Patients at Moffitt Cancer Center participated in the CheckMate trials.