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Pembrolizumab substantially improves long-term survival in non-small cell lung cancer
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CHICAGO — Pembrolizumab appeared to substantially increase OS compared with historical control rates among patients with advanced non-small cell lung cancer, according to 5-year data from the phase 1b KEYNOTE-001 study presented at ASCO Annual Meeting.
"The KEYNOTE-001 study has been reported multiple times before; it led to the approval of pembrolizumab (Keytruda, Merck) in melanoma and NSCLC and also led to the approval of the PD-L1 diagnostic assay," Edward B. Garon, MD, assistant clinical professor and director of medical oncology at David Geffen School of Medicine at UCLA, said in an interview with HemOnc Today. “We have, over time, periodically updated the study, because it’s been felt to be of high clinical relevance as the longest duration of follow-up we have on patients treated with pembrolizumab. We now have follow-up exceeding 5 years, and thought it was appropriate to again assess the data.”
In the multicohort, phase 1b study, Garon and colleagues evaluated 550 patients with confirmed, locally advanced/metastatic NSCLC (treatment-naive, n = 101; previously treated, n = 449).
At the trial outset, patients received 2 mg/kg pembrolizumab every 3 weeks or 10 mg/kg every 2 weeks or 3 weeks. However, as pembrolizumab had been used more frequently in clinical practice throughout the duration of the study, researchers changed the protocol to reflect standard practice and treated each patient with a single 200-mg fixed dose every 3 weeks.
Overall response rate served as the primary efficacy endpoint, and OS served as a secondary endpoint.
The median follow-up at data cutoff of Nov. 5, 2018, was 60.6 months (range, 51.8-77.9). At this point, 82% (n = 450 of 550) patients had died. Sixty patients (treatment-naive, n = 14; previously treated, n = 46) had received at least 2 years of treatment. The median duration of treatment for these patients was 36 months (range, 17.3-75.9).
Results showed 5-year OS rates of 23.2% among treatment-naive patients and 15.5% among previously treated patients.
In comparison, historical 5-year OS rates prior to the immunotherapy era were 5.5% for advanced NSCLC.
Higher levels of PD-L1 expression appeared predictive of longer survival. Among the treatment-naive patients, 29.6% of those with PD-L1 expression of 50% or higher were alive after 5 years vs. 15.7% of those with levels below 50%.
Treatment-naive patients demonstrated an ORR — as determined by investigator per independent regulatory review commission — of 42% (95% CI, 32-52), while previously treated patients had an ORR of 23% (95% CI, 19-27).
Of the patients who received 2 years or more of treatment, the 5-year OS rate was 78.6% among treatment-naive patients and 75.8% among previously treated patients, with corresponding ORR rates of 86% for the treatment-naive patients and 91% for the previously treated patients.
The median duration of response was 52 months (range, 10.2–55.7 +) in treatment-naive patients and not reached (range, 12.5-71.8+) in previously treated patients.
At the time of data cutoff, the ongoing response rate was 58% in treatment-naive patients and 71% in previously treated patients.
Seventeen percent of patients experienced an immune-mediated adverse event, the most common of which was hypothyroidism.
The researchers intend to gain a better understanding of which patients benefited most from pembrolizumab and hope to explore potential combination therapies of pembrolizumab, either with conventional treatments or other immunotherapies, according to Garon.
“This study is a validation of the promise of immunotherapy, not only because we have a therapy that leads to tumor shrinkage, but because we now have this sizeable group of patients with advanced NSCLC who are out there, doing well years later,” Garon told HemOnc Today. “We have these patients who can be expected to have this kind of long-term survival. In many respects, because of the success we’ve had, we’ve forgotten how amazing this is compared to where we were when we started the trial. It’s exciting to see how the nature of our clinic has changed. It’s very encouraging.” – by Jennifer Byrne
Reference:
Garon EB, et al. Abstract LBA9015. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Garon reports consultant/advisory roles with Dracen and research funding to his institution from AstraZeneca, Bristol-Myers Squibb, Dynavax, Genentech, Iovance Biotherapeutics, Lilly, Merck, Mirati Therapeutics, Neon Therapeutics and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Nathan Pennell, MD, PhD
Patients with lung cancer typically have a 5-year survival rate of approximately 15%, and that’s been true for decades. Patients with stage IV lung cancer, meanwhile, have a 5-year survival rate of less than 5%.
One of the largest chemotherapy trials in lung cancer, between 2000 and 2002, had a 2-year survival rate of 12%. This illustrates how dismal the prognosis is for patients with lung cancer.
Now, long-term survival data for pembrolizumab show that previously untreated patients have a 23% survival rate at 5 years. This is extraordinary for advanced lung cancer; we have never seen results like this.
Previously, if a patient came to me with late-stage lung cancer, I would have to tell them that they had very little chance of being alive in 2 years. Now, I can tell patients there is a very good chance they may be alive 5 years from now.
This study confirms what we already know in that this drug is the standard of care, when appropriate, compared with chemotherapy. The results will not change clinical practice, but they will change the discussions we have with patients. This is the type of data that can really give hope to the people we treat.
There is a lot of nihilism out there — both among patients and doctors — when it comes to treating lung cancer. No longer should patients with late-stage lung cancer be routed to hospice or other end-of-life care; they should see an oncologist, because these patients could now live long enough to die of old age instead of lung cancer.
Perspective
Back to TopDavid L. Graham, MD, FACP, FASCO
Over the past few years at the ASCO Annual Meeting, we have seen a lot of impressive data in immunotherapy. This report by Dr. Garon and colleagues highlights two very important things we need to think about.
The first is that when we use immunotherapy in appropriate patients, we need to start thinking about how we can deal with patients in different ways than we used to. In previous years, we would see a patient with metastatic NSCLC and unfortunately, we’d have to paint a pretty gloomy picture. Their chances of being alive five years down the road were 5% m sometimes even less.
Now, when we look at these data of patients appropriately treated with pembrolizumab, we see that one in four of them are going to be around five years from now, and that completely changes our mindset about these patients.
The other very important thing this report highlights is the importance of appropriately funded studies to gather these data. Working just in practice patterns in the community, we would never have learned this from the patients without an appropriately funded study. To gather these data over time, we never would have found out about this group of patients. So, we continue to highlight the need for these studies, and we continue to learn from our patients.
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