Statistical modeling of long-term survival from the KEYNOTE trials of the programmed cell death protein 1 (PD-1)–inhibitor pembrolizumab (Keytruda) estimates that one-quarter of appropriately selected patients with advanced non–small cell lung cancer (NSCLC) may attain long-term survival.1
These aren’t just numbers on a curve or dots on a plot. These are patients. The lives and expectations of these folks are remarkably changed now.— Matthew D. Hellmann, MD
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“In the context of the pembrolizumab program, these are the furthest-out data that we have so far, and I think they represent a remarkable step forward,” commented Matthew D. Hellmann, MD, of Memorial Sloan Kettering Cancer Center, New York, who presented the analysis at the 2017 ASCO-SITC (Society for Immunotherapy of Cancer) Clinical Immuno-Oncology Symposium.
Dr. Hellmann and his team derived estimations of long-term survival using a distinct statistical model that is appropriate for immunotherapy. He explained that while conventional parametric models assume that all late-stage disease will eventually progress, statistical models for immunotherapies account for a variable risk of disease progression over time and allow for the possibility of durable responses and long-term survival.
“In the context of immunotherapy, progression and death are not necessarily inevitable. Long-term survival models take into account the possibility of a plateaued survival when estimating outcomes further out. The point at which the plateau occurs is what we’ve termed ‘long-term survival rate,’” he said. For example, overall survival for melanoma patients treated with the checkpoint inhibitor ipilimumab (Yervoy) plateaus around year 3 in some 20% of patients, and so far extends out to 10 years, he noted.
“We’re cautious to use these sorts of words, and understandably so, but these outcomes really do start to approach the concept of cure for patients with advanced cancer,” he said. “Given that these outcomes are possible with immunotherapy, ones that are characterized by long-term survival and a plateau in the survival curve, distinct statistical models are needed to estimate survival.”
Long-Term Survival Model
The patients in Dr. Hellmann’s analysis had advanced NSCLC that expressed the programmed cell death ligand 1 (PD-L1). The aim was to estimate the percentage of patients with long-term survival (eg, exceeding 5 years), following treatment with pembrolizumab, as analyzed by the long-term survival model.
The researchers used intermediate-term survival data (median follow-up ~ 24 months) from 306 patients in the KEYNOTE-001 study to generate an initial estimate of the long-term survival rate for those receiving the PD-1 inhibitor. They validated their estimate using the larger set of data from 690 patients in the KEYNOTE-010 trial.
Long-Term Survival With Pembrolizumab in NSCLC
- Using a unique statistical model that is appropriate for immunotherapy, researchers determined the long-term survival for patients with PD-L1–positive advanced non–small cell lung cancer treated with pembrolizumab.
- In two KEYNOTE trials, estimated survival beyond 5 years was figured at 21% to 25%. Patients receiving docetaxel had an estimated long-term survival of 4%.
- New models such as this one are necessary for more accurately determining outcomes with immunotherapies.
“The goal of this analysis is to benchmark just how much progress we’ve made toward that goal of raising the survival curve through treatment with pembrolizumab,” he said.
An estimated 25.4% of patients were predicted to survive long term with pembrolizumab therapy, based on the KEYNOTE-001 data, and this figure matched up well with the KEYNOTE-010 estimate of 25.3%. Further analysis using an extended KEYNOTE-010 cutoff date (6 additional months of follow-up) yielded a long-term survival estimate of 21.5%, Dr. Hellmann reported.
“For context and contrast, we estimated the long-term survival rate to be 4% among patients in KEYNOTE-010 who were randomized to docetaxel,” he added.
“These aren’t just numbers on a curve or dots on a plot. These are patients,” Dr. Hellmann emphasized. “The lives and expectations of these folks are remarkably changed now,” based on the availability of pembrolizumab. He added that the results also highlight the role and utility of distinct statistical models that take into account the possibility of plateaued survival. ■
Disclosure: Dr. Hellmann has had advisory/consulting roles with AstraZeneca/MedImmune, Bristol-Myers Squibb, Genentech, Janssen, Merck, and Novartis and has received research funding from Genentech/Roche and Bristol-Myers Squibb. The study was funded by Merck.
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