Robin Kate Kelley, MD, Professor of Clinical Medicine in the Division of Hematology/Oncology, University of California, San Francisco discusses treatment options for biliary tract cancers and the KEYNOTE-966 trial.
Transcription:
The KEYNOTE-966 trial was building upon the prior data that I mentioned that a checkpoint inhibitor, specifically pembrolizumab, targeting the PD-1 checkpoint protein, as monotherapy, had a relatively low response rate, 5.8%, in the KEYNOTE-158 trial. That’s disappointing to those of us who would, obviously, like to see a much, much higher response rate like we see in microcell and stability patients. That said, though, it does tell us there are a subset of patients that do have an immune response, even without microcell and stability, and when these responses occur, they do tend to be deep and durable, and worth trying to harness and achieve if we can.
The premise of the KEYNOTE-966 trial was taking pembrolizumab, which has a small monotherapy efficacy, and adding it to our standard chemotherapy backbone that we use for first-line biliary tract cancer is called gemcitabine plus cisplatin and acknowledging that both cisplatin and gemcitabine have mechanisms of cytotoxicity that may be pro-immunogenic in combination with a checkpoint inhibitor. There have been some nice preclinical studies that suggest that adding gemcitabine or cisplatin to a checkpoint inhibitor can increase the chances of creating an immune response down the road.
The KEYNOTE-966 trial randomized patients with advanced or unresectable cholangiocarcinoma, or gallbladder cancer, to either gemcitabine, cisplatin and placebo as the control arm, or gemcitabine, cisplatin and pembrolizumab as the active experimental arm, and followed patients for the primary endpoint of overall survival.
What the study showed was that there was a significant improvement in median overall survival with the addition to pembrolizumab with a median of 12.7 months by comparison to 10.9 months for the control arm, and a hazard ratio of 0.83. Importantly, from the clinical perspective, that while this median is significant and definitely important, in and of itself, when we look at landmarks, we can see that the proportion of patients at 12 months, and then later on at 24 months, is preserved, meaning that this benefit so far appears to be quite durable. That’s what we hope for and expect of an immune checkpoint inhibitor response. The great hope in the clinic is that we’re converting a subset of patients from mere chemotherapy responders to those durable, holy grail immunotherapy responders that can have responses that last much longer. A median of 12.7 versus 10.9 is incremental when one just looks at the median.
In the clinic, when talking to cancer patients, I’m saying we’re obviously not aiming just to be the median, we’re aiming for you to be one of those people on the tail. That’s where I think back to the 24-month landmark, that’s so important to say this isn’t just something that happens at that 12-month mark. This is a durable benefit that keeps going. Because that subset of patients that it’s converting from just a chemotherapy-type pattern of response that might be a couple of months more. If we can get those durable immune therapy responses, that’s the tail of the curve that can, theoretically, stay flat and stable for a long time, if truly, we’re getting immune responses.
The question, of course, in terms of kinetics, it’s hard to flesh out when you have a triple therapy, where you have active drugs, gem and cis have a great response rate, in and of themselves, around 25%. I think, when patients are on the triplet treatment, it’ll be hard to flesh out what is the component contribution of efficacy for each of the three drugs.
I think landmark of time points down the road will be helpful, especially people can’t tolerate cisplatin indefinitely because of neuropathy, hearing loss, kidney injury. In fact, the trial design mirroring standard of care stops cisplatin after six months. Again, that’s how the regimen is administered, in most cancers, the biliary tract cancer in particular, we stop the cisplatin after about six months of exposure, due to the risk of cumulative toxicity. I think over time, it’ll be very helpful to be able to understand a little bit more, what is the pembrolizumab contributing and in which patients, by seeing how the landmarks play out.
To learn more about bilary tract cancer and other rare cancers, visit https://checkrare.com/diseases/cancers/
