Julie R. Brahmer, MD
Immune checkpoint inhibitors targeted against PD-1 and its ligand PD-L1 have rapidly advanced as treatments for patients with melanoma and non—small cell lung cancer (NSCLC), following their initial debut in 2012.
In the past 4 months alone, the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) have each gained separate approvals as treatments for patients with advanced melanoma. Additionally, in mid-January, phase III findings from the CheckMate-017 study demonstrated that nivolumab extended overall survival compared with docetaxel in patients with pretreated squamous cell NSCLC.
Based on these findings and those from phase II studies, Bristol-Myers Squibb (BMS) is currently in the process of submitting a New Drug Application to the FDA for nivolumab as a third-line treatment for patients with squamous cell NSCLC. Furthermore, several phase III studies are currently examining the agent across a variety of tumor types.
Julie R. Brahmer, MD, and Suzanne L. Topalian, MD, presented seminal research on PD-1/PD-L1 inhibition at the 2012 ASCO Annual Meeting. Results from these studies laid the foundation for future advances and shaped the development of PD-1 inhibition in cancer.
In an interview, Brahmer, the interim director of the Sidney Kimmel Comprehensive Cancer Center, spoke with OncLive
about the rapid development of PD-1/PD-L1 inhibition and her thoughts on the future of this novel treatment approach.OncLive:Â Have you been surprised by the rapid advancement of anti-PD-1 and PD-L1 agents?Brahmer:
I think it has been amazing to see such therapies–which have the ability to use your own immune system to attack your cancer–take off. What is particularly amazing is that the antibodies that are being tested now really have consistency among cancers. It is not just one antibody that has activity. It is a whole class of antibodies that have activity in lung cancer.Do you think there is a possibility of a PD-1 lung cancer approval this year?
I think there is the possibility for a new approval over the next year. As reported by BMS, there is one phase III study that did show an improvement in survival with patients treated with their anti—PD-1 antibody nivolumab in squamous cell lung cancer. Hopefully in the next 6 months to a year we will get the full data from that study—and we’ll hopefully be using that agent as well. There is also other data coming out on another anti—PD-1 antibody: pembrolizumab.
I think we will see at least one of those two antibodies getting approved this year. Having these agents available would be a great advance for our patients with lung cancer.What do you see in the future for PD-1 inhibitors in lung cancer?
For the future I think it is really about trying to personalize therapy. The response rates that we are seeing for the PD-1s are excellent, but certainly it does not work in all patients.
We need to try and figure out ways to help patients’ immune systems to be able to attack their lung cancer, which for the majority of patients will require a combination of therapies. Or we need to try to figure out how the immune system is able to best attack the tumor and then develop therapies to manipulate on that and capitalize on that. That is what I think the future will be.
These PD-1 antibodies or PD-L1 antibodies are just a small part of the story in lung cancer and I think combinations of therapies will be what we use in the future.Do you think we are any closer to finding a biomarker?
The biomarker story needs a lot more work and collaboration across all the companies involved, and all the investigators involved, in order to come up with the best type of biomarker. I think the PD-1 biomarker story is just going to be part of the puzzle when it comes to predicting who would benefit from this type of single-agent therapy.
Because there are multiple moving parts of the puzzle it is hard to predict who might benefit. We know particular biopsies might not show the complete picture of a patient’s tumor throughout their body as well as the fact that biopsies may just miss PD-L1 expression.
We are looking at how PD-L1 expression relates to tumor-infiltrating immune cells and how the combination of the two markers might better predict response. Several groups are looking at mutational burden in a patient’s tumor. We know that smokers tend to respond more to the anti-PD-L1 or PD-1 antibodies compared with never smokers. Mutation burden might be part of the story as well.Are there particular drug combinations you see as having potential?