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. What's next?
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 four months alone, the PD-1 inhibitors Opdivo (nivolumab) and Keytruda (pembrolizumab) have each gained separate approvals as treatments for patients with advanced melanoma. Additionally, in mid-January, phase 3 findings from the CheckMate-017 study demonstrated that Opdivo extended overall survival compared with docetaxel in patients with pretreated squamous cell NSCLC.
Based on these findings and those from phase 2 studies, it’s likely that Opdivo may soon be submitted for FDA review as a third-line treatment for patients with squamous cell NSCLC. Furthermore, several phase 3 studies are currently examining the agent across a variety of tumor types.
Julie R. Brahmer, interim director of the Sidney Kimmel Comprehensive Cancer Center, along with Suzanne L. Topalian, presented research on PD-1/PD-L1 inhibition at the 2012 annual meeting of the American Society of Clinical Oncology. Results from these studies laid the foundation for future advances and shaped the development of PD-1 inhibition in cancer.
Brahmer discussed the rapid development of PD-1/PD-L1 inhibition and shares her thoughts on the future of this novel treatment approach.
CURE: 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 (Bristol Myers Squibb), there is one phase 3 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 six 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.
[Read more about personalization of cancer therapy in “Personalized Therapy: What’s Next?”]
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?
There are several combinations currently being tested that are very interesting, which use checkpoint inhibitors with either PD-1 or PD-L1 antibodies. Those studies are ongoing and the most exciting fact is that they are pure immunotherapy combinations. I think that combining these antibodies with radiation therapy and other types of targeted therapy may be successful as well.
What role do you see Johns Hopkins Kimmel Cancer Center playing in all of this?
We’ve been involved with anti-PD-1 antibodies since some of the first in human trials, particularly with nivolumab, and we have remained involved through the phase 3 trials. But we have several other antibodies as well that we are working with and certainly our specialty is phase 1 clinical trials. So we are really on the cutting-edge of combining checkpoint inhibitors with other therapies.