Novel Checkpoint Inhibitor Combinations for Lung Cancer

At the Great Debates & Updates in Lung Cancer meeting in New York, New York, Hossein Borghaei, DO, MS, Fox Chase Cancer Center, Philadelphia, Pennsylvania, discussed the development of novel combinations of checkpoint inhibitors to optimize treatment for patients with refractory lung cancers.

Transcript: 

I am Hossein Borghaei, I am a Medical Oncologist at Fox Chase Cancer Center and I see patients with thoracic malignancies. I'm here at Great Debates & Updates in Lung Cancer 2023.

As part of the educational component of this year's event, my task was to discuss new and novel combinations. Right off the bat, new and novel combinations, usually we use novel combinations or newer combinations in a disease refractory setting, meaning patient population in whom, either immunotherapy or chemoimmunotherapy has not been effective and there's the evidence of disease progression. That's where we test most of our ideas with some of the newer drugs. Clearly, some of the newer drugs are being tested in the first-line setting, and I think that's appropriate.

What I started with was a discussion around the available data to suggest what potential resistance mechanisms we're seeing in that particular patient population. I think we all realized that we have patients that we can label as having primary refractory disease, meaning that the best response to a checkpoint inhibitor is disease progression, which is unfortunate, it's a very aggressive disease. And then, we have patients who have some response maintained over a period of time. And then, unfortunately, there's evidence of disease progression, and we label those as acquired resistance. And we think the mechanisms are completely different and I think there's some data to suggest that.

This is an area where there's a lot of cross-pollination between lung cancer, and melanoma, and some of the other diseases, just because it's a little bit more difficult to get tissue samples from patients with lung cancer. It's a little bit easier in melanoma. We're learning from that world as to what is the impact of tumor microenvironment and how to go about identifying these patients. My biggest issue is that we are unable to do these real-time biopsies at the time of progression, identifying a mechanism, and then trying to figure out what should be the best treatment option. What we're doing is we're giving everybody the same drug combination.

The combinations that seem to be very exciting right now, checkpoint inhibitors plus [T-cell immunoglobulin and ITIM domain] TIGIT. There are a couple of studies pending, probably more than that in a phase 3 setting. We're hoping that those will indicate a particular patient population who would benefit from TIGIT.

There's a lot of interest in LAC-3. There are a couple of different ways to target LAC-3. I talked about the soluble LAC-3 study that was presented at ASCO last year. We know that there are LAC-3 monoclonal antibodies that have also entered clinical trials so we're waiting to see the results of some of that.

We've had some really exciting data in the combination of a checkpoint inhibitor plus a VEGF inhibitor, and that's the SWOG 1800A as part of Lung Cancer Master Protocol, with a combination of pembrolizumab and ramucirumab had an overall survival advantage compared to standard chemotherapy plus ramucirumab, and that idea is now in a phase 3, testing the hypothesis.

There are some exciting developments, but really, in the disease-refractory setting, we haven't had a lot of success. Many of the studies combining a TKI with a checkpoint inhibitor have been negative, unfortunately. Again, makes us think, well, what are we doing wrong? And perhaps having a better way of selecting patients that goes back to our biomarker discussion would be a more fruitful way of actually treating our patients. A lot more work and a lot more studies that are ongoing. Hopefully, in future meetings, we'll get to learn about some of these studies, and hopefully some of them will be successful.

Source:

Borghaei, H. Unique Immune Combinations with CPIs. Presented at Great Debates & Updates in Lung Cancer; September 21-23; New York, NY.