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Overcoming Diversity Challenges and Exploring Immune Checkpoint Inhibitor Strategies in mNSCLC Treatment


Professionals deliberate the progression of Immuno-Oncology combinations while also engaging in conversations regarding the issue of immunotherapy resistance.

Mark Socinski, MD: I do remember the original docetaxel trials had to be 20-plus years ago and to the extent that we’ve had a number of new agents that have been tested in the second-line setting against docetaxel, which remains a regulatory standard, although in my practice, most of the time I will use docetaxel plus ramucirumab in that setting. Do you have any particular new agent in that setting? And we recently had a press release about a Trop-2 ADC [antibody-drug conjugate] in that setting. So we may move finally beyond the docetaxel age if you will.

Joshua Sabari, MD: The idea of immunotherapy, or IO [immuno-oncology] combinations, was always so tantalizing and so exciting. Doing this now for about 10 years, I’ve seen multiple negative or failed studies in that setting. We’ve moved back now to sort of dressed-up chemotherapy. And that’s really what the Trop-2 ADCs is are and some of the other ADCs that we’re using, you know, amazing that we saw an improvement in progression-free survival in that press release. We’ll have to see the overall survival. And we also have to see the toxicities, you know, whether this is something that we will offer to our patients. But yeah, maybe it’s an incremental move forward, but it’s nowhere near what we saw in 2014, 2015, where we saw PD-1, PD-L1 inhibitors approved in the second-line setting where we were actually leading to durable cures. I don’t think the ADCs are going to lead to durability. I mean, they may be better than docetaxel per se, but I’m not sure that they’re going to revolutionize practice.

Mark Socinski, MD: One of the other issues that I think is a challenge for us in that is getting into the driver in the nondriver subsets. There’s so much heterogeneity that the ability to do clinical trials rapidly is actually getting tougher and tougher. I remember when I started in this business, you know, the eligibility criteria were non–small cell lung cancer and now, of course, you have to exclude all the drivers. You have to know PD-L1 status. You might have to know, in the case of G12C, I mean, that limits the population. How are you thinking about that? And how does that impact your clinical trial menu? What which trials do you choose, which trials don’t you choose, and all that?

Joshua Sabari, MD: So I sort of think a lot more about sort of time to progression for patients. If you have a patient who’s deriving a lot of benefit from immunotherapy, let’s say 12 months–plus, and then has slow progression, I may use local therapy, and there are lots of studies now utilizing local therapy to oligo-progressive disease or oligo-metastatic disease, as opposed to a patient who has rapid progression on a PD-1 or PD-L1 inhibitor. I might use more of a chemotherapeutic approach in that patient. And I think we’re trying to better understand how immunotherapy resistance allows us to then look at new therapies. Maybe some of the therapies we’ve looked at in the clinic could have been successful in other patient populations. We’re just, like you said, looking at all non–small cell lung cancers, second line. So a lot of our trials now are requiring 12 months of stability, for example, or prior response on immunotherapy before going to an IO-IO combination. But like you said, we need to have better biomarkers in this setting, and we don’t have those yet.

Mark Socinski, MD: Let’s get away from the driver populations and get back to the nondriver populations. I think you would agree that we have seen the incorporation of PD-1, PD-L1 inhibitors really step up. We can talk about a 5-year survival…in my training I was trained to think that…stage IV non–small cell is a treatable disease but not a curable disease. Are we curing some patients?

Joshua Sabari, MD: So in my training, I saw this sort of transition, and I remember when the immunotherapies were just being approved in the second-line setting and mentors of mine were saying to not allow someone to enroll in hospice care, for example, without trying a PD-1 or PD-L1 inhibitor. We were seeing these Lazarus effects, right? Again, not in everybody, not across the board, but in some patient populations. We now know that it’s those patients who have a higher PD-L1 expression and we are seeing durable responses. Right? A third of patients with a PD-L1 greater than 50% are alive at 5 years—alive and well, I should add. Right. So, yeah, I do think non–small cell lung cancer stage IV is becoming a potentially curable disease, not to all patients. Right. That’s important. But for some patients and, you know, these have really changed the landscape, as great as targeted therapies are, we haven’t seen the durability that we are seeing in a subset of patients who receive immunotherapy who are driver mutation negative. So a game changer for our patients.

Mark Socinski, MD: And I’m sure like me, you have patients and I typically give them the standard 2 years—I don’t know if that’s right or not, but that’s what we do in practice. Two years of therapy. Then I stop and we know that if you’re in a solid remission at that point and CTs show control of the disease, the majority of those patients, even 3 years later, are still having control of their disease. Is that a cure?

Joshua Sabari, MD: It’s quite remarkable. I mean, I think we define cure in different ways. And I think for a patient, a cure is, you know, being alive, being well without evidence of disease that is growing. Right. And without having symptoms related to their cancer. So I do think we are…the therapies and patients are being cured with stage IV lung cancer. But I think the key the takeaway here is that we need more cures in this patient population. Right. We’re definitely not seeing cures across the board. We’re not at, you know, CML [chronic myelocytic leukemia] yet. And, in non–small cell lung cancer, I think we can get there over the next 10, 15, maybe even 20 years.

Transcript is AI-generated and edited for clarity and readability.

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