Mark Socinski, MD: As I mentioned before, we’ve seen a step up in outcomes with the addition of PD-1, PD-L1 [inhibitors]. You pointed out these were initially second-line treatments. We graphed them on to the standard first-line regimens, and we’re seeing these outcomes that we have not seen before. We’ve had a couple of recent approvals of the CTLA-4 drugs. First, the nivolumab/ipilimumab combination, both from CheckMate 227 and 9LA [trials] and then the POSEIDON trial, which incorporated tremelimumab with durvalumab. [What are your] thoughts on the CTLA-4 addition? How are you using it? Is there a specific patient population where you think about it?
Joshua Sabari, MD: Yes, I remember seeing the CTLA-4 [inhibitors] in the clinic 10 years ago in phase 1 dose escalation. I’ll be honest with you; I was afraid of them. We were giving doses at 10 mg/kg, for example, of ipilimumab. And the concern with these immunotherapeutics is that the patients get immune-related adverse events. So despite there being a high potential durability or cure rate, there is the negative side of immunotherapy where patients have terrible adverse effects potentially. And learning how to harness those is important. I’ve become a lot more comfortable and fluent in my practice with utilizing these CTLA-4 inhibitors. We’re using doses that are much lower than what we were thinking about 10 years ago. If you talk to a colleague who’s [managing] melanoma or a colleague who’s [managing] renal cell cancer or even…a cellular carcinoma, they have a lot more experience than us [as] thoracic medical oncologists where we were leading this space 5 or 10 years ago. So I do utilize these agents, the CTLA-4 inhibitors, [for] certain subsets of my patients who are [at] higher risk who I don’t feel will derive a significant benefit from immunotherapy or even chemotherapy and immunotherapy alone.
Mark Socinski, MD: We learned from the POSEIDON [trial findings] that perhaps a limited exposure to anti–CTLA-4 antibodies, rather than continuing them for a long duration, may not necessarily [affect] the efficacy but could [affect] the toxicity of them.
Joshua Sabari, MD: The name of the game here is how you prime the immune system. How do you get more people to look like our [patients with] PD-L1 [expression] greater than 50% who derive these significant durable benefits? You have patients with low PD-L1 expression, and we’ll talk about some of the high-risk subsets, some of the genomic alterations that may portend poor response or poor durability. How do we get those patients to respond better? And adding a CTLA-4 inhibitor, as you mentioned earlier, stepping up the game to allow patients to have more durable responses is critical.
Mark Socinski, MD: We’ve talked about PD-L1 and how it’s not a perfect test, but it’s a useful test from a clinical point of view. [PD-L1 expression is] most useful when it’s high, and you might consider using immuno-monotherapy. Otherwise, I don’t find myself using it in the lows or the negatives. Are you using anything beyond PD-L1 in terms of a biomarker that would affect your clinical behavior?
Joshua Sabari, MD: As good as PD-L1 expression is, it’s not the end-all be-all. It’s also a subjective test. If you’ve ever looked at the reports from your biologists, there are some all over the map. Or if you have multiple [biopsy results from] a patient, PD-L1 [expression] can be heterogeneous; it can be dynamic.
Mark Socinski, MD: And we find that in many of our clinical trials where there has to be central testing that the local testing and the central testing don’t match up, correct?
Joshua Sabari, MD: I’ve had my own pathologists run PD-L1 expression twice or 3 times on the same sample. And you see a discrepancy there as well, depending [on] what time of day it was read, how much coffee the pathologist had. So it’s not a 0 or 1 test.
Mark Socinski, MD: It’s not like an EGFR mutation [where] you have it or you don’t. Here, it’s a spectrum.
Joshua Sabari, MD: It’s subjective. Other things that you hear about in this setting are things [such as] tumor mutational burden, for example. And lots of work have been done looking at the mutational burden, how many mutations per genome megabase sequence. And we think that higher mutation load [means] better, more durable response. You’ve looked at this a lot [in] your work, but what it [shows] is that it’s not a predictive biomarker, right? It’s really a prognostic biomarker. So patients have higher mutational burden [and] do well with all therapies, not just immunotherapy. Of late, I’ve been looking more at genomic alterations by NGS [next-generation sequencing], not the driver mutations that we had talked about earlier, but mutations that allow me to better understand the biology of the patient’s tumor and some of those high-risk genomic features. KRAS, for example, patients who have KRAS mutations. We’ve talked a lot about KRAS G12C in the past. Those are patients who we think derive benefit from immunotherapy. Those are patients who are smokers. But if you have coalterations in other genes such as STK11 and KEAP1, we know that those patients do not derive as much clinical benefit from the immunotherapy. That’s where we need to step up our game in that patient population. And there are many other high-risk features, things [such as] PTEN loss or SMARCA4 . You meet these patients in the clinic, and the last 10 patients I’ve seen with this alteration have not done well. Maybe these patients need more in clinical practice.
Transcript is AI generated and edited for clarity and readability.
