Considering Use of I-O Therapy in Driver Mutation NSCLC

Justin Gainor, MD:Over the past 15 years, there have been 2 major new paradigms that have transformed the management of non—small cell lung cancer: targeted therapy and immunotherapy. I can say that today, they still have very important roles in the management of our patients. Each has been guided by a different biomarker, and the importance of those biomarkers, I would say, are still very important today. So, patients with newly diagnosed advanced non–small cell lung cancer should still have comprehensive genetic profiling as well as PD-L1 expression scores. I think those are just baseline what we should expect to see in all of our patients.

The question, though, is, what are the roles of immunotherapies in certain genetic subsets of patients with non—small cell lung cancer? Early on, there was enthusiasm for exploring the role of immunotherapies in patients with defined oncogenic drivers. Early on, we recognize that the activity of immunotherapy as a single agent really pales in comparison with targeted therapies in patients withEGFRmutations andALKrearrangements.

Alexander Drilon, MD:The question as to whether or not to use immune therapy for patients whose cancer is harboring an actionable driver is really a question of when to use immune therapy. So, it boils down to sequencing, essentially. We know that for patients withEGFRmutations, recurrent gene rearrangements involvingALK,ROS1, orRET;METexon 14 alterations;HER2mutations; orBRAFmutations that there are targeted therapies in development, several of which have very high response rates and good progression-free survival. So, when choosing therapies for patients, it’s all about the odds of responding to treatment. And you could argue that because for certain subsets of these driver-positive patients, likeEGFR,ALK,ROS1, for example, where there are FDA-approved therapies andBRAF, that you should start with a targeted therapeutic because you’re seeing response rates in excess of 60% and very good progression-free survival.

Now, what do we know about immune therapy for these driver-positive lung cancers? Well, there have been several reports now, both retrospective and subset analyses of prospective trials, showing that the likelihood of response with immune therapy and most of this data with single-agent immune checkpoint inhibition is much lower in these populations. So, one example is a retrospective study out of Boston, withEGFRandALK,where the likelihood of response was 3% forEGFR- andALK-positive lung cancers compared with an historic response rate of 20% in unselected cases.

So, when you see numbers like that and compare them with a response rate of 60% to 80%, you know that you should save these therapies potentially in your back pocket for the future and not use them up front. There are much more recent data, some from our institution on the likelihood of response in MET exon 14—altered lung cancers and a separate series inBRAF-mutant lung cancers. Again, we’re seeing response rates that are less than 15%. And so, I think that if you were to think about a single-agent immune checkpoint inhibitor, this would be given relatively late in the course of therapy. And I would argue that after targeted therapy, if you’re going to use chemotherapy alone, then you might use chemotherapy before going to single-agent immune checkpoint inhibitor.

Things are changing now because of the addition of immune therapy to chemotherapy. And beyond platinum/pemetrexed/pembrolizumab, there were recent data with the IMpower study, which randomized patients to carboplatin/Taxol (paclitaxel)/bevacizumab plus/minus atezolizumab, showing that there was a signal for benefit in the driver-positive subsets that includedEGFR. So, this may be a potential role for incorporating immune therapy in the treatment paradigm for driver-positive lung cancers where after you’ve explored targeted therapy either with one drug or with a sequence of drugs, if that’s available for that subset, we might carefully think about the utility of doing chemotherapy plus immune checkpoint inhibition therapy for these patients. But it’s an evolving question, and I hope that much more data come out supporting the utility of immune checkpoint inhibition and where exactly to include that in the sequence and treatments.

If we look at patients whose cancers don’t harbor a driver, we’ll note that a substantial proportion of those cancers are smoking-related cancers, where we’ve known that if you look at the number of mutations in those cancers, there tends to be a higher TMB, or tumor mutational burden, compared with cancers that are driver positive or those in never-smokers. And so, it seems like this is a subpopulation of patients who don’t have a driver but have a substantial history of prior exposure to carcinogens and may be much more predisposed to response to immune therapy versus patients whose cancers have a driver or patients who maybe have never smoked in the past.

Transcript edited for clarity.