Driver Mutation NSCLC: Combining Targeted and I-O Therapy

Alexander Drilon, MD:The question of whether or not to add immunotherapy to targeted therapy is an evolving question. There is a likelihood of potentially boosting response when you add an immune therapeutic to a targeted therapeutic. But at the same time, there’s also a likelihood of increasing side effects in patients. And so, we have some examples ofEGFR-mutant lung cancer trials where an EGFR TKI was combined with an immune therapeutic, and we saw higher incidence of pneumonitis. And so, while on a hypothetical level this might seem appealing, I wouldn’t personally do this as standard of care for patients. And this current point in time remains something that we explore on clinical trials. The bottom line is, right now, there are no strong data to support the use of a TKI together with immune therapy for any driver-positive subset.

Justin Gainor, MD:The hope had always been to combine targeted therapies—taking an advantage of the high response rates of targeted therapies—with immunotherapies, with the hopes for durability of responses with a way to get both high response rates and durable responses. Unfortunately, the approaches of combining targeted therapies with immunotherapies have been fraught with difficulty in non—small cell lung cancer. And the principal challenge has been toxicity, and it hasn’t been the same toxicity. It’s actually varied depending on which combinations have been explored. So, for example, combining an EGFR inhibitor such as osimertinib with checkpoint blockade, in this case durvalumab in the TATTON trial, resulted in very high rates of pneumonitis, prompting discontinuation of that approach.

Similarly, the combination of crizotinib plus nivolumab for patients withALK-positive lung cancer was also stopped early, after enrolling only 13 patients, when it was observed that severe hepatic toxicity was seen in about 38% of patients, including 2 of 13 patients who actually died from hepatic events. So, I think those are just 2 examples of where the combinations of targeted therapies plus immunotherapies resulted in the synergistic toxicity, and it’s not immediately clear from the data that we’ve seen so far that it actually resulted in better clinical outcomes. Moving forward, I don’t think that the approach of combining targeted therapies with immune therapies right now is the best path forward for patients with oncogenic driver mutations.

Transcript edited for clarity.