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ESMO 2025 | Understanding immunotherapy resistance in early-stage lung cancer
Jay Lee, MD, University of California, Los Angeles, CA, comments on the challenges of understanding resistance mechanisms to immunotherapy in early-stage lung cancer, highlighting the limited use of next-generation sequencing (NGS) testing globally and in the US. Some patients may be inherently resistant to immune checkpoint inhibitors and could benefit from targeted therapies instead, and novel immunotherapy combinations are being explored in the early-stage setting to overcome resistance mechanisms. This interview took place at the European Society for Medical Oncology (ESMO) 2025 Congress in Berlin, Germany.
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Transcript
Yes, this is like the holy grail about what are the resistance mechanisms and, you know, you can go on for hours about this. I think part of the problem in early stage disease is that NGS testing has not been universally accepted and is not being performed, certainly at a global level and within the U.S. So part of it is when you look at subsequent therapies after neoadjuvant chemo IO or perioperative chemo IO and in the adjuvant trials, when you look at what is the next subsequent therapy after receiving checkpoint inhibition, and about 15% of patients will go into targeted therapies, which implies that maybe that 15% should have never gotten chemo IO, and had this been in the metastatic setting, maybe they would have gotten first-line targeted therapy instead...
Yes, this is like the holy grail about what are the resistance mechanisms and, you know, you can go on for hours about this. I think part of the problem in early stage disease is that NGS testing has not been universally accepted and is not being performed, certainly at a global level and within the U.S. So part of it is when you look at subsequent therapies after neoadjuvant chemo IO or perioperative chemo IO and in the adjuvant trials, when you look at what is the next subsequent therapy after receiving checkpoint inhibition, and about 15% of patients will go into targeted therapies, which implies that maybe that 15% should have never gotten chemo IO, and had this been in the metastatic setting, maybe they would have gotten first-line targeted therapy instead. And that’s speculation, but I think it is a hint that some of these resistance pathways are probably immune checkpoint inhibitor refractory, and maybe those patients would have been better off with a targeted therapy agent. The other mechanisms are unclear. They weren’t collected, they weren’t studied, at least not reported from the phase three trials. But this is where all of the development in the late stage setting applies in the early stage. All of the new data with bispecific antibodies, the ADCs, the VEGF checkpoint inhibitor combination bispecifics, and dual checkpoint inhibitors. And now the combination of IO with targeted therapies, like in the KRAS G12C space, where we’re combining targeted therapy with IO. So there’s a lot of new things that are occurring in the metastatic setting that are being brought into the early stage setting. And hopefully that will offset some of these resistance mechanisms.
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