Combating Resistance to EGFR Tyrosine Kinase Inhibitors in Patients With Lung Cancer

At the 2023 Great Debates and Updates Conference in Chicago, Illinois, Helena Yu, MD, Memorial Sloan Kettering Cancer Center, New York, NY, discusses the challenges of primary and secondary resistance to EGFR tyrosine kinase inhibitors (TKIs) for patients with lung cancer.

Dr Yu focused on resistance to osimertinib in the first line and the agents that can be used in later-lines of therapy.

Transcript

Hi everyone, my name is Helena Yu. I am a medical oncologist at Memorial Sloan Kettering in New York City, and I am here today at Great Debates in Chicago and gave a talk about EGFR-mutant lung cancer and problems with primary and secondary resistance.

In my talk, I first went over acquired resistance to first-line osimertinib, which is the EGFR TKI monotherapy of choice for most providers. We talked about how resistance to osimertinib can be divided into different subgroups. We see on-target resistance, so acquired alterations in EGFR. We see off-target resistance, acquired mutations or alterations in bypass signaling pathways. We see histologic transformation, and, in most cases, we don’t see a genomic mechanism of resistance. These are important to identify because they can often be targeted and we have data from our series at Memorial Sloan Kettering that demonstrates if somebody has an identifiable reason that their cancer became resistant to osimertinib and we target that, their survival is improved.

Anytime we find a mutation, we of course want to treat it. In terms of targeted therapies after osimertinib, currently there actually are no approved therapies after first-line osimertinib, but there are some promising things in clinical development, including patritumab deruxtecan. That is HER3 antibody drug conjugate that's been assessed in patients after osimertinib, after chemotherapy and does appear to be quite active with a response rate around 40%. The other combination that really shows promise is amivantamab and lazertinib. Amivantamab is an EGFR-MET bispecific antibody. Lazertinib is a third-generation EGFR inhibitor, and that combo, after osimertinib, also showed a response rate of 40%. That was quite durable. Both of these are promising new options that might be available after first-line osimertinib. For standard patients, it's standard platinum doublet chemotherapy. I always recommend, if possible, to do local therapy if there is oligoprogression, and some sites can be managed with local therapy and osimertinib can be continued.

An area of primary resistance to the classical EGFR Inhibitors is our EGFR exon 20 insertion. This is a unique subtype of EGFR mutations that are not responsive to the historical EGFR inhibitors, but there have been two new drugs that have been approved in this space. One of them is amivantamab, which I just mentioned, that EGFR-MET antibody. The other one is mobocertinib, which is an EGFR exon 20 TKI. Both recently approved, I think they are good drugs with good efficacy. There are significant side effects, primarily EGFR- and MET-directed side effects. There are other EGFR exon 20 inhibitors that are newer that are looking to potentially be more effective or potentially have less toxicity. Finally, we talked about toxicities related to these EGFR inhibitors. There are most commonly mucocutaneous toxicities. We see rash, mucositis, nail fissures, paronychia, and I would just say that these things are so critical and important to patients. They cause a real decrease in their quality of life and are so bothersome to them. Early intervention and management of these and in cooperation with dermatologists or podiatrists really are critical.

Source:

Yu, H. “Immune modulation of innate and adaptive responses by CARG-2020 restore immunosurveillance and establish anti-tumoral immunological memory.” Presented at Great Debates & Updates in Lung Cancers. May 4-6, 2023; Chicago, IL