Mobocertinib Treatment-Emergent EGFR Mutations and Subsequent Therapy Selection

EP: 1.Biomarkers and Biomarker Testing in NSCLC

EP: 2.A Commentary on High PD-L1 Expression in NSCLC

EP: 3.Broad Molecular Testing Use in Adenocarcinoma versus Squamous Cell Carcinoma

EP: 4.Reflex Testing of Next Generation Sequencing (NGS)-Based Panels in NSCLC

EP: 5.Common Biomarker Testing Methodologies Utilized in NSCLC

EP: 6.Case 1: Metastatic NSCLC with an EGFR Exon 20 Insertion

EP: 7.A Pathologist Outlines Typical Tumor Tissue Processing Steps after Biopsy in NSCLC

EP: 8.First- and Second-Line Treatment Options for Patients with mNSCLC and an EGFR Exon 20 Mutation

EP: 9.Considerations for First-Line Treatment Selection for Patients with mNSCLC and Brain Metastases

EP: 10.Repeat Liquid and Tissue Biopsy Practices in mNSCLC

EP: 11.Targeted Therapy Options for EGFR Exon 20-Mutated mNSCLC

EP: 12.Mobocertinib Safety and Efficacy Data in Patients with mNSCLC and an EGFR Exon 20 Mutation

EP: 13.CHRYSALIS Data on Amivantamab and a Comparative Efficacy Analysis of Mobocertinib vs Amivantamab

EP: 14.A Pathologist’s Commentary on The Heterogeneity of EGFR Exon 20 Insertions Found in NSCLC and Considerations for Results Reporting

EP: 15.Molecular Results Interpretation and Subsequent Treatment Selection for EGFR Exon 20 Mutation-Positive mNSCLC

EP: 16.Management of Adverse Events Following Mobocertinib and Strategies for Treatment Modification

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EP: 17.Mobocertinib Treatment-Emergent EGFR Mutations and Subsequent Therapy Selection

EP: 18.RET Fusion-Positive mNSCLC: Case 2 Presentation and Molecular Testing Strategies

EP: 19.Selpercatinib and Pralsetinib for RET Fusion-Positive mNSCLC and Supporting Efficacy Data

EP: 20.Occurrence and Management of Selpercatinib- and Pralsetinib-Related AEs in Patients with RET Fusion-Positive mNSCLC

EP: 21.Potential Immunotherapy Use in Patients with mNSCLC and RET Alterations

EP: 22.Looking Towards the Future of Molecular Testing and Additional Treatment Options for Patients with mNSCLC

Joel Neal, MD, PhD: After mobocertinib, patient gets progression. Let's say they do a repeat biopsy like we talked about before. Interestingly, we showed some data from ASCO that says that not a small number of these patients out of a series of nine patients with repeat liquid biopsies developed EGFR T790M mutations. That's actually an on-target mutation. It's an acquired resistance mutation historically most commonly seen for the common EGFR mutations and first and second-generation EGFR TKIs. But both T790M mutations happened as well as a variety of secondary EGFR Exon 20 insertion mutations that develop suggesting that these compound EGFR Exon 20 insertions are particularly troublesome. Zosia, if you repeat biopsy and you saw an EGFR T790M or a compound EGFR Exon 20 by liquid biopsy, would you hesitate to give the other approved drug next, amivantamab?

Zosia Piotrowska, MD: I think one thing to say is this is a very small number of patients, and we don't have a lot of data to guide us here yet, and I hope we will in the future. But the short answer is no. I think I would move amivantamab. I would feel encouraged that the patient developed in on-target resistance mutation hopefully is still dependent on EGFR and therefore, amivantamab is an appealing strategy. One word of caution is for many years we saw T790M, and we thought, OK, T790M positive, let's use a third-generation EGFR inhibitor like osimertinib. And I don't think that can be the reflex here because I think all of the caveats that we talked about earlier about the fact that Osimertinib in general for these mutations is not as effective for the Exon 20 insertions. That's due to the structure of the Exon 20 insertions and the way that osimertinib fits into that pocket. And I think even with a T790M mutation, the reflex should not be here to use osimertinib as it might be in other types of EGFR mutations. I would go for amivantamab in this patient next unless I had a clinical trial option to offer them.

Joel Neal, MD, PhD: And I think as you said earlier, some of those newer clinical trial TKI seem a little bit more effective, tolerable, and may have better CNS penetration. I think thinking about clinical trials even before the patient gets the TKI is worthwhile. And some of these, the next steps now are these drugs are moving toward the frontline setting. There's a head-to-head trial ongoing now of mobocertinib versus carboplatin and pemetrexed chemotherapy as well as an amivantamab plus carboplatin and pemetrexed chemotherapy both versus the chemotherapy arm alone. We may see emergence of these therapies into the frontline setting, either in combination with chemotherapy or by themselves. Then as I think about subsequent lines of therapy outside of clinical trials after mobocertinib and amivantamab, I think about single-agent chemotherapies. For this patient with high PD-L1, we'd think about immunotherapy probably as a single agent after we're done with the TKI specifically. And many patients in my experience at least, do have many lines of therapy even after the EGFR Exon 20 drugs and tend to respond well overall.