EGFR-Targeted Therapy in NSCLC: Optimizing Sequencing and Combinations


Focusing on the broader treatment armamentarium for EGFR-mutated NSCLC, Sandip Patel, MD, considers possible sequencing and combination strategies.


Sandip P. Patel, MD: There’s a variety of treatment options for patients with EGFR-mutated metastatic non–small cell lung cancer. For patients with canonical EGFR mutations, these are exon 19 and L858R, which represent 80% to 85% of these mutations, I’ll start with osimertinib as the standard of care outside a clinical trial. There are many clinical trials combining drugs like osimertinib with either EGFR or MET bispecific antibodies, with antiangiogenics, or with chemotherapy. But in terms of the standard-of-care setting, osimertinib in the front line—given its CNS [central nervous system] penetration—represents my standard of care in that setting.

For patients with exon 20 insertion mutations who are refractory to platinum-based chemotherapy, I most commonly use carboplatin-pemetrexed. Mobocertinib, which is a small-molecule inhibitor approved for the use of an exon 20 insertion EGFR-mutated lung cancer, or amivantamab, which is a bispecific antibody against EGFR and MET, represent reasonable standard-of-care options.

For atypical mutations in EGFR—these are rare mutations in exon 18 or exon 20—afatinib has very strong data, particularly for patients without CNS metastases. In the frontline space, there are multiple options. It’s not enough to say a patient has an EGFR mutation. What mutation do they have? What’s the street name? What’s the actual address? On progression, I’ll often repeat a biopsy tissue for a concern with small cell transformation, rapid progression, or liquid if we’re not able to get a tissue or slow progression. In doing so, we can sometimes find emergent targetable driver mutations, but those are most optimally treated in the context of a clinical trial.

The small molecule EGFR inhibitors represent the base upon which we can build an optimal therapeutic regimen for patients. Whether we stratify patients who may need additional treatment, based on cell-free DNA or other MRD [minimal residual disease]–based detection modalities, remains to be seen. Combinatorial partners for small molecule EGFR inhibitors include bispecifics against EGFR and MET, like amivantamab; antiangiogenics, such as bevacizumab or biosimilars; or chemotherapy—adding carboplatin-pemetrexed to osimertinib or an FDA-approved combination like lapatinib-ramucirumab. There are multiple options.

The key characteristic we want to emphasize is trying to match the right therapy to the right patient. There are some patients in which the toxicities of a combinatorial regimen in the noncurative intent setting are representing their goals in terms of overall quality of life. Similarly, there will be patients who may want a very aggressive treatment but who are high risk, so a single agent may not be sufficient. For example, if they continue to have a high-level shed of cell-free DNA after initiation of small-molecule EGFR/TKI, then they may need 1 of these partnering strategies to optimize their therapeutic outcome.

We hope to see data over the next couple of years as we expand the breadth of the EGFR gene, in terms of coverage with exon 20 insertion–targeting therapies, but also the depth. We want to ensure that patients do well for as long as possible, with an eye toward optimizing the benefit while mitigating these toxicities because the patients will be on these therapies for years. It’s important for us to understand how much benefit they’re getting relative to the potential toxicity of adding agents to the regimen.

Transcript edited for clarity.

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