Dr Jänne on Second-Line Treatment Evolutions in EGFR-Mutated NSCLC

“The data on MARIPOSA-2, which was a trial that evaluated the addition of amivantamab to chemotherapy or amivantamab and lazertinib to chemotherapy compared to chemotherapy…have led to a significant uptake of amivantamab/chemotherapy in the second-line setting, for patients who start with first line osimertinib.”

Pasi A. Jänne, MD, PhD, senior vice president for Translational Medicine, director of the Belfer Center for Applied Cancer Science, director of the Chen-Huang Center for EGFR Mutant Lung Cancers, a senior physician, and the David M. Livingston, MD, Chair at Dana-Farber Cancer Institute; as well as a professor of medicine at Harvard Medical School, discussed notable recent changes to the second-line treatment paradigm for patients with EGFR-mutated non–small cell lung cancer (NSCLC). He also explained disease features that factor into his treatment decision-making process in the second-line EGFR-mutated NSCLC setting.

There have been several notable developments in the second-line treatment paradigm for patients with EGFR-mutated NSCLC, Jänne began. One key update stems from the phase 3 MARIPOSA-2 trial (NCT04988295), which evaluated the efficacy of amivantamab-vmjw (Rybrevant) in combination with chemotherapy with or without lazertinib (Lazcluze), compared with chemotherapy alone, according to Jänne. Findings from MARIPOSA-2 demonstrated a significant improvement in progression-free survival for both amivantamab-containing regimens vs chemotherapy alone, prompting increased clinical adoption of amivantamab plus chemotherapy in the second-line setting, particularly for patients who have previously received first-line osimertinib (Tagrisso), he said.

The selection of second-line therapy following disease progression on osimertinib is often informed by the underlying mechanism of resistance, Jänne explained. For example, in cases of MET amplification, the addition of a MET inhibitor to osimertinib may be beneficial, leveraging a targeted approach to overcome acquired resistance, he stated. In contrast, for patients without an identifiable or targetable resistance mechanism, standard cytotoxic chemotherapy remains a cornerstone of therapy, he noted. The combination of chemotherapy and amivantamab may also be considered in this context to enhance efficacy, he continued.

Another option under consideration in later lines of therapy is datopotamab deruxtecan-dlnk (Dato-DXd; Datroway), a TROP-2–targeted antibody-drug conjugate. Although recently approved by the FDA, Dato-DXd is typically reserved for third-line treatment, specifically for patients who have previously received both an EGFR TKI and chemotherapy. However, an exception may apply for patients who received EGFR-targeted therapy and chemotherapy concurrently in the first-line setting, Jänne concluded.