The treatment landscape for non-small cell lung cancer (NSCLC) is rapidly evolving, marked by recent FDA approvals and ongoing investigations into novel therapeutic strategies. These advancements offer new hope for patients with specific genetic mutations and resectable disease, according to Noman Ashraf, MD, a hematologist-oncologist at Tampa General Hospital and an associate professor of medicine at the University of South Florida Health Morsani College of Medicine.
Amivantamab Plus Chemotherapy for EGFR-Mutated NSCLC
In September 2024, the FDA approved amivantamab-vmjw (Rybrevant) in combination with chemotherapy for patients with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on prior EGFR tyrosine kinase inhibitors (TKIs). The phase 3 MARIPOSA-2 trial (NCT04988295) demonstrated the benefit of this combination in patients who had progressed on third-generation TKIs like osimertinib. Amivantamab, a bispecific antibody targeting both EGFR and MET, addresses potential resistance mechanisms, as approximately one-third of patients progressing on osimertinib have MET amplifications or mutations. More recently, amivantamab was approved in the frontline setting in combination with lazertinib, also a third-generation TKI.
Perioperative Immunotherapy in Resectable NSCLC
Recent approvals have expanded the role of perioperative immunotherapy in resectable NSCLC. In August 2024, perioperative durvalumab (Imfinzi) plus chemotherapy was approved, followed by the October 2024 approval of perioperative nivolumab (Opdivo), both for patients with resectable NSCLC without known EGFR mutations or ALK rearrangements. These approvals are based on trials such as the phase 3 KEYNOTE-671 trial (NCT03425643) with durvalumab and the phase 3 CheckMate 816 study (NCT02998528) of nivolumab with chemotherapy.
Questions remain regarding the optimal duration of immunotherapy in patients achieving a complete pathologic response after surgery. Data from CheckMate 816 only included a preoperative arm, while the phase 3 CheckMate 77T study (NCT04025879) and the AEGEAN trial (NCT03800134) evaluated perioperative chemoimmunotherapy. Currently, the decision to continue immunotherapy post-surgery is made on a case-by-case basis, considering patient preferences and potential adverse effects.
HER2-Targeted Therapy with Fam-Trastuzumab Deruxtecan-nxki
Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), a HER2-directed antibody-drug conjugate (ADC), is emerging as a significant treatment option for patients with HER2-mutated NSCLC. For patients with a HER2 mutation, Ashraf would opt for using the ADC T-DXd at the time of progression.
Evolving Treatment Paradigm
The NSCLC treatment landscape is rapidly evolving, offering an increasing number of options for patients with advanced and localized disease. These include earlier generation TKIs, third-generation TKIs like osimertinib, lazertinib with amivantamab, osimertinib with chemotherapy in the first line, and amivantamab combined with chemotherapy in the second line. This represents a significant advancement for patients who previously had limited treatment choices.
