Clinical Pearls & Morning Reports
Published November 29, 2023
Zhou et al. conducted the phase 3, international, randomized PAPILLON trial to assess the efficacy and safety of amivantamab plus chemotherapy as compared with standard chemotherapy alone as first-line treatment in patients with advanced non–small-cell lung cancer (NSCLC) with EGFR exon 20 insertions. Read the NEJM Original Article here.
Q: How common is NSCLC with insertions in EGFR exon 20?
A: Alterations in the gene encoding epidermal growth factor receptor (EGFR) are among the most frequent activating mutations in NSCLC. Insertions in exon 20 are the third most common type of EGFR mutation, representing up to 12% of all EGFR-mutated NSCLCs. Because of an altered conformation at the kinase-active site that limits the binding of tyrosine kinase inhibitors, NSCLC with insertions in EGFR exon 20 is largely insensitive to tyrosine kinase inhibitors that have been approved for the treatment of patients with common EGFR-mutated NSCLC.
Q: Is NSCLC with EGFR exon 20 insertions responsive to immunotherapy?
A: The first-line standard therapy for locally advanced or metastatic NSCLC with EGFR exon 20 insertions remains platinum-based chemotherapy, owing to the lack of targeted therapies and no demonstrated benefit from immunotherapies. In such cases, platinum-based chemotherapy is associated with an objective response of 23 to 29% and a median progression-free survival of 3.4 to 6.9 months. Although patients with common EGFR-mutated NSCLC have a median overall survival of up to 38.6 months, recent analyses of real-world data obtained from patients with advanced NSCLC with EGFR exon 20 insertions showed a median overall survival ranging from 16.2 to 24.3 months, with a 5-year overall survival of 8%.
A: The authors found that the receipt of amivantamab–chemotherapy treatment significantly prolonged progression-free survival as compared with chemotherapy alone according to blinded independent central review (hazard ratio for disease progression or death, 0.40; 95% CI, 0.30 to 0.53; P<0.001). Similar progression-free survival benefit was observed according to investigator assessment. Moreover, the progression-free survival benefit was observed across all prespecified subgroups according to race, age, sex, history of smoking, ECOG performance-status score, and history of brain metastases. The majority of grade 3 or higher adverse events were driven by skin-related EGFR toxic effects observed with amivantamab, such as rash, paronychia, and dermatitis acneiform, and reversible hematologic effects, such as neutropenia, associated with chemotherapy.
A: Although the number of deaths in the trial was too few to provide robust conclusions, the interim overall survival analysis (at 33% data maturity) showed evidence of improved survival with first-line amivantamab–chemotherapy despite a high frequency of crossover to second-line amivantamab monotherapy in the chemotherapy group. A final overall survival analysis is planned at approximately 48 months after the first patient underwent randomization.