Adding amivantamab to chemotherapy improves efficacy outcomes in patients with non-small cell lung cancer harbouring EGFR exon 20 insertion mutations
Patients diagnosed with non-small cell lung cancer (NSCLC) harbouring EGFR exon 20 insertion mutations (Ex20ins) face a poor survival prospect. The standard of care for these patients has long been platinum-based chemotherapy, despite its limited efficacy. The results of the phase III PAPILLON study now demonstrate that adding amivantamab to chemotherapy (ami-chemo) significantly delays disease progression in these patients and results in a higher rate of more durable responses. Based on these results, ami-chemo has the potential to become the new standard of care for first-line EGFR Ex20ins NSCLC.
Background
NSCLC patients with exon 20 insertion mutations in EGFR (EX20ins) face poor outcomes, with a median overall survival (OS) ranging from 16 to 24 months, and a 5-year OS rate of only 8%. Ex20ins are largely insensitive to common EGFR TKIs, and checkpoint inhibitors have failed to show a benefit in this setting. As a result, platinum-based chemotherapy has remained the standard of care for these patients, despite limited efficacy. Amivantamab (ami), an EGFR-MET bispecific antibody, combined with carboplatin/pemetrexed (ami-chemo) was shown to be safety and effective in the phase 1 CHRYSALIS study in patients with advanced NSCLC. Importantly, four out of five patients with treatment-naïve EGFR Ex20ins NSCLC in this trial achieved a partial response as best response to this treatment. These findings formed the basis for the phase III PAPILLON study, evaluating ami-chemo vs. chemo as first-line treatment for patients with advanced EGFR Ex20ins NSCLC.
Methods
The phase III PAPILLON study enrolled patients with treatment-naïve, locally advanced or metastatic NSCLC and a documented EGFR Ex20ins mutation. In total, 308 patients were randomly assigned (1:1) to receive ami-chemo (N= 153) or chemo alone (N= 155) in 21-day cycles. Ami was administered at a dose of 1,400 mg (1,750 mg if ≥80 kg) every three weeks, starting at week 7 (first day of cycle 3). Chemo was administered on the first day of each cycle (carboplatin AUC5 for the first four cycles, pemetrexed 500 mg/m2 until disease progression). The primary endpoint was progression-free survival (PFS), while econdary endpoints included objective response rate (ORR), PFS after first subsequent therapy (PFS2), overall survival (OS), and safety. Crossover to ami monotherapy was allowed for patients with disease progression in the chemotherapy alone arm.
Results
After a median follow-up of 14.9 months, ami-chemo significantly prolonged the PFS compared to chemo alone, with a median PFS of 11.4 and 6.7 months, respectively (HR[95%CI]: 0.395[0.30-0,53]; p<0.0001). At 12 months, this translated into a 48% PFS rate for patients in the ami-chemo arm as compared to 13% with chemo alone. Corresponding rates at 18 months were 31% and 3%. Additionally, patients treated with ami-chemo were more likely to respond to the therapy and responses were also deeper than what was observed with chemo alone. In fact, the ORR reached 73% with ami-chemo as compared to 47% with chemo alone. Additionally, the duration of response (DoR) was significantly prolonged with ami-chemo at a median of 9.7 months as compared to 4.4 months in the chemotherapy group. Importantly, at the time of data cutoff, responses were still ongoing in 49% of patients in the ami-chemo group vs. 17% in the chemo group. Ami-chemo also reduced the risk of second progression or death by over 50% (median PFS2 not reached vs. 17.2 months, respectively; HR[95%CI]: 0.493[0.32-0.76]; p=0.001). At the time of the analysis, the median OS was not reached in either arm, but preliminary data show a trend for a better survival in patients receiving the ami-chemo combination (HR[95%CI]: 0.675[0.42-1.09); p=0.106). Of note, this positive trend was observed despite the fact that 66% (71 out of 107) patients in the chemo arm crossed over to ami at the time of progression.
The incidence of adverse events (AEs) was higher in the ami-chemo group than with chemotherapy alone. In this, it has to be noted that the median treatment duration was markedly longer in the ami-chemo arm than with chemo alone (9.7 vs. 6.7 months, respectively). The rate of serious AEs (37% vs. 31% in the ami-chemo and chemo arms, respectively) and AEs leading to death (5% vs. 3%) were similar in the two arms. The same held true for treatment discontinuation rate of all study agents (8% in both arms). As expected, EGFR- and MET-related AEs were increased with ami-chemo, but they were primarily grade 1-2. Chemotherapy-associated haematologic and GI toxicities were comparable between the arms except for higher incidence of neutropenia in the ami-chemo arm (all grades, 59% vs. 45% in the chemo arm). Finally, pneumonitis was reported in 3% of patients in the ami-chemo arm.
Conclusions
Ami-chemo significantly improved the PFS compared to chemotherapy alone in the first line treatment of patients with advanced NSCLC harbouring an EGFR Ex20ins mutation. In addition, ami-chemo was associated with a higher ORR, a longer DoR and a favourable OS trend. The safety profile remained consistent with that of each individual agent. Based on these results, ami-chemo has the potential to become the new standard of care first-line treatment in this setting.
Reference
Girard N, et al. Amivantamab plus chemotherapy vs chemotherapy as first-line treatment in EGFR Exon 20 insertion-mutated advanced non-small cell lung cancer (NSCLC): Primary results from PAPILLON, a randomised phase III global study. Presented at ESMO 2023; Abstract LBA5.
