A pivotal phase 3 clinical trial has demonstrated significant benefits of adding the bispecific antibody amivantamab to standard chemotherapy as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations. The international PAPILLON trial, funded by Janssen Research and Development, was published in the New England Journal of Medicine on November 30, 2023.
This randomized, open-label study sought to evaluate the efficacy and safety of amivantamab plus carboplatin-pemetrexed chemotherapy compared to chemotherapy alone in previously untreated patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertions. EGFR exon 20 insertions represent up to 12% of all EGFR-mutated NSCLCs but have historically been challenging to treat, with poor responses to standard EGFR tyrosine kinase inhibitors.
The trial enrolled 308 patients across multiple countries, randomizing 153 to receive amivantamab plus chemotherapy and 155 to receive chemotherapy alone. Key eligibility criteria included having advanced NSCLC with confirmed EGFR exon 20 insertions and no prior systemic therapy, though brief treatment with an approved EGFR tyrosine kinase inhibitor was allowed if lack of response was documented. Patients with treated, stable brain metastases were eligible.
The study population was representative of the typical demographics seen in EGFR-mutated NSCLC, with a high proportion of female patients (58%), Asian patients (61%), and never-smokers (58%). The median age was 61-62 years across the two arms.
The primary endpoint was progression-free survival as assessed by blinded independent central review. Secondary endpoints included objective response rate, overall survival, duration of response, and safety.
The results showed a striking benefit with the addition of amivantamab to chemotherapy. Median progression-free survival was 11.4 months in the amivantamab-chemotherapy arm compared to 6.7 months with chemotherapy alone (hazard ratio 0.40, p<0.001). The progression-free survival advantage was consistent across all pre-specified subgroups.
Objective response rates were also significantly higher with amivantamab-chemotherapy (73% vs 47%, p<0.001), and responses were more durable (median duration 9.7 vs 4.4 months). At 18 months, 31% of patients in the amivantamab-chemotherapy arm remained progression-free compared to just 3% in the chemotherapy-alone arm.
While overall survival data were not mature at the time of this interim analysis, there was a trend towards improved survival with amivantamab-chemotherapy (hazard ratio 0.67, p=0.11) despite high crossover rates. Sixty-six percent of patients in the chemotherapy arm crossed over to receive amivantamab monotherapy upon disease progression.
The safety profile was generally consistent with the known effects of the individual agents. The most common adverse events with amivantamab-chemotherapy were neutropenia (59%), paronychia (56%), and rash (54%). Grade 3 or higher adverse events occurred in 75% of patients receiving amivantamab-chemotherapy versus 54% with chemotherapy alone, driven primarily by skin toxicities and hematologic effects.
Infusion-related reactions occurred in 42% of patients receiving amivantamab-chemotherapy, lower than rates seen in previous studies of amivantamab monotherapy. This may be related to increased use of premedication steroids for chemotherapy. Seven percent of patients discontinued amivantamab due to adverse events.
The study had some limitations, including its open-label design and the relatively short follow-up for overall survival data. Additionally, as with many oncology trials, the study population may not fully represent the general patient population in clinical practice.
Nevertheless, the authors concluded that amivantamab plus chemotherapy demonstrated superior efficacy compared to chemotherapy alone as first-line treatment for patients with advanced NSCLC harboring EGFR exon 20 insertions. The combination resulted in significantly longer progression-free survival, higher response rates, and more durable responses.
The potential clinical impact of these findings is substantial. EGFR exon 20 insertion-positive NSCLC has been a challenging subtype to treat, with poorer outcomes compared to more common EGFR mutations. The PAPILLON trial establishes a new potential standard of care for first-line treatment of these patients. The magnitude of benefit seen with the addition of amivantamab to chemotherapy is clinically meaningful and may change practice patterns.
These results also underscore the importance of comprehensive molecular testing in advanced NSCLC to identify actionable mutations like EGFR exon 20 insertions. The study supports recommendations to perform next-generation sequencing rather than relying on more limited PCR-based assays, which may miss up to 50% of EGFR exon 20 insertions.
Furthermore, the trial highlights the potential of bispecific antibodies like amivantamab in overcoming resistance mechanisms that limit the efficacy of tyrosine kinase inhibitors in this subtype of NSCLC. The multiple mechanisms of action of amivantamab, including EGFR and MET inhibition as well as potential immune cell engagement, may contribute to its efficacy.
While the safety profile requires careful management, particularly for skin toxicities and infusion reactions, most adverse events were manageable with supportive care and dose modifications. Ongoing studies are evaluating strategies to mitigate infusion reactions, including a subcutaneous formulation of amivantamab.
As with any new treatment regimen, long-term follow-up will be important to assess durability of responses and overall survival benefit. The final overall survival analysis from PAPILLON is planned at approximately 48 months after the first patient was randomized.
In conclusion, the PAPILLON trial represents a significant advance in the treatment of EGFR exon 20 insertion-positive NSCLC. It provides robust evidence supporting the addition of amivantamab to standard platinum-based chemotherapy as a new first-line treatment option for these patients. The results may lead to updated treatment guidelines and regulatory approvals, potentially changing the standard of care for this molecularly defined subgroup of NSCLC patients.
References
Zhou C, Tang KJ, Cho BC, et al. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med. 2023;389(22):2039-2051. doi:10.1056/NEJMoa2306441
