Results of the phase 1 CHRYSALIS trial demonstrated the safety and efficacy of amivantamab in patients with previously treated non–small cell lung cancer harboring EGFR exon 20 insertion mutations.
In patients receiving amivantamab (formerly JNJ-6372) for previously treated non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, deep and durable responses as well as promising survival were reported at the 2020 World Conference on Lung Cancer (WCLC) Singapore from the phase 1 CHRYSALIS trial (NCT02609776).1
Of note, 63% of patients who achieved responses maintained their response for at least 6 months and 47% remained on therapy after a median follow-up of over 9 months.
“There is a significant need for new treatment options for patients with NSCLC and EGFR exon 20 insertion mutations whose disease generally does not respond well to chemotherapy and the tyrosine kinase inhibitors [TKIs] used to treat other EGFR mutations,” Joshua K. Sabari, MD, presenting investigator from New York University Langone’s Perlmutter Cancer Center, said in a press release. “Results from the CHRYSALIS study presented today demonstrate the potential for amivantamab to address this critical unmet need and provide an important clinical benefit to patients.”
The study comprised dose-escalation and -expansion portions, with the recommended phase 2 dose (RP2D) of 1050 mg in patients weighing less than 80 kg and 1400 kg in patients 80 kg and above having been previously established in the escalation cohorts. The data presented at this meeting included patients in the post-platinum setting who harbor exon 21 insertion mutations who were treated at the RP2D for the safety analysis (n = 114) and those with 3 or more disease assessments at clinical cut-off as part of the efficacy population (n = 81). The primary end point was the overall response rate (ORR), and key secondary outcomes were the clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
The median follow-up at the clinical cut-off in October 2020 was 9.7 months (range, 1.1-29.3). The ORR was 40% (95% CI, 29%-51%), which was made up of 3 complete responses and 29 partial responses, and the DOR was 11.1 months (95% CI, 6.9-not reached [NR]). Stable disease was noted in 39 patients (48%), for a CBR of 74% (95% CI, 63%-83%), and 8 (10%) had progressive disease.
Among the 63 patients with EGFR exon insertions mutations detectable by circulating tumor DNA, there were 25 distinct variants noted in the helical (n = 1), near loop (n = 54), and far loop (n = 8) regions. These differences did not appear to affect the response.
The median PFS was 8.3 months (95% CI, 6.5-10.9) and the median OS was 22.8 months (95% CI, 14.6%-NR).
Treatment-related adverse effects (TRAEs) occurred in almost all patients, with 16% of patients experiencing these at grade 3 or greater severity. Serious TRAEs were seen in 9%, and 4% had treatment-related events that led to discontinuation. Dose reductions and interruptions deemed to be related to therapy occurred at rates of 13% and 21%, respectively.
The safety profile was considered consistent with the known profiles of agents inhibiting the EGFR and MET pathways. The most common TRAEs of any grade related to EGFR inhibition were rash (86%), paronychia (42%), stomatitis (18%), and pruritis (17%); those related to the MET pathway were hypoalbuminemia (15%) and peripheral edema (10%). Other treatment-related events, such as infusion-related reactions (66%) and fatigue (12%), were also noted. Almost all infusion-related reactions occurred at the first treatment and rarely impacted patients’ ability to continue on therapy.
Baseline patient demographics indicated a cohort that was majority female (59%), with a median age of 62 years (range, 42-84). Patients were equally divided between smokers (47%) and nonsmokers (53%). Forty-nine percent of patients were Asian, 37% were White, and 3% were black. Median time from diagnosis was 17 months (range, 1-130) and previous therapies included platinum-based doublet chemotherapy in all patients, immunotherapy in 46%, and EGFR TKIs in 25%. The median number of prior therapies was 2 (range, 1-7).
“Amivantamab activity compares favorably to currently available treatment options for exon 20 insertion–mutant non–small cell lung cancer,” Sabari said. “Based on amivantamab efficacy, combination approaches are being pursued.”
Mutations in exon 20 insertion are the third most common in EGFR, after L858R and exon 19 deletions, and are insensitive to EGFR TKIs due to an altered conformation of the kinase active site. Tumors with these mutations represent a clinically unmet need as there are no approved targeted therapies available and platinum-doublet chemotherapy remains as the standard of care for these patients.
The fully human EGFR/c-Met bispecific antibody has immune-cell directing activity that targets activating and resistance in EGFR and MET mutations as well as amplifications of MET by 3 demonstrated mechanisms of activity. The agent works on tumor cells by trogocytosis, or “cellular gnawing,” of macrophages and natural killer cells and by receptor degradation via the lysosomal pathway.
“By binding the extracellular site of the domain of the receptors, amivantamab can bypass primary and secondary TKI resistance at the active site,” Sabari said.
In early 2020, the Janssen Pharmaceutical Companies of Johnson & Johnson announced that the FDA had granted amivantamab breakthrough therapy designation for the treatment of patients with NSCLC and an EGFR exon 20 insertion mutation following frontline chemotherapy.2 In December of the same year, the company submitted a biologics license application for approval in the indicated patient population.3
1. Sabari JK, Shu CA, Park K, et al. Amivantamab in post-platinum EGFR Exon 20 insertion mutant non–small cell lung cancer. Presented at: IASLC 2020 World Conference on Lung Cancer Singapore. January 28-31, 2021. Abstract OA04.04
2. Janssen announces U.S. FDA breakthrough therapy designation granted for JNJ-6372 for the treatment of non-small cell lung cancer. FDA. March 10, 2020. Accessed January 29, 2021. https://bit.ly/3op7SdC
3. Janssen submits application to U.S. FDA seeking approval of amivantamab for the treatment of patients with metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. FDA. December 3, 2020. Accessed January 29, 2021. https://bit.ly/3puSRID