EGFR-MET Bispecific Antibody Amivantamab Excels in Advanced EGFR-Mutant NSCLC


The combination of amivantamab and lazertinib demonstrated high response rates and was well tolerated in treatment-naïve and osimertinib-resistant patients with advanced EGFR-mutant non–small cell lung cancer.

Byoung Chul Cho, MD, PhD

The combination of amivantamab (JNJ-61186372; JNJ-6372) and lazertinib demonstrated high response rates and was well tolerated in treatment-naïve and osimertinib (Tagrisso)-resistant patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC), according to findings from the phase 1 CHRYSALIS study that were presented during the 2020 ESMO Virtual Congress.

At a median follow-up of 7 months in treatment-naïve patients, the objective response rate (ORR) and the clinical benefit rate (CBR) was 100% (95% CI, 83%-100%), consisting of 20 partial responses (PRs).

At a median follow-up of 4 months in osimertinib-resistant, chemotherapy-naïve patients, the ORR was 36% (95% CI, 22%-51%). The ORR consisted of 1 complete response (CR) and 15 PRs, with 1 pending confirmation of PR. The CBR was 60% (95% CI, 44%-74%).

“Amivantamab with lazertinib is efficacious in advanced EGFR-mutant NSCLC and can be safety combined,” said Byoung Chul Cho, MD, PhD, lead study author and professor in the Division of Medical Oncology at Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, in a virtual presentation of the data.

Amivantamab is a fully human bispecific antibody that targets EGFR and MET. The antibody has immune cell-directing activity, including antibody-dependent cell cytotoxicity, and demonstrated clinical activity in patients with primary and acquired EGFR resistance mutations.

Lazertinib is a potent third-generation EGFR TKI that demonstrated activity in patients with activating EGFRmutations, T790M resistance mutations, and central nervous system (CNS) disease. With low rates of EGFR-related toxicity, such as rash and diarrhea, the safety profile of the agent supports its use in combination with other EGFR inhibitors.

On March 10, 2020, the FDA granted a breakthrough therapy designation to amivantamab for the treatment of patients with EGFR-positive metastatic NSCLC who harbor exon 20 insertion mutations, and whose disease has progressed on or after platinum-based chemotherapy.2

The designation is supported by earlier findings from CHRYSALIS, in which amivantamab elicited preliminary responses in patients with NSCLC, including those who have relapsed EGFR-mutant disease and those with exon 20 insertions.3

To be eligible for enrollment in the study, patients had to have metastatic or unresectable NSCLC and an EGFR exon19 deletion or L858R mutation. In the expansion cohort, patients had to have measurable disease.

In the dose-escalation portion of the study, patients first received a weight-dependent dose of intravenous amivantamab (700 mg, < 80 kg; 1050 mg, ≥ 80 kg) every week for 4 weeks and every 2 weeks thereafter plus 240 mg of oral lazertinib once daily. Patients were then escalated to 1050 mg (< 80 kg) and 1400 mg (≥ 80 kg) of amivantamab. Among the 26 patients in the dose-escalation cohort, no dose-limiting toxicity was reported, and the recommended phase 2 dose was 1050/1400 mg of amivantamab and 240 mg of lazertinib.

“The recommended phase 2 combination dose was equivalent to the recommended monotherapy doses of each molecule,” said Cho.

The expansion cohorts included patients with osimertinib-resistant, chemotherapy-naïve EGFR-mutant NSCLC (n = 45) and treatment-naïve EGFR-mutant NSCLC (n = 20).

The patient characteristics are consistent with those of patients with EGFR-mutant NSCLC, said Cho. The median age was 61, and more than half of patients were female (n = 52; 57%) and never smokers (n = 50; 55%). A total of 34 patients (37%) had previously reported brain metastases at baseline. Additionally, patients had received a median of 2 prior lines of therapy (range, 0-9), and the majority (n = 53; 58%) had received a prior third-generation EGFR TKI.

In the treatment-naïve cohort, the median treatment duration was 7 months (range, 3-10). The time to first response was rapid, at a median of 1.5 months (range, 1.2-2.6). The median duration of response was not estimable.

“All patients showed deep responses, regardless of EGFR genotype,” said Cho.

In the osimertinib-resistant, chemotherapy-naïve cohort, the median duration of treatment was 5 months (range, 0.3-15). Notably, responses were observed regardless of whether patients received osimertinib in the first- or second-line setting, or had any prior exposure to lazertinib.

Moreover, 14 of 16 patients have ongoing response, and 4 patients are continuing treatment beyond progression. Only 4 of 45 patients required dose reductions.

“With a median follow-up of 4 months, the majority of patients are still [on treatment],” said Cho. “Responses seem to be rapid and durable.” 

Regarding safety in the total population (n = 91), the adverse effects (AEs) that occurred in at least 15% of patients included rash (85%), paronychia (53%), stomatitis (33%), pruritus (28%), diarrhea (18%), hypoalbuminemia (37%), peripheral edema (18%), infusion-related reaction (IRR; 65%), nausea (28%), decreased appetite (20%), increase alanine aminotransferase (21%), paresthesia (20%), constipation (18%), increased aspartate aminotransferase (18%), dizziness (17%), and fatigue (15%).

The majority of IRRs (65%) occurred during the first infusion and all were grade 1/2. Moreover, no discontinuations nor any impact on subsequent dosing due to IRRs was reported.

All-cause serious AEs occurred in 29% of patients, 6% of which were treatment related. All-cause and treatment-related grade 3 or greater AEs occurred in 34% and 11% of patients, respectively.

Grade 3 or greater treatment-related AEs included rash (4%), hypoalbuminemia (2%), increased gamma-glutamyl transferase (1%), hyponatremia (1%), paronychia (1%), and interstitial lung disease (1%). The median time to onset for rash was 16 days, with a median duration of 29 days (range, 1-272). One patient discontinued the combination due to rash.

All-cause AEs leading to death occurred in 3 patients; 1 treatment-related death was reported and was attributed to progressive disease. Related AEs that led to dose interruption or reduction of either or both drugs occurred in 19% of patients. Related AEs that led to discontinuation of either or both drugs occurred in 5 patients. 

“There was similar incidence of adverse events across dose-escalation, treatment-naïve, and osimertinib-resistant cohorts,” said Cho. 

Based on the promising safety and efficacy data reported herein, new studies with amivantamab and lazertinib have been initiated, including the phase 3 MARIPOSA and phase 2 CHRYSALIS-2 studies in the frontline and chemotherapy-relapsed settings, respectively, concluded Cho.


  1. Cho BC, Lee KH, Cho EK, et al. Amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation EGFR tyrosine kinase inhibitor, in advanced EGFR-mutant NSCLC. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 1258O.
  2. Janssen announces U.S. FDA breakthrough therapy designation granted for JNJ-6372 for the treatment of non-small cell lung cancer. News release. March 10, 2020. Accessed September 20, 2020.
  3. Haura EB, Cho BC, Lee JS, et al. JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(suppl 15):9009. doi:10.1200/JCO.2019.37.15_suppl.9009
Related Videos
Peter Schmid, MD, PhD
Seema A. Khan, MD
Stephanie L. Graff, MD
Senthil Damodaran, MD, PhD
Jason Jincong Freeman, PhD
Heather A. Parsons, MD, MPH
A panel of 5 experts on lung cancer seated at a long table
Joshua K. Sabari, MD, and Marina Chiara Garassino, MD, experts on non-small cell lung cancer
A panel of 5 experts on lung cancer
A panel of 5 experts on lung cancer