Chipping Away at Targetable Mutations in NSCLC: Amivantamab in NSCLC With MET Exon 14 Skipping Mutations

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Dual targeting with the bispecific antibody amivantamab-vmjw showed antitumor activity and tolerability in patients with metastatic non–small cell lung cancer (NSCLC) and MET exon 14 skipping mutations, according to results of the ongoing phase I CHRYSALIS study.1,2 Updated results were presented by lead author Matthew Krebs, MD, PhD, Clinical Senior Lecturer in Experimental Cancer Medicine at The University of Manchester and a consultant in medical oncology at The Christie Hospital, Manchester, United Kingdom at the 2022 ASCO Annual Meeting.

These findings add to the growing body of evidence supporting therapies targeted to rare mutations in NSCLC. First, drug targeting EGFR were developed, and now there are therapies targeting ALK, ROS, RET, and KRAS. Most recently, the rarer mutations are getting attention—for example, EGFR exon 20 insertions and MET exon 14 skipping mutations—increasing the population of patients with NSCLC who are suitable for targeted therapy.

Study Background

“Until recently, there haven’t been therapies targeted to NSCLC with MET exon 14 skipping mutations, which accounts for only about 3% of all NSCLC cases,” said Dr. Krebs. Now two tyrosine kinase inhibitors are approved in the United States andthe European Union for NSCLC with MET exon 14 skipping mutations: capmatinib and tepotinib.

With these drugs, response rates have been around 41% to 43% in patients with metastatic NSCLC with MET exon 14 skipping mutations, many of whom have been treated with more than one prior line of therapy. “The response rate for treatment-naive patients is higher,” Dr. Krebs noted.

“Amivantamab has a different mechanism of action than tyrosine kinase inhibitors. It is a bispecific antibody that targets both EGFR and MET.”
— Matthew Krebs, MD, PhD

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“Amivantamab has a different mechanism of action than tyrosine kinase inhibitors. It is a bispecific antibody that targets both EGFR and MET. That’s why it can work in both NSCLC with EGFR 20 insertions and NSCLC with MET exon 14 skipping mutations. Together, these populations account for about 4.5% of all lung cancers,” Dr. Krebs explained.

Both genetic abnormalities tend to be more prevalent in adenocarcinoma patients, females, and nonsmokers. “There are not a lot of data on this relatively rare mutation set. Historically, these patients have been treated with standard chemoimmunotherapy. My feeling is that the prognosis [for both mutation groups] has been similar to non–genomically driven NSCLC,” he continued.

Amivantamab is approved for the treatment of NSCLC with EGFR exon 20 insertions in the postplatinum setting, with a response rate of 40% and median duration of response of 11.1 months, Dr. Krebs explained.

“We know amivantamab can work for EGFR-mutated (exon 20 insertion) NSCLC. This study was initiated to explore the MET side. Amivantamab has a higher affinity for MET than EGFR,” he noted.


The multicenter, multicohort phase I CHRYSALIS study results reported by Dr. Krebs pertain to the cohort of 55 patients with metastatic NSCLC and MET exon 14 skipping mutations. At baseline, 9 patients were treatment-naive, 18 had previous treatment but no prior MET inhibitor therapy, and 28 were previously treated with chemotherapy with or without immunotherapy and a prior MET inhibitor. The median age was 70, and there were slightly more females than males.

“The group previously treated with a MET inhibitor had a worse prognosis, as they had received more prior lines of therapy and had a higher incidence of previous brain metastasis than the ­previously treated patients who had not previously received a MET inhibitor,” Dr. Krebs said.

Among the 55 patients in the cohort, about 50% were smokers and the other 50% were nonsmokers. “This is an important point,” Dr. Krebs emphasized. “The common perception is that nonsmokers are the patients with genetically driven disease. It would be a mistake to think that a smoker may not herald one of thesemutations.”

In countries like the United States and United Kingdom, next-generation sequencing is available and should be done on all NSCLC patients, because it will detect these specific subsets of mutations that are targetable. “Just testing for EGFR will not pick up some of the rare mutations. You need next-generation sequencing,” he stated.

Patients weighing less than 80 kg were treated with amivanta­mab at 1,050 mg, and those who weighed 80 kg or more received 1,400 mg. Patients received one cycle with weekly treatments, and thereafter, biweekly until disease progression.

Key Findings

The confirmed overall response rate with amivantamab monotherapy was 33% in all patients. “When you look at the details, prior treatment accounted for the difference,” Dr. Krebs explained.

The overall response rate in treatment-naive patients was 57%; in patients not treated with a prior MET inhibitor, the overall response rate was 47% (“which is comparable to that of the two U.S. Food and Drug Administration (FDA)-approved tyrosine kinase inhibitors,” he said). Among patients who had received a prior MET inhibitor, the overall response rate was 17%.

Commenting on the latter group, Dr. Krebs said: “The overall response rates are modest, but this is a poor prognostic group, with more prior therapy, more brain metastasis, and prior treatment with a MET inhibitor.” A total of 11 of 15 patients who responded have an ongoing response, and 10 patients responded for 6 months or longer. “The longest ongoing responder is at 76 weeks. We are seeing durable benefit,” he emphasized.

The clinical benefit rate, which included patients who responded and those with stable disease on treatment, was 59% for the whole cohort, 71% in treatment-naive patients, and 53% in those with no prior MET inhibitor therapy.

“Interestingly, the clinical benefit rate was still 58% in those with prior MET inhibitor treatment, even though the response rate was only 17% for this subgroup. So a significant proportion of these patients had durable benefit with disease stability,” he continued.

Median progression-free survival among all patients was 6.7 months, not evaluable for treatment-naive patients, 8.3 months for those who had not received prior MET inhibitor therapy, and 4.2 months for those who had received a prior MET inhibitor. The median time to response was 1.6 months.

Adverse Events

“Adverse events for this patient group are similar to the larger safety population of multiple cohorts in CHRYSALIS. The safety signals are similar in NSCLC with MET exon 14 skipping mutations,” Dr. Krebs noted. “The toxicities are in keeping with EGFR and MET inhibition—rash, paronychia with EGFR inhibition, and hyperalbuminemia and peripheral edema with MET inhibition. These are on-target effects.”

Infusion-related reactions occur with amivantamab, and these are mainly grades 1 and 2. They tend to occur mainly with the first exposure to the drug and can be managed by infusion interruption, standard supportive medicines, and by restarting the infusion at a slower rate.

Future Directions

“The takeaway message of this ongoing phase I study is that amivantamab has promising activity in this group of patients with MET exon 14 skipping mutations, with response rates that are similar to those with FDA-approved [tyrosine kinase inhibitors]. The durability of response is promising. We will look at this more closely as we accrue more patients,” he said. The investigators plan to accrue up to a total of 100 patients in the phase II expansion.

Dr. Krebs said: “The durability appears promising. If the duration of response and progression-free survival data continue to show that amivantamab is comparable or favorable to that of the approved [tyrosine kinase inhibitors], it could provide an alternative option for patients either in the postplatinum setting or even upfront treatment (although further data are needed). Amivantamab could also have a role in the post-[tyrosine kinase inhibitor] setting given the durability of treatment response and stability in those patients. It depends on what the emerging data show,” he noted.

“The toxicity profile may be more favorable, but this needs to be borne out,” he continued. “We don’t have any data yet on the effect of this drug on brain metastasis for patients with MET exon 14 skipping mutations. This will be important information to have when choosing treatment. To me, the important question is how to sequence the available drugs and understand resistance mechanisms to tyrosine kinase inhibitors, to decide which patients could benefit from a tyrosine kinase inhibitor or amivantamab.”

Dr. Krebs said that, to his knowledge, there are no other bispecific antibodies in development that target NSCLC MET exon 14 skipping mutations. 


DISCLOSURE: Dr. Krebs has received honoraria from Roche; has served as a consultant or advisor to Achilles Therapeutics, Bayer, Guardant Health, Janssen, OM Pharma, Roche, and Seattle Genetics; has served on a speakers bureau for Janssen and Roche; has received institutional research funding from Roche; and has received reimbursement for travel, accommodations, or other expenses from AstraZeneca, BerGenBio, and Immutep.


1. Krebs M, Spira AI, Cho BC, et al: Amivantamab in patients with NSCLC with MET exon14 skipping mutation: Updated results from the CHRYSALIS study. 2022 ASCO Annual Meeting. Abstract 9008. Presented June 3, 2022.

2. Park K, Hara EB, Leighl NB, et al: Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: Initial results from the CHRYSALIS phase I study. J Clin Oncol 39:3391-3402, 2021.

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Ben Creelan, MD, Associate Member of Moffitt Cancer Center, Tampa, Florida, provided some context for the CHRYSALIS study. “This dual bispecific antibody targeting both EGFR and MET clearly has potent single-agent activity in patients with MET exon 14 skipping NSCLC,” he said.