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Amivantamab Shows Promise in Challenging EGFR-Mutated NSCLC

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A novel drug, the immune cell-directing antibody amivantamab (under development by Janssen), has shown promise for the treatment of patients with non–small cell lung cancer (NSCLC) with exon 20 insertion mutations in the epidermal growth factor receptor gene (EGFR) after disease progression with chemotherapy.

Results from the phase 1 CHRYSALIS study show that efficacy of the drug is “robust,” with antitumor activity “observed in all patient subgroups,” commented lead researcher Joshua K. Sabari, MD, assistant professor, Department of Medicine, New York University School of Medicine, New York, City.

He added that the tolerability profile of the drug is in line with expectations.

The study was presented at the World Conference on Lung Cancer (WCLC) 2020 on January 29.

Amivantamab is currently awaiting approval in the United States and Europe for use in the treatment of patients with NSCLC and EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. No therapies are currently approved for cancers with this mutation, the company noted. The new drug has been granted breakthrough therapy designation.

“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 used to treat other EGFR mutations,” Sabari commented in the press release.

“This is good news for our patients,” commented Karen Reckamp, MD, director, Division of Medical Oncology, Cedars-Sinai Cancer Institute, Los Angeles, California, who was not involved in the study.

She explained that the percentage of NSCLC cases in which there is an EGFR mutation varies from 15% to 20% among mixed Western populations and is 70% among Asian populations. The exon 20 insertion accounts for about 10% of all EGFR mutations.

“With a worldwide incidence of 2 million cases, this is a substantial group of patients who may benefit from novel therapies,” she told Medscape Medical News.

The management of these patients has been a “challenge”; however, “unlike activating mutations, the conformation does not allow for optimal binding of standard EGFR tyrosine kinase inhibitors [TKIs], resulting in limited efficacy,” she said.

Reckamp pointed out that the population included in the current study was “heterogeneous with respect to number of prior therapies, and the follow-up is less than a year, so these results will need to mature.”

Nevertheless, “if the numbers remain in the range of these phase 1 data, this therapy would benefit most patients with EGFR exon 20–mutant NSCLC,” she said; the activity of the drug is “promising,” and the toxicity is “as we would expect.”

Details of CHRYSALIS Results

Amivantamab is a fully human bispecific antibody that targets both activating and resistance EGFR mutations and MET mutations and amplifications. It has been shown to be active as monotherapy for patients with a range of EGFR mutations.

The current analysis from the CHRYSALIS trial was based on 81 patients with NSCLC with EGFR exon 20 insertions who had experienced disease progression with platinum-based chemotherapy. The median age of the patients was 62 years, and 41% were men.

The majority of patients were Asian (49%) or White (37%). Just over half (53%) were nonsmokers. The median number of prior lines of therapy was two; 46% had undergone immunotherapy in addition to chemotherapy, and 25% had received a TKI.

All patients received amivantamab. Patients who weighed <80 kg received a dose 1050 mg, and those who weighed ≥80 kg received a dose of 1400 mg.

After a median follow-up of 9.7 months, for patients who received amivantamab, the overall response rate was 40% at a median duration of response of 11.1 months. The clinical benefit rate, defined as a complete or partial response or stable disease on at least two disease assessments, was 74%.

The drug appeared to be equally effective across subgroups based on age, sex, race, prior lines of therapy, and history of smoking.

On the basis of the current data, the team calculates that the median progression-free survival with amivantamab was 8.3 months and that the median overall survival was 22.8 months.

Commenting on these results on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, DC, said the dosing schedule for the drug is “suboptimal for convenience” but that it is “effective and well tolerated.”

Consequently, he looks forward to “having this as an option.”


A safety analysis based on this study and on a prior dose-escalation study showed that the most common treatment-emergent adverse events were rash (86%), infusion-related reactions (66%) and paronychia (45%). Stomatitis (21%) and pruritus (17%) were also reported. Sabari noted that diarrhea occurred in 12% of patients; for 3.5% of patients, the diarrhea was of grade 3.

Adverse events of grade ≥3 were reported in 35% of patients; 16% of those events were considered treatment related. Rash (4%) and infusion-related reactions (3%) were were the most frequent.

No treatment-related deaths were reported. Treatment-related adverse events led to dose reductions in 13% of patients and to discontinuation in 4%.

The manufacturer notes that clinical development of amivantamab in untreated advanced EGFR-mutated NSCLC is continuing in the phase 3 MARIPOSA and PAPILLON combination trials.

The study was sponsored by Janssen Research & Development, LLC. Sabari has relationships with AstraZeneca, Genentech, Janssen, Navire, Pfizer, Regeneron, Sanofi Genzyme, Takeda. Reckamp has relationships with Janssen.

World Conference on Lung Cancer (WCLC) 2020: Abstract OA04.04. Presented January 29, 2021.

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