Lung Cancers With Rare EGFR Mutations Being Tackled by Novel Agents

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Next-generation inhibitors of epidermal growth factor receptor (EGFR) exon 20 insertion mutations showed promise in patients with advanced non–small cell lung cancer (NSCLC) in early-phase trials presented during the International Association Society for Lung Cancer 2020 World Conference on Lung Cancer in Singapore, which was held virtually in January 2021.1,2

Mutations in exon 20 insertion are the third most common mutation in EGFR, after exon 19 deletions and L858R, and are insensitive to EGFR tyrosine kinase inhibitors. These challenging tumors lack an approved targeted agent, and platinum-doublet chemotherapy remains the standard of care. Agents that selectively target this alteration are expected to be more effective in treating this NSCLC subset than currently available EGFR inhibitors.

Both amivantamab (JNJ-6372) and mobocertinib (TAK-788), which were evaluated in the studies reported at this meeting, have received Breakthrough Therapy designation from the U.S. Food and Drug Administration for patients with EGFR exon 20 insertion–mutant metastatic NSCLC whose disease has progressed on or after front-line therapy.

The EGFR-MET–bispecific antibody amivantamab elicited sustained responses in pretreated patients in the phase I CHRYSALIS trial.1 Response was maintained for 6 months or longer for 63% of responders, and 47% remained on the drug for more than 9 months, reported Joshua K. Sabari, MD, of New York University Langone’s Perlmutter Cancer Center. “Amivantamab shows robust efficacy,” he said.

Joshua K. Sabari, MD

Joshua K. Sabari, MD

Caicun Zhou, MD

Caicun Zhou, MD

Similarly, in a phase I/II trial reported at the meeting, the EGFR tyrosine kinase inhibitor mobocertinib yielded confirmed responses in 23% to 26% of previously treated patients per independent review and in 32% to 36% per investigator assessment.2 The median progression-free survival exceeded 7 months, according to Caicun Zhou, MD, of Shanghai Pulmonary Hospital, China.

Sustained Responses With Amivantamab

“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,” said Dr. Sabari, who presented these study findings. “Results from the CHRYSALIS study demonstrate the potential for amivantamab to address this critical unmet need and provide an important clinical benefit to patients.”

Amivantamab is a fully human EGFR-MET–bispecific antibody with immune cell–directing activity. It targets activating and resistance EGFR mutations and MET mutations and amplifications. Amivantamab has shown single-agent activity in patients with diverse EGFR-mutated disease, including tumors with EGFR exon 19 deletions, L868R mutations, as well as T790M and C797S resistance mutations; and exon 20 insertions and MET amplifications. By binding the extracellular site of the domain of the receptors, amivantamab can bypass primary and secondary resistance to tyrosine kinase inhibitors at the active site, explained Dr. Sabari.

Amivantamab activity compares favorably to currently available treatment options for exon 20 insertion–mutant non–small cell lung cancer.
— Joshua K. Sabari, MD

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The ongoing phase I CHRYSALIS study of amivantamab comprised dose-escalation and dose-expansion portions; patients received the recommended phase II dose of 1,050 mg if they were < 80 kg and 1,400 kg if they were ≥ 80 kg. Of the 114 patients in the safety population, 81 had at least 3 disease assessments at data cutoff and comprised the efficacy population. The primary endpoint was overall response rate.

At a median follow-up of 9.7 months, the objective response rate was 40%, including 3 complete responses and 29 partial responses; the median duration of response was 11.1 months. Stable disease was achieved by 39 patients (48%), for a clinical benefit rate of 74%. 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 more than 9 months. Antitumor activity was observed in all subgroups and across insertion regions of EGFR exon 20. Median progression-free survival was 8.3 months, and median overall survival was 22.8 months, Dr. Sabari reported.

Treatment-related adverse effects occurred in almost all patients, but just 16% were grade ≥ 3. Serious treatment-related adverse events were seen in 9%, but only 4% led to treatment discontinuation. Dose reductions and interruptions occurred in 13% and 21%, respectively. Diarrhea was reported in 12%.

“Amivantamab has a tolerable safety profile consistent with inhibition of EGFR and MET pathways. Treatment-related adverse events were primarily grade 1 or 2, and the rate of treatment-related discontinuation was low. Infusion-related reactions were frequently observed with the first infusion but did not impact the ability to continue with subsequent treatments,” he said.

“Amivantamab activity compares favorably to currently available treatment options for exon 20 insertion–mutant NSCLC,” Dr. Sabari said. “Based on amivantamab’s efficacy, combination approaches are being pursued.”

Mobocertinib Activity

Mobocertinib is a small-molecule tyrosine kinase inhibitor designed to selectively target EGFR exon 20 insertion mutations. The drug was studied in a clinical trial that incorporated a phase I dose-escalation and a phase II dose-expansion phase, comprising seven different cohorts.

“We are reporting the first results from the EXCLAIM extension cohort of a phase I/II study. We also are sharing the results in patients with EGFR exon 20 insertion–mutant NSCLC who received prior platinum-based therapy from the dose-escalation/expansion parts of the study and the EXCLAIM extension cohort,” Dr. Zhou said.

Clinically meaningful improvements were observed for dyspnea, coughing, and chest pain [with mobocertinib].
— Caicun Zhou, MD

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In the platinum-pretreated population, subjects were drawn from the dose-escalation and dose-expansion phases. In the phase II extension cohort, known as EXCLAIM, 90% had received prior platinum. In addition, 25% of the platinum-pretreated population cohort and 31% of the EXCLAIM cohort had received an EGFR tyrosine kinase inhibitor, and 43% and 34%, respectively, had received immunotherapy.

All patients were treated with the 160-mg daily dose. The percentage of patients who had received at least two prior lines of therapy was 32% in the platinum-pretreated population cohort and 31% in the EXCLAIM cohort; 27% and 18%, respectively, had received at least three prior treatments. The primary endpoint for the study was confirmed objective response rate by independent central review.

In the platinum-pretreated population cohort, 94 of 114 patients (86%) experienced a reduction from baseline in the diameter of the target lesion. Results were similar in the EXCLAIM cohort, with reductions achieved by 77 of 96 patients (80%).

Dr. Zhou also reported that, based on the European Organisation for Research and Treatment of Cancer quality-of-life scales, “Clinically meaningful improvements were observed for dyspnea, coughing, and chest pain. Mean changes from baseline in scores for these scales were evident in cycle 2 and maintained throughout treatment.”

The safety profile of mobocertinib was consistent with the known profiles of other EGFR tyrosine kinase inhibitors, and side effects were reported to be manageable. The most common treatment-related adverse events included diarrhea, rash, paronychia, nausea, decreased appetite, dry skin, and vomiting. 

DISCLOSURE: Dr. Sabari has served as a consultant or advisor to AstraZeneca, Janssen Oncology, Medscape, Navire Pharma, Pfizer, Regeneron, and Takeda. Dr. Zhou has received honoraria from Boehringer Ingelheim, Hengrui Therapeutics, Innovent Biologics, Lilly, MSD, Qilu Pharmaceutical, and Roche; and has served as a consultant or advisor to Amoy Diagnostics, Hengrui Therapeutics, Innovent Biologics, and Qilu Pharmaceutical.


1. Sabari JK, Shu CA, Park K, et al: Amivantamab in post-platinum EGFR exon 20 insertion mutant non–small cell lung cancer. 2020 World Conference on Lung Cancer. Abstract OA04.04. Presented January 29, 2021.

2. Zhou C, Ramalingam S, Li B, et al: Mobocertinib in NSCLC with EGFR exon 20 insertions: Results from EXCLAIM and pooled platinum-pretreated patient populations. 2020 World Conference on Lung Cancer. Abstract OA04.03. Presented January 29, 2021.

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