Amivantamab OK'd for EGFR-Mutant NSCLC

The FDA granted accelerated approval to amivantamab (Rybrevant; Janssen) in May. The bispecific antibody is the first treatment for patients with non–small cell lung cancer (NCSLC) whose tumors have EGFR exon 20 insertion mutations.

Those patients, who account for 2% to 3% of NSCLC cases, derive little benefit from small-molecule inhibitors aimed at more common EGFR alterations. However, with amivantamab—which is directed against EGFR and MET—the phase I CHRYSALIS study documented a 40% response rate among patients with exon 20 insertions whose disease had progressed despite platinum-based chemotherapy; another 34% of participants experienced stable disease for 11 weeks or longer.

As trial investigator Joshua Sabari, MD, of New York University Langone Health in New York, reported at the 2020 World Conference on Lung Cancer, convened in January 2021, responses were durable, lasting about 11 months on average. Median progression-free survival (PFS) was 8.3 months and median overall survival (OS) was 22.8 months.

“The fact that this is the first FDA-approved targeted therapy in exon 20 is a huge win,” Sabari says. “Now the question is, ‘How do we move this into a frontline setting?’” Trials are under way to make that happen. The randomized PAPILLON study, for example, is comparing amivantamab plus chemotherapy versus chemotherapy alone in patients with exon 20–mutated disease.

Also, unlike other oncologic bispecifics that bind one tumor antigen, with the second arm recruiting T cells, amivantamab is the first to target two tumor antigens—a design that Dietmar Zaiss, PhD, of the University of Edinburgh in the UK, describes as “the next way forward.”

Amivantamab inhibits tumor growth and progression by three distinct mechanisms. As Byoung Chul Cho, MD, PhD, and his colleagues at Yonsei University in Seoul, South Korea, reported last year, the drug blocks ligand binding to its target receptors; it inactivates those receptors via degradation; and it induces immune-directed antitumor activity through the antibody's Fc effector function (Cancer Discov 2020;10:1194–209).

The therapeutic effect is largely mediated by amivantamab's binding to EGFR. But, as Cho points out, MET amplifications are a common cause of acquired resistance to EGFR inhibitors, “so targeting MET in addition to EGFR may prevent or delay resistance.”

Dual targeting also enhances safety, Cho notes, because it ensures the antibody binds to cells that highly express both receptors, a feature of tumors but not normal tissues. That could explain why severe diarrhea and skin rashes—toxicities common to nonselective EGFR inhibitors—are less of an issue with amivantamab, which generally causes only mild inflammatory reactions.

Unlike some experimental EGFR inhibitors, however, amivantamab was not designed specifically to target exon 20 insertion mutations; it binds both wild-type and mutant receptors. Looking to limit target promiscuity, several drug makers have advanced mutation-selective EGFR agents—including BDTX-189 (Black Diamond Therapeutics), CLN-081 (Cullinan Oncology), and DZD9008 (Dizal Pharma)—into phase I testing; some data were presented at the American Society of Clinical Oncology 2021 Annual Meeting, June 4–8.

Like any large antibody drug, amivantamab is not thought to cross the blood–brain barrier, potentially minimizing its clinical utility.

Thus, although Lecia Sequist, MD, MPH, of Massachusetts General Hospital in Boston, says amivantamab's approval is of “landmark importance,” she also views the therapy as “a scaffolding to build upon.” To that end, Janssen is evaluating amivantamab plus lazertinib, its third-generation, brain-penetrant small-molecule EGFR inhibitor, in patients with all manner of EGFR mutations. –Elie Dolgin

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