FDA Approves First Targeted Therapy for EGFR Lung Cancer with Exon 20 Mutations

Just a couple of months after receiving the FDA’s breakthrough therapy designation, Janssen’s Rybrevant has notched an accelerated approval. On May 21, the novel bispecific antibody was greenlit by the agency for treating locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring a rare EGFR mutation. The regulator also approved Guardant Health’s liquid biopsy blood test, Guardant360 CDx, as a companion diagnostic to detect the biomarker.

Rybrevant is the first fully-human, bispecific antibody directed against EGFR and MET genes. While there are many EGFR-targeting drugs in the market for NSCLC, Rybrevant is the first to be FDA-approved for patients with EGFR exon 20 insertion mutations who have progressed on or after platinum-based chemotherapy. Patients with this rare mutation have a worse prognosis and have a median survival of fewer than 17 months.

“The approval of RYBREVANT, along with the companion diagnostic test, addresses high unmet need in the treatment of people with genetically defined non-small cell lung cancer,” said Peter Lebowitz, M.D., Ph.D., Global Therapeutic Area Head, Oncology, Janssen Research & Development, LLC.

Edge Over Existing Treatments

Tyrosine kinase inhibitors (TKIs) such as AstraZeneca’s Tagrisso targets EGFR from inside the cell. However, Rybrevant binds extra-cellularly, enabling it to bypass resistance to existing TKIs. While existing EGFR inhibitors can counteract the more common EGFR alterations at exon 19 and 21, they fail against exon 20 insertions.

Notably, Rybrevant binds to EGFR and MET, directly targeting the tumor cell whilst also recruiting immune cells to mount a response against cancer. Thus, it is anticipated that this unique mechanism of action could make Rybrevant less likely to stimulate tumor resistance than its closest rivals Tagrisso, Iressa, and Roche’s Tarceva.

CHRYSALIS Trial

Rybrevant proved its mettle in a first-in-human study (CHRYSALIS) that enrolled 81 patients whose disease had progressed on or after platinum-based chemotherapy. The Phase 1 trial showed that Rybrevant significantly reduced tumors generating an overall response rate (ORR) of 40%, with a median duration of response of just over 11 months.

Two-thirds (~63%) of them had a response that lasted for at least six months. Median progression free survival (PFS) was 8.3 months, and patients in the trial lived a median of 22.8 months. The study also included an arm that evaluated the safety and efficacy of Rybrevant plus lazertinib, an experimental EGFR tyrosine kinase inhibitor (TKI) that J&J licensed from South Korea’s Yuhan in 2018. The combo registered a 100% ORR in previously untreated EGFR-mutant NSCLC.

Market Competition

Rybrevant’s FDA nod in the exon 20 population, has given Jannsen an opportunity to dominate the market for now, but competition is looming. Japanese drugmaker Takeda’s mobocertinib (TAK-788) is under FDA priority review for chemotherapy-pretreated NSCLC patients with exon 20 insertion mutations.

Janssen is currently eyeing a broader use of Rybrevant. Besides evaluating the bispecific antibody against the more common EGFR alterations at exon 19 and 21, it is also investigating the efficacy of Rybrevant, lazertinib combination.

Preliminary data unveiled at last year’s ESMO meeting showed that the combo reduced the tumors in all of the 20 newly diagnosed EGFR-positive patients. These encouraging results have pushed Janssen to launch a Phase 3 MARIPOSA trial where the combo is pitted against AZ’s Tagrisso. Interestingly, in data released ahead of the ASCO meeting, the combo has demonstrated an impressive clinical response in ~36% of Tagrisso-refractory patients.

By Isha Kapoor, Ph.D.

Editor: Rajaneesh K. Gopinath, Ph.D.

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Isha Kapoor