Johnson & Johnson snares FDA nod for first exon 20-targeted drug in EGFR lung cancer

FDA Building 2
Johnson & Johnson is also testing Rybrevant in combination with lazertinib as a chemo alternative in certain non-small cell lung cancer patients. (FDA)

Just a few short months after Johnson & Johnson's Janssen unit sent its targeted non-small cell lung cancer (NSCLC) drug amivantamab to the FDA, the regulator has come back with a green light—a very specific one.

Now christened Rybrevant, the drug is the first treatment for NSCLC with a group of epidermal growth factor receptor (EGFR) mutations found in 2% to 3% of patients, the FDA said.

The regulator on Friday approved Rybrevant for NSCLC patients whose tumors bear exon 20 mutations and have progressed on or after platinum-based chemotherapy, Janssen said (PDF) in a release. 

Rybrevant is a bispecific antibody that targets EGFR and MET. While other tyrosine kinase inhibitors (TKIs) such as AstraZeneca’s market-leading Tagrisso hit EGFR from inside the cell, Rybrevant attacks from the outside, enabling it to bypass resistance to existing TKIs.

Those earlier EGFR inhibitors are able to tackle two more common EGFR alterations at exon 19 and exon 21, but they don’t work in those with exon 20 insertions.

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Rybrevant proved its mettle in a study of 81 patients whose disease had progressed on or after platinum-based chemo. Because of a lack of proven treatment options, almost all of the patients had also received immuno-oncology therapies, and a quarter had received other TKIs, Mark Wildgust, Janssen’s vice president of global medical affairs, pointed out in an interview. Rybrevant significantly shrank tumors in 40% of patients, with the response lasting a median 11.1 months.

Patients in the trial lived a median 22.8 months, thanks to Rybrevant. That’s compared with 13.1 months for a historic control group of 126 chemo-pretreated patients who got other drugs off-label in the real world, according to an analysis to be presented next month at the virtual American Society of Clinical Oncology meeting.

The comparison “really speaks to the transformational nature of [Rybrevant] and I think really [starts] to address the significant unmet need for these individuals,” Wildgust said.

With the current nod in the exon 20 population, Rybrevant has a niche EGFR NSCLC market all to itself for now, but competition’s looming. Takeda’s oral TKI mobocertinib is also under FDA priority review for chemotherapy-pretreated NSCLC patients with exon 20 insertion mutations. But the small-molecule drug’s efficacy profile doesn’t look as strong in its own clinical trial.

In the study, mobocertinib triggered a response in 26% of 114 patients. The drug didn’t eradicate signs of cancer in any patient, while Rybrevant achieved the so-called complete response in three patients in its separate trial. Cross-trial comparisons have their intrinsic problems, such as different baseline patient characteristics, but industry watchers as well as physicians often do it anyway.

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J&J is also eyeing broader use of Rybrevant in those more common EGFR-mutated lung cancers. The drug’s ability to mobilize immune cells, plus its dual targeting of MET—which is a resistance mechanism by EGFR-driven NSCLC—could make it work there, Wildgust said.

To further secure success, the company is testing the drug alongside lazertinib, a small-molecule EGFR inhibitor Janssen picked up from South Korea's Yuhan in 2018. The combo could target EGFR from both outside and inside the cell, and “we think that type of complete blockade of the receptors could be highly effective,” Wildgust said.

Early data have been encouraging. In 20 newly diagnosed EGFR-positive patients, the combo shrunk tumors in all of them, according to data unveiled at last year’s European Society for Medical Oncology virtual meeting.

J&J’s so confident in the combo that it has launched a phase 3 trial dubbed Mariposa pitting it against current standard-of-care Tagrisso in front-line disease.

At least the cocktail appeared to work in patients whose disease worsened after Tagrisso. In data released ahead of the ASCO meeting, the Rybrevant-lazertinib combo turned out a response in 36% of Tagrisso-refractory patients. 

The company now aims to fine-tune its genetic testing to ID patients most likely to respond.