EGFR exon 20

Johnson & Johnson believes its lung cancer regimen of Rybrevant and lazertinib could together reach more than $5 billion in peak sales. Johnson & Johnson continues to grow its oncology franchise with a new FDA approval that opens the lung cancer drug Rybrevant to treating certain newly diagnosed patients. Friday’s approval allows Rybrevant to be used alongside the chemotherapies carboplatin and pemetrexed as a first-line treatment for advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations. Simultaneously, Rybrevant’s original accelerated approval as a single agent for chemo-pretreated tumors has been converted to a full approval, the agency said. Rybrevant’s first-line nod comes five months after Takeda announced a voluntary market withdrawal of its rival EGFR exon 20 NSCLC drug, Exkivity, which failed as a monotherapy in its own first-line trial. Before their divergent phase 3 reports, the two drugs were sharing the second-line market roughly 50-50. The FDA considered positive data from the phase 3 PAPILLON trial in granting Rybrevant the first-line indication. Compared with chemo alone, the combination of Rybrevant and chemo cut the risk of progression or death by 60% in patients with NSCLC with EGFR exon 20 insertion mutations. Patients who received the J&J bispecific went 11.4 months without their disease worsening, compared with 6.7 months for those in the control arm. While patient survival data remained immature—with only 44% of deaths required for the final overall survival analysis—“no trend towards a detriment was observed,” the FDA noted in Rybrevant’s new label. Previously, with 33% data maturity, the Rybrevant-chemo regimen showed a trend toward a 33% reduction in the risk of death. Nearly half of patients in the chemo-alone arm later went on to receive single-agent Rybrevant following disease progression. Although Takeda’s Exkivity is out of the picture, other small-molecule agents targeting EGFR exon 20 NSCLC are biding their time to challenge J&J’s antibody drug. ArriVent BioPharma, which recently staged an upsized IPO, is working on a pan-EGFR mutant inhibitor called furmonertinib. The drug, licensed to ArriVent by Allist Pharma, was approved in China originally for second-line treatment of NSCLC with certain EGFR mutations; it moved into the first line in 2022. Following a similar development strategy as Takeda’s approach, Arrivent is currently running the phase 3 FURVENT trial testing furmonertinib monotherapy against chemo in previously untreated NSCLC with EGFR exon 20 insertion mutations. Meanwhile, AstraZeneca spinout Dizal Pharmaceutical is also looking to bring its China-approved sunvozertinib to EGFR exon 20 NSCLC in the U.S. market. Dizal also has a phase 3 trial evaluating the drug by itself against chemo in the first-line setting, and the company recently told Fierce Biotech that it was talking to Big Pharma companies about a potential partnership. EGFR exon 20 mutations only represent a small market, with an estimated frequency of about 0.1% to 4% of all NSCLC cases. For Rybrevant, the most important indication would be first-line NSCLC with the more prevalent exon 19 or exon 21 abnormalities, where AstraZeneca’s blockbuster Tagrisso is king. There, J&J recently earned FDA priority review for its application of Rybrevant and its Yuhan-partnered lazertinib based on a head-to-head win against Tagrisso in the phase 3 MARIPOSA trial. If approved, the Rybrevant-lazertinib regimen would need to challenge both Tagrisso monotherapy and a Tagrisso-chemo combination. During a recent investor event, J&J laid out an ambition to snag about half of first-line patients in EGFR-mutant NSCLC. J&J believes the Rybrevant-lazertinib regimen could reach over $5 billion in peak sales. In 2023, AZ’s Tagrisso generated $5.9 billion in sales, good for 9% growth at constant exchange rates.

The FDA has granted full approval to J&J's Rybrevant, in combination with chemotherapy, as a first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that presents with epidermal growth factor receptor (EGFR) exon 20 insertion mutations. The recent approval upgrades the drug's May 2021 accelerated approval following the outcomes of the phase 3 PAPILLON study, which demonstrated a notable improvement in progression-free survival among this patient demographic. The PAPILLON study's results underscored the drug’s efficacy combined with chemotherapy, highlighting a 61% reduction in the risk of disease progression or death when compared to chemotherapy alone, positioning the regimen as a potential standard-of-care for the first-line treatment of NSCLC patients with EGFR exon 20 insertion mutations. The National Comprehensive Cancer Network has updated its Clinical Practice Guidelines to recommend this combination as a preferred first-line therapy for these patients. Lung cancer remains one of the leading causes of cancer-related deaths globally, with NSCLC accounting for the majority of cases. Patients with EGFR exon 20 insertion mutations have historically faced poorer outcomes and limited treatment benefits from existing third-generation EGFR tyrosine kinase inhibitors and chemotherapy. The full approval of Rybrevant plus chemotherapy marks a crucial development in offering a targeted treatment approach.

Pictured: J&J building in Madrid, Spain/iStock, BrasilNut1 The FDA on Friday approved Johnson & Johnson’s bispecific antibody Rybrevant (amivantamab-vmjw) for the first-line treatment of locally advanced non-small cell lung cancer in combination with carboplatin and pemetrexed. Friday’s regulatory victory, which also converts Rybrevant’s accelerated approval into a traditional approval, allows the use of the Rybrevant-based combination regimen in patients with confirmed exon 20 insertion mutations in the EGFR gene, as determined by an FDA-approved test. The approval also makes Rybrevant, when used with a chemotherapy regimen, the “first targeted approach approved for the first-line treatment” of this specific patient population, Kiran Patel, vice president of clinical development, solid tumors at J&J Innovative Medicines, said in a statement. The FDA’s decision was backed by data from the randomized, open-label Phase III PAPILLON trial, which demonstrated that the Rybrevant-based regimen cut the risk of disease progression or death by 60% versus chemotherapy alone. The objective response rate was also significantly improved following treatment with the Rybrevant combo, according to an October 2023 readout. At the time, overall survival also showed a positive trend in favor of the Rybrevant combo, though this result did not reach statistical significance. Administered via an intravenous infusion, Rybrevant is a bispecific antibody that targets both the EGF sand MET receptors. This mechanism of action allows Rybrevant to block the EGF and MET signaling cascades, preventing the cancer cells’ uncontrolled division and proliferation while also tagging these receptors for degradation, according to the website of J&J subsidiary Janssen.