Janssen's EGFR/c-MET Bispecific Antibody Rybrevant Receives FDA Approval with 52% Reduction in Progression or Death Risk for NSCLC

On September 20, Johnson & Johnson announced that the FDA had approved its EGFR/c-MET bispecific antibody Rybrevant (amivantamab-vmjw) in combination with standard chemotherapy (carboplatin + pemetrexed) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) exon 19 deletion (ex19del) or L858R substitution mutations and whose disease has progressed during or after treatment with EGFR tyrosine kinase inhibitors (TKIs).

Rybrevant is a fully human bispecific antibody targeting EGFR and MET, which can bind to the EGFR receptor and C-MET receptor on the cell surface respectively, block the activation of their signaling pathways and downstream signal transmission, and inhibit the proliferation of tumor cells with related expression.

This approval marks the third new indication for Rybrevant this year. In March, the FDA approved its combination with chemotherapy (carboplatin + pemetrexed) as a first-line treatment for locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. In August, the FDA approved the drug in combination with the third-generation EGFR inhibitor Lazcluze (lazertinib) as a first-line treatment for locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations.

EGFR mutations are the most common driver mutations in NSCLC, with 10%-15% of Western adenocarcinoma NSCLC patients and 40%-50% of Asian patients reported to have EGFR mutations. EGFR exon 19 deletion or EGFR L858R mutation is the most common type of EGFR mutation.

The 5-year survival rate for all patients with advanced EGFR-mutant NSCLC is less than 20%. The mechanisms of acquired resistance after single-agent TKI treatment are diverse and complex, making targeted therapy after progression more challenging and limiting its efficacy post-progression. The addition of immunotherapy to chemotherapy has also failed to demonstrate clinically meaningful improvement.

The FDA approval this time is based on the results of the Phase III MARIPOSA-2 (NCT04988295) study. The study evaluated the efficacy and safety of Rybrevant in combination with chemotherapy in patients with locally advanced or metastatic EGFR exon 19 deletion (ex19del) or exon 21 L858R mutation NSCLC who experienced disease progression during or after treatment with Tagrisso (osimertinib). These patients carry EGFR ex19del or L858R substitution mutations.

The primary efficacy outcome measure of the study was progression-free survival (PFS); key secondary efficacy outcome measures were overall objective response rate (ORR) and overall survival (OS).

Study results show that, compared with chemotherapy alone, the combination of Rybrevant and chemotherapy reduced the risk of disease progression or death (progression-free survival, PFS) by 52%, achieving the primary endpoint of the study. The median PFS for patients receiving Rybrevant plus chemotherapy was 6.3 months, compared to 4.2 months for those receiving chemotherapy alone. Additionally, the ORR for Rybrevant plus chemotherapy was 53%, versus 29% in the chemotherapy group. Data from a pre-specified second interim OS analysis showed no statistically significant difference in OS.

In terms of safety, the most common adverse reactions (≥20%) are rash, infusion-related reactions, fatigue, nail disorders, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, etc. The safety of Rybrevant in combination with chemotherapy is consistent with the safety observed in previous trials.

Lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) based on cell morphology. NSCLC accounts for approximately 85% of cases, with its main characteristic subtypes being squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Molecular targeted therapy, known for its strong specificity and high safety, has become the preferred treatment for NSCLC.

According to the American Society of Clinical Oncology, the mutation frequency of the EGFR gene is 10%-35%, making it one of the driver genes with the highest mutation frequency in NSCLC. In China, this figure is even higher, accounting for about 40% of NSCLC patients. According to Guoxin Securities, there are approximately 300,000 newly diagnosed NSCLC patients with EGFR mutations in China each year. Currently, first-, second-, and third-generation EGFR-TKI drugs have been launched in China, but there remains a significant unmet clinical need.

EGFR-TKI is the core treatment for EGFR-mutant NSCLC, with multiple EGFR-TKIs having become standard first-line/second-line therapies, including first-generation/second-generation EGFR-TKIs (afatinib, dacomitinib, gefitinib, erlotinib, icotinib) and third-generation EGFR-TKIs (osimertinib, almonertinib, furmonertinib, belfotinib).

Among them, AstraZeneca's Osimertinib is undoubtedly the leader. According to AstraZeneca's 2023 annual report, global sales of Osimertinib reached $5.8 billion, a year-on-year increase of 7%. In 2022, Osimertinib had the highest sales in China, reaching 4.3 billion yuan. Hansoh Pharma's Almonertinib came second with sales of 2.4 billion yuan in 2022. Elains Pharma's Furmonertinib ranked third with 790 million yuan.

However, patients generally develop resistance after receiving EGFR-TKI treatment for a period of time. Among patients who develop resistance after first-generation/second-generation EGFR-TKI treatment, 50%-60% carry the T790M mutation, and third-generation EGFR-TKI can be used for second-line treatment. In the latest 2023 CSCO guidelines, Osimertinib, Aumolertinib, and Furmonertinib are also preferentially recommended. Compared with first-generation/second-generation EGFR-TKIs, third-generation EGFR-TKIs have PFS and OS advantages in first-line treatment.

Therefore, with the availability of domestically produced EGFR-TKIs such as Aumolertinib and Furmonertinib, which have been included in the medical insurance, drug accessibility has continuously improved. The market share of third-generation EGFR-TKIs has rapidly increased and they have now become the primary medication for patients. Patients who develop resistance to third-generation EGFR-TKIs (such as Osimertinib) lack effective treatment options, and the current standard treatment remains platinum-based doublet chemotherapy.

Drug resistance has become an urgent problem to be solved in EGFR-TKI treatment.

EGFR is a transmembrane receptor with tyrosine kinase activity. Structurally, it consists of an extracellular domain, a hydrophobic transmembrane domain (TM domain), a juxtamembrane domain (JM domain), an intracellular protein tyrosine kinase domain that binds to ligands, and a C-terminal domain.

EGFR is composed of 28 exons, with exons 18 to 24 encoding the EGFR kinase domain. Mutated EGFR exhibits oncogenic activity, and mutations in the EGFR kinase domain are most commonly found in exons 18 to 21. The exon 19 deletion E746-A750 and the exon 21 L858R mutation are referred to as classic sensitive mutations. Clinical studies have shown that these two mutations account for approximately 90% of all EGFR mutation types.

For first/second-generation EGFR-TKIs, the main mechanism of resistance is caused by the EGFR T790M mutation. This mutation does not prevent the drug from binding to the receptor but increases the affinity for ATP, thereby generating resistance.

The resistance mechanisms of third-generation EGFR-TKIs are complex. Taking osimertinib as an example, patients who develop resistance exhibit a wide range of resistance mechanisms. Resistance caused by single gene mutations or pathway activations accounts for a small proportion of the total population. Additionally, there are slight differences in the spectrum of resistance mechanisms between first-line and second-line use of osimertinib. Common resistance mechanisms include EGFR C797X mutations, MET amplification, and HER2 amplification. At the same time, approximately 40% of resistant patients do not present with a clear mechanism.

Rybrevant in combination with chemotherapy is the only Category 1 treatment option recommended by the NCCN guidelines for EGFR-mutated NSCLC patients who have progressed after osimertinib treatment and present with multiple lesions.

Based on the aforementioned context, Rybrevant in combination with chemotherapy has the potential to address the most common resistance mechanisms of third-generation EGFR-TKIs (such as first-line use of osimertinib). Compared to chemotherapy alone, this combination of Rybrevant and chemotherapy extends PFS and improves ORR, offering patients an important and effective new second-line treatment option.

Kiran Patel, M.D., Vice President of Clinical Development at Johnson & Johnson Innovative Medicine, stated: "This milestone reinforces Rybrevant as a significant treatment option for patients with EGFR-mutated NSCLC, who continue to face a high level of unmet need following disease progression during or after TKI therapy."

In recent years, Chinese pharmaceutical companies have made rapid progress in the bispecific antibody drug field. Many domestically produced bispecific antibody drugs have not only achieved significant advancements within China but have also realized important business expansions in the international market.

Among them, the most eye-catching is the PD-1/VEGF bispecific antibody new drug, Eftilagimod Alpha, independently developed by Akeso Biopharma. In December 2022, Akeso Biopharma reached a collaboration and licensing agreement with Summit Therapeutics for the PD-1/VEGF bispecific antibody Eftilagimod Alpha, with an upfront payment of up to $500 million, and the total transaction amount is expected to reach $5 billion. As a leading company in this field, Akeso Biopharma has successfully launched two bispecific antibody drugs, Cadonilimab and Eftilagimod Alpha. In addition, Akeso's Eftilagimod Alpha has shown excellent efficacy in key Phase III clinical trials, further enhancing its competitiveness in the global market.

Besides Yivoki, BL-B01D1 from Baili Tianheng is also a representative product. In December 2023, Baili Tianheng granted BL-B01D1 to BMS for up to 8.4 billion US dollars, setting a new record for overseas licensing of domestically produced ADC drugs. Currently, BL-B01D1 has seven ongoing Phase III clinical trials, including lung cancer, breast cancer, nasopharyngeal cancer, and esophageal squamous cell carcinoma, among others. Additionally, 14 Phase II clinical trials are also underway, covering more than 10 types of tumors.

In terms of BD transactions, I-Mab Biopharma and Tongrun Bio have also made significant BD progress in the bispecific antibody field. In early August 2024, I-Mab Biopharma granted Instil Bio the rights to PD-L1/VEGF bispecific antibody IMM2510 and next-generation CTLA-4 antibody IMM27M outside of Greater China, with a total deal value exceeding 2 billion US dollars. In late August, I-Mab Biopharma received the first payment of 10 million US dollars.

On August 9, 2024, Merck & Co. reached an agreement with Tongrun Bio to acquire the global rights to the CD3/CD19 bispecific antibody CN201, paying a $700 million upfront fee.

In addition, domestic pharmaceutical companies such as 3SBio, RemeGen, Junshi Biosciences, and Sinocelltech are also actively advancing the research and clinical trials of their bispecific antibody drugs. These drugs cover several popular targets such as PD-1/VEGF and have demonstrated good efficacy and safety in clinical studies.

In the future, as these bispecific antibody drugs enter the market, China's bispecific antibody drugs will occupy a more important position in the global pharmaceutical market and are expected to provide patients with more effective treatment options.

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Johnson & Johnson's Dual Antibody Challenges the Third-Generation "EGFR-TKI" Drug Resistance Stalemate —— VCBeat