U.S. Food and Drug Administration (FDA) approved RYBREVANT® (amivantamab-vmjw) in combination with standard of care chemotherapy (carboplatin and pemetrexed) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions (ex19del) or L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor (TKI).

A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2:2:1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy....progression-free survival and key secondary endpoints, such as objective response rate, duration of response, and intracranial progression-free survival, were significantly improved with amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy compared with chemotherapy in patients with EGFR-mutated advanced NSCLC with disease progression on or after osimertinib.

The Janssen Pharmaceutical Companies of Johnson & Johnson today announced positive topline results from the three-arm Phase 3 MARIPOSA-2 study evaluating RYBREVANT® (amivantamab-vmjw), a bispecific antibody targeting epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET), given with and without lazertinib, an oral, third-generation EGFR tyrosine kinase inhibitor (TKI), combined with chemotherapy (carboplatin and pemetrexed) versus chemotherapy alone. MARIPOSA-2 enrolled patients with locally advanced or metastatic EGFR exon 19 deletions (ex19del) or L858R substitution NSCLC after disease progression on or after osimertinib. The study met its dual primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS versus chemotherapy alone in both experimental treatment arms.

...For Part 2 Cohorts C, D, MET-1, and MET-2 only: Participants must also have disease with a previously diagnosed activating epidermal growth factor receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as Exon 19 deletion and L858R (Cohort C, E, and MET-1), as well as marketed TKI-resistant mutations such as Exon 20 insertion (Cohort C, D and MET-1) or activating cMet Exon 14 skipping mutation (Cohort MET-2)....

...For Part 2 Cohorts C, D, MET-1, and MET-2 only: Participants must also have disease with a previously diagnosed activating epidermal growth factor receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as Exon 19 deletion and L858R (Cohort C, E, and MET-1), as well as marketed TKI-resistant mutations such as Exon 20 insertion (Cohort C, D and MET-1) or activating cMet Exon 14 skipping mutation (Cohort MET-2)....

...For Part 2 Cohorts C, D, MET-1, and MET-2 only: Participants must also have disease with a previously diagnosed activating epidermal growth factor receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as Exon 19 deletion and L858R (Cohort C, E, and MET-1), as well as marketed TKI-resistant mutations such as Exon 20 insertion (Cohort C, D and MET-1) or activating cMet Exon 14 skipping mutation (Cohort MET-2)....

...For Part 2 Cohorts C, D, MET-1, and MET-2 only: Participants must also have disease with a previously diagnosed activating epidermal growth factor receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as Exon 19 deletion and L858R (Cohort C, E, and MET-1), as well as marketed TKI-resistant mutations such as Exon 20 insertion (Cohort C, D and MET-1) or activating cMet Exon 14 skipping mutation (Cohort MET-2)....

...For Part 2 Cohorts C, D, MET-1, and MET-2 only: Participants must also have disease with a previously diagnosed activating epidermal growth factor receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as Exon 19 deletion and L858R (Cohort C, E, and MET-1), as well as marketed TKI-resistant mutations such as Exon 20 insertion (Cohort C, D and MET-1) or activating cMet Exon 14 skipping mutation (Cohort MET-2)....

In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR-mutant NSCLC...For patients with EGFR ex19 del (n = 30) or L858R (n = 14), the ORR was 33% (95% CI, 17–53) and 43% (95% CI, 18–71), respectively.

Of the 30 response-evaluable pts with EGFRmut disease, treated at doses ≥700 mg, there are 8 partial responses (PRs; 4 confirmed PRs). This includes 6 pts with L858R or Exon19del primary mutations, and acquired resistance to first and/or third-generation EGFR tyrosine kinase inhibitors (TKIs), and 2 pts with primary Exon20ins disease.... Preliminary evidence suggests JNJ-372 can have activity in EGFR-driven NSCLC, including pts resistant to EGFR TKIs.

JNJ-372 significantly decreased cell proliferation rate and EGFR downstream signaling in BaF3 cell harboring Del19 (L858R)/T790M/C797S mutant and PDC model harboring Del19/T790M/C797S mutant with amplified KRAS and loss of Rb.