Johnson & Johnson...the U.S. Food and Drug Administration (FDA) approved RYBREVANT® (amivantamab-vmjw) plus LAZCLUZE™ (lazertinib) for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.

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.

...- Mandatory submission of unstained tissue from tumor (in a quantity sufficient to allow for central analysis of EGFR mutation status and blood (for circulating tumor deoxyribonucleic acid [ctDNA], digital droplet polymerase chain reaction [ddPCR], and pharmacogenomic analysis)...

...A copy of the test report documenting the EGFR mutation must be included in the participant records and must also be submitted to the sponsor prior to enrollment; 4....

...Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) with previously epidermal growth factor receptor (EGFR) mutation (identified locally in a Clinical Laboratory Improvement Amendments [CLIA]-certified laboratory [or equivalent]) that is metastatic or unresectable, and have progressed after standard of care front-line therapy, and exhausted available options with targeted therapy....

...- Have a tumor that harbors an epidermal growth factor receptor (EGFR) exon 19del or exon 21 L858R substitution, as detected by an Food and Drug Administration (FDA)-approved or other validated test in a clinical laboratory improvement amendments (CLIA)-certified laboratory (sites in the United States) or an accredited local laboratory (sites outside of the United States) in accordance with site standard of care...

...- Participant must have histologically or cytologically confirmed, locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC), characterized at or after the time of locally advanced or metastatic disease diagnosis by either epidermal growth factor receptor (EGFR) Exon 19del or Exon 21 L858R mutation...

...Participant must have histologically or cytologically confirmed, locally advanced or metastatic, non-squamous NSCLC, characterized at or after the time of locally advanced metastatic disease diagnosis by either EGFR Exon 19del or Exon 21 L858R mutation, by an FDA-approved or other validated test of either ctDNA or tumor tissue in a CLIA certified laboratory (sites in the US) or an accredited local laboratory (sites outside of the US). ...

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.

The treatment-naive cohort enrolled pts with EGFR exon 19 deletion (ex19del) or L858R mutated advanced NSCLC. All pts received 1050 mg IV ami (1400 mg if ≥80 kg) and 240 mg oral laz....Ten (50%) pts were progression-free and remained on treatment, including 7 of 11 (64%) with ex19del and 3 of 9 (33%) with L858R.

The treatment-naive cohort enrolled pts with EGFR exon 19 deletion (ex19del) or L858R mutated advanced NSCLC. All pts received 1050 mg IV ami (1400 mg if ≥80 kg) and 240 mg oral laz....Ten (50%) pts were progression-free and remained on treatment, including 7 of 11 (64%) with ex19del and 3 of 9 (33%) with L858R.

Cohort A evaluated ami and laz in pts with EGFR exon 19 deletion or L858R NSCLC...Of 50 efficacy-evaluable pts in the target population, the overall response rate (ORR) by BICR was 36% (95% CI, 23–51), with 1 complete response (CR) and 17 partial responses (PRs), and the clinical benefit rate (CBR) was 58%...ami and laz demonstrates encouraging antitumor activity with a manageable safety profile.

CHRYSALIS-2 (NCT04077463) is an ongoing open-label study that includes a single-arm cohort (Cohort A) examining ami + laz in patients (pts) with EGFR Exon19del or L858R NSCLC…Of 28 response-evaluable pts...12...reported partial response (PR) as best response; of the 12 responses, 9 were confirmed (3 pending), for an overall response rate (ORR) of 32%...Of 45 pts in the heavily-pretreated population, 7 reported best response of PR, of which 6 were confirmed (1 pending), for an ORR of 13% (95% CI, 5–27)....Ami + laz is showing encouraging early activity in a population that progressed on both standard of care osi and platinum chemotherapy.

Pts with EGFR exon 19 deletion or L858R mutation NSCLC, who had progressed on osi without intervening chemotherapy, were enrolled in the combination cohort of the ongoing CHRYSALIS study (NCT02609776)....Of the 45 osi-relapsed pts, 36% (95% CI, 22–51) had a confirmed response (1 complete response and 15 partial responses [PR])...The median progression-free survival (mPFS) was 4.9 mo (95% CI, 3.7–8.3)....Treatment with the combination of amivantamab and lazertinib yielded responses in 36% of chemotherapy-naïve pts who progressed on osi.