FDA Grants Breakthrough Designation to JNJ-6372 for EGFR Exon 20-Mutant NSCLC

The FDA has granted a breakthrough therapy designation to JNJ-61186372 (JNJ-6372) for the treatment of patients with EGFR-positive metastatic non—small cell lung cancer (NSCLC) who harbor exon 20 insertion mutations, and whose disease has progressed on or after platinum-based chemotherapy.¹

The designation is supported by findings from a phase I trial (NCT02609776), in which JNJ-6372 elicited preliminary responses in patients with NSCLC, including those who have relapsed EGFR-mutant disease and those with exon 20 insertions.² The therapy was also found to have a manageable safety profile.

"JNJ-6372 is a novel bispecific antibody that we believe has the potential to benefit patients with Exon 20 mutation insertions who often do not respond to currently available oral EGFR-targeted or immune checkpoint inhibitor therapies," Peter Lebowitz, MD, PhD, global therapeutic area head, Oncology, Janssen Research & Development, LLC. "This breakthrough therapy designation is a significant milestone in our ongoing efforts to advance JNJ-6372 in clinical development and target genetically-defined lung cancer."

Patients with NSCLC who have EGFR exon 20 insertion mutations have a form of disease typically do not respond to EGFR TKIs and are said to have a worse prognosis versus those with more common EGFR mutations, such as exon 19 deletions and L858R substitution. Currently, this patient population is treated with conventional cytotoxic chemotherapy.

JNJ-6372 is an EGFR-MET bispecific antibody that targets activating and resistant EGFR and MET mutations and amplifications.

In the first-in-human, open-label, multicenter phase I study, investigators are evaluating the safety, pharmacokinetics and preliminary efficacy of JNJ-6372 monotherapy and in combination with lazertinib, which is a novel third-generation EGFR TKI, in approximately 400 adult patients with advanced NSCLC, including in sub-populations with genomic alterations such as those with C797S resistance mutation or MET amplification.

In part 1 of the trial, investigators are seeking to determine the recommended phase II dose in patients with advanced NSCLC. Enrollment into the part II dose-expansion cohorts is ongoing.

The primary endpoint of part 1 of the trial is dose-limiting toxicity; the primary endpoints in part 2 are adverse events (AEs) and serious AEs, objective response rates, duration of response, and clinical benefit rate. Secondary endpoints include pharmacokinetics, anti-drug antibodies, progression-free survival, time-to-treatment failure, and overall survival.

Preliminary data were presented at the 2019 ASCO Annual Meeting. As of January 17, 2019, 116 patients were enrolled and treated. The median age was 63 years, 38% of patients were male, and 77% were Asian. Most (97%) of patients had EGFR mutations.

Results showed that the mean duration of treatment was 3.8 months, with the longest exposure being 20 cycles. Among 88 response-evaluable patients, 28% achieved best timepoint response of partial response (PR). Ten of 47 patients who had prior therapy with a third-generation EGFR inhibitor had a best timepoint response of PR, 6 of which were confirmed— including 4 with C797S mutations, 1 with cMet amplification, and 5 without identifiable EGFR/cMet-dependent resistance. Six of 20 patients who had exon 20 insertions had best timepoint response of PR, with 3 confirmed.

Regarding safety, AEs (≥20%) that were included rash (59%), infusion-related reaction (58%), paronychia (28%), and constipation (22%). Moreover, EGFR/cMet—related AEs include stomatitis (17%), pruritis (15%), peripheral edema (11%), and diarrhea (7%).

Grade ≥3 AEs were reported in 34% of patients; 8% of which were related to treatment, and included dyspnea (6%) and pneumonia (3%) as those that were most frequently observed.

References

1. Janssen announces U.S. FDA breakthrough therapy designation granted for JNJ-6372 for the treatment of non-small cell lung cancer [news release]: Raritan, NJ. Published March 10, 2020. https://prn.to/2Q0EhsA. Accessed March 10, 2020.
2. Haura EB, Cho BC, Lee JS, et al. JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(suppl 15; abstr 9009). doi: 10.1200/JCO.2019.37.15_suppl.9009