FDA Grants Mobocertinib Breakthrough Designation for EGFR Exon 20–Mutant NSCLC

Mobocertinib (TAK-788) has received an FDA breakthrough therapy designation for the treatment of patients with EGFR exon 20-mutant non–small cell lung cancer.

The FDA has granted a breakthrough therapy designation to mobocertinib (TAK-788) for the treatment of patients with EGFR exon 20—mutant non–small cell lung cancer (NSCLC) with disease progression following platinum-based chemotherapy, according to Takeda Pharmaceutical Company Limited, the manufacturer of the small-molecule TKI.1

Results from an ongoing phase 1/2 trial showed that mobocertinib induced a confirmed overall response rate (ORR) of 43% in patients with locally advanced or metastatic EGFR exon 20 insertion—mutant NSCLC. The median progression-free survival (PFS) was 7.3 months.

The breakthrough designation will expedite the development and review of mobocertinib in this setting.

“We are pleased that the FDA has recognized the therapeutic potential mobocertinib offers for patients with EGFR exon 20 insertion—mutant NSCLC who are desperately in need of effective treatment options,” Christopher Arendt, PhD, head, Oncology Therapeutic Area Unit, Takeda, said in a press release. “At Takeda, we are committed to developing novel medicines for hard-to-treat diseases. Establishing breakthrough therapy designation for mobocertinib is one step forward in our efforts to help change the current standard of care for this underserved population.”

The phase 1/2 trial is administering mobocertinib at a dosage of 160 mg once daily. The ORR comprised 12 responses in 28 evaluable patients. The safety population included 72 patients. The most frequently occurring adverse events across all grades were diarrhea (85%), nausea (43%), rash (36%), vomiting (29%) and decreased appetite (25%).

Takeda noted in the press release that there are no FDA-approved agents specifically for patients with EGFR exon 20—mutant NSCLC. However, treatments for this NSCLC subtype are advancing through the pipeline. For example, the FDA also granted a breakthrough therapy designation to JNJ-61186372 (JNJ-6372) for the treatment of patients with EGFR-positive metastatic NSCLC who harbor exon 20 insertion mutations. The designation is for patients whose disease has progressed on or after platinum-based chemotherapy.

In a phase 1 trial (NCT02609776), JNJ-6372 elicited preliminary responses in patients with NSCLC, including those who have relapsed EGFR-mutant disease and those with exon 20 insertions.2 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 1 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.

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.


  1. Takeda Announces U.S. FDA Breakthrough Therapy Designation for Mobocertinib (TAK-788) for the Treatment of NSCLC Patients with EGFR Exon 20 Insertion Mutations Published April 27, 2020. Accessed April 27, 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
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