FDA Grants Priority Review to Mobocertinib for Advanced EGFR Exon 20–Mutant NSCLC

The FDA has granted a priority review designation to a new drug application (NDA) for mobocertinib (TAK-788) for the treatment of adult patients with EGFR exon 20 insertion mutation–positive metastatic non–small cell lung cancer (NSCLC), as detected via an FDA-approved assay, who have received previous platinum-based chemotherapy.¹

The designation is based primarily on findings from a phase 1/2 trial, in which mobocertinib elicited a confirmed objective response rate (ORR) of 26% (95% CI, 19%-35%) per an independent review committee (IRC) and a 35% investigator-assessed ORR (95% CI, 26%-45%).2 Additionally, the median progression-free survival (PFS) was 7.3 months and was from both IRC and investigator assessment.

Mobocertinib marks the first oral treatment that can selectively target the patient population of NSCLC with EGFR exon 20 insertion mutations. Under the Prescription Drug User Fee Act, the FDA will make a decision on the NDA by October 26, 2021.

“Patients with EGFR exon 20 insertion–positive [metastatic] NSCLC face considerable challenges, as current treatment options provide limited benefit, resulting in poor survival outcomes,” said Christopher Arendt, head, Oncology Therapeutic Area Unit, of Takeda, the developer of mobocertinib. “We are excited to be one step closer to offering mobocertinib as an effective oral therapy for NSCLC patients with EGFR exon 20 insertions that have received prior platinum-based chemotherapy and look forward to continuing conversations with regulatory agencies in the U.S. and around the globe."

Mobocertinib, an investigational, first-in-class, oral TKI, was previously granted breakthrough therapy designation by the FDA in April 2020 as a potential treatment for this patient population. Additionally, Takeda established an Expanded Access Program for patients in the United States who could receive mobocertinib during the FDA’s review of the application.

In the dose-escalation, dose-expansion study, investigators explored mobocertinib alone and in combination with chemotherapy (phase 1), and also investigated the antitumor activity of mobocertinib in 7 different cohorts, plus an extension cohort (phase 2).

The study also included a platinum-pretreated population (PPP) cohort analysis investigated 114 patients with EGFR exon 20 insertion–mutant metastatic NSCLC who received prior platinum-based treatment from the dose-escalation and -expansion phases of the phase 1/2 trial and were treated with mobocertinib at a 160-mg, once-daily dose.

The phase 2 extension cohort, which was known as EXCLAIM, was comprised of 96 previously treated patients with EGFR exon 20 insertion–mutant metastatic NSCLC who were treated with mobocertinib at the 160-mg dose.

The primary endpoint for the study was confirmed, IRC-assessed ORR; secondary endpoints included safety, tolerability, and efficacy.

In the analysis of the PPP cohort (n = 114), the median age was 60 years (range, 27-84), 66% were female, and 60% were of Asian descent. Thirty-two percent of patients had received at least 2 prior systemic anticancer therapies (range, 1-7). Moreover, the median time on treatment was 7.0 months (range, 0-31).

In EXCLAIM (n = 96), the median age of patients was 59 years (range, 27-80). Sixty-five percent of patients were female, 69% were of Asian descent, and 31% had more than 2 prior systemic lines of therapy (range, 1-4). The median time on treatment was 6.5 months (range, 0-14). The median duration of response, per Kaplan-Meier estimates, was not estimable.

Amongst the PPP cohort, mobocertinib resulted in reductions of target lesions volume, with 82% of patients (n = 94) experiencing a reduction from baseline in the sum of target lesion diameter. Results were similar in the EXCLAIM cohort, with 80% of patients (n = 77) also experiencing a reduction from baseline in the sum of target lesion diameter.

The confirmed ORRs with mobocertinib were similar among all prespecified subgroups in the phase 1/2 trial. In Asian versus non-Asian patients in the PPP cohort, the ORRs were 28% and 22%, respectively. In the EXCLAIM cohorts, the ORRs were 24% and 20%, respectively.

For patients who received prior immunotherapy vs those without in the PPP cohort, the ORRs were 25% and 28%, respectively, while this subgroup in the EXCLAIM cohort had ORRs of 21% and 24%, respectively.

Patients who prior EGFR TKI versus those who did not in the PPP cohort had ORRs of 21% and 28%, respectively. In the EXCLAIM cohort, these rates were 15% and 26%, respectively.

Further findings in the phase 1/2 trial showed that, in a second cohort of patients who received a prior EGFR TKI, the confirmed ORR was 23% (95% CI, 15%-33%) per IRC, and 32% (95% CI, 23%-43%) per investigator assessment; the median PFS was 7.3 months. By investigator assessment, it was 7.1 months.

Regarding safety, some of the most common treatment-related adverse events (TRAEs; ≥20%) in platinum-pretreated patients were diarrhea (90%), rash (45%), paronychia (34%), nausea (32%), decreased appetite (32%), dry skin (30%) and vomiting (30%).

Grade 3 or higher TRAEs (≥5%) included diarrhea (21%). Nineteen patients (17%) discontinued due to AEs, most commonly due to diarrhea (4%), nausea (4%), vomiting (2%), decreased appetite (2%), and stomatitis (2%). The safety profile observed in EXCLAIM was largely consistent with that observed in the platinum-pretreated population.

References

1. Takeda announces U.S. FDA grants priority review for new drug application for mobocertinib (TAK-788) as a treatment for EGFR exon20 insertion+ metastatic non-small cell lung cancer. News release. Takeda. April 27, 2021. Accessed April 28, 2021. https://bit.ly/3aLxIV3
2. Zhou C, Ramalingam S, Li B, et al. Mobocertinib in NSCLC with EGFR exon 20 insertions: results from EXCLAIM and pooled platinum-pretreated patient populations. Presented at: International Association for the Study of Lung Cancer (IASLC) 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual.