FDA Approves Mobocertinib for EGFR Exon 20 Insertion+ NSCLC

The FDA has granted an accelerated approval to mobocertinib (Exkivity) for the treatment of adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.¹

The agency also gave the green light to the Thermo Fisher Scientific’s Oncomine Dx Target Test as a next-generation sequencing companion diagnostic for the agent to identify patients with NSCLC harboring EGFR exon 20 insertions.

The regulatory decision was based on results from a phase 1/2 trial (NCT02716116) on a cohort of 114 patients with EGFR exon 20 insertion–positive NSCLC who received prior platinum-based therapy and received the agent at a dose of 160 mg.

Results showed that mobocertinib elicited a confirmed overall response rate (ORR) of 28% (95% CI, 20%-37%) per independent review committee (IRC) assessment, with a median duration of response (DOR) of 17.5 months (95% CI, 7.4-20.3). Moreover, the median progression-free survival achieved with mobocertinib in this cohort was 7.3 months (95% CI, 5.5-9.2), and the median overall survival was 24.0 months (95% CI, 14.6-28.8).

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

“EGFR exon 20 insertion–positive NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs,” Pasi A. Jänne, MD, PhD, Dana-Farber Cancer Institute, stated in a press release. “The approval of mobocertinib marks another important step forward that provides physicians and their patients with a new targeted oral therapy specifically designed for this patient population that has shown clinically meaningful and sustained responses.”

Part 1 of the trial had a dose-escalation, 3+3 design and included patients with advanced NSCLC who had an ECOG performance status of less than 2.² Six of these patients previously received platinum therapy. In the second part of the research, the expansion phase, mobocertinib was evaluated at a daily dose of 160 mg in the following 7 cohorts:

• Cohort 1 (n = 22): Patients who received prior platinum, who had refractory EGFR exon 20 insertion–positive disease and did not have active, measurable central nervous system (CNS) metastases
• Cohort 2: Patients with refractory disease and HER2 exon 20 insertion or point mutations and did not have active, measurable CNS metastases

• Cohort 3: Patients with refractory disease and EGFR or HER2 exon 20 insertions or point mutations and measurable, active CNS metastases
• Cohort 4: Treatment-naïve patients or those with refractory disease who had other EGFR mutations with or without T790 mutations, uncommon EGFR mutations
• Cohort 5: Patients with refractory disease and EGFR exon 20 insertion who previously responded to EGFR TKIs
• Cohort 6: Treatment-naïve patients with EGFR exon 20 insertions
• Cohort 7: Patients with refractory disease and other tumor types (non-NSCLC) with EGFR/HER2 mutations

The primary end point in the phase 2 portion of the trial was ORR per RECIST v1.1 criteria and key secondary end points comprised safety, tolerability, pharmacokinetics, and efficacy.

Part 3 of the trial included an EXCLAIM extension cohort of 96 patients with EGFR exon 20 insertion positivity who previously received platinum therapy (n = 86).

In the cohort of patients who received prior platinum therapy, the median age was 60 years (range, 27-84) and 66% were female. Sixty percent of patients were Asian, 98% had adenocarcinoma histology, 75% had an ECOG performance status of 1, and 71% were never smokers. Notably, 35% of these patients had brain metastases at baseline.

Moreover, 41% received 1 prior systemic regimen, 32% received 2 prior regimens, and 27% received 3 or more. All patients previously received platinum-based chemotherapy and 43% received prior immunotherapy. Twenty-five percent of patients received a prior EGFR TKI.

Additional data presented during the 2021 ASCO Annual Meeting demonstrated that the confirmed ORR per investigator assessment in the cohort of patients who received prior platinum was 35% (95% CI, 26%-45%) with a median DOR of 11.2 months (95% CI, 5.6–not evaluable [NE]). The confirmed disease control rate (DCR) in this cohort per investigator assessment was 78% (95% CI, 69%-85%).

Moreover, the IRC-assessed confirmed ORR in the EXCLAIM cohort was 25% (95% CI, 17.0%-35.0%), with a median DOR that was NE (95% CI, 5.6–NE). The confirmed DCR in this cohort was 76% (95% CI, 66.0%-84.0%). Per investigator assessment, the confirmed ORR with mobocertinib was 32% (95% CI, 23%-43%) and the median DOR was 11.2 months (95% CI, 7.0–NE). The investigator-assessed confirmed DCR in this cohort was 75% (95% CI, 65%-83%).

In the EXCLAIM cohort, mean improvements in EORTC QLQ-LC13 scores for dyspnea, cough, and pain in chest were noted at cycle 2 vs baseline; this was maintained throughout treatment. Moreover, the mean EORTC QLQ-C30 Global Health Status/Quality-of-Life scores were maintained over the study period, despite worsening gastrointestinal-associated symptom scores, like diarrhea scores, during treatment.

Regarding safety, the most common adverse effects included diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain.

The prescribing information for mobocertinib includes a boxed warning for QTc prolongation and Torsades de Pointes, as well as warnings and precautions for interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea.

“The approval of [mobocertinib] introduces a new and effective treatment option for patients with EGFR exon 20 insertion–positive NSCLC, fulfilling an urgent need for this difficult-to-treat cancer,” Teresa Bitetti, president, Global Oncology Business Unit, at Takeda, stated in a press release. “[Mobocertinib] is the first and only oral therapy specifically designed to target EGFR exon 20 insertions, and we are particularly encouraged by the duration of the responses observed with a median of approximately 1.5 years. This approval milestone reinforces our commitment to meeting the needs of underserved patient populations within the oncology community.”

References

1. Takeda's EXKIVITY (mobocertinib) approved by US FDA as the first oral therapy specifically designed for patients with EGFR exon20 insertion+ NSCLC. News release. Takeda Pharmaceutical Company. September 15, 2021. Accessed September 15, 2021. https://bit.ly/2Xm3WSY
2. Ramalingam SS, Zhou C, Kim TM, et al. Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic NSCLC (mNSCLC): additional results from platinum-pretreated patients (pts) and EXCLAIM cohort of phase 1/2 study. J Clin Oncol. 2021;39(suppl 15):9014. doi:10.1200/JCO.2021.39.15_suppl.9014