Takeda Announces Promising Phase 1/2 Data for Mobocertinib in EGFR Exon20 Insertion+ NSCLC with 35% Investigator-Assessed ORR

January 29, 2021/Bio ValleyBIOON/--Takeda Pharmaceutical Company Limited (Takeda) recently at the 21st World Conference on Lung Cancer (WCLC) 2020, hosted online by the International Association for the Study of Lung CancerConferenceOral Report on Phase 1/2 Study of Oral Targeted Anticancer Drug Mobocertinib (TAK-788) for Lung CancerClinical Trialsthe latest data. The study was conducted in patients with metastatic non-small cell lung cancer (NSCLC) who had disease progression after prior platinum-based therapy and harbored epidermal growth factor receptor (EGFR) exon 20 insertion mutations (EGFR Exon20 insertion+).

Currently, there are no approved targeted therapies for this patient population, and existing treatment options offer limited benefits. Mobocertinib is a small-molecule tyrosine kinase inhibitor (TKI) designed to selectively target EGFR and human epidermal growth factor receptor 2 (HER2) exon 20 insertion mutations. Notably, mobocertinib has been granted Breakthrough Therapy Designation for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations in both the United States and China.

The results announced at this meeting showed that mobocertinib treatment demonstrated clinically meaningful anti-TumorEfficacy: (1) Confirmed by investigator assessmentObjective Response Rate (ORR) was 35%(40/114; 95% CI: 26-45), and the objective response rate (ORR) confirmed by independent review committee (IRC) assessment was 28% (32/114; 95% CI: 20-37). (2) Mobocertinib treatment demonstrated durable responses, as assessed by the IRC.Median Duration of Response (DOR) was 17.5 months(95% CI: 7.4–20.3). (3) Confirmed by IRC assessmentMedian progression-free survival (PFS) was 7.3 months(95%CI:5.5-9.2)、Disease Control Rate (DCR) was 78%(89/114；95%CI:69-85)。

In the study, the observed safety profile was manageable. As of the May data cutoff, the most common treatment-related adverse events (TRAEs; ≥20%) in patients pretreated with platinum-based agents were diarrhea (90%), rash (45%), paronychia (34%), nausea (32%), decreased appetite (32%), dry skin (30%), and vomiting (30%). Grade ≥3 TRAEs (≥5%) included diarrhea (21%). Nineteen patients (17%) discontinued treatment due to adverse events, most commonly diarrhea (4%) and nausea (4%). The safety profile at the November data cutoff was consistent with that at the May data cutoff.

Pasi A. Jänne, MD, of the Dana-Farber Cancer Institute, commented, “The study results demonstrate that mobocertinib exhibits a clinically meaningful response rate and a significant duration of response in patients with EGFR exon 20 insertion–positive metastatic non-small cell lung cancer (mNSCLC). These data are highly encouraging and provide further evidence supporting mobocertinib as a potential oral therapy for patients with EGFR exon 20 insertion–positive mNSCLC, who have an urgent need for targeted treatment options.”

Chemical Structure of Mobocertinib (Image source: medchemexpress.cn)

Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most common type, accounting for approximately 85% of all lung cancer cases. Patients with EGFR exon 20 insertion mutations represent only 1–2% of those with NSCLC and have a poorer prognosis compared to other EGFR mutation subtypes. Currently, there are no approved therapies specifically targeting exon 20 mutations, and existing EGFR tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy offer limited clinical benefit for this patient population.

Mobocertinib is a potent small-molecule tyrosine kinase inhibitor (TKI) designed to selectively target EGFR and HER2 exon 20 insertion mutations. In 2019, the U.S. FDA granted mobocertinib orphan drug designation (ODD) for the treatment of patients with lung cancer harboring HER2 or EGFR mutations (including exon 20 insertion mutations). In April 2020, the United StatesFDAMobocertinib was granted Breakthrough Therapy Designation for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations, whose disease has progressed during or after platinum-based chemotherapy. In October 2020, mobocertinib was granted Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) for the same indication.

Mechanism of Action of Johnson & Johnson’s Amivantamab (Image source: literature—doi:10.1158/2159-8290.CD-20-0116)

In December 2020, Johnson & Johnson to the United StatesFDAand submitted to the EUMonoclonal Antibody DrugsMarketing application for amivantamab (JNJ-61186372, JNJ-6372) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, whose disease has progressed after failure of platinum-based chemotherapy.

Notably, this marks the first regulatory submission in the European Union and the United States for the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations. If approved, amivantamab will become the first therapy specifically targeting NSCLC with EGFR exon 20 insertion mutations.

Amivantamab is an investigational fully human EGFR-mesenchymal-epithelial transition factor (MET) bispecific antibody with immune cell-directed activity, targeting activating and resistance-conferring EGFR and MET mutations and amplifications.TumorThe production and development of amivantamab followed the license agreement signed between Janssen Biotech, Inc. and Genmab for the use of the DuoBody technology platform.

The regulatory application for amivantamab is based on the results of the Phase I CHRYSALIS study (NCT02609776). The data showed that in patients with advanced NSCLC carrying EGFR exon 20 insertion mutations, treatment with amivantamab demonstrated durable responses: (1) among all evaluable patients, the overall response rate (ORR) was 36%, the median duration of response (DOR) was 10 months, and the clinical benefit rate (≥partial response [PR] + stable disease ≥12 weeks) was 67%; (2) among previously platinum-treated evaluable patients,ORR was 41%, median DOR was 7 months, and clinical benefit rate was 72%.

Based on the ORR and DOR data from the CHRYSALIS study, in March 2020, the United StatesFDAGranting of Breakthrough Therapy Designation (BTD) to amivantamab for the treatment of patients with metastatic NSCLC harboring EGFR exon 20 insertion mutations who have progressed after platinum-based chemotherapy. (Bioon.com)

Original Source: Takeda Presents Positive Results For Mobocertinib in Patients with EGFR Exon20 insertion+ mNSCLC Who Received Prior Platinum-based Chemotherapy