Mobocertinib

TAK-788 is a next-generation, potent and selective small molecule tyrosine kinase inhibitor (TKI) intelligently designed and clinically investigated to inhibit epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) exon 20 mutation with selectivity for wild-type (WT) EGFR. Non-clinical studies have shown that it has anti-tumor activity against de novo EGFR mutations (including EGFR exon 20 insertions and acquired resistance mutation T790M). In October 2018, the ongoing Phase 1/2 TAK-788 trial will be revised to add the pivotal extension cohort EXCLAIM, which is designed to evaluate the efficacy and safety of TAK-788 dose 160 mg once daily in previously treated patients with EGFR exon 20 insertion. The trial is actively recruiting.

The TAK-788 development program is initially initiated in the non-small cell lung cancer (NSCLC) population and is expected to be expanded to additional underserved tumor types. TAK-788 is an investigational drug, and its effectiveness and safety have not yet been established.

About ALK+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of the approximately 1.8 million newly diagnosed lung cancer cases worldwide each year, according to the World Health Organization. 1,2. Genetic studies have shown that chromosomal rearrangement of anaplastic lymphoma kinase (ALK) is a key driver in a subset of NSCLC patients. Approximately 3 to 5% of patients with metastatic NSCLC have ALK gene rearrangements6,7,8.

Among EGFR-mutated NSCLC patients, approximately 6% have EGFR exon 20 insertion mutations. Currently approved EGFR TKIs (tyrosine kinase inhibitors) are effective against EGFR mutations that are common in patients with non-small cell lung cancer, but are basically ineffective against patients with EGFR exon 20 insertion mutations.

Clinical Data

NCT02716116 is an open-label trial. A total of 137 NSCLC patients were enrolled in the trial, including 28 patients with EGFR exon 20 insertion mutations. Fifty-five patients received TAK-788 once daily, 5 to 180 mg each time (dose escalation trial); the remaining 72 patients (including 28 patients with EGFR exon 20 insertion mutations) received TAK-788 once daily, 160 mg each time.

The demographic characteristics of all patients are: the median age is 61 years old, and 71% are female. 75% are white, 14% are Asian, 6% are black, and 5% are of other races. 94% of patients had adenocarcinoma. 26% of patients had an ECOG score of 0, and 73% of patients had an ECOG score of 1.

The median number of treatment options for patients was 3. 4% of patients had received no prior treatment, 23% had received 1 prior treatment regimen, 25% had received 2 prior treatment regimens, and 48% had received 3 or more prior treatment regimens. 31% of patients had previously received EGFR/HER2 For TKI treatment, 44% of patients had previously received checkpoint inhibitor therapy.

71% of patients were never smokers and 29% were former smokers. 47% of patients had brain metastases at baseline.

The trial results showed that patients with EGFR exon 20 insertion mutations had an ORR of 43%, a PR of 43%, and an SD of 43%. The disease control rate was 86%, and the median PFS was 7.3 months.

Among patients with EGFR exon 20 insertion mutations, 12 patients had brain metastases at baseline and 16 patients had no brain metastases. The ORR of the two groups of patients (with brain metastases vs. without brain metastases) was 25% vs. 56%, PR was 25% VS 56%, SD was 42% VS 44%, disease control rate was 67% VS 100%, and median PFS was 3.7 months VS 8.1 months.

Adverse reactions

Among all patients, the most common adverse reactions were: diarrhea (74%), nausea (33%), rash (26%), vomiting (22%), decreased appetite (22%), stomatitis (14%), increased lipase (8%), and increased amylase (8%).

Among all patients, the most common grade 3 or above adverse reactions were: diarrhea (12%), nausea (4%), stomatitis (3%), increased lipase (3%), increased amylase (3%), vomiting (2%), rash (1%), and decreased appetite (1%).

Among patients who received the 160 mg dose, the most common adverse reactions were: diarrhea (85%), nausea (43%), rash (36%), vomiting (29%), decreased appetite (25%), stomatitis (18%), increased lipase (10%), and increased amylase (8%).

Among patients who received the 160 mg dose, the most common grade 3 or above adverse reactions were: diarrhea (18%), nausea (6%), increased lipase (6%), stomatitis (4%), increased amylase (4%), vomiting (3%), rash (1%), and decreased appetite (1%).

TAK-788 (160 mg once daily) has anti-tumor activity in patients with EGFR exon 20 insertion mutations, with an ORR of 43% and a median PFS of 7.3 months;

The adverse reactions of TAK-788 are consistent with other EGFR TKIs and are controllable.