Mobocertinib is the first specially designed oral TKI that selectively targets EGFR exon 20 insert mutations, which obtains selectivity by targeting proteins near the α-C-helix, and exerts anti-tumor activity through substitution on the cadine ring.

The efficacy and effects of Mobocertinib

On March 6, 2023, China approved the first oral innovative drug Mobocertinib succinate capsule for non-small cell lung cancer, a EGFR exon20 Insertion mutation (EGFR exon20 Insertion). Mobocertinib prescribed the first national prescription and officially entered the stage of clinical application in China. This news marks the end of the dilemma of "no specific targeted therapeutic drugs available" in China's lung cancer patients with mutations in exon EGFR No. 20 exon has entered a new era of targeted therapy. Mobocertinib approval provides patients with a new treatment option that promises to improve their treatment effectiveness and quality of life.

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The effects of Mobocertinib

Mobocertinib (TAK-788) is an oral EGFR-TKI targeting EGFR ex20ins, designed to form a covalent interaction with cysteine 797 in EGFR. It is unique in that it can identify and target substructure differences between proteins near the αC-helix and produce irreversible binding. Compared with the reversible binding mechanism, this irreversible binding mechanism has a higher affinity and can produce longer-lasting inhibition of ECFR kinase activity and greater overall selectivity, resulting in increased titer.

The efficacy of Mobocertinib

The basis for the approval of Mobocertinib is based on a Phase I/II clinical study (NCT02716116). 114 patients who had previously received platinum-containing chemotherapy [i.e., platinum-based treatment population (PPP), including the dose escalation study (n=6), extended cohort (n=22), and EXCLAIM extended cohort (n=86)] were combined for analysis. The treatment regimen for the PPP population was Mobocertinib 160 mg once a day (35% of patients had baseline with brain metastasis, 59% had previously received ≥ second-line treatment, and 43% had previously received immunotherapy).

The main study endpoints showed that the ORR confirmed by the Independent Review Committee (IRC) was 28% (32/114), and the ORR confirmed by the investigator (INV) was 35% (40/114); the median duration of response (DOR) for IRC was 17.5 months, and the DOR assessed by INV was 11.2 months; the DCR confirmed by INV and IRC were 78% (89/114); the median PFS confirmed by IRC was 7.3 months and the median OS was 24.0 months.

The safety of Mobocertinib

Mobocertinib safety is consistent with the known EGFR-TKI toxicity characteristics, characterized by gastrointestinal and dermal mucosal adverse events (AEs) [1]. Almost all patients had any treatment-related AEs, the top three were diarrhea (91%), rash (45%), and dextrositis (38%). The incidence of any grade ≥3 AE associated with treatment was 47%, and the incidence of AEs resulting in a reduction or discontinuation was 25% and 17%, respectively. 

The most common AEs that lead to discontinuation include diarrhea (4%), nausea (4%), vomiting (2%), loss of appetite (2%), and stomatitis (2%). The ORR (21%, n=29) in patients who decreased due to AE was lower than those who did not decrease due to AE (31%, n=85), and the median DOR (5.7 months vs 17.5 months) and median PFS were shorter (5.9 months vs 7.3 months). This highlights the importance of early identification and active management of gastrointestinal and skin-related toxic reactions during Mobocertinib treatment.

Mobocertinib is an oral targeted drug designed for non-small cell lung cancer with EGFR exon 20 insertion mutations. Its unique irreversible binding mechanism makes it have higher affinity and longer-lasting inhibitory ability of kinase activity, thereby improving the therapeutic effect. 

The approval of Mobocertinib provides patients with a new treatment option that is expected to improve the quality of life of patients, marking a new era of targeted therapy for lung cancer patients with exon insertion mutations in EGFR No. 20 in China.