Mobocertinib Continues to Show Clinical Activity in EGFR Exon 20–Mutant NSCLC

Gregory J. Riely, MD, PhD

Mobocertinib (TAK-788) elicited a 43% objective response rate (ORR) and an 86% disease control rate in select patients with non–small cell lung cancer (NSCLC) who have EGFR exon 20 insertion mutations, according to updated results of a phase 1/2 trial (NCT02716116) that were presented at the 2020 ESMO Congress.¹

Results showed that both the partial response (PR) rate and stable disease (SD) rate was 43% for this patient population that received mobocertinib at a 160-mg dose, which was previously identified as the recommended phase 2 dose. Two of the 28 patients had progressive disease.

The median duration of response (DOR) was 13.9 months (96% CI, 5.0–not reached). In all patients, including those with baseline central nervous system (CNS) metastases, the median progression-free survival was 7.3 months.

“Mobocertinib at the recommended phase 2 dose showed antitumor activity in patients with EGFR exon 20 insertion mutations,” lead study author Gregory J. Riely, MD, PhD, vice chair of Clinical Research in the Department of Medicine, and medical oncologist, at Memorial Sloan Kettering Cancer Center, said in a virtual presentation during the meeting. “There were 43% confirmed objective partial responses, and a 14-month median duration of response.”

In April 2020, the FDA has granted a breakthrough therapy designation to mobocertinib for the treatment of patients with EGFR exon 20—mutant NSCLC with disease progression following platinum-based chemotherapy.²

Prior dose-escalation findings of the phase 1/2 trial, which was conducted in a 3 + 3 design of patients with NSCLC, showcased the dose-limiting toxicities (DLTs) during dose escalation, which included diarrhea, mucositis, and pneumonitis, as well as patients missing more than 25% of the planned dose due to treatment-related adverse effects (TRAEs).³ After evaluating TAK-788 at once-daily doses such as 80 mg, 120 mg, 160 mg, and 180 mg, the recommended phase 2 dose of mobocertinib was determined to be 160 mg daily.

The data presented during the ESMO meeting specifically comprised the 28 patients with EGFR exon 20 insertion mutations, had received prior therapy, and were treated with the 160-mg daily dose of mobocertinib.

The median age was 62 years (range, 28-84) and 75% of patients were female. Most patients (71%) were White, and 96% of patients had adenocarcinoma in the lung. Seventy-nine percent of patients had an ECOG performance status of 1, and 54% had previously 3 or more anticancer regimens; 21% had prior EGFR/HER2 TKIs and 61% had prior checkpoint inhibition. Sixty-one percent had a history of smoking and 43% of patients had baseline brain metastases.

As of January 27, 2020, 7 patients (25%) who were treated with the 160-mg dose and harbored EGFR exon 20 insertion mutations remain on study, with a median time on treatment of 12 months (range, 0.4-24.7).

Regarding safety, the tolerability profile was found to be manageable and consistent to that of other EGFR TKIs, Riely explained. All-grade and grade 3 or higher TRAEs included diarrhea (82% and 32%, respectively), nausea (39% and 11%), rash (46% and 0%), vomiting (36% and 7%), decreased appetite (39% and 0%), dry skin (18% and 0%), and fatigue (14% and 4%).

“As a result of these early toxicity data, the adverse event management guideline for diarrhea have been updated to allow symptomatic treatment at first evidence of increased frequency of bowel movement or grade 1 diarrhea,” Riely said.

Dose reductions occurred in 5 patients with NSCLC who harbor EGFR exon 20 insertion mutations who received the recommended phase 2 dose; reductions occurred in 23 patients overall who received the 160-mg dose, and in 28 patients who were given any dose of mobocertinib.

References

1. Riely GJ, Neal JW, Camidge DR, et al. Updated results from a phase 1/2 study of mobocertinib (TAK-788) in NSCLC with EGFR exon 20 insertions. Presented at: 2020 ESMO Congress; September 19-21, 2020; virtual. Abstract 1261M0.
2. Takeda announces U.S. FDA Breakthrough Therapy Designation for mobocertinib (TAK-788) for the treatment of NSCLC patients with EGFR exon 20 insertion mutations. April 27, 2020. https://bwnews.pr/2y3hRRM. Accessed April 27, 2020.
3. Neal J, Doebele R, Riely G, et al. Safety, PK, and preliminary antitumor activity of the oral EGFR/HER2 exon 20 inhibitor TAK-788 in NSCLC. J Thorac Oncol. 2018;13(10):S599. doi:10.1016/j.jtho.2018.08.901