FDA Grants BI-1482694 Breakthrough Designation for T790M-Positive NSCLC

Keunchil Park, MD, PhD

The FDA has granted a breakthrough therapy designation to the third-generation EGFR TKI BI-1482694 as a potential treatment for patients with T790M-positive non—small cell lung cancer (NSCLC), based on phase I/II data presented at the 2015 ESMO Asia Congress.

In the study, the objective response rate by independent assessment with BI-1482694 was 62% for patients with T790M-positive NSCLC. When looking specifically at those with a response confirmed on subsequent scans, the response rate with BI-1482694 was 46%. The overall disease control rate with BI-1482694 was 91% by independent review.

“These data further validate BI-1482694 as a potential treatment for lung cancer patients who encounter resistance to first- or second-generation EGFR targeting treatments," coinvestigator Keunchil Park, MD, PhD, professor at the Samsung Medical Center at Sungkyunkwan University School of Medicine in Seoul, South Korea, said in a statement.

In the phase I/II study, 203 patients received BI-1482694 daily at doses ranging from 70 mg to 1200 mg. Overall, 76 patients received the recommended phase II dose of BI-1482694 that was identified as 800 mg daily. All patients in the study were Korean and had received at least one prior EGFR TKI. Patients receiving prior chemotherapy were not excluded from the study.

In the 800 mg daily arm, all patients had confirmed T790M-positive NSCLC. Overall, 58% of patients in this group were female and 80% had an ECOG PS of 1 and 20% had an ECOG PS of 2. Patients had received a median of 2 prior chemotherapy regimens (range, 1-9). An EGFR TKI was received immediately prior to the study for 61% of patients.

Treatment duration ranged from 0.3 to 9.9 months, with 50% of patients remaining on therapy at the time of the data cutoff for the abstract. Median duration of response had not yet been reached at the time of the analysis. The secondary endpoint of progression-free survival and overall survival were not yet mature.

"Being able to improve outcomes of EGFR mutation-positive patients with minimum burden on their overall well-being is the goal for both patients and oncologists, so we eagerly await the duration of response and progression-free survival data from this study, as well as results of the broader clinical program which is underway,” said Park.

BI-1482694 (also known as HM61713) is an oral EGFR mutant-specific TKI, which is active against EGFR isoforms, including T790M. The agent is not specific to wild-type EGFR, possibly impacting adverse events (AEs).

The most common treatment-related all-grade AEs with BI-1482694 were diarrhea (55%), nausea (37%), rash (38%), and pruritus (36%). Grade 3 AEs were not common and consisted of rash (5%) and pruritus (1%).

"The T790M mutation is the most common resistance mechanism found in about half of the patients previously treated with currently available EGFR TKIs," Mehdi Shahidi, MD, medical head, Solid Tumour Oncology, Boehringer Ingelheim, the company developing the drug, noted in a statement. "Our aim at Boehringer Ingelheim is to prolong the continuum of treatment with targeted therapies for patients with EGFR mutation-positive lung cancer with a treatment that could potentially be efficacious even after the inevitable occurrence of resistance to the initial treatment.”

A potentially pivotal phase II study known as ELUXA-1 is currently recruiting patients with NSCLC with T790M-mediated resistance after first-line treatment with an EGFR TKI. The first patient was enrolled in this study in November 2015. The ELUXA clinical trial program will also include a phase III study, which is scheduled to launch in 2016.

Boehringer Ingelheim received exclusive rights from Hanmi Pharmaceutical Co. Ltd for BI-1482694 to market and develop the medication outside of South Korea, China, and Hong Kong. In October 2015, Hanmi submitted a new drug application in Korea for BI-1482694.

“The clinical trial results we have seen so far for BI-1482694 are very encouraging and have led to the FDA breakthrough designation and a first regulatory submission in Korea," said Shahidi.

Given the standard timeline for clinical development, Boehringer Ingelheim hopes to gain approval for BI-1482694 in Europe and the United States for patients with NSCLC in 2017.

Lee J, Park K, Han J, et al. Clinical activity and safety of the EGFR mutant-specific inhibitor, BI1482694, in patients (pts) with T790M-positive NSCLC. Presented at: 2015 ESMO Asia Congress; Singapore; December 18-21, 2015. Abstract 425PD.