TAK-788 demonstrates efficacy, manageable safety profile in NSCLC subtype

CHICAGO — An oral investigational EGFR/HER2 inhibitor, TAK-788, demonstrated antitumor activity in hard-to-treat patients with non-small cell lung cancer whose tumors harbor EGFR exon 20 insertions, according to phase 1/2 data presented at the ASCO Annual Meeting.

Results further showed that TAK-788 (Millennium Pharmaceuticals/Takeda) had a manageable safety profile that was comparable with that of other EGFR inhibitors.

“We know EGFR mutations are relatively common, occurring in 15% to 20% of people with NSCLC,” Gregory J. Riely, MD, PhD, vice chair of clinical research at Memorial Sloan Kettering Cancer Center, said during a presentation. “But about 6% of all EGFR mutations are a relatively uncommon variant called EGFR exon 20 insertions.”

In general, EGFR exon 20 insertions are associated with resistance to currently-approved EGFR TKIs, resulting in poor response rates, according to Riely and colleagues. Preclinical data have shown that TAK-788 has potent and selective inhibitory activity against these EGFR exon 20 insertions.

For the phase 1/2 trial, Riely and colleagues enrolled patients into seven different cohorts. These cohorts were categorized by various combinations of tumor histology, exon 20 insertion mutations in EGFR vs. HER2, prior treatments and history of brain metastases.

The current protocol-specified analysis focuses on patients with refractory EGFR exon 20 insertions who received one or more prior systemic treatments. Eligibility criteria allowed patients to have either active brain metastases less than 1 cm or previously-treated brain metastases that were larger than 1 cm.

The efficacy of TAK-788 was assessed in 28 patients who received 160 mg of TAK-788 daily, which was previously determined to be the maximum-tolerated dose in a phase 1, dose-escalation trial. Among these patients, 12 had baseline brain metastases, including seven with active metastases less than 1 cm and five with previously-treated metastases.

The safety profile was evaluated in two cohorts: all patients who received TAK-788 at any dose during the phase 1 dose-escalation trial and phase 2 expansion trial (n = 137), and only patients who received at least one 160 mg dose (n = 72) during either trial.

In the efficacy cohort, the median duration of treatment was 7.9 months. Fourteen patients (50%) were still receiving TAK-788 at the time the data were presented. The other 14 patients discontinued treatment due to progressive disease (n = 7), adverse events (n = 3) physician decision (n = 3) or death (n = 1).

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The confirmed objective response rate (ORR) was 43% (95% CI, 24-63). However, three additional partial responses were identified and, if confirmed, could potentially increase the overall ORR, according to Riely. The median PFS was 7.3 months.

Although the cohort was small, Riely noted that patients with baseline brain metastases had a lower ORR (25% vs. 56%) and shorter median PFS (3.7 months vs. 8.1 months) than patients without baseline brain metastases.

In the safety analysis, 40% of patients who received 160 mg and 32% who received any dose of TAK-788 had a grade 3 or 4 treatment-related adverse event. In the 160-mg group, 25% of patients had a dose reduction due to an adverse event, 50% had a dose interruption due to an adverse event and 14% discontinued treatment due to a treatment-related adverse event. Among patients who received any dose, 18% had a dose reduction due to an adverse event, 51% had a dose interruption due to an adverse event and 13% discontinued treatment due to a treatment-related adverse event. The most common adverse events in both groups were diarrhea, nausea, vomiting, stomatitis, increased lipase and increased amylase.

“To summarize, TAK-788 at the recommended phase 2 dose of 160 mg showed antitumor activity in patients with EGFR exon 20 insertion mutations,” Riely said. “TAK-788 demonstrates responses in patients with diverse EGFR exon 20 insertion variants. The TAK-788 adverse event profile was manageable and consistent with that of other EGFR TKIs.”

The researchers will continue to examine TAK-788 in the recently-launched EXCLAIM extension cohort. This trial will enroll 91 pretreated patients with locally-advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertions. The trial will be conducted in the United States, Europe, China, Taiwan and South Korea. The primary endpoint will be confirmed ORR. – by Stephanie Viguers

Reference:

Jänne PA, et al. Abstract 9007. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosure: Riely reports receiving research funding on behalf of his institution from ARIAD Pharmaceuticals, GlaxoSmithKline, Infinity Pharmaceuticals, Merck, Millennium, Mirati Therapeutics, Novartis, Pfizer and Roche/Genentech, as well as paid travel accommodations and expenses by Merck Sharp & Dohme. He also reports submitting a patent application on behalf of his institution for pulsatile use of erlotinib to treat or prevent brain metastases.