Entrectinib Achieves High Objective Response Rates Across Solid Tumors

NTRK,ROS-1, orALKrearrangements, according to updated data reported at the 2016 AACR Annual Meeting.

Of 24 evaluable patients in the study, 19 had objective responses to entrectinib. The agent also achieved durable responses in primary brain tumors and brain metastases, including one complete response.

A global phase II basket study of entrectinib has begun and will involve patients with locally advanced or metastatic solid tumors withNTRK,ROS-1, orALK-positive tumors, said Alexander Drilon, MD, an assistant attending physician at Memorial Sloan Kettering Cancer Center.

“We observed rapid [within 1 months of treatment initiation] and prolonged responses, including 11 of 13 patients withROS1-rearranged non—small cell lung cancer and an additional patient with melanoma,” Drilon said during a press conference. “The long ongoing response is approaching 2 years and 3 months.”

Findings were reported from the phase I development program of entrectinib, involving the STARTRK-1 and ALKA-372-001 trials. In the STARTRK-1 trial, entrectinib was given continuously to 65 patients in the United States, Europe, and Asia. ALKA-372-001 involved 54 Italian patients treated with intermittent and continuous dosing. All 119 patients in both studies had tumors withNTRK/ROS1/ALKalterations.

The 19 patients whose tumors responded to entrectinib represented diverse malignancies: non—small cell lung cancer (NSCLC), colorectal cancer, melanoma, and mammary analog secretory carcinoma (MASC). Patients withNTRK1/2/3,ROS1, andALKgene fusions responded to the agent.

In a subgroup withROS1-rearranged tumors and no prior exposure to a tyrosine kinase inhibitor (n = 14), treatment with entrectinib led to objective responses in 12 patients (86%). Two patients had complete responses. Eleven of the responding patients had NSCLC and the other had melanoma. In theALK-mutated group (n = 7), 57% of patients experienced a response. The majority of patients in this group had NSCLC (n = 5).

Entrectinib’s activity in NSCLC was particularly noteworthy in that one patient had a partial extracranial response but a complete response in the brain. This patient had received 4 prior therapies, including a PD-1 inhibitor, and had a poor baseline performance status. The patient remains on entrectinib and has been progression-free for >12 months, Drilon reported.

“This was noteworthy because the brain is a relatively common site for NSCLC metastasis and other therapeutics may not be as effective against brain metastases,” he said.

In the subgroup ofNTRK-rearranged cancers (n = 5), 100% of patients with various tumor histologies and fusion types responded to entrectinib. The agent resulted in “dramatic intracranial activity” in all three patients with central nervous system disease (CNS).

“Thus far, entrectinib is the only Trk inhibitor that has demonstrated CNS activity,” said Drilon.

According to the abstract, the most common treatment-related adverse events at the 600 mg daily dose were fatigue/asthenia (47%), dysgeusia (32%), constipation (26%), dizziness (21%), paresthesia (21%), diarrhea (16%), myalgia (16%), and weight gain (16%).

“We do need to validate these results in larger numbers of patients, but patients and their physicians should strongly consider comprehensive genetic profiling to determine whether these gene fusions are present in the patient’s tumors," said Drilon. "If they are, there is a good chance that treatment with a Trk inhibitor like entrectinib will result in very meaningful benefit.”

Patient accrual has already begun in the larger phase II STARTRK-2 trial, designed to confirm the results observed in the STARTRK-1 and ALKA-1 trials. The recommended phase II dose from the earlier studies was identified as 600 mg daily. The study is enrolling those withNTRK1/2/3,ROS-1, andALKrearrangements (NCT02568267).

Entrectinib (RXDX-101) is an orally available, ATP-competitive tyrosine kinase inhibitor that has demonstrated low to subnanomolar efficacy against 5 kinases (TrkA, B, and C; ROS1 and ALK). The agent has exhibited in vitro and in vivo activity againstNTRK1/2/3-,ROS1-, andALK-rearranged cancers.

NTRK1/2/3,ROS1, andALKoccur in multiple types of cancer, especially some of the less common malignancies, such as glioblastoma, Spitz melanoma, cholangiocarcinomas, and papilloma thyroid cancer. No currently available cancer therapies address all of those mutations, Drilon noted.

Brain metastases occur in 20% to 40% of patients with cancer and are especially prevalent in lung and breast cancer and melanoma. Some types of primary brain tumors have associations withNTRKfusions, including astrocytoma, glioblastoma, and pediatric gliomas.

“An optimal therapy would address by systemic and central nervous system disease,” said Drilon.

References

1. Drilon A, De Braud FG, Siena S, et al. Entrectinib, an oral pan-Trk, ROS1, and ALK inhibitor in TKI-naïve patients with advanced solid tumors harboring gene rearrangements. Presented at the 2016 AACR Annual Meeting; April 16-20, New Orleans, Louisiana. Abstract CT007.