Alexander M. Castellino, PhD

April 19, 2016

UPDATED May 19, 2016 // NEW ORLEANS — An investigational agent that targets TrkA/B/C, ROS1, and ALK gene fusions has shown objective response rates (ORR) of over 80% across several solid tumors, according to updated data presented here at the American Association for Clinical Research (AACR) annual meeting. The new drug, entrectinib, is being developed by Ignyta.

"Fusions involving the genes NTRKA/B/C, ROS1, and ALK are readily detected in the clinic," lead author Alexander Drilon, MD, assistant attending physician of the Developmental Therapeutics Clinic and the Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York City, told Medscape Medical News.

"Now we have drugs that provide dramatic and durable responses. Our study shows that entrectinib can achieve rapid and durable responses in patients across many solid malignancies," he added.

"Entrectinib is an active targeted therapy for NTRK-, ROS1-, and ALK-rearranged cancers and was developed to cross the blood-brain barrier," Dr Drilon said.

Dr Alexander Drilon

Entrectinib and another investigational agent, LOXO-101, are not the only inhibitors of TRKA/B/C, but they are the furthest along in clinical development, commented Leena Gandhi, MD, PhD, of the Dana-Farber Cancer Institute, New York City, in her discussion.

Data From Two Studies

The new data come from a combined analysis of two phase 1 studies, known as STARTRK-1 and ALKA-372-001. Both studies were undertaken in patients with NTRK/ROS/ALK alterations in their tumors. However, the dosing schedules differed. In STARTRK-1, dosing was continuous, whereas in ALKA-372-001, intermittent and continuous dosing was used.

The combined data were first presented in September 2015 at annual meeting of the European Society of Medical Oncology. These studies established the recommended dose for phase 2 studies as 600 mg administered orally once daily.

Dr Drilon provided updated safety data for 119 patients as well as data for the subpopulation of patients who satisfied the entry criteria of the phase 2 study. Patients entering the phase 2 study were required to have tumors with NTRKA/B/C, ROS1, or ALK gene fusions and to have had no prior treatment with therapies directed to these fusions.

Combined Efficacy

Efficacy data were reported for 24 patients who responded to therapy. Medscape Medical News asked about the 95 patients who were not included in the analysis. "The focus of this analysis is on the 24 patients who showed a response and were representative of those being enrolled in the phase 2 study. All patients were also naive to treatment with TKIs [tyrosine kinase inhibitors]," Dr Drilon said.

Confirmed responses were observed in 19 of 24 (79%) patients with extracranial solid tumors. Evidence of tumor shrinkage was observed in a patient with NTRK+ astrocytoma.

"Responses were rapid and occurred within the first month of treatment," he added, noting that they occurred within 4 weeks.

Dr Drilon reported that in ROS1 rearranged cancers, the overall response rate (ORR) was reported in 12 of 14 (86%) patients, of whom two responded completely. Of these, 11 of 13 (85%) of patients with non–small cell lung cancer (NSCLC) experienced an overall response. One patient with ROS1 rearrangement experienced a response for 27 months, which is still ongoing.

In cancers with NRTK rearrangement, responses were seen in 5 of 5 (100%) patients with a variety of cancers and fusion types. These included colorectal cancer (LMNA-NTRK1), astrocytoma (BCAN-NTRK1), infantile fibrosarcoma (ETV6-NTRK3), NSCLC (SQSTM1-NTRK1), and mammary analogue secretory carcinoma (MASC) (ETV6-NTRK3).

"The five total responses [to NTRK fusions] show that entrectinib has activity against a wide spectrum of fusions and tumor types," Dr Gandhi said.

However, only 57% of patients with ALK rearrangements in their tumors showed responses to entrectinib. "This response is comparable to crizotinib," Dr Gandhi said. "With the next generation of ALK inhibitors likely to replace crizotinib, the bar is set high for targeting ALK," she added.

Dramatic intracranial activity was seen in all of patients with central nervous system (CNS) tumors, and entrectinib is the only TrK inhibitor with CNS activity that is available thus far, Dr Drilon noted.

Entrectinib was safe and well tolerated, with 45 patients in the phase 1 studies being treated with the phase 2 dose of 600 mg daily.

Common treatment-related toxicities in the 119 patients across the phase 1 study included fatigue/asthenia, dysgeusia, constipation, dizziness, paraesthesia, diarrhea, myalgia, and weight gain.

What's Next for Entrectinib?

"Our preliminary data show that tumors with these genetic alterations can be exquisitely sensitive to entrectinib," Dr Drilon told Medscape Medical News, but he added: "We do need to validate these results in larger numbers of patients."

STARTRK-2, an ongoing phase 2 basket study for patients with solid tumors harboring NTRK1/2/3, ROS1, or ALK gene rearrangements, is aimed to confirm the results of the phase 2 studies in a larger cohort of patients. More information is available on the STARTRK-2 website.

"NTRK1/2/3 gene fusions can be rare within some types of cancer but occur across many different cancers. They occur at a higher frequency in some rare cancers, such as mammary analogue secretory carcinoma and breast secretory cancer," Dr Drilon said.

Given that histology-based trials are not feasible for patients with these driver mutations but for which there are potent drugs, such as entrectinib, the paradigm of a basket trial has been propagated. Patients are enrolled in basket trials regardless of cancer type and histology but for which there are appropriate drivers of therapy.

Dr Drilon indicated that in the future, drug approvals may be dependent on genetic profiling, not histology.

"Larger slices of the pie are easy pickings, and these have already been taken," Dr Drilon said. "We are now left with 1% slices, and the regulatory agencies have to reconsider how drugs get approved," he added.

In her discussion, Dr Gandhi indicated that resistance to therapy has to be considered during treatment. Given the potency of entrectinib, she referenced studies that highlighted the development of resistance with entrectinib. One study was an investigation of acquired resistance in colorectal cancer, and the other was of resistance in MASC. "With five other inhibitors in clinical development, it will be necessary to differentiate between the different agents," she said.

The study was funded by Ignyta. Dr Drilon receives honoraria from Ignyta and is on its speakers bureau.

American Association for Cancer Research (AACR) 2016 Annual Meeting: Abstract CT007, presented April 17, 2016.

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