LOXO-101, which targets proteins encoded by gene fusions involving NTRK1, NTRK2, and NTRK3, and entrectinib, which targets fusion proteins encoded by translocations in ROS1 and ALK, yielded dramatic clinical activity in patients with a variety of cancers in separate phase I trials. The data were presented at the American Association for Cancer Research Annual Meeting 2016, April 16–20, in New Orleans, LA.

In separate phase I trials, two investigational anticancer therapies—LOXO-101 (Loxo Oncology) and entrectinib (Ignyta)—showed dramatic clinical activity in patients with a variety of cancers in separate phase I trials, according to data presented at the American Association for Cancer Research (AACR) Annual Meeting 2016, held in New Orleans, LA, April 16–20.

Both drugs selectively inhibit a family of proteins called neurotropic tyrosine kinases, including TrkA, TrkB, and TrkC, which are overexpressed as a result of relatively rare gene fusions involving NTRK1, NTRK2, and NTRK3. Entrectinib also targets these proteins, as well as two fusion proteins encoded by translocations involving ROS1 and ALK. All five proteins promote cancer cell proliferation and survival.

In November 2015, David Hong, MD, deputy chair and associate professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston, reported on three patients with NTRK gene fusions enrolled in the LOXO-101 study, all of whom demonstrated partial responses to the treatment.

At the AACR meeting, Hong presented data on three more patients with NTRK fusions and noted that a seventh recently joined the study but has yet to be assessed. The seven have five different types of malignancy: sarcoma, papillary thyroid cancer, mammary analog secretory carcinoma (MASC) of the salivary glands, non–small cell lung cancer (NSCLC), and gastrointestinal stromal tumor. Five of the six evaluable patients had a partial response, while the sixth patient's tumor shrank by 18%. In addition, Hong said, brain metastases regressed significantly in one patient.

Even though patients lacking NTRK fusions could enroll in the trial, none of them have had a response to LOXO-101, Hong noted. Consequently, a phase II trial of LOXO-101 now under way will enroll only patients who have tested positive for an NTRK gene fusion.

“The phase II study is important not only for generating additional data on LOXO-101 in patients with NTRK-fusion cancers, but we anticipate it will further broaden the range of tumor types that we've tested thus far,” explained Hong.

Responses to entrectinib were equally dramatic. Data reported in September 2015 from two phase I studies involving a total of 119 patients showed an objective response rate of 72% among the 18 whose tumors harbored one of the five gene fusions.

Alexander Drilon, MD, assistant attending physician of the Developmental Therapeutics Clinic and the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center in New York, NY, provided additional data at the AACR meeting, reporting on 24 patients. Overall, 79% responded to the drug, including all three patients with NTRK rearrangements, 12 of 14 with ROS1 rearrangements, and four of seven with ALK rearrangements. Responses were seen in NSCLC, MASC, astrocytoma, colorectal cancer, renal cell carcinoma, melanoma, and infantile fibrosarcoma.

“Responses to entrectinib were brisk,” commented Drilon, “and the majority of them were really seen at the first time point patients were imaged—within the first 4 to 8 weeks.” In addition, the majority of the patients have had ongoing responses, with half responding for 6 months. One patient continues to respond after more than 2 years.

During preclinical work, researchers repeatedly refined entrectinib, aiming to get it to cross the blood–brain barrier in people, Drilon said. It worked. All three patients with a primary brain tumor or brain metastases experienced dramatic intracranial drug activity. In one case Drilon presented, a patient with NSCLC experienced just a 47% reduction in lung tumor volume after 26 days, but at that same time, all 15 to 20 of his brain metastases had completely disappeared. After nearly a year, the lung tumors had decreased by 79%, and the brain lesions have not returned.

Based on this data, Drilon announced that a global phase II trial of entrectinib, for which he will serve as the principal investigator, has been launched. Only patients with an NTRK, ROS1, or ALK gene fusion will be enrolled.

“I want to emphasize that this [study outcome] is the product of many decades of very sophisticated research that was conducted to understand the genetic abnormalities that drive human cancers,” said Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. “This work was basic, it wasn't clearly going to lead anywhere when it started, it was persistent, it was expensive, it was hard to get done. … And here we are, witnessing what I would consider a glory moment, showing that all of us benefit from the patient research that was done.” –Suzanne Rose

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