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LOXO-101 shows promise for solid tumors with NTRK gene fusions
NEW ORLEANS — The investigational agent LOXO-101 demonstrated clinical activity in patients with solid tumors that had neurotrophic tyrosine receptor kinase gene fusions, according to study results presented at the American Association for Cancer Research Annual Meeting.
Neurotrophic tyrosine receptor kinase (NTRK) gene fusions, observed in a variety of tumor types, “can lead to constitutively-active TRKA, B and C kinases,” David S. Hong, MD, deputy chair and associate professor in the department of investigational cancer therapeutics at The University of Texas MD Anderson Cancer Center, and colleagues wrote.
David S. Hong
The researchers designed an open-label, multicenter study to evaluate LOXO-101 (Loxo Oncology), an oral, selective pan-TRK inhibitor in patients with solid tumors that have NTRK gene fusions.
“There have been a short list of gene fusions associated with approved targeted drugs for cancer,” Hong said during his presentation. “Kinase fusions happen to be highly actionable. We believe that NTRK gene fusions will soon join this list.”
Investigators enrolled 41 patients with tumors refractory to other available therapies. Patients received LOXO-101 orally once or twice daily for continuous 28-day cycles.
Seven of the patients had gene fusions involving NTRK1 or NTRK3. Tumor types in this subset included non–small cell lung cancer, sarcoma, papillary thyroid cancer, gastrointestinal stromal tumor or mammary analog secretory carcinoma of the salivary glands.
At data cutoff, six of these seven patients were evaluable, and all six had demonstrated clinical response.
Five had achieved confirmed partial responses defined by RECIST criteria. Researchers reported 21% tumor regression in the sixth patient.
All seven patients with NTRK gene fusions remain on study, with therapy durations ranging from one to 13 cycles. None of these patients have demonstrated any evidence of progressive disease, according to researchers.
Hong and colleagues have not observed anti-tumor activity in LOXO-101–treated patients who did not have an NTRK fusion.
The 41 patients enrolled in the study received LOXO-101 at one of five dose levels: 50 mg daily, 100 mg daily, 200 mg daily, 100 mg twice daily or 150 mg twice daily.
The agent appeared well tolerated, according to researchers. The maximum tolerated dose has not been reached. The most frequently reported adverse events were grade 1 or grade 2 fatigue (29%), dizziness (24%) and nausea (20%).
The findings support the design of an ongoing global, multicenter, single-arm open-label basket trial that includes patients with solid tumors that harbor NTRK gene fusions, Hong and colleagues wrote. The trial is expected to include 20 to 30 clinical sites.
“This is clearly an active drug,” Hong said. “It has shown exciting antitumor activity. I am very happy to be part of the global phase 2 basket study.” – by Mark Leiser and Cameron Kelsall
Reference:
Hong DS, et al. Abstract CT008. Presented at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans.
Di sclosure: Hong reports grant support from and a speakers bureau role with Loxo Oncology. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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As of February 2016, Hong and colleagues had enrolled 41 patients, seven of whom harbored NTRK gene fusions. Six of the efficacy-eligible patients with NTRK gene fusions have reportedly had disease regression and five patients have had confirmed partial responses. The tumor types of responders include sarcoma, papillary thyroid, salivary gland, non–small cell lung cancer and gastrointestinal stromal tumor. No responses were observed in patients whose tumors do not have NTRK gene fusions.
The overall incidence of NTRK gene fusions in cancer is low but still evolving. As demonstrated in tumors such as NSCLC, ALK has become a standard target despite having a 4% incidence rate.
We are always hopeful that early responses in biomarker-directed therapy will lead to overall efficacy. The efficacy based on data from six patients certainly needs validation that is forthcoming in a phase 2 basket study. If results are reproduced — especially in rare cancers with high unmet need — then one can be optimistic about a down-the-road regulatory path.
Without knowing the specifics of the phase 1 trial design, I wonder why 36 additional patients were enrolled, as there is reportedly very little activity in patients without NTRK gene fusions. If it was simply for dose finding and toxicity, then we may need to evaluate how biomarker-directed phase 1 studies are designed, especially when early results clearly demonstrate activity in a biomarker-specific subset.
Larger genomic panels performed in a greater number of patients with cancer will help identify increasing number of patients with rare mutations like NTRK. Additional data from clinical trials will need to demonstrate robust responses, as well as improved PFS and OS.