Larotrectinib ‘potential standard of care’ for adult, pediatric TRK fusion tumors
medwireNews: Preliminary findings for larotrectinib (LOXO-101) suggest that the agent may offer an effective tumor type-agnostic treatment for adults and children presenting with tropomyosin receptor kinase (TRK) fusions.
“One of the distinguishing characteristics of TRK fusions is that they occur in a wide distribution of cancer types,” David Hyman, from Memorial Sloan Kettering Cancer Center in New York, USA, told delegates at the 2017 annual meeting of the American Society of Clinical Oncology, held in Chicago, Illinois, USA.
TRK fusions are detected in 0.5–1.0% of common cancers and are found almost universally in some rare tumor types, he said, explaining that the current estimated rate of 1500–5000 affected US adult and pediatric patients per year may be low because of a lack of screening.
“Larotectinib is the first and only pan-TRK inhibitor in clinical development”
“Larotrectinib is the first and only selective pan-TRK inhibitor in clinical development,” Hyman explained, noting that the agent is potent against the TRKA, TRKB, and TRKC isoforms. And he highlighted the short development timeline of the agent, from first in-patient treatment in March 2015 to US FDA breakthrough therapy designation in July 2016, and completion of enrolment in the pivotal trial by February 2017.
In all, eight patients were recruited to an adult phase I study of advanced solid tumors, 12 patients to the SCOUT pediatric phase I/II study, and 35 patients to the NAVIGATE phase II basket trial for patients aged 12 years and older with TRK fusion-positive solid tumours. Patients were given larotrectinib predominantly at a dose of 100 mg twice daily as a continuous monotherapy.
The median age was 45.0 years, but this ranged from age 4 months to 76 years, with a quarter of patients aged 15–39 years. The majority of patients had an ECOG performance status of 0 (49%) or 1 (40%), and most had received no or one prior chemotherapy (55%), although 15% had received two and 31% had used three or more treatments.
Patients had one of 17 different cancer types, most commonly salivary gland tumors (22%), infantile fibrosarcoma (13%), and thyroid cancer (9%). The presenter noted that just one of the patients had central nervous system metastases, “suggesting that this site of spread may be relatively uncommon in cancers that harbor TRK fusions.”
An overall response rate of 76%
The overall response rate in the 50 patients with confirmed scan findings was 76%, with a complete response in 12% and a partial response in 64%, while stable disease and progressive disease were both reported in 12% each. Five patients remain on study and are awaiting a scan to confirm their active responses.
Objective responses were “generally quite deep,” Hyman said. This included two pediatric patients with locally advanced, unresectable disease who achieved a complete response that allowed potentially curative surgery that subsequently resulted in a pathological complete response. Both patients are off-drug and disease free.
Efficacy was not associated with patient age or tumor type, or by NTRK gene or the upstream fusion partner, and the only identifiable predictor of response to larotrectinib was the presence of a TRK fusion, Hyman said.
Speaking to medwireNews at a press conference, Hyman observed that less than 24% of patients had not responded to treatment as a number of participants had experienced a subthreshold partial response, but that it was unclear why some patients were primary nonresponders.
Noting that TRK fusion assays had been performed in one of 15 certified community laboratories rather than centrally tested, he suggested that there may be variability between centers in the detection of the aberration.
“I think that the response rate that you see here represents what we would expect if larotrectinib was approved for use in the real world, based on real tests that are not specifically assessed for validity for TRK fusion,” he commented, but added that this is “just a suspicion.”
Of note, 93% of responding patients remain on treatment and 75% of all patients remain on treatment or have undergone surgery with curative intent, with the first patient to be given the agent having an ongoing response at 25 months.
Patients responded “quite early” at a median of 1.8 months but Hyman remarked that this finding reflected time of scanning and that patients in the clinic with symptomatic cancers reported “near immediate improvement” in symptoms. Four patients continued to receive treatment after progression and derived benefits.
Median duration of response has not yet been established as 91% of patients have continued to respond at 6 months, and median progression-free survival has not been determined as 75% of patients are progression-free at 6 months.
“One of the defining experiences of using larotrectinib in the clinic is its safety profile,” Hyman said. Just 13% of patients required a dose modification because of adverse events and all maintained tumor regression while on a reduced dose. None of the patients discontinued treatment because of side effects.
Identical mutation found in five of the six patients who developed larotrectinib resistance
Hyman also told medwireNews that five of the six patients who had stopped responding to treatment by time of data analysis show identical TRK solvent front mutations.
“And this morning we have published a manuscript in Cancer Discovery describing this phenomenon and also describing the preclinical and accelerated initial clinical development of LOXO-195 which is the next generation of TRK inhibitor, which maintains activity in the presence of this common resistance mechanism,” he continued.
“In fact, the first two patients to ever develop resistance to larotrectinib on this study were both successfully treated with LOXO-195 so there is really no gap between the emergence of resistance in this study and actually having patients re-respond to a next-generation inhibitor that overcomes that mechanism.”
“Larotrectinib may offer a potential new standard of care”
Hyman concluded his presentation: “For patients with TRK fusion cancer, larotrectinib may offer a potential new standard of care.
“Routine pan-cancer screening will be important to identify these patients, as well as those with other tumor-agnostic biomarkers.”
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