Gerald S. Falchook, MD, MS
Patients with mutations in NTRK, RET, MET, HER2,
G12C have limited therapeutic options, but potentially promising agents are on the horizon, said Gerald S. Falchook, MD, MS, adding that these rare oncogeneic drivers in non–small cell lung cancer (NSCLC) are beginning to be better understood.
In a presentation during the 2018 OncLive®
State of the Science Summit™ on Advanced Non–Small Cell Lung Cancer, Falchook, director of Drug Development of Sarah Cannon Research Institute at HealthONE, discussed these oncogenic drivers in advanced disease.
There are 3 members in this family, Falchook explained—TRKA, TRKB, and TRKC. These are encoded by NTRK1, NTRK2,
TRK causes downstream activation of MAPK, PI3K, and PLCg pathways, which results in cell proliferation and increase cell survival and migration, leading to tumor growth.
“Fusions in NTRK
are not common as [up to] 5000 people in the country each year, across all tumor types, have TRK
fusion–positive cancers—they are not seen only in lung cancer,” said Falchook. “In lung cancer, [incidence] is in about 3% of patients. But, you will not know if a patient has it unless you are looking for it.”
In addition to NSCLC, NTRK
fusions occur in pediatric highgrade glioma, cholangiocarcinoma, and papillary thyroid carcinoma. They are also seen as pathognomonic of rare cancers, such as congenital fibrosarcoma, secretory breast cancer, and mammary analogue secretory carcinoma of the salivary gland.
TRK inhibitors currently in clinical trials are larotrectinib (LOXO-101), which inhibits TRK1/2/3; entrectinib, which inhibits ALK, ROS1, and TRK1/2/3; repotrectinib (TPX-0005), which inhibits ALK, ROS1, and TRK; and belizatinib (TSR-011), which inhibits ALK and TRK.
Larotrectinib has some of the most mature data, Falchook said. In results published in the New England Journal of Medicine
, the pan-TRK inhibitor showed an objective response rate of 75% (95% CI, 61%-85%) by independent review and 80% (95% CI, 67%-90%) by investigator assessment in 55 evaluable patients.1
Additionally, there were 7 (13%) complete responses, 34 (62%) partial responses, and 5 (9%) patients with stable disease. At 1 year, 55% of patients remained progression free, and 71% of responses were ongoing.
Three-month patient follow-up data presented at the 2017 ASCO Annual Meeting comprised the first 55 enrolled adult and pediatric patients from a phase I adult trial, the phase II NAVIGATE trial, and the phase I/II SCOUT pediatric trial. Findings showed that 93% of responding patients and 75% of all patients remain on treatment or underwent surgery with curative intent.
“The drug is very well tolerated. Among the treatmentrelated adverse events (AEs), there were no grade 4 events and a handful of grade 3 events,” explained Falchook. “Thirteen percent of patients did require dose reductions; however, even with a reduction, most of them were able to maintain their tumor response. No patients discontinued treatment because of toxicity.”
In May 2018, the FDA granted a priority review to a new drug application for larotrectinib for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors with an NTRK gene fusion.
fusions are chromosomal rearrangements that create a fusion between RET and other proteins, activating the RET receptor as well as the MAPK and EGFR pathways. These fusions occur in about 2% of NSCLC cases—usually in patients younger than 60 years old who are never smokers or former light smokers with a poorly differentiated histology and early lymph node metastasis.
Current inhibitors in the NSCLC landscape for RET
fusion–positive patients include vandetanib (Caprelsa), cabozantinib (Cabometyx), regorafenib (Stivarga), lenvatinib (Lenvima), sorafenib (Nexavar), sunitinib (Sutent), apatinib, alectinib (Alecensa), RXDX-105, BLU-667, and LOXO-292.
“There are a lot RET inhibitors in the clinic now. The first 2, vandetanib and cabozantinib, are not ‘clean’ RET inhibitors. They are multikinase inhibitors with a lot of other targets involved,” explained Falchook. “As time has gone on, more selective inhibitors have been developed.”
LIBRETTO-001 is a phase I study of LOXO-292 in patients with RET
-altered cancers (NCT03157128). The potent and highly selective RET inhibitor LOXO-292 induced an overall response rate (ORR) of 77% across RET fusion–positive cancers, according to findings presented at the 2018 ASCO Annual Meeting.3
Responses were observed with RET V804M gatekeeper mutations, which Falchook said are known to cause resistance to multikinase inhibitors. Among patients with NSCLC, the ORR was 77% (95% CI, 58%-90%).