Anna F. Farago, MD, PhD
Loxo Oncology completed a rolling new drug application (NDA) to the FDA in March 2018 for larotrectinib (LOXO-101), a pan-TRK inhibitor codeveloped by Bayer. If approved, larotrectinib would be available as a treatment for both adult and pediatric patients with locally advanced or metastatic solid tumors harboring an NTRK
The ongoing simultaneous evaluation of larotrectinib in adult and pediatric patients is a rarity in the oncology space, said Anna Farago, MD, PhD, a coinvestigator on the phase I/II study submitted for the NDA.
“What is striking is that you can see [NTRK
] in a variety of solid tumors, both in adults and in children,” said Farago. “Regardless of the tissue of origin or age of patient, we see that these tumors are highly dependent on TRK
signaling and highly sensitive to larotrectinib.”
The pan-TRK inhibitor induced an objective response rate (ORR) of 75% (95% CI, 61%-85%) by independent review and 80% (95% CI, 67%-90%) by investigator assessment in 55 evaluable patients.1
In pediatric patients with TRK fusion–positive solid tumors specifically, larotrectinib induced an ORR of 93%.2
In an interview with OncLive
, Farago, instructor of medicine at Harvard Medical School, and assistant in medicine in the Division of Hematology/Oncology at Massachusetts General Hospital, discussed the biology of larotrectinib, as well as the importance of genetic testing for molecular alterations like TRK
in patients with locally advanced solid tumors.
OncLive: Can you provide some background on larotrectinib?
: There have been 3 trials with this drug. There was a phase I study with adult patients, a phase I/II trial for pediatric patients, and a phase II study for adolescents and adults. Those data were put together for a presentation at the 2017 ASCO Annual Meeting, and then in a recent publication in the New England Journal of Medicine
. We participated in the phase I adult study and in the phase II adolescent and adult study.
The drug itself is a small molecule tyrosine kinase inhibitor of TRKA, TRKB, and TRKC. It binds to the ATP binding site of those receptor tyrosine kinases. We know from the literature, over the past 15 years, that gene fusions involving genes that encode TRKA
, and TRKC
, and also TRK1
, and TRK3
have been described in a variety of solid tumors.
The way that these fusions are configured is that there generally is a 5-prime upstream partner that contains some type of dimerization domain. Then, there is a 3-prime downstream NTRK1
, or NTRK3
gene that is involved with a kinase domain of that gene. Based on that, and by analogy with other fusion-positive cancers such as ALK
- and ROS1
-positive lung cancers. The prediction was that these fusion proteins may act as oncogenic drivers in these cancers. That appeared to be the case based on several preclinical studies.
Until recently, we haven't had the opportunity to treat patients with a highly targeted and selective TRK inhibitor. Larotrectinib is one of the very few targeted and selective TRK inhibitors that is currently in development. The phase I trial that I participated in was open to patients with any kind of alteration in TRK proteins. It became clear that the responses we were seeing were in patients who specifically had a fusion involving TRKA
, or TRKC
. Therefore, that became the group that was targeted for subsequent development was enrolled in the phase II study.
Biologically, from what we know about this drug being an inhibitor of TRK signaling and the configuration of these fusions that lead to constitutive activation of the TRK kinase domain, it makes sense to me that a drug that is an inhibitor of kinase signaling would be active in cancers in which that TRK signaling is acting as an oncogenic driver.
How would an FDA approval of larotrectinib impact the oncology field?
In some cancer types, TRK
fusions are very rare. I am primarily a thoracic oncologist and, in lung cancer, these fusions occur at a frequency of well under 1%. In less common cancer types, they are more common. For example, these are fusions that are commonly seen in pediatric fibrosarcoma. The total number of patients who may benefit is slightly difficult to predict at this point, but for patients whose cancer has a TRK
fusion, these drugs can be tremendously effective.