NTRK Gene Alteration Type Dictates Larotrectinib Response

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Solid tumour patients with an NTRK fusion are more likely to respond to larotrectinib treatment than those with other types of NTRK alterations, indicates research reported at the 2020 AACR Virtual Annual Meeting I. 

“These data strongly support the clinical importance of testing for NTRK gene fusions in order to identify patients who would benefit from larotrectinib treatment”, said presenting author David Hong, from The University of Texas MD Anderson Cancer Center in Houston, USA. 

The researchers reviewed data from three studies of the first-in-class selective TRK inhibitor in patients with solid tumours, noting that larotrectinib is currently approved in many countries for the treatment of adult and paediatric tumours harbouring NTRK fusions. 

This included 12 fusion and 62 non-fusion adult participants of a phase I trial, 50 fusion and 11 non-fusion paediatric patients from the SCOUT phase I–II trial, and 97 fusion patients from the phase II NAVIGATE basket trial for adults and adolescents. 

The investigator told delegates that baseline characteristics were “well balanced” between the NTRK fusion and non-fusion groups, except fusion patients were younger and had received fewer lines of prior treatment. 

NTRK alterations present in these patients included NTRK1 (n=64), NTRK2 (n=4) and NTRK3 (n=87) fusions, point mutations (n=8), amplifications (n=5), rearrangements (n=3) and a deletion (n=1). A third of the non-fusion patients also carried other oncogenic alterations, such as mutations in EGFR, MET and KRAS. 

Soft tissue sarcoma was the most common of the 17 NTRK fusion solid tumour types present (23%), followed by infantile fibrosarcoma (18%), thyroid tumour (16%) and salivary gland tumour (13%). Lung cancer was the most common of the 25 solid tumour types represented with an NTRK non-fusion alteration (14%), followed by soft tissue sarcoma (12%), colon cancer (11%) and primary central nervous system tumours (8%). 

An objective response was achieved in 79% of the patients with a NTRK fusion, including a complete response in 16% and a partial response in 63%, while a further 12% had stable disease. By contrast, just 1% of those with a non-fusion alteration achieved an objective response, and 23% had stable disease. 

This difference in response was reflected in the corresponding durations of treatment, with 64% of NTRK fusion tumour patients remaining on treatment for up to 47.0 months at the time of data cutoff, whereas treatment was discontinued by non-fusion patients after an average of 2.5 months, except for one patient who remained on larotrectinib for 27.0 months. 

Duration of response was a median of 35.2 months for the NTRK fusion group versus 3.7 months for the non-fusion group. And NTRK fusion patients had significantly longer progression-free survival and overall survival than their non-fusion counterparts, at 28.3 versus 1.8 months, and 44.4 versus 10.7 months, respectively. 

David Hong noted that side effects with larotrectinib were “mostly” grade 1 or 2, but that the NTRK fusion group were less likely to discontinue treatment citing treatment-related adverse events than the non-fusion patients (6 vs 25%). 

“Larotrectinib demonstrated robust and durable responses in adult and paediatric patients with NTRK gene fusions”, the presenter summarised. 

“Patients with non-fusion alterations in NTRK genes, including point mutations and amplifications, had limited benefit from larotrectinib.” 

Reference 

Hong DS, Dowlati A, Burris H, et al. Efficacy and safety of larotrectinib in patients with cancer and NTRK gene fusions or other alterations. American Association of Cancer Research Virtual Annual Meeting I; 27–28 April 2020 (Abstract CT062).