Clinical data for Larotrectinib ( Vitrakvi ), an oral, selective, and CNS-active TRK inhibitor, in adult and pediatric patients with TRK fusion cancers, were presented at the European Society for Medical Oncology ( ESMO ) 2018 Congress.
The update included approximately one year of additional follow-up for the 55 patients described in the Larotrectinib New England Journal of Medicine ( NEJM ) publication from February 2018.
In addition, the update included data for an additional 67 patients who were subsequently enrolled across the Larotrectinib development program.
As of a data cut-off date of July 30, 2018, median duration of response ( DOR ) had not been reached in either dataset.
The ESMO presentation included additional follow-up for the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancers treated across phase 1 adult trial, phase 2 trial ( NAVIGATE ), and phase 1/2 pediatric trial ( SCOUT ).
These patients were the subject of NEJM publication from February 2018, and constitute the primary analysis population supporting Larotrectinib’s NDA filing.
The presentation also included data for the 67 TRK fusion patients subsequently enrolled.
The datasets adhered to the intent to treat ( ITT ) principle and included patients with RECIST-evaluable disease enrolled to the three clinical trials, regardless of prior therapy or tumor tissue diagnostic method used to establish their TRK fusion diagnosis.
In the ESMO presentation, response evaluations were based on investigator assessment.
The 122-patient integrated dataset included both adult and pediatric patients, who ranged in age from one month to 80 years and carried 24 unique TRK fusion-positive tumor diagnoses.
Tumor types included 10 distinct soft tissue sarcomas, salivary gland, infantile fibrosarcoma, thyroid, lung, melanoma, colon, gastrointestinal stromal tumor ( GIST ), breast, bone sarcoma, cholangiocarcinoma, carcinoma of unknown primary, congenital mesoblastic nephroma, appendiceal, and pancreas cancers.
In the primary dataset, the overall response rate ( ORR ) was 80% ( 44/55 ) ( 95% CI: 67-90% ), with a 62% partial response rate and an 18% complete response rate.
In the supplementary dataset, the ORR was 81% ( 44/54 ) ( 95% CI: 69-91% ), with a 65% partial response rate and a 17% complete response rate.
Across both datasets, the ORR was 81% ( 88/109 ) ( 95% CI: 72-88% ), with a 63% partial response rate and 17% complete response rate.
The ORR analyses for the supplementary and integrated datasets included nine patients with unconfirmed partial responses awaiting confirmatory response assessments, but did not include 13 patients who were awaiting an initial response assessment and continuing on study.
Median duration of response ( DOR ) had not been reached in either the primary dataset or supplementary dataset, with median follow-up of 17.6 months and 7.4 months, respectively.
In the primary dataset, Kaplan-Meier landmark analyses improved since the July 2017 data cut-off date. At 6 months, 88% of responses were ongoing ( 83% based on the July 2017 data cut-off date ).
At 12 months, 75% of responses were ongoing ( 71% based on the July 2017 data cut-off date ). Kaplan-Meier landmark analyses of the supplementary dataset were highly concordant with the primary dataset.
At 6 months, 93% of responses were ongoing and at 12 months, 81% of responses were ongoing.
Across the integrated dataset, as of the July 2018 data cut-off date, 84% of responding patients remained on treatment or had undergone surgery with curative intent.
Of 8 TRK fusion patients treated in the phase 1 trial, 6 remained in response and on therapy at 22, 30, 33, 34, 37, and 41 months of follow up.
With median follow-up for progression-free survival ( PFS ) of 19.6 months in the primary dataset, median PFS had been reached, at 28.3 months ( 95% CI: 9.9 months – not estimable ). This estimate is not statistically stable due to a low number of progression events, as evidenced by the wide confidence interval.
The safety data presented at ESMO encompassed the entire Larotrectinib safety database in cancer patients ( n=207 ), which includes 70 patients without a TRK fusion diagnosis.
Larotrectinib was well tolerated, with the majority of adverse events recorded as grade 1 or 2.
No treatment-related grade 3 or 4 adverse events occurred in more than 5% of patients.
Eleven patients ( 9% ) required Larotrectinib dose reductions.
In all cases, patients whose doses were reduced maintained their best response at the lower dose. One patient ( less than 1% ) discontinued Larotrectinib due to an adverse event.
Larotrectinib is an oral, selective, and CNS-active investigational tropomyosin receptor kinase ( TRK ) inhibitor in clinical development for the treatment of patients with cancers that harbor a neurotrophic tyrosine receptor kinase ( NTRK ) gene fusion.
Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body.
In clinical trials, Larotrectinib demonstrated anti-tumor activity in patients with tumors harboring NTRK gene fusions, regardless of patient age or tumor type.
In an analysis of 55 RECIST-evaluable adult and pediatric patients with NTRK gene fusions, using a July 17, 2017 data cutoff, Larotrectinib demonstrated a 75% centrally-assessed confirmed overall response rate ( ORR ) and an 80% investigator-assessed confirmed ORR, across many different types of solid tumors. ( Xagena )
The majority ( 93% ) of all adverse events were grade 1 or 2.
Source: Loxo Oncology & Bayer, 2018