Bayer today announced that the Center of Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) approved larotrectinib, under the brand name Vitrakvi™, for the treatment of adult and pediatric patients with advanced solid tumors that harbor a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion.

Bayer announced today that the Japanese Ministry of Health, Labor and Welfare (MHLW) has granted marketing authorization for larotrectinib, under the brand name Vitrakvi, for the treatment of Neurotrophic Tyrosine Receptor Kinase (NTRK) fusion-positive advanced or recurrent solid tumors.

Vitrakvi as monotherapy is indicated for the treatment of adult and paediatric patients with solid tumours that display a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion...

VITRAKVI is a kinase inhibitor indicated for the treatment of adult and pediatric patients with solid tumors that...have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation.

Recommendations...Larotrectinib is an option for the treatment of adults and adolescents aged ≥12 years with metastatic NTRK fusion-positive solid tumours, not amenable to surgery, that have progressed following treatment...

...entrectinib and larotrectinib are recommended as second-line or subsequent treatment options for patients with NTRK gene fusion-positive solid tumors…

...VITRAKVI (larotrectinib) was recommended by the National Institute for Health and Care Excellence (NICE) for the treatment of advanced neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours...

...Dose escalation: Birth through 21 years of age at C1D1 with a locally advanced or metastatic solid tumor or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and for which no standard or available systemic curative therapy exists; OR Infants from birth and older with a diagnosis of malignancy and with a documented NTRK fusion that has progressed or was nonresponsive to available therapies, and for which no standard or available curative therapy exists; OR Patients with locally advanced infantile fibrosarcoma who would require, in the opinion of the investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection. Phase I dose escalation cohorts are closed to enrollment...

...Proof of a malignancy harboring a NTRK fusion...

In this expanded dataset with extended follow-up, larotrectinib continues to demonstrate rapid and durable responses, extended survival, and a favorable safety profile in adults with TRK fusion cancer, including those with CNS metastases.

The overall best ORR was 74% (95% confidence interval [CI] 67–81): 50 (30%) complete response (CR), including 10 (6%) pathological CR, 72 (44%) partial response, 22 (13%) stable disease...The 48-month OS rate was 66% (95% CI 57–75)….With an extended follow-up, larotrectinib demonstrated durable and deepening responses, extended survival benefit and a favourable safety profile. This highlights the importance of identifying NTRK gene fusions in cancer pts.

85 larotrectinib patients and 28 SoC patients were included. After matching, log-rank testing suggested no difference between the 2 groups (P=0.26), and larotrectinib was associated with a 78% lower risk of death (adjusted HR: 0.22 [95% confidence interval: 0.09, 0.54]; P=0.001), compared to SoC....This analysis suggests longer overall survival with larotrectinib, compared to SoC, in adult patients with TRK fusion cancer.

The INV-assessed best ORR for the 93 evaluable pts was 84% (95% confidence interval [CI] 75–91): 35 (38%) complete response (CR; including two pending confirmation and 10 pathological CR), 43 (46%) partial response (two pending confirmation), 11 (12%) stable disease, two (2%) progressive disease...In this expanded dataset, larotrectinib continues to demonstrate rapid and durable tumor-agnostic efficacy, extended survival, and a favorable safety profile in pediatric pts with TRK fusion-positive cancer.

Data were pooled from three clinical trials of patients with non-CNS TRK fusion cancer treated with larotrectinib...Across all patients, the ORR was 75% (95% confidence interval [CI] 68–81), median DoR (mDoR) was 49.3 months (95% CI 27.3–not estimable [NE]), median PFS (mPFS) was 35.4 months (95% CI 23.4–55.7) and the 36-month OS rate was 77% (95% CI 69–84).... larotrectinib benefitted patients across varying degrees of pre-treatment and baseline ECOG PS.

We report an updated analysis of the efficacy and safety of larotrectinib in adult pts with TRK fusion cancer....ORR was 67% (95% CI 58–75): 12% complete responses; 55% partial responses (3 pts pending confirmation); 20% stable disease; 9% progressive disease; and 4% not determined. ORR in 15 evaluable pts with baseline CNS metastases was 73% (95% CI 45–92)....larotrectinib continues to demonstrate robust and durable tumour-agnostic efficacy with extended survival benefits in adults with TRK fusion cancer, including those with CNS metastases.

These data confirm that treatment with larotrectinib offers extended survival benefit in pts with TRK fusion cancer. Larotrectinib continued to demonstrate a favourable long-term safety profile. Screening pts for NTRK gene fusions should be actively considered.

...TRK fusions involved...NTRK3 (54%)...The ORR was 71% (95% CI 62-79): 10% complete response, 60% partial response...In patients with brain metastases, the ORR was 71% (95% CI 42-92; 10 of 14 patients, all partial responses)....In an expanded data set of adults with TRK fusion cancer, larotrectinib demonstrated robust and durable tumor-agnostic efficacy and favorable safety, supporting TRK testing in patients with solid tumors of any type.

Larotrectinib is an effective tumor-agnostic treatment for TRK fusion cancer with a favorable safety profile. Screening patients for NTRK gene fusions in solid tumors should be actively considered.

This multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumors...The TRK inhibitor larotrectinib was well tolerated in paediatric patients and showed encouraging antitumour activity in all patients with TRK fusion-positive tumors.

In conclusion, TRK fusions defined a unique molecular subgroup of advanced solid tumors in children and adults in whom larotrectinib was highly active. Durable responses were observed without regard to the age of the patient, tumor tissue, and fusion status.