Efficacy
The efficacy results of the LOXO-TRK-14001, SCOUT and NAVIGATE clinical trials have been presented in a pooled analysis including a pooled population of n=225 and are summarized in the table below (extracted from European SmPC of larotrectinib [2]]. Overall, in the adult sub-population of the pooled analysis (n=122), the Overall Response Rate (ORR) was 64%. In the paediatric sub-population (n=70), the ORR was 87%.
Pooled efficacy results in solid tumours, in the LOXO-TRK-14001, SCOUT and NAVIGATE clinical trials
(Source: Larotrectinib EMA Summary of medicinal Product Characteristics 2022)
Efficacy parameter |
Solid tumours excluding |
Solid tumours including |
ORR [95% CI] |
72% [65 - 79] (n=139) |
65% [59 - 72] (n=147) |
CR |
23% (n=44) |
21% (n=47) |
pCRc |
7% (n=13) |
6% (n=13) |
PR |
43% (n=82) |
39% (n=87)d |
Median time to first response [range] |
1.84 months [0.89 - 16.20] |
1.84 months [0.89 - 16.20] |
Median DOR [range] |
34.5 months [1.6+, 58.5+] |
34.5% [1.6+, 58.5+] |
DOR (%) ≥ 12 months |
79% |
79% |
DOR (%) ≥ 24 months |
66% |
66% |
CI: confidence Intervals, CNS: Central Nervous System, CR: Complete Response, DOR: Duration OF Response, ORR: Overall Response Rate, pCR: pathological Complete Response, PR: Partial Response
+ denotes ongoing
a Independent review committee analysis by RECIST v1.1 for solid tumours except primary CNS tumours (192 patients).
b Investigator assessment using either RANO or RECIST v1.1 criteria for primary CNS tumours (33 patients).
c A pathological CR was a CR achieved by patients who were treated with larotrectinib and subsequently underwent surgical resection with no viable tumour cells and negative margins on post-surgical pathology evaluation. The pre-surgical best response for these patients was reclassified pathological CR after surgery following RECIST v.1.1.
d An additional 1% (2 patients with primary CNS tumours) had partial responses, pending confirmation.
An overview of the ORR and Duration of Response (DOR) observed in the pooled data analysis from the three clinical trials, is shown in the table below [extracted from 2]. It should be noted however that considering the rarity of TRK fusion-positive cancers efficacy estimates per tumour type may not necessarily reflect the expected response in a specific tumour type.
Long term updated analysis
Long term clinical data from an integrated analysis across three larotrectinib trials (NCT02576431, NCT02122913, and NCT02637687) in patients with non-primary CNS NTRK fusion cancer has concluded that larotrectinib continued to demonstrate rapid and durable responses, extended survival benefit, and a favorable safety profile across tumour types [3]. At the data cut-off (20th July 2021), among 244 larotrectinib-treated evaluable patients including both adult and paediatric patients and 25 different tumour types, the ORR was 69% (95% CI 63–75). There were 64 (26%) CRs, including 13 (5%) pCR, 104 (43%) PR, 41 (17%) SD, 20 (8%) PD, and 15 (6%) not determined.
The median time to response was 1.8 months (range 0.9–16.2) and Treatment duration ranged from 0.1 to 67.9 months. After a median follow-up of 28.3 months the median DoR was 32.9 months (95% CI 27.3–41.7). After a median follow-up was 29.3 months, the median PFS was 29.4 months (95% CI 19.3–34.3) and after a median follow-up of 32.2 months the OS was not reached; the 48-mo OS rate was 64% (95% CI 55–73). In terms of safety, there were no new or unexpected signals and treatment-related adverse events AEs were mainly grade 1/2.
References
- VITRAKVI® (larotrectinib), USA Prescribing Information. 2021.
- VITRAKVI® (larotrectinib), EMA Summary of medicinal Product Characteristics. 2022.