Laro is a highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumour-agnostic use in pts with TRK fusion cancer based on a rapid, robust and durable objective response rate (ORR) in both adult and paediatric pts. We report data on laro-treated pts without prior systemic therapy. Pts with treatment-naïve non-primary CNS TRK fusion cancer from three laro clinical trials were included. Laro was administered at 100 mg twice daily in most pts. Responses were assessed per independent review committee (IRC) using RECIST v1.1. As of July 2022, 84 pts were eligible for efficacy analyses by IRC; three pts (all adults) had known brain metastases at baseline. There were 12 different tumour types; the most common were soft tissue sarcoma (n=24; 29%), infantile fibrosarcoma (n=18; 21%), thyroid (n=15; 18%) and salivary gland (n=14; 17%). Median age was 31.5 years (range 0–90). The gene fusions involved were NTRK1 (n=30; 36%), NTRK2 (n=3; 4%) and NTRK3 (n=51; 61%). ORR was 80% (95% confidence interval [CI] 70–88): 42 (50%) complete response (CR; including six pathologic CR), 25 (30%) partial response, 10 (12%) stable disease, six (7%) progressive disease and one (1%) not evaluable. Median time to response was 1.8 months. Median duration of response was 44.5 months (95% CI 31.4–not estimable [NE]) at a median follow-up of 26.7 months. Medians for progression-free survival and overall survival (OS) were 46.2 months (95% CI 32.0–NE) and not reached, respectively, at median follow-ups of 30.4 and 41.3 months. The 48-month OS rate was 82% (95% CI 71–92). Treatment duration was 0–64+ months. Treatment-related adverse events (TRAEs) were mainly Grade 1/2. Grade 3/4 TRAEs occurred in 20 (24%) pts. Two pts discontinued due to a TRAE (malaise and hypoventilation occurred in one pt each). Laro demonstrated rapid and durable responses, extended survival and a favourable safety profile in pts without prior systemic therapy. This supports the use of laro in a first-line setting and the wider adoption of next-generation sequencing panels that include NTRK gene fusions to identify pts who may benefit from treatment.

Laro, a highly selective, central nervous system (CNS)-active TRK inhibitor approved for adult and paediatric pts with TRK fusion cancer, showed rapid and durable responses in three phase I/II single-arm studies. The growth modulation index (GMI) is an intra-pt comparison that compares progression-free survival (PFS) on current therapy against time to progression or treatment failure (TTP) on most recent prior therapy. A GMI ratio ≥1.33 is a threshold for meaningful clinical activity. We report the GMI of 140 laro-treated pts with an extended follow-up, and of an expanded dataset with an additional 36 pts (176 pts in total) to assess the treatment effect of laro more extensively in pts with non-primary CNS TRK fusion cancer previously treated with ≥1 line of therapy. Adult and paediatric pts treated in three laro clinical trials (NCT02576431, NCT02122913, and NCT02637687) were analysed retrospectively. TTP on prior line of therapy was investigator-assessed. PFS on laro was determined by an independent review committee (RECIST v1.1). Pts without progression were censored as of last visit. Median GMI, TTP, and PFS were estimated by Kaplan–Meier analyses. Data cut-off: July 2021. GMI results are shown in the table for the 140 pts with extended follow-up and the expanded dataset of 176 pts. Of the 53 pts with a GMI <1.33 in the expanded dataset, 10 were censored and continuing treatment. Of pts with 1, 2, or ≥3 prior lines of therapy, 47 (69%), 29 (59%), and 47 (80%) pts, respectively, had a GMI of ≥1.33 on laro. Median TTP on prior therapy was 3.0 months. Median PFS on laro was 19.6 months.Table: 464PLaro-treated pts (N)Data cut-offGMI≥1.33,n (%)≥1 to <1.33,n (%)<1,n (%)Median(95% CI)140 (Extended follow-up)July 2020 (Italiano et al, ASCO 2021)103 (74)7 (5)30 (21)8.9(6.2–17.4)July 2021105 (75)6 (4)29 (21)7.9(5.8–11.7)176 (Expanded dataset)July 2021123 (70)9 (5)44 (25)7.2(5.5–10.0) Open table in a new tab With extended follow-up, 75% of laro-treated pts with TRK fusion cancer had prolonged PFS compared with most recent prior therapy, irrespective of the number of prior lines of therapy received. This reinforces the benefits of using laro to treat pts with TRK fusion cancer.

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers. Larotrectinib, a highly selective, central nervous system-active tropomyosin receptor kinase (TRK) inhibitor, demonstrated a 75% objective response rate (ORR) in 206 patients (Hong et al. ASCO 2021). We report efficacy and safety with circulating tumour DNA (ctDNA) analysis for patients (pts) with TRK fusion lung cancer treated with larotrectinib. Pts with TRK fusion lung cancer who were treated with larotrectinib in 2 clinical trials (NCT02122913, NCT02576431) were analysed. NTRK gene fusions were determined by local testing prior to enrolment. Larotrectinib was administered at 100 mg BID. Response was assessed by an independent review committee (IRC) per RECIST v1.1. ctDNA was analysed using the liquid biopsy tests Guardant360 and GuardantOMNI. As of 20 July 2020, 20 pts with metastatic lung cancer were enrolled. Among 15 pts, (NTRK1 [n=12] and NTRK3 [n=3]), evaluable per IRC, ORR was 87% (95% confidence interval [CI] 60–98; 2 complete response, 11 partial response, 2 stable disease). Median duration of response (DoR) was not reached (95% CI 5.5–not estimable [NE]), with a 12-month DoR rate of 64%. Median progression-free survival was 33.0 months (95% CI 7.6–NE). Median overall survival was 40.7 months (95% CI 17.2–NE). Treatment-related adverse events were mostly Grade 1–2. ctDNA data were available for 14 evaluable pts; 13 in which somatic alterations were detected. ctDNA analysis detected NTRK gene fusions in 46% of the pts at treatment start. By the data cut-off, 6 pts had a progression event with ctDNA data available for 5 pts. Potential acquired mutations were identified in 3 pts: one with NTRK1 F589L and G595R, one with SMAD4 R361C and the third with ARID1A K1238fs and FGFR2 R210Q mutations. Larotrectinib demonstrated durable and robust responses, extended survival benefit, and a favourable safety profile. ctDNA next-generation sequencing represents a promising technology but its optimal integration into testing NTRK gene fusions or resistance mutations still remains to be determined. Known resistance mutations in NTRK may cause progression, but further studies are warranted.

Serious fractures have been reported in patients (pts) with tropomyosin receptor kinase (TRK) fusion cancer receiving non-selective TRK inhibitors (Frampton, Drugs 2021). Larotrectinib is a first-in-class, highly selective TRK inhibitor approved in over 40 countries for the treatment of adult and paediatric pts with TRK fusion cancer. Here we report the incidence of fractures in pts with cancer treated with larotrectinib.

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in a range of adult and pediatric malignancies but are generally rare in patients with gastrointestinal (GI) cancer, with a prevalence of around 0.3% in colorectal cancer (CRC; Forsythe et al, Ther Adv Med Oncol 2021). Larotrectinib is a first-in-class, central nervous system (CNS)-active, highly selective tyrosine receptor kinase (TRK) inhibitor approved for the treatment of adult and pediatric patients with TRK fusion-positive cancer, demonstrating an objective response rate (ORR) of 78% across 175 adult and pediatric patients with various non-CNS cancers (McDermott et al, ESMO 2020). We report data on an expanded dataset of patients with TRK fusion-positive GI tumors. Patients with TRK fusion-positive GI cancer treated with larotrectinib in the phase II clinical trial NAVIGATE (NCT02576431) were included in this analysis. Response was investigator-assessed using RECIST v1.1. As of July 20, 2020, 18 patients with metastatic TRK fusion-positive GI cancer were enrolled. Median age was 67.0 years (range 32.0 to 84.0 years). Of the 10 patients with CRC, 7 were microsatellite instability-high (MSI-H), 2 were microsatellite stable (MSS) and phenotype was unknown in 1 patient. The other tumor types were cholangiocarcinoma (n=3), pancreatic (n=2), appendiceal (n=1), esophageal (n=1), and hepatocellular carcinoma (n=1). Overall, 13 patients (72%) had received ≥2 prior lines of therapy, 3 (17%) of whom had received immunotherapy. The best response to last prior therapy was 2 partial responses (PR), 6 stable disease (SD), 3 progressive disease (PD), and 7 unknown, unevaluable or not applicable. ORR in the 17 evaluable patients was 41% (95% CI 18–67): 1 complete response (CR), 6 PR (1 pending confirmation), 7 SD, 2 PD and 1 not determined. Median time to response in the 6 confirmed responders was 1.9 months (range 1.7 to 5.0 months). Median duration of response (DoR) was 5.5 months (95% CI 3.5–27.3). Median progression-free survival (PFS) was 5.4 months (95% CI 2.2–11.6) at a median follow-up of 20.3 months. Median overall survival (OS) was 14.1 months (95% CI 2.8–33.4) at a median follow-up of 7.8 months. In the 10 patients with CRC, ORR was 50% (95% CI 19–81): 1 CR, 4 PR (1 pending confirmation), and 5 SD. For these patients, median DoR was 15.5 months (95% CI 3.7–27.3), median PFS was 5.5 months (95%CI 2.2–29.4) and median OS was 29.4 months (95% CI 2.8–36.5). Duration of treatment for all GI patients ranged from 0.26+ to 29.3 months. At data cut-off, 10 patients had progressed, with 3 continuing treatment post-progression. Adverse events were mostly Grade 1–2. Treatment-related adverse events (TRAEs) occurred in 11 patients. Grade 3/4 TRAEs occurred in 2 patients (increased alanine aminotransferase, increased aspartate aminotransferase, and nausea). There were no treatment discontinuations due to TRAEs. In patients with TRK fusion-positive GI cancer, larotrectinib demonstrated rapid responses with high survival rates and a favorable safety profile. These results support testing for NTRK gene fusions in patients with GI cancer, particularly in patients with MSI-H CRC.

Larotrectinib is a first-in-class, CNS-active, EMA- and FDA-approved selective tropomyosin receptor kinase (TRK) inhibitor. TRK proteins are encoded by the NTRK genes; gene fusions involving NTRK are rare oncogenic drivers seen in a range of paediatric and adult tumour types. Pooled analysis of three clinical trials showed that larotrectinib induced an investigator-assessed overall response rate (ORR) of 79%, median progression-free survival (PFS) of 28.3 months (95% CI 22.1–NE) and median overall survival (OS) of 44.4 months (95% 36.5–NE) in 159 patients (pts) with TRK fusion cancer (Hong et al, Lancet Oncol. 2020). Here we report updated survival data with longer follow-up in an integrated dataset of 175 pts with TRK fusion cancer treated with larotrectinib. Data were pooled from three clinical trials of pts with non-primary CNS TRK fusion cancer treated with larotrectinib. Disease status was assessed by investigators using RECIST v1.1. Primary endpoint was ORR and secondary endpoints included PFS, OS, duration of response (DoR) and safety outcomes. Data cut-off: 15 July 2019. A total of 175 pts were included in the integrated dataset. The median age was 43 y (range 0.1–84.0). The ORR was 78% (95% CI 71–84): 19% complete response, 59% partial response, 13% stable disease and 7% progressive disease. Median DoR was not estimable (NE) at a median follow-up of 13.5 months, with a 12-month DoR rate of 81% (95% CI 73–89). At a median follow-up of 13.8 months, median PFS was 36.8 months (95% CI 25.7–NE), showing extended benefit compared to previous analysis. Although median OS had not been reached with a median follow-up of 15.3 months, the 12-month OS rate was 90% (95% CI 85–95). Larotrectinib-related adverse events (AEs) were mainly Grade 1/2 with no new safety signals identified; two pts discontinued due to larotrectinib-related AEs. 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.

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions occur in a range of tumour types. Larotrectinib, a central nervous system (CNS)-active and highly selective EMA- and FDA-approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% and a median duration of response (DoR) of 35.2 months across multiple cancers (Hong et al. Lancet Oncol 2020). We report updated data on patients with lung cancer treated with larotrectinib. Patients with lung cancer harbouring an NTRK gene fusion enrolled in two clinical trials were pooled for this analysis. Larotrectinib 100 mg BID was administered on a continuous 28-day schedule. Response was assessed by the investigator per RECIST v1.1. As of 15 July 2019, 14 patients with metastatic TRK fusion lung cancer were enrolled: 13 with non-small cell lung cancer and 1 with small cell lung cancer. The median age was 52 years (range 25–76). Eleven patients had fusions involving NTRK1 and three patients had fusions involving NTRK3. Seven patients had baseline CNS metastases. Patients were heavily pre-treated with a median of three prior therapies (range 1–5); nine patients had received ≥2 prior therapies. The ORR with larotrectinib was 71% (95% CI 42–92%): one patient had a complete response, nine had partial responses, three had stable disease and one had progressive disease. The ORR in patients with CNS metastases was 57% (95% CI 18–90). The overall DoR ranged from 1.9+ to 28.7+ months. The median progression-free survival (PFS) had not been reached (range 1.8–30.3+ months), with an estimated PFS rate at 12 months of 69%. Treatment duration ranged from 2.1 to 39.6+ months. Larotrectinib was well tolerated, with treatment-emergent adverse events being mainly grade 1–2. In this updated analysis, larotrectinib was shown to be highly active in patients with advanced lung cancer harbouring NTRK gene fusions, including those with CNS metastases. The drug has a favourable safety profile. These results support inclusion of NTRK gene fusions in routine molecular testing of patients with lung cancer.

Larotrectinib is a first-in-class, central nervous system-active, highly selective tropomyosin receptor kinase (TRK) inhibitor approved by the EMA and FDA for the treatment of adult and paediatric patients (pts) with TRK fusion cancer. Larotrectinib produced an objective response rate (ORR) of 79% and a median duration of response (DoR) of 35.2 months in pts with TRK fusion cancer across various tumour types (Hong et al. Lancet Oncol. 2020). Here, we report the efficacy and safety of larotrectinib in the subset of pts with TRK fusion thyroid cancer. Data in pts with locally advanced or metastatic thyroid cancer harbouring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion were pooled from two larotrectinib clinical trials (NCT02122913 and NCT02576431). Adult and paediatric patients received larotrectinib 100 mg and 100 mg/m2 twice daily, respectively, on a continuous 28-day schedule. Responses were investigator-assessed per RECIST v1.1 (data cut-off: 15 July 2019). A total of 28 pts with TRK fusion thyroid cancer were included: 19 papillary, 7 anaplastic and 2 follicular. Median age was 62 years (range 6–80). Twelve (43%) pts had a NTRK1 fusion and 16 (57%) pts had a NTRK3 fusion. All pts had received prior treatment, including surgery (100%), radiotherapy (61%), radioiodine (75%) and ≥1 prior systemic therapy (89%). Eleven (44%) pts had received ≥3 prior systemic therapies. ORR was 75% (95% confidence interval [CI] 55–89), including 29% for pts with anaplastic disease (Table). DoR ranged from 1.9+ to 41.0+ months. Median progression-free survival (PFS) was not reached (95% CI 16.6–NE) and the 12-month PFS rate was 81%. Adverse events (AEs) were mostly Grade 1–2. Grade ≥3 AEs occurred in 46% of pts and 7% of pts had Grade ≥3 AEs related to larotrectinib. Larotrectinib was highly efficacious and demonstrated a favourable safety profile. These findings support routine testing for NTRK gene fusions in pts with non-medullary, advanced thyroid cancer.Table: 1916PDifferentiated (N=21)Anaplastic (N=7)All patients (N=28)ORR, % (95% CI)†90 (70–99)29 (4–71)75 (55–89)CR, n (%)2 (10)02 (7)PR, n (%)17 (81)2 (29)19 (68)SD, n (%)2 (10)1 (14)3 (11)PD, n (%)03 (43)3 (11)ND, n (%)01 (14)1 (4)†Per investigator assessment. CI, confidence interval; CR, complete response; ND, not determined; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. Open table in a new tab

Background: In pre-clinical models enhanced anti-tumour activity was observed when SU-014813, an oral multi-targeted tyrosine kinase inhibitor was combined with docetaxel. This synergy might be explained by improvement of the penetration of cytotoxic agents into tumours as a result of both VEGFR and PDGFR inhibition. We assessed the maximal tolerated dose (MTD), evaluated the pharmacokinetics and preliminary anti-tumour efficacy of oral SU-014813 administered continuously in combination with docetaxel to patients with advanced solid tumours.Methods: In this phase I study successive patient cohorts received docetaxel 60 or 75 mg/m(2) every 3 weeks in combination with chronic daily dosing of SU-014813. Dose limiting toxicity was assessed both in the first and second treatment cycle.Results: Twenty-five patients were entered on study of which 24 started treatment. Dose limiting toxicities were prolonged neutropenia, neutropenic fever, fatigue and diarrhoea. Other toxicities included fatigue, alopecia, nausea, vomiting, anorexia, rash, hypertension and hair discolouration. The recommended phase II dose was determined to be docetaxel 75 mg/m(2) in combination with SU-014813 50 mg/day. There was no clinically relevant pharmacokinetic drug-drug interaction. Two patients (8%) achieved a partial response (PR) and 7 patients (29%) had stabilisation of their disease (SD) >6 months, for a clinical benefit rate of 37.5%. The activity observed in patients with melanoma and sunitinib refractory gastrointestinal stromal tumours (GIST) was particularly noteworthy.Conclusions: Oral SU-014813 50 mg/day with docetaxel 75 mg/m(2) is a clinically feasible regimen with a manageable safety profile and anti-tumour activity. Further development is warranted in patients with melanoma and GIST. (C) 2011 Elsevier Ltd. All rights reserved.

BACKGROUND this phase I, open-label, dose-escalation study investigated SU14813, an oral multitargeted tyrosine kinase inhibitor, in adults with solid tumors. PATIENTS AND METHODS seventy-seven patients received once-daily SU14813, either for 4 weeks followed by 1 week off treatment (schedule 4/1) or continuously [continuous daily dosing (CDD)]. The primary end point was to determine the maximum tolerated dose (MTD). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. RESULTS MTDs were 200 mg/day on schedule 4/1 and 100 mg/day with CDD. Adverse events included fatigue (64%), diarrhea (61%), nausea (44%), anorexia (43%), and vomiting (42%). SU14813 steady state was attained by day 8. Exposure increased in a generally dose-proportional manner and SU14813 was eliminated with a mean terminal half-life of 9-34 h. Target plasma concentrations (>100 ng/ml SU14813) were achieved and sustained over 12 h at ≥ 100 mg/day. Progression-free survival among the 1 complete responder and 12 partial responders was 1.4-53.2 months. Fifteen patients remained on treatment at 1 year and 3 patients at 2 years. CONCLUSION SU14813 has manageable safety and tolerability and allows once-daily continuous oral dosing. SU14813 shows dose-proportional pharmacokinetics, with target plasma concentrations achieved at doses ≥ 100 mg/day. Clinically meaningful activity with durable responses was observed, meriting further study.

3062 Background: The S-phase and G2-checkpoints are critical mediators of the cell cycle response to cytotoxic therapy. PF-736 is a selective inhibitor of the S/G2-checkpoint kinase CHK1, displaying >10-fold selectivity over CHK2. Preclinical studies show that PF-736 can enhance response to GEM that is associated with abrogation of the S/G2 checkpoint with cells entering mitosis prematurely. Methods: We undertook a phase I, dose escalation study to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics of PF-736 in combination with GEM in sequential cohorts of 3 to 6 gemcitabine naive patients (Pts) with advanced solid tumors. Pts received IV PF-736 alone on days 1 and 8 in cycle 0 (C0) and then started the combination of GEM and PF-736 in C1, days 1 and 8 and 2 and 9 respectively, with PF-736 starting 20-24 hrs after completion of GEM, in 21-day cycles. C0 and C1 were considered for dose-limiting toxicity (DLT). Results: 36 Pts to date have been treated with GEM 750mg/m2 and escalating doses of PF-736. 17 Pts were treated in cohorts of 3-8 with PF-736 50-80 mg infused over 3 h. 19 Pts have been treated in cohorts of 3-7 with PF-736 80-340 mg infused over 24 h. AEs were infrequent in C0. DLT of thrombocytopenia, sudden death, mucositis, and elevated lipase were seen in C1. The MTD was 270mg of PF-736 with GEM 750mg/m2. One Pt treated at PF-736 80 mg was admitted with elevated liver function tests on C10D9 and died from hepatic veno-occlusive disease 3 weeks later. Common drug-related AEs occurring in >30% Pts were pyrexia, fatigue, neutropenia, nausea, vomiting, and diarrhea. 42% of Pts had dose delays due to G3 neutropenia making the days 1 and 8 schedule difficult to maintain. The exposure of PF-736 increased proportionally with increased dose from 50mg to 270mg. Mean T 1/2 ranged from 8 to 20 hrs. Three partial responses were observed in Pts with SCC of the skin, non-small cell lung cancer, and mesothelioma. Conclusions: The combination of PF-736 and GEM 750mg/m2 is clinically active, and can be safely given to Pts. Future studies will determine the MTD of PF-736 with GEM 1,000mg/m2 and examine biomarkers, including inhibition of the S/G2 checkpoint by serial tumor biopsies at the MTD. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer