Tropomyosin Receptor Kinase Fusion Research Articles

Discovery, Optimization, and Evaluation of Novel Pyridin-2(1H)-one Analogues as Potent TRK Inhibitors for Cancer Treatment.

Tropomyosin receptor kinase (TRK) fusion, an oncogenic form of kinase with pan-tumor occurrence, is a clinically validated important antitumor target. In this study, we screened our in-house kinase inhibitor library against TRK and identified a promising hit compound 4 with a novel pyridin-2(1H)-one scaffold. Through a combination of structure-based drug design and structure-activity relationship (SAR) study, compound 14q was identified as a potent TRK inhibitor with good kinase selectivity. It also blocked cellular TRK signaling, thereby inhibiting TRK-dependent cell viability. Additionally, 14q displayed acceptable pharmacokinetic properties with 37.8% oral bioavailability in mice. Strong in vivo tumor growth inhibition of 14q was observed in subcutaneous M091 and KM12 tumor xenograft models with TRK fusion, causing significant tumor inhibition or even complete tumor regression.

Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase fusion sarcomas.

Larotrectinib, a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor, has demonstrated efficacy in adult and pediatric patients with various solid tumors harboring NTRK gene fusions. This subset analysis focuses on the efficacy and safety of larotrectinib in an expanded cohort of adult patients with TRK fusion sarcomas. Patients (≥18years old) with sarcomas harboring NTRK gene fusions were identified from three clinical trials. Patients received larotrectinib 100mg orally twice daily. Response was investigator-assessed per RECIST v1.1. Data cutoff was July 20, 2021. At the data cutoff, 36 adult patients with TRK fusion sarcomas had initiated larotrectinib therapy: two (6%) patients had bone sarcomas, four (11%) had gastrointestinal stromal tumors, and 30 (83%) had soft tissue sarcomas. All patients were evaluable for response and demonstrated an objective response rate of 58% (95% confidence interval, 41-74). Patients responded well to larotrectinib regardless of number of prior lines of therapy. Adverse events (AEs) were mostly grade 1/2. Grade 3 treatment-emergent AEs (TEAEs) occurred in 15 (42%) patients. There were no grade 4 TEAEs. Two grade 5 TEAEs were reported, neither of which were considered related to larotrectinib. Four (11%) patients permanently discontinued treatment due to TEAEs. Larotrectinib demonstrated robust and durable responses, extended survival benefit, and a favorable safety profile in adult patients with TRK fusion sarcomas with longer follow-up. These results continue to demonstrate that testing for NTRK gene fusions should be incorporated into the clinical management of adult patients with various types of sarcomas. Tropomyosin receptor kinase (TRK) fusion proteins result from translocations involving the NTRK gene and cause cancer in a range of tumor types. Larotrectinib is an agent that specifically targets TRK fusion proteins and is approved for the treatment of patients with TRK fusion cancer. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. Over half of patients had a durable response to larotrectinib, with no unexpected side effects. These results show that larotrectinib is safe and effective in adult patients with TRK fusion sarcomas.

Larotrectinib (laro) long-term efficacy and safety in patients (pts) with tropomyosin receptor kinase (TRK) fusion thyroid carcinoma (TC).

6091 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in a variety of tumor types, including TC. Laro is a first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pts with TRK fusion cancer based on a rapid, robust, and durable objective response rate (ORR) in both adult and pediatric pts with various cancers. Here, we report data on the subset of pts with TRK fusion TC treated with larotrectinib with long-term follow-up. Methods: Pts with TRK fusion TC enrolled in three laro clinical trials (NCT02576431, NCT02122913, NCT02637687) were included. Laro was administered at 100 mg twice daily to most pts; two pediatric pts received 100 mg/m2. Responses were assessed per independent review committee (IRC) using RECIST v1.1. Data cut-off: July 20, 2022. Results: As of data cut-off, 30 pts were eligible for efficacy assessment by IRC. The median age was 61.5 years (range 6–80) and the median time since initial cancer diagnosis was 5.0 years (range 0–46). The gene fusions involved NTRK1 (n =14; 47%) or NTRK3 (n =16; 53%). Fifteen pts (50%) received no prior systemic therapies, and six (20%) received ≥2; 23 (77%) received prior radioiodine. ORR was 63% (95% confidence interval [CI] 44–80): three (10%) complete response, 16 (53%) partial response (PR), five (17%) stable disease, four (13%) progressive disease, and two (7%) not evaluable. For pts classified as differentiated TC (DTC; n = 23), the ORR was 78% (95% CI 56–93). For pts classified as anaplastic TC (ATC; n = 7), the ORR was 14% (95% CI 0–58). All four pts with CNS metastases at baseline had a PR. Median time to response was 1.9 months, and median duration of response (DoR) was 43.3 months (95% CI 21.6–not estimable [NE]) at a median follow-up of 32.3 months. Median progression-free survival was 35.5 months (95% CI 23.4–NE) at a median follow-up of 34.0 months. Median overall survival (OS) was not reached (NR; 95% CI 48.7–NE) at a median follow-up of 46.4 months; the 48-month OS rate was 71% (95% CI 54–88). Median OS was NR (95% CI 48.7–NE) in DTC and 8.8 months (95% CI 2.6–NE) in ATC. At data cut-off, five pts who had disease progression continued treatment for ≥4 weeks due to continued clinical benefit. Treatment-related adverse events (TRAEs) were predominantly Grade 1–2. Grade ≥3 TRAEs were reported in two (7%) pts (anemia and decreased lymphocyte count). There were no treatment discontinuations due to TRAEs. Conclusions: Laro continues to demonstrate a rapid and durable response, extended survival, and a favorable safety profile in pts with TRK fusion DTC. Limited single-agent activity was observed in ATC. These results support the wider adoption of next generation sequencing panels, which include NTRK gene fusions, in pts with advanced TC prior to the initiation of any systemic therapy. Clinical trial information: NCT02576431 , NCT02122913 , NCT02637687 .

Larotrectinib long-term efficacy and safety in adult patients (pts) with tropomyosin receptor kinase (TRK) fusion cancer.

3141 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in a broad array of tumor types. Larotrectinib is a first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pts with TRK fusion cancer based on a rapid, robust, and durable objective response rate (ORR) in both adult and pediatric pts with various non-primary CNS cancers. Here, we report data on an expanded cohort of adult pts with TRK fusion cancer treated with larotrectinib. Methods: Adults with non-primary CNS TRK fusion cancer treated in three larotrectinib clinical trials (NCT02576431, NCT02122913, and NCT02637687) were included. Larotrectinib was administered at 100 mg twice daily in most pts. Responses were assessed per Independent Review Committee (IRC) using RECIST v1.1. Data cut-off: July 2022. Results: As of July 2022, there were 194 adult pts enrolled, with 180 eligible for efficacy analyses by IRC; 22 pts had known brain metastases at baseline. There were 24 different tumor types; the most common were lung (n=30; 15%), soft tissue sarcoma (n=30; 15%), thyroid (n=28; 14%), salivary gland (n=25; 13%), and colon (n=23; 12%). Median age was 57 years (range 19–90). The gene fusions involved NTRK1 (n=90; 46%), NTRK2 (n=7; 4%), or NTRK3 (n=97; 50%). Pts had previously received a median of one systemic therapy (range 0–10). ORR was 57% (95% CI 50–65): 29 (16%) complete response (including one pathological complete response), 74 (41%) partial response, 39 (22%) stable disease, 23 (13%) progressive disease, and 15 (8%) not evaluable. ORR in 22 evaluable pts with baseline CNS metastases was 68% (95% CI 45–86). Median time to response was 1.8 months, and median duration of response was 43.3 months (95% CI 29.2–not estimable [NE]) at a median follow-up of 32.3 months. Median progression-free survival was 24.6 months (95% CI 11.3–34.5) at a median follow-up of 28.5 months. Median overall survival was 48.7 months (95% CI 38.5–NE) at a median follow-up of 33.8 months. At data cut-off, 39 of the 73 pts who had disease progression continued treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) were predominantly Grade 1/2. Grade 3/4 TRAEs occurred in 27 (14%) pts. Treatment discontinuation due to TRAEs was reported in one pt (increased alanine aminotransferase and aspartate aminotransferase). Conclusions: 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. These results support the wider adoption of next-generation sequencing panels that include NTRK gene fusions when testing pts with solid tumors; this ensures that pts are offered the right medicine for their disease as soon as possible. Clinical trial information: NCT02576431 , NCT02122913 , NCT02637687 .

Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer.

9056 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in a variety of tumor types, including lung cancer. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor that demonstrated rapid, deep, and durable responses in patients (pts) with TRK fusion lung cancer (Drilon et al. ASCO 2022) and is considered a preferred first-line therapy option for these pts (Owen et al. J Clin Oncol 2022). We report updated data from a larger cohort with longer follow-up. Methods: Pts with TRK fusion lung cancer enrolled in 2 larotrectinib clinical trials (NCT02576431 and NCT02122913) were included in this analysis. Larotrectinib was administered at 100 mg twice daily, and response was assessed by independent review committee (IRC) per RECIST v1.1. Results: As of July 20, 2022, 30 pts with a median age of 55.5 years (range 25–81) with TRK fusion lung cancer enrolled, including 12 pts with CNS metastases at baseline. The gene fusions involved NTRK1 (n = 24; 80%) or NTRK3 (n = 6; 20%). Pts received a median of 2 prior lines of systemic therapies, with 20 pts (67%) receiving ≥2. Among 27 pts eligible for IRC assessment, the objective response rate (ORR) was 74% (95% CI 54–89): 3 complete responses, 17 partial responses (PR), 4 stable disease (SD), 2 progressive disease (PD), and 1 not evaluable. Among the 12 pts with baseline CNS metastases, the ORR was 67% (95% CI 35–90): 8 PR, 2 SD, and 2 PD. The median time to response for all responders was 1.8 months. Median duration of response (DoR) was 33.9 months (95% CI 9.5–not estimable [NE]); median follow-up was 22.9 months. Median progression-free survival (PFS) was 33.0 months (95% CI 11.3–NE); median follow-up was 24.7 months. Median overall survival (OS) was 39.3 months (95% CI 17.2–NE); median follow-up was 23.1 months. For the 12 pts with CNS metastases, the medians for DoR, PFS, and OS were 9.5, 9.9, and 19.4 months, with median follow-ups of 17.4, 19.3, and 22.2 months, respectively. Duration of treatment for all pts evaluable per IRC ranged from 0.3+ to 75.2+ months. At data cut-off, 10 pts had progressed, with 6 continuing treatment post-progression for ≥4 weeks due to continued clinical benefit. Treatment-related adverse events (TRAEs) were predominantly Grade 1–2. Grade 3–4 TRAEs were reported in 5 pts (2 each increased aspartate aminotransferase, increased weight; 1 each increased alanine aminotransferase, myalgia, hypersensitivity). There were no treatment discontinuations due to TRAEs. Conclusions: In this larger dataset with longer follow-up, larotrectinib continued to demonstrate rapid and durable responses, extended survival, and favorable long-term safety in pts with advanced TRK fusion lung cancer, including those with CNS metastases. These results support the wider adoption of next-generation sequencing testing for NTRK1–3 gene fusions in pts with lung cancer. Clinical trial information: NCT02576431 , NCT02122913 .

Abstract CT228: Concordance between tissue and circulating tumor DNA (ctDNA) testing for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in larotrectinib (laro) clinical trials

Abstract Background: NTRK gene fusions are oncogenic drivers in various tumor types. Laro, a highly selective and central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor, is approved for the treatment of patients (pts) with TRK fusion cancer. Laro demonstrated an objective response rate (ORR) of 69% in 244 pts with solid (non-primary CNS) tumors (Drilon et al. ASCO 2022). Here, we report on the concordance between baseline local tissue-based testing with central tissue-based and liquid biopsy-based ctDNA testing to identify NTRK gene fusions. Methods: Pts with non-primary CNS TRK fusion cancer who underwent independent review committee assessments by July 15, 2019, in three laro clinical trials (NCT02122913, NCT02576431, and NCT02637687) were included. Tumor NTRK gene fusion status was determined locally by a variety of methods, and centrally by next-generation sequencing in both tissue (using Illumina TruSight™ Oncology Comprehensive) and ctDNA (using Guardant360® or GuardantOMNI®) at baseline. Data cut-off: July 20, 2021. Results: Of the 164 pts with NTRK fusions identified by local testing, 117 had evaluable tissue samples for central testing, and 99 had evaluable liquid biopsy samples. In total, 81.2% (95/117) of tumors had the fusion confirmed by central tissue testing. ctDNA testing detected NTRK gene fusions in 33.3% (33/99) of patients. Positive predictive values for each NTRK gene fusion are shown in the Table. The ORR for pts with NTRK gene fusions determined by local and central testing will be presented. Conclusions: A high proportion of tumors with locally identified NTRK gene fusions were confirmed centrally. At present, analysis of ctDNA is significantly less sensitive at detecting NTRK gene fusions. A negative ctDNA result requires next-generation sequencing testing of a tissue biopsy. Further research is needed to improve the sensitivity of ctDNA gene fusion detection. Table NTRK gene fusion Tissue-based LT Tissue-based CT ctDNA-based CT with LB Fusion confirmed, n Fusion confirmed, n Fusion not detected, n Unavailable samples, n† PPV‡: CT vs tissue-based LT, % Fusion confirmed, n Fusion not detected, n Unavailable samples, n† PPV‡: LB vs tissue-based LT, % NTRK1 68 35 14 19 71.4 20 34 14 37.0 NTRK2 4 3 1 0 75.0 0 4 0 0 NTRK3 92§ 57 7 28 89.1 13 28 51 31.7 †Includes no sample available and sample QC failed. ‡Calculated as a percentage of the number of confirmed fusions over the number of available samples. §Includes 9 inferred NTRK3 fusions. CT, central testing; ctDNA, circulating tumor DNA; LB, liquid biopsy; LT, local testing; NTRK, neurotrophic tyrosine receptor kinase; PPV, positive predictive value; QC, quality control. Citation Format: Erin R. Rudzinski, Marc Ladanyi, Lauren L. Ritterhouse, Felix Sahm, Ricarda Norenberg, Hong Zheng, Chi Chen, Vadim Bernard-Gauthier, Nicoletta Brega, Cornelis M. van Tilburg, Jessica J. Lin, Marcia S. Brose, Ulrik N. Lassen, Ray McDermott, Theodore W. Laetsch, David S. Hong, Alexander Drilon, Sinchita Roy-Chowdhuri. Concordance between tissue and circulating tumor DNA (ctDNA) testing for neurotrophic tyrosine receptor kinase (NTRK) gene fusions in larotrectinib (laro) clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT228.

Testing methods to diagnose TRK fusion cancer - a plain language summary and patient perspective.

This is a plain language summary of a 2022 study published in Cancer Genetics. This study describes the different tests used to detect a rare type of cancer called TRK (tropomyosin receptor kinase) fusion cancer in people taking part in three clinical trials testing the medication larotrectinib. Larotrectinib targets TRK fusion proteins, abnormal proteins that result from abnormal NTRK (neurotrophic tyrosine receptor kinase) gene fusions. People who were shown to have solid tumors containing TRK fusion proteins were able to participate in clinical trials that evaluated larotrectinib. Different testing methods were used to identify participants with TRK fusion cancer. Which test was used depended on different factors such as how commonly NTRK gene fusions are found in a specific cancer type, and the cost and accessibility of the test. Participants with different types of cancer were included in the study, which allowed researchers to identify which TRK fusion proteins were found across various types of tumor. The results of this study provide a guidance for healthcare professionals on the methods used for testing to identify patients that have TRK fusion cancer. By characterizing the types of testing done across cancer types, patients and their caregivers can gain an understanding of the importance of testing. This plain language summary also includes insights and perspectives from a person affected by TRK fusion cancer, and from patient advocates. Clinical Trial Registration: NCT02122913 (ClinicalTrials.gov) Clinical Trial Registration: NCT02637687 (ClinicalTrials.gov) Clinical Trial Registration: NCT02576431 (ClinicalTrials.gov).

222O Updated efficacy and safety of larotrectinib in patients with TRK fusion salivary gland tumours

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers of various tumour types, including salivary gland tumours (SGTs). Secretory carcinoma of the salivary gland, a rare subset of SGTs, is characterised by an ETV6-NTRK3 gene fusion found in ≥80% of cases. Larotrectinib is a highly selective, central nervous system-active, tropomyosin receptor kinase (TRK) inhibitor with an objective response rate (ORR) of 92% across 24 evaluable patients (pts) with a variety of SGTs, as of July 2020 (Le et al.

464P Intra-patient (Pt) comparison from larotrectinib (Laro) clinical trials in tropomyosin receptor kinase (TRK) fusion cancer: An expanded dataset

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.

667P Updated efficacy and safety of larotrectinib in patients with TRK fusion salivary gland tumours

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers of various tumour types, including salivary gland tumours (SGTs). Secretory carcinoma of the salivary gland, a rare subset of SGTs, is characterised by an ETV6-NTRK3 gene fusion found in ≥80% of cases. Larotrectinib is a highly selective, central nervous system-active, tropomyosin receptor kinase (TRK) inhibitor with an objective response rate (ORR) of 92% across 24 evaluable patients (pts) with a variety of SGTs, as of July 2020 (Le et al. Oncologist 2022 [in press]). We report updated efficacy and safety of larotrectinib in pts with TRK fusion SGTs with longer follow-up. Pts with TRK fusion SGTs were identified from two larotrectinib clinical trials (NCT02122913, NCT02576431). Pts received larotrectinib 100 mg twice a day (BID) except for one pt who received 150 mg BID in the phase 1 trial (NCT02122913). Response was assessed by independent review committee (per Response Evaluation Criteria in Solid Tumours v1.1). As of July 2021, 25 pts with TRK fusion SGTs were identified, including 24 with an additional year of follow-up. Median age was 59.0 years (range 28–80). All pts had ETV6-NTRK3 gene fusions. ORR was 84% (95% CI 64–95%): 8 complete responses, 13 partial responses, 2 stable disease and 2 progressive disease. Median time to response was 1.8 months. Median duration of response (DoR) was not reached; median follow-up was 39.6 months. Median progression-free survival (PFS) was 56.0 months (95% CI 30.8–not estimable) at a median follow-up of 41.3 months. Median overall survival (OS) was not reached at a median follow-up of 43.7 months. The 36-month DoR, PFS, and OS rates were 71%, 64%, and 82%. Duration of treatment ranged from 1.0 to 68.0 months. At data cut-off, 8 pts had progressed, with 5 pts continuing treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) were mostly Grade 1–2. Grade 3–4 TRAEs were reported in 6 pts (24%). There were no treatment discontinuations due to TRAEs. Larotrectinib demonstrated rapid and durable efficacy with a favourable safety profile in pts with TRK fusion SGTs. These data highlight the importance of identifying NTRK gene fusions in pts with SGTs.

463P Efficacy and safety of larotrectinib in a pooled analysis of patients (Pts) with tropomyosin receptor kinase (TRK) fusion cancer with an extended follow-up

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in multiple tumour types. Larotrectinib, a highly selective TRK inhibitor, demonstrated an investigator-assessed objective response rate (ORR) of 75% across 206 pts with non-central nervous system (CNS) primary, TRK fusion-positive cancers (Hong et al, ASCO 2021). To better determine outcomes in a more mature dataset with a longer follow-up, we report on the first 164 pts enrolled as of February 2019 with a data cut-off of July 2021. Data were pooled from three clinical trials (NCT02576431, NCT02122913, and NCT02637687) of larotrectinib-treated pts with non-CNS primary, TRK fusion cancer. ORR was assessed by independent review committee (IRC) per RECIST v1.1. A total of 164 pts were evaluable for efficacy by IRC. There were 17 different cancer types; the most common were soft tissue sarcoma (42%), thyroid (16%), salivary gland (13%), and lung (8%). Fifty-five (34%) pts were <18 years. Fourteen (9%) pts had CNS metastases at baseline. 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, 13 (8%) progressive disease and seven (4%) not determined. After longer follow-up, 17 pts (10%) had an improved best overall response over that from the July 2019 data cut. Median time to response was 1.8 months (range 0.9–16.2). Median duration of response was 34.5 months (95% CI 27.6–43.3); median follow-up was 34.1 months. Median progression-free survival was 32.0 months (95% CI 23.4–40.2); median follow-up was 35.8 months. Median overall survival (OS) was not reached; median follow-up was 38.0 months. The 48-month OS rate was 66% (95% CI 57–75). Treatment duration ranged from 0.1 to 67.9 months. Treatment-related adverse events (TRAEs) were mainly Grade 1–2; 32 (20%) pts had Grade 3–4 TRAEs. 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.

EP08.02-148 Extended Follow-up of Efficacy and Safety of Larotrectinib in Patients With TRK Fusion Lung Cancer

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in a variety of tumour types, including lung cancer. Larotrectinib is a highly selective, central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor that demonstrated an objective response rate (ORR) of 87% across 15 independent review committee (IRC)-evaluable patients with TRK fusion lung cancer as of July 2020 (Drilon et al, JCO Precis Oncol 2021). We report data on these patients with longer follow-up and on an expanded dataset of patients with TRK fusion lung cancer treated with larotrectinib.

Abstract CT545: Variability in NTRK gene fusions does not appear to impact response to larotrectinib

Abstract Introduction: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumor types. Gene fusions arise from inter- and intrachromosomal rearrangements involving the 3’ region of the NTRK gene and the 5’ end of a fusion partner gene, leading to the expression of a constitutively active tropomyosin receptor kinase (TRK) fusion protein. Larotrectinib is a highly selective and central nervous system (CNS)-active TRK inhibitor approved for the treatment of adult and pediatric patients with TRK fusion cancer. Larotrectinib has previously demonstrated an objective response rate (ORR) of 75% in 206 patients with non-primary CNS solid tumors (Hong et al, ASCO 2021). Here, we report on the TRK fusion exon junction organization in patients with TRK fusion cancer receiving larotrectinib. Methods: Patients with non-primary CNS TRK fusion cancer treated with larotrectinib were identified from three clinical trials (NCT02122913, NCT02576431, and NCT02637687). NTRK gene fusion data were determined by local molecular testing. The testing method, NTRK gene fusions, and exon structure were extracted from the molecular pathology reports from 212 patients. The data cut-off was July 20, 2020. Results: TRK fusion exon junction data were available for 80 patients from 14 different tumor types. Median age was 47 years (range 0.5-84 years). The ORR for these patients was 82.5% (95% confidence interval [CI] 72.4-90.1). Patients had gene fusions involving NTRK1 (40%), NTRK2 (4%), or NTRK3 (56%), a pattern similar to that seen in the larger dataset. We detected 20 different NTRK gene fusions; the most common were ETV6-NTRK3, TPM3-NTRK1, and LMNA-NTRK1 detected in 39 (49%), ten (13%), and seven (9%) patients, respectively. There were 12, three, and five different fusion partners associated with NTRK1, NTRK2, and NTRK3, respectively. The majority (12/20; 60%) of fusions were intrachromosomal rearrangement events: 8/12 (67%) related to NTRK1, 2/3 (67%) related to NTRK2, and 2/5 (40%) related to NTRK3. There were 35 different 5’/3’ gene breakpoint combinations: 3’ fusion points were located at NTRK1 exon 8 (n = 2), NTRK1 exon 9 (n = 5), NTRK1 exon 10 (n = 15), NTRK1 exon 11 (n = 6), NTRK1 exon 12 (n = 3), NTRK1 exon 13 (n = 1), NTRK2 exon 15 (n = 2), NTRK2 exon 16 (n = 1), NTRK3 exon 14 (n = 21), and NTRK3 exon 15 (n = 24). For ETV6-NTRK3 fusions, the NTRK3 fusion point was at exon 14 in ten of 11 thyroid carcinomas, but in only three of 13 salivary gland tumors. Conclusions: Among 80 patients with TRK fusion cancer, we detected 20 different NTRK gene fusions, of which 55% occurred in only one patient each. There were 36 different fusion variants. Despite the variability of the fusion structure, larotrectinib was equally efficacious. The large number of potential different fusion partners and involvement of various breakpoints highlight the need for validated and appropriate testing methodologies that are agnostic of 5’ partners and breakpoints. Citation Format: Marc Ladanyi, Sinchita Roy-Chowdhuri, Lauren Ritterhouse, Felix Sahm, Ricarda Norenberg, Kui Shen, Chi Chen, Marc Fellous, Nicoletta Brega, Cornelis M. van Tilburg, Jessica J. Lin, Marcia S. Brose, Ulrik N. Lassen, Ray McDermott, Theodore W. Laetsch, David S. Hong, Alexander Drilon, Erin R. Rudzinski. Variability in NTRK gene fusions does not appear to impact response to larotrectinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT545.

HGG-11. Clinical characteristics and clinical evolution of a large cohort of pediatric patients with primary central nervous system (CNS) tumors and tropomyosin receptor kinase (TRK) fusion.

BACKGROUND: TRK fusions are detected in less than 3% of CNS tumors. Given their rarity, there are limited data on the clinical course of these patients. METHODS: We contacted 166 oncology centers worldwide to retrieve data on patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, NTRK gene fusion, treatment modalities and outcomes. Patients less than 18 years of age at diagnosis were included in this analysis. RESULTS: Seventy-three pediatric patients with TRK fusion-driven primary CNS tumors were identified. Median age at diagnosis was 2.4 years (range 0.0–17.8) and 60.2 % were male. NTRK2 gene fusions were found in 37 patients (50.7%), NTRK1 and NTRK3 aberrations were detected in 19 (26.0%) and 17 (23.3%), respectively. Tumor types included 38 high-grade gliomas (HGG; 52.1%), 20 low-grade gliomas (LGG; 27.4%), 4 embryonal tumors (5.5%) and 11 others (15.1%). Median follow-up was 46.5 months (range 3-226). During the course of their disease, a total of 62 (84.9%) patients underwent surgery with a treatment intent, 50 (68.5%) patients received chemotherapy, 35 (47.9%) patients received radiation therapy, while 34 (46.6%) patients received NTRK inhibitors (3 as first line treatment). Twenty-four (32.9%) had no progression including 9 LGG (45%) and 9 HGG (23.6%). At last follow-up, only one (5.6%-18 evaluable) patient with LGG died compared to 11 with HGG (35.5%-31 evaluable). For LGG the median progression-free survival (PFS) after the first line of treatment was 17 months (95% CI: 0.0-35.5) and median overall survival (OS) was not reached. For patients with HGG the median PFS was 30 months (95% CI: 11.9-48.1) and median OS was 182 months (95% CI 20.2-343.8). CONCLUSIONS: We report the largest cohort of pediatric patients with TRK fusion-driven primary CNS tumors. These results will help us to better understand clinical evolution and compare outcomes with ongoing clinical trials.

SO-31 Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion gastrointestinal (GI) cancer: An expanded dataset

Neurotrophic tyrosine receptor kinase ( NTRK ) gene fusions are oncogenic drivers in various tumour types. Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved for use in adult and paediatric patients with TRK fusion cancer, demonstrating an objective response rate (ORR) of 41% across 18 patients with gastrointestinal (GI) cancer (Boni et al, WCGI 2021). We report an updated analysis from an expanded dataset of patients with TRK fusion GI cancer with longer follow-up. Patients with TRK fusion GI cancer treated with larotrectinib in the phase II clinical trial NAVIGATE (NCT02576431) were included in this analysis. Responses were investigator-assessed using RECIST v1.1. Data cut-off was 20 July 2021. As of data cut-off, 34 patients with metastatic TRK fusion GI cancer were enrolled. Median age was 63.5 years (range 32–90). The tumour types included were colorectal (CRC; n=19), pancreatic (n=6), cholangiocarcinoma (n=4), appendiceal (n=1), duodenal (n=1), gastric (n=1), hepatocellular carcinoma (n=1) and oesophageal (n=1). Among the patients with CRC, 10 were microsatellite instability high (MSI-H), seven were MSI-H not detected (including stable) and two were unknown. Overall, 32%, 35% and 18% of patients had received 1, 2, or ≥3 prior lines of systemic therapy, respectively. ORR in the 33 evaluable patients was 33% (95% confidence interval [CI] 18–52): one complete response (CR; 3%), 10 partial responses (PR; three pending confirmation [30%]), 15 stable disease (SD; 45%), four progressive disease (PD; 12%) and three not determined (ND; 9%). Median time to response was 1.9 months (range 1.7–5.0). Median duration of response (DoR) was 7.3 months (95% CI 3.5–27.3); median follow-up was 26.4 months. Median progression-free survival (PFS) was 5.4 months (95% CI 2.7–9.0); median follow-up was 5.4 months. Median overall survival (OS) was 12.5 months (95% CI 6.1–33.4); median follow-up was 7.7 months. In the 19 patients with CRC, ORR was 47% (95% CI 24–71): one CR (5%), eight PR (three pending confirmation [42%]), eight SD (42%), one PD (5%) and one ND (5%). Of the nine responders, six were MSI-H. The median DoR was not reliably estimable, but the 12-month rate was 67% (95% CI 29–100); median follow-up was 17.8 months. Median PFS was 5.5 months (95% CI 2.7–not estimable); median follow-up was 5.6 months. Median OS was 12.5 months (95% CI 6.1–36.5); median follow-up was 7.8 months. Treatment duration for all GI patients ranged from 0.2+ to 32.2+ months. At data cut-off, 14 patients had progressed; four continued treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) occurred in 65% of patients (27% were Grade [G]1, 21% G2, 12% G3 and 6% G4). No patients discontinued treatment due to TRAEs. In this expanded dataset with longer follow-up, larotrectinib continues to demonstrate rapid, durable responses, extended survival and a favourable safety profile in patients with TRK fusion GI cancer, particularly in those with CRC. These results highlight the importance of identifying NTRK gene fusions in patients with GI cancer, particularly in those with MSI-H CRC.

Overall survival (OS) of patients with TRK fusion–positive cancer receiving larotrectinib versus standard of care (SoC): A matching-adjusted indirect comparison (MAIC) using real-world data (RWD).

6579 Background: Larotrectinib trials in Tropomyosin Receptor Kinase (TRK) fusion cancer population were single arm trials and therefore limited comparative effectiveness data with larotrectinib are available.MAIC is typically used to balance population characteristics to facilitate cross-study comparisons. The objective of this study was to use MAIC to compare efficacy of the highly specific TRK inhibitor larotrectinib vs. SoC. Methods: Individual patient data from larotrectinib trials (NCT02122913, NCT02637687, NCT02576431) were compared with published aggregate SoC data from patients with locally advanced/metastatic TRK fusion cancer identified in the Flatiron Health/Foundation Medicine clinico-genomic database (Demetri et al. Ann Oncol. 2021). Prior to matching, eligible patients were ≥18 years and had to have received ≤4 lines of prior therapy (LoPT). Patients were matched on available common baseline characteristics (Table). Overall survival was the only endpoint assessed and was defined as time from locally advanced/metastatic disease diagnosis to death. The analyses included: 1) a log-rank test of equality to test whether the two groups were similar before larotrectinib initiation; and 2) estimation of treatment effect of larotrectinib vs. SoC. Hazard ratios (HRs) were used to compare the 2 groups. MAIC assumes that all observed and unobserved prognostic factors are adjusted for in the analysis. Results: 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. Conclusions: This analysis suggests longer overall survival with larotrectinib, compared to SoC, in adult patients with TRK fusion cancer. The current analysis was limited to the prognostic variables available in the RWD. Further data are warranted to confirm those results. [Table: see text]

Long-term efficacy and safety of larotrectinib in a pooled analysis of patients with tropomyosin receptor kinase (TRK) fusion cancer.

3100 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in multiple tumors. Larotrectinib is a highly selective, central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor, approved to treat adult and pediatric patients (pts) with TRK fusion cancer. In an integrated analysis of 206 pts with non-primary CNS TRK fusion cancer, larotrectinib demonstrated an investigator-assessed objective response rate (ORR) of 75%; median progression-free survival (PFS) was 35.4 months (mo; Hong et al, ASCO 2021). We report updated efficacy and safety data based on central review assessments in an expanded dataset. Methods: Data were pooled from three clinical trials (NCT02576431, NCT02122913, and NCT02637687) of pts with non-primary CNS TRK fusion cancer treated with larotrectinib. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. ORR was assessed by independent review committee (IRC) per RECIST v1.1. Data cut-off was July 20, 2021. Results: As of data cut-off, 244 of 269 larotrectinib-treated pts were evaluable for efficacy by IRC. There were 25 different tumor types. The most common were soft tissue sarcoma (STS [43%], including infantile fibrosarcoma [18%] and other STS [25%]), thyroid (11%), lung (10%), salivary gland (9%), and colorectal (7% [colon, n = 18; rectal, n = 1]). Ninety-four (35%) pts were aged &lt; 18 years; 175 (65%) were ≥18 years. Pts had gene fusions involving NTRK1 (46%), NTRK2 (3%), or NTRK3 (51%). A total of 27%, 28%, and 45% of pts had 0, 1, and ≥2 prior lines of systemic therapy, respectively. The ORR was 69% (95% confidence interval [CI] 63–75): 64 (26%) complete response (CR), including 13 (5%) pathological CR, 104 (43%) partial response,41 (17%) stable disease, 20 (8%) progressive disease, and 15 (6%) not determined. Median time to response was 1.8 mo (range 0.9–16.2). Median duration of response (DoR) was 32.9 mo (95% CI 27.3–41.7); median follow-up was 28.3 mo. Median PFS was 29.4 mo (95% CI 19.3–34.3); median follow-up was 29.3 mo. At a median follow-up of 32.2 mo, median overall survival (OS) was not reached; the 48-mo OS rate was 64% (95% CI 55–73). Treatment duration ranged from 0.1 to 67.9 months. Treatment-related adverse events (TRAEs) were mainly Grade 1–2; 50 (20%) pts had Grade 3–4 TRAEs. Five (2%) pts discontinued treatment due to TRAEs. To exclude the possible confounding effect of ongoing enrollment on median DoR, we conducted an exploratory analysis in the subset of 164 pts who were analyzed as of July 2019. The ORR was 74% (95% CI 67–81) and median DoR was 34.5 mo (95% CI 27.6–43.3); median follow-up was 34.1 mo. Conclusions: With longer follow-up, larotrectinib continued to demonstrate rapid and durable responses, extended survival benefit, and a favorable safety profile. These results highlight the importance of testing for NTRK gene fusions in cancer pts. Clinical trial information: NCT02576431, NCT02122913, NCT02637687.

Updated efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion lung cancer.

9024 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions have been identified as oncogenic drivers in a variety of tumor types, including lung cancer. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor that demonstrated an objective response rate (ORR) of 73% across 15 investigator-assessed patients (pts) with lung cancer (Drilon et al, JCO Precis Oncol 2022). We report data on an expanded cohort of pts with TRK fusion lung cancer treated with larotrectinib. Methods: Pts with TRK fusion lung cancer enrolled in two larotrectinib clinical trials (NCT02576431 and NCT02122913) were included for this analysis. Larotrectinib was administered at 100 mg twice daily. Response was assessed by independent review committee (IRC) per RECIST v1.1. Results: As of July 20, 2021, a total of 26 pts with TRK fusion lung cancer (24 non-small cell lung cancer, 1 atypical carcinoid, 1 neuroendocrine) were enrolled, including 10 pts with CNS metastases at baseline. Median age was 51.5 years (range 25.0–76.0). The gene fusions involved NTRK1 (n =21; 81%) or NTRK3 (n =5; 19%). Pts received a median of 2 prior lines of systemic therapies with 19 (73%) receiving ≥2. Among 23 pts evaluable per IRC, the ORR was 83% (95% confidence interval [CI] 61–95): two complete responses, 17 partial responses (PR), and four stable disease (SD). The median time to response was 1.8 months. Among 10 evaluable pts with baseline CNS metastases, the ORR was 80% (95% CI 44–97): eight PR and two SD. Median duration of response (DoR) and progression-free survival (PFS) were not reached; median follow-up was 12.9 and 14.6 months, respectively. The 24-month rates for DoR and PFS were 72% and 67%, respectively. Median follow-up for overall survival (OS) was 12.9 months. The 24-month and 36-month rates for OS were both 72%. For the 10 evaluable pts with CNS metastases, the 12-month DoR, PFS, and OS rates were 26%, 22%, and 78%, respectively. Duration of treatment for all pts evaluable per IRC ranged from 2.1 to 52.7+ months. At data cut-off, six pts had progressed, with all six continuing treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) were predominantly Grade 1–2. Grade 3–4 TRAEs were reported in five pts (increased alanine aminotransferase, increased aspartate aminotransferase, hypersensitivity, myalgia, and increased weight). There were no treatment discontinuations due to TRAEs. Conclusions: In this larger dataset, larotrectinib demonstrated rapid and durable responses, extended survival, and a favorable long-term safety profile in pts with advanced lung cancer harboring NTRK gene fusions, including in pts with CNS metastases. These results support testing for NTRK gene fusions in pts with lung cancer. Clinical trial information: NCT02576431, NCT02122913.

Long-term control and safety of larotrectinib in a cohort of adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion primary central nervous system (CNS) tumors.

2010 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are known oncogenic drivers in a variety of tumor types. Larotrectinib is a highly selective, CNS-active TRK inhibitor that demonstrated an objective response rate (ORR) of 30% and a 24-week disease control rate (DCR) of 73% across 33 evaluable adult and pediatric patients with TRK fusion primary CNS tumors, as of July 2020 (Doz et al, Neuro Oncol 2021). We report updated data on an expanded dataset of patients. Methods: Patients with TRK fusion primary CNS tumors in two clinical trials (NCT02637687, NCT02576431) were included. Larotrectinib was administered at 100 mg twice daily (BID) in adults and 100 mg/m2 (max 100 mg) BID in pediatric patients. Response was investigator-assessed. Results: As of July 2021, 38 adult and pediatric patients with TRK fusion primary CNS tumors were identified: high-grade glioma (HGG; n =23), low-grade glioma (LGG; n =9), and other (n =6; includes glioneuronal, neuroepithelial, diffuse leptomeningeal, neuroblastoma, recurrent small round blue cell, and not otherwise specified). Median age at enrollment was 10.8 years (range 1.3–79.0; 28 [74%] patients &lt; 18 years old). The gene fusions involved NTRK2 (n = 28), NTRK1 (n = 6), and NTRK3 (n = 4). Sixteen (42%) patients received one prior line of systemic therapy and 16 (42%) received ≥2 prior lines. The ORR for 37 evaluable patients was 30% (95% confidence interval [CI] 16–47): three complete responses, eight partial responses, 21 stable disease (16 patients ≥24 weeks), and five progressive disease. The 24-week DCR was 73% (95% CI 56–86) for all patients, 68% (95% CI 45–86) for patients with HGG, and 89% (95% CI 52–100) for patients with LGG. Twenty-five of 31 patients (81%) with measurable disease at baseline had tumor shrinkage. Median time to response was 1.9 months. Median duration of response (DoR) was not reached; median follow-up was 25.6 months. The 12-month DoR rate was 64%. Median progression-free survival (PFS) was 16.5 months (95% CI 6.7–not estimable); median follow-up was 27.4 months. Median overall survival (OS) was not reached; median follow-up was 26.7 months. The 24-month OS rate was 65%. Treatment duration ranged from 0.1+ to 38.7+ months. Twenty-two patients (58%) progressed on treatment and three continued treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) were reported in 21 patients (55%); the majority of these patients (18/21 [86%]) reported Grade 1 or 2 TRAEs. No Grade 3 or higher treatment-related neurological adverse events were reported. There were no treatment discontinuations due to TRAEs. Conclusions: Larotrectinib achieved a high DCR, rapid and durable responses, and a manageable safety profile in patients with TRK fusion primary CNS tumors. These results support testing for NTRK gene fusions in patients with CNS tumors. Clinical trial information: NCT02637687, NCT02576431.

Clinical characteristics and outcome of a large cohort of patients with primary central nervous system (CNS) tumors and tropomyosin receptor kinase (TRK) fusion.

2052 Background: TRK fusions are detected in less than 3% of central nervous system (CNS) tumors. Given their rarity, there are limited data on the clinical course of affected patients. Methods: We contacted 166 oncology centers worldwide to retrieve data on patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, TRK gene fusion, treatment modalities and outcomes. Results: Ninety-two patients with TRK fusion-driven primary CNS tumors were identified including 76 pediatric patients (82.6%), 15 adults (16.3%) and 1 not specified (1.1%). Median age at diagnosis was 4.4 years (range 0.0–78.3) and 58.7 % were male. NTRK2 gene fusions were found in 45 patients (48.9%), NTRK1 and NTRK3 aberrations were detected in 27 (29.3%) and 20 (21.7%), respectively. Tumor types included 56 high-grade gliomas (HGG; 60.9%), 20 low-grade gliomas (LGG; 21.7%), 4 embryonal tumors (4.3%) and 12 others (13.0%). Median follow-up was 40.5 months (range 3–226). During the course of their disease, 75 (81.5%) patients underwent surgery with a treatment intent, 67 (72.8%) patients received chemotherapy, 50 (54.3%) patients received radiation therapy, while 47 (51.1%) patients received NTRK inhibitors (6 as first line treatment). There were significant differences in the median progression-free (PFS) and overall survival (OS) between pediatric patients compared to adults. The pediatric median PFS was 32 months (95% CI: 15.5–48.5) compared to 8 months for the adult (95% CI: 4.5–11.5, p = 0.015). The pediatric median OS was 182 months (95% CI: 25.1–338.9) compared to 24 months (95% CI: 18.3–29.7 p &lt; 0.001) for adult patients. There was no difference in the PFS of LGG compared to HGG. However, the OS was significantly worse for the HGG when compared to LGG (p = 0.039). The median OS for LGG was not reached and the median OS for HGG was 70 months (95% CI 7.5–132.5). Nineteen patients with HGG (38.0 % 19/50 evaluable patients) died compared to only one patient with LGG (5.6% 1/18 evaluable patients, p = 0.014). Conclusions: We report the largest cohort of patients with TRK fusion-driven primary CNS tumors. These results will help us to better understand clinical evolution and compare outcomes with ongoing clinical trials.