Neurotrophic Tyrosine Receptor Kinase Gene Fusions Research Articles

Efficacy and safety of larotrectinib in adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive primary central nervous system tumors.

2002 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in various tumor types, including central nervous system (CNS) tumors. Larotrectinib is a first-in-class, highly selective TRK inhibitor approved for the treatment of adult and pediatric patients with TRK fusion cancer, with 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 patients with TRK fusion-positive primary CNS tumors. Methods: Patients with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed. Results: As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified: 19 high-grade gliomas (HGG), 8 low-grade gliomas (LGG), 2 glioneuronal tumors, 2 neuroepithelial tumors, 1 CNS neuroblastoma, and 1 small round blue cell tumor. The patients had gene fusions involving NTRK2 (n = 24; 73%), NTRK1 (n = 5; 15%), and NTRK3 (n = 4; 12%). Median age was 8.9 years (range 1.3–79.0); 26 patients were pediatric ( < 18 years). Patients were heavily pre-treated with 45% having 2 or more prior lines of systemic therapy. The ORR in all patients was 30% (95% CI 16–49): 3 complete responses (all in pediatric patients), 7 partial responses (2 pending confirmation), 20 stable disease (including 15 pts > 6 months), and 3 progressive disease. The ORR in patients with HGG and LGG were 26% (95% CI 9–51) and 38% (95% CI 9–76), respectively. In all patients, the 24-week disease control rate was 73% (95% CI 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The median time to response was 1.9 months. Median duration of response (DoR) was not reached (95% CI 3.8–not estimable [NE]) at a median follow-up of 12.0 months. The 12-month DoR rate was 75% (95% CI 45–100). Median PFS was 18.3 months (95% CI 6.7–NE) at a median follow-up of 16.5 months. Median overall survival (OS) was not reached (95% CI 16.9–NE) at a median follow-up of 16.5 months, with a 12-month OS rate of 85% (95% CI 71–99). Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events (TRAE) were reported by 20 patients and were Grade 3–4 in 3 patients (9%). There were no treatment discontinuations due to TRAEs. Conclusions: In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile. These results support testing for NTRK gene fusions in patients of all ages with CNS tumors. Clinical trial information: NCT02637687, NCT02576431.

Long-term efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancer.

9109 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions have been identified as oncogenic drivers in a diverse array of tumor types including lung cancer. Larotrectinib is a first-in-class, highly selective, central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of adult and pediatric patients (pts) with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). Here, we report the updated data on pts with lung cancer treated with larotrectinib. Methods: Pts with lung cancer harboring a NTRK gene fusion enrolled in two clinical trials (NCT02576431 and NCT02122913) were identified for this analysis. Larotrectinib 100 mg PO BID was administered on a continuous 28-day schedule until disease progression, withdrawal, or unacceptable toxicity. Response was assessed by the investigator per RECIST v1.1. Results: As of July 20, 2020, a total of 20 pts with TRK fusion-positive lung cancer (19 with non-small cell lung cancer and 1 with small cell lung cancer) were enrolled. Median age was 48.5 years (range 25.0–76.0). The gene fusions involved NTRK1 (n = 16; 80%) or NTRK3 (n = 4; 20%). Pts were heavily pre-treated with a median of 3 systemic therapies (range 0–6). Among 15 evaluable pts, the confirmed ORR was 73% (95% CI 45–92): 1 complete response, 10 partial responses (PR), 3 stable disease (SD) and 1 progressive disease (PD). The median time to response was 1.8 months. Among 8 evaluable pts with baseline measurable and non-measurable CNS metastases, the ORR was 63% (95% CI 25–91): 5 PR, 2 SD, and 1 PD. In all evaluable pts, the 12-month rates for duration of response and progression-free survival were 81% and 65%, respectively. Median overall survival was 40.7 months (95% CI 17.2 to not estimable) at a median follow-up of 16.2 months. Duration of treatment ranged from 0.03+ to 51.55+ months. Adverse events (AEs) were predominantly Grade 1–2. Treatment-related AEs were reported in 16 pts, of which 2 experienced Grade 3 events (myalgia, hypersensitivity, weight increase). There were no treatment discontinuations due to AEs. Conclusions: These data confirm that larotrectinib is highly active with rapid and durable responses, extended survival benefit, 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 underscore the importance of screening for NTRK gene fusions in pts with lung cancer. Clinical trial information: NCT02576431 and NCT02122913.

Long-term efficacy and safety of larotrectinib in an integrated dataset of patients with TRK fusion cancer.

3108 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions encode tropomyosin receptor kinase (TRK) fusion proteins, which are oncogenic drivers in various tumor types. Larotrectinib is a first-in-class, highly selective, CNS-active TRK inhibitor approved to treat adult and pediatric patients with TRK fusion cancer. Larotrectinib demonstrated an objective response rate (ORR) of 78% and a median progression-free survival (PFS) of 36.8 months in an integrated analysis of 175 patients with non-primary CNS TRK fusion cancer (McDermott et al, ESMO 2020). We report updated efficacy and safety data with longer follow-up in an expanded dataset. Methods: Data were pooled from three clinical trials of patients with non-primary CNS TRK fusion cancer treated with larotrectinib. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was assessed by investigators using RECIST v1.1. Data cutoff: July 20, 2020. Results: As of data cutoff, 218 patients were treated with larotrectinib, of which 206 were evaluable for efficacy. There were 21 different tumor types, the most common being soft tissue sarcoma (STS [46%], including infantile fibrosarcoma [20%] and other STS [26%]), thyroid (13%), salivary gland (11%), lung (9%), and colorectal (5%). The median age was 38.0 years (range 0.1–84.0). Patients were heavily pretreated with 45% having received 2 or more prior lines of systemic therapy; 27% had 0 prior lines of systemic therapy. The ORR was 75% (95% CI 68–81): 45 (22%) complete response, 109 (53%) partial response (PR), 33 (16%) stable disease (SD), and 13 (6%) progressive disease (PD). Nineteen patients had brain metastases at baseline, with 15 evaluable for efficacy. The ORR for patients with brain metastases was 73% (95% CI 45–92): 11 PR, 2 SD, and 2 PD. Among all evaluable patients, the median time to response was 1.8 months (range 0.9–9.1). With a median follow up of 22.3 months, the median duration of response was 49.3 months (95% CI 27.3–not estimable). Treatment duration ranged from 0.03+ to 60.4+ months. Median PFS was 35.4 months (95% CI 23.4–55.7) with a median follow up of 20.3 months. At a median follow-up of 22.3 months, median overall survival (OS) was not reached and 36-month OS was 77% (95% CI 69–84). Treatment-related adverse events (TRAEs) were mainly Grade 1–2, with 18% having Grade 3–4 TRAEs. Only 2% of patients discontinued due to TRAEs. Conclusions: These results highlight the importance of testing for NTRK gene fusions in patients with cancer because the majority of patients with TRK fusion cancer treated with larotrectinib had long-term clinical benefit. The safety profile continued to be favorable and no new safety signals were identified. Clinical trial information: NCT02576431, NCT02122913, NCT02637687.

MA11.09 Efficacy and Safety of Larotrectinib in Patients with Tropomyosin Receptor Kinase (TRK) Fusion Lung Cancer

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers that occur in a wide range of tumor types. Larotrectinib, a highly selective Food and Drug Administration and European Medicines Agency approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% and a median duration of response (DoR) of 35 months across multiple cancers (Hong et al. Lancet Oncol 2020). Here we report updated data for patients with TRK fusion lung cancer assessed by independent review committee (IRC) and investigators (INV). Patients with lung cancer harboring an NTRK gene fusion enrolled in two clinical trials (NCT02122913 and NCT02576431) were included in this analysis. Larotrectinib 100 mg twice daily was administered on a continuous 28-day schedule. Response was assessed by IRC and by INV per RECIST v1.1. As of July 15, 2019, 14 patients with metastatic TRK fusion lung cancer were enrolled: 13 with non-small cell lung cancer (NSCLC) and 1 patient with small cell lung cancer (SCLC). Seven (6 NSCLC, 1 SCLC) patients had baseline central nervous system (CNS) metastases. The median age was 52 years (range 25–76). Eleven patients (79%) had fusions involving NTRK1 and three patients (21%) had fusions involving NTRK3. Patients were heavily pre-treated with a median of three prior therapies (range 1–5). Among 13 IRC-evaluable patients the ORR was 77% (95% confidence interval [CI] 46–95). ORR was 71% (95% CI 42–92) per INV. ORR in patients with CNS metastases was 71% (95% CI 29–96) and 57% (95% CI 18–90) per IRC and per INV, respectively (Table). The overall DoR per IRC ranged from 3.6 to 36.8+ months. The median progression-free survival (PFS) had not been reached (range 1.8 to 30.3+ months), with an estimated PFS rate at 12 months of 69%. Larotrectinib was well tolerated, with treatment-emergent adverse events being mainly Grade 1–2.Tabled 1All patients (N=14)Patients with brain metastases at baseline (n=7)INVIRC†INVIRCORR, % (95% CI)71 (42–92)77 (46–95)57 (18–90)71 (29–96)CR, n (%)1 (7)2 (15)00PR, n (%)9 (64)8 (62)4 (57)5 (71)SD, n (%)3 (21)3 (23)2 (29)2 (29)PD, n (%)1 (7)‡01 (14)‡0†IRC data missing for one patient. ‡Extracranial progression detected. CI, confidence interval; CR, complete response; INV, investigator assessment; IRC, independent review committee assessment; PD, progressive disease; PR, partial response; SD, stable disease. Open table in a new tab †IRC data missing for one patient. ‡Extracranial progression detected. CI, confidence interval; CR, complete response; INV, investigator assessment; IRC, independent review committee assessment; PD, progressive disease; PR, partial response; SD, stable disease. In this updated dataset, larotrectinib was shown to be highly active in patients with advanced lung cancer harboring NTRK gene fusions, including those with CNS metastases. The drug has a favorable safety profile. These results support inclusion of NTRK gene fusions in the routine molecular testing of patients with lung cancer.

Abstract PS11-06: Efficacy and safety of larotrectinib in patients with TRK fusion breast cancer

Abstract Introduction: Larotrectinib is a first-in-class, CNS-active, highly selective tropomyosin receptor kinase (TRK) inhibitor approved by the US Food and Drug Administration and European Medicines Agency for the treatment of adult and pediatric patients with tumor agnostic indication for TRK fusion-positive cancer. Larotrectinib produced an objective response rate (ORR) of 79% in 159 patients with TRK fusion-positive cancer across various tumor types (Hong DS et al. Lancet Oncol. 2020). Here we report the efficacy and safety of larotrectinib in the six patients from the NAVIGATE phase II study (NCT02576431) with TRK fusion-positive breast cancer. Methods: Data were obtained for patients with breast cancer harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and treated with larotrectinib in the NAVIGATE study. All patients received 100 mg twice daily on a continuous 28-day schedule. Responses were investigator-assessed per RECIST v1.1 (data cut-off: July 15, 2019). Results: A total of 6 patients with TRK fusion breast cancer were included: 3 with secretory carcinomas, 2 with triple-negative breast cancer (TNBC), and 1 with ER+/HER2− disease. The median age was 49 years (range 32-65). One of the patients with secretory breast cancer was male. All of the secretory cases and 1 TNBC patient harbored an ETV6-NTRK3 fusion, 1 TNBC patient had an LMNA-NTRK1 fusion, and the ER+/HER2− patient had a TPM3-NTRK1 fusion. Four patients had received ≥3 prior systemic therapies. The majority of patients had metastatic disease (n=5); 1 patient had locally advanced disease. The ORR was 83% (95% confidence interval [CI] 36-100) with 5 partial responses, while the ER+/HER2− patient had progressive disease. One of the TNBC patients had brain metastasis with complete resolution of CNS disease while on therapy. The median time to response was 1.7 months (range 0.9-1.9) and the duration of treatment ranged from 0.9 to 12+ months, with 4 patients (3 secretory and 1 TNBC) continuing on therapy at time of data cut. Median duration of response was not reached (95% CI 8.2-NE). Median progression-free survival was 9.1 months (95% CI 1.0-NE). Median overall survival was not reached at a median follow-up of 7.4 months. Four of the 6 patients had worst-grade adverse events (AEs) Grade 1-2; the most common Grade 1-2 AEs were dizziness and nausea. One patient had Grade 3 hepatocellular injury and Grade 4 hepatitis that were related to larotrectinib. There were no discontinuations due to AEs. Conclusion: Larotrectinib demonstrated an ORR in breast cancer patients similar to the ORR reported for larotrectinib across all tumor types, which supports the routine testing for NTRK gene fusions in patients with breast cancer regardless of histology. Citation Format: Ezra Y. Rosen, Antoine Italiano, Dejan Juric, John A. Reeves, Laura Dima, Nicoletta Brega, Alexander Drilon. Efficacy and safety of larotrectinib in patients with TRK fusion breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-06.

NTRK fusion analysis reveals enrichment in Middle Eastern BRAF wild-type PTC.

Fusions involving neurotrophic tyrosine receptor kinase (NTRK) are known oncogenic drivers in a broad range of tumor types. It recently gained attention as a predictor of targeted therapy since selective NTRK inhibitors are now approved in the US and Europe for patients with solid tumors harboring gene fusions. However, estimation of NTRK gene fusion/alteration frequency and its clinicopathological characteristics in papillary thyroid cancer (PTC) is limited, especially in a population with high incidence for PTC like Middle Eastern population. This study aims to characterize the NTRK gene fusion frequency and investigate the utility of pan-Trk immunohistochemistry (IHC) as predictor of NTRK fusion in a large cohort of Middle Eastern PTC. FISH analysis for NTRK gene fusions and pan-Trk IHC was performed on 315 Middle Eastern PTCs. Correlation of NTRK gene fusion and protein expression with clinicopathological markers and patient outcome were determined. In our cohort, 6.0% (19/315) patients showed NTRK gene fusions and were significantly associated with pediatric PTC (P = 0.0143), lymph node metastasis (P = 0.0428) and BRAF WT tumors (P < 0.0001). Pan-Trk IHC was positive in 9.2% (29/315) of cases and significantly associated with NTRK fusions, with a sensitivity of 73.7% and specificity of 94.9% in this cohort. This study confirms the presence of NTRK fusions in Middle Eastern PTC which is significantly enriched in BRAF WT as well as pediatric age group and proposes the usefulness of IHC to screen for PTC patients with NTRK fusion that might benefit from TRK inhibitors.

NTRK Fusions and TRK Inhibitors: Potential Targeted Therapies for Adult Glioblastoma.

IntroductionGlioblastoma multiforme (GBM) is the most common primary central nervous (CNS) system malignancy with a poor prognosis. The standard treatment for GBM is neurosurgical resection, followed by radiochemotherapy and adjuvant temozolomide chemotherapy. Predictive biomarkers, such as methylation of the promoter region of the O6-methylguanine DNA methyltransferase (MGMT) gene, can successfully distinguish subgroups with different prognosis after temozolomide chemotherapy. Based on multiomics studies, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), BRAF V600E mutation, neurotrophic tyrosine receptor kinase (NTRK) fusions and other potential therapy targets have been found.MethodsWe have reviewed the preclinical and clinical evidence for NTRK fusions and TRK inhibitors therapy in cancers with NTRK fusions in pan-cancer and gliomas.ResultsSeveral NTRK1/2/3 fusions have been reported in GBM and preclinical studies have proven that NTRK fusions are potential driver mutations in some high-grade gliomas. Tropomyosin receptor kinase (TRK) inhibitors have shown efficacy as targeted therapies for extracranial tumors with NTRK fusions in recent clinical trials, with potential CNS tolerability and activity. However, whether NTRK gene fusions can affect survival status, the efficacy and resistance of TRK inhibitors in GBMs are lacking high-level evidences.ConclusionsFor GBM patients, NTRK fusions and TRK inhibitors are potential target therapy strategy but remain biological mechanism and clinical significance unclarified. More clinical data and future clinical trials are needed to provide more evidence that supports targeted therapy for GBM with NTRK fusions.

Neurotrophic tyrosine kinase inhibitors: A review of implications for patients, clinicians and healthcare services.

Neurotrophic tyrosine receptor kinase (NTRK) inhibitors represent the latest advancement as a treatment option in targeted therapies for malignant disease. NTRK gene fusions involving NTRK1, 2 or 3 are implicated as genetics drivers for a number of tumour types which arise within adult and paedatric patients. NTRK inhibitors (Larotrectinib and Entrectinib) are effective agents which have demonstrated clinical benefit in the treatment of NTRK fusion positive solid tumours. Larotrectinib represents the first targeted agent to receive approval from international authorisation and commissioning bodies for the treatment of a specific genetic expression indiscriminate of the site from which the tumour has arisen. As such NTRK inhibitors could pave the way for international healthcare bodies to adopt a similar approach for future targeted therapies thereby altering the manner in which healthcare providers and patients are able to access and utilise innovative, targeted treatment options in future. The potential implications of this new approach are likely to impact upon several aspects of the traditional authorisation and commissioning pathways with potential changes to the design of clinical trials, the review and approval process by regulatory bodies and immunohistopathology services.

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.

NTRK gene fusions in melanoma: detection, prevalence and potential therapeutic implications.

Fusions involving neurotrophic tyrosine receptor kinase (NTRK) are known drivers of oncogenesis and also occur in melanoma, although very rarely. A particularly high incidence of NTRK gene fusions is reported in infantile fibrosarcoma (>90%) or the secretory type of breast cancer (>90%). Recently, larotrectinib (a tropomyosin receptor kinase [TRK] inhibitor) was approved, and we wondered whether TRK inhibitors might also be helpful for melanoma patients. We therefore screened the literature and obtained relevant results. NTRK fusions are relatively common in spitzoid melanoma, with a prevalence of 21-29% compared to <1% in cutaneous or mucosal melanoma and 2.5% in acral melanoma. It appears that fusion proteins are mutually exclusive for most common oncogenic drivers such as BRAF or NRAS. A further indicator of an increased probability of detecting NTRK-positive tumors could be a low mutation load. Since TRK inhibitors are already available for patients with NTRK fusions, the challenge will be to implement screening for NTRK gene fusions in clinical practice. A possible approach could be to screen BRAF, NRAS and KIT wild-type melanoma patients with next-generation sequencing as soon as they need systemic treatment or at the latest when they have no tumor control on checkpoint inhibitors.

Abstract 09: Cancers with NTRK gene fusions: Molecular characteristics and prognosis

Abstract Introduction: The neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, 2, and 3 have emerged as oncogenic drivers, and their resultant tropomyosin receptor kinase (TRK) proteins are targets for precision medicines. Larotrectinib, a selective TRK inhibitor, and entrectinib, a multikinase inhibitor, have been approved for patients (pts) with TRK fusion cancer. This study was conducted to evaluate the molecular characteristics and prognosis of TRK fusion cancer in a real-world setting. Methods: This is a retrospective study using the de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB) that includes pts with a diagnosis of cancer who had comprehensive genomic profiling (CGP) between Jan 2011 and Jul 2018 (Version Nov. 2018). Pts were classified based on the status of their NTRK gene: cohort 1 included pts with NTRK gene fusions and cohort 2 included pts with wild-type NTRK genes (WT-TRK). Within each tumor type, matching was conducted between the two cohorts using the Mahalanobis distance method with a ratio of 1:4 (cohort 1: cohort 2) on demographic and clinical characteristics including age, albumin, antineoplastic use, ECOG performance status, practice type, and year of CGP report. Descriptive analyses were provided for patient and molecular characteristics. Kaplan-Meier method and Cox regression were used for overall survival (OS) analysis with the date of the CGP report as the index date. Results: Of 33,398 pts in the CGDB, 29 pts across 18 histologies had an NTRK gene fusion and 12,456 pts had the same histologies with WT-TRK. In pts with NTRK gene fusions, NTRK1 was involved in 18 (62.1%), NTRK2 in 3 (10.3%), and NTRK3 in 8 (27.6%) of the observed fusion events. Co-occurrence of specific biomarkers (ALK, BRAF, ERBB2, EGFR, ROS1, KRAS) was rare, and lower in pts with NTRK gene fusions than in WT-TRK pts; however, high TMB and MSI were more common in pts with NTRK gene fusions than in WT-TRK pts (TMB high 20.7% vs. 2.8% and MSI high 10.3% vs. 0.9%, respectively). 27 pts from cohort 1 were matched with 102 pts in cohort 2. Demographic and baseline clinical characteristics were generally similar between the matched cohorts. A median OS from CGP report date of 16.5 months (95% CI 11.5-22.5) was observed for the WT-TRK pts, compared with 12.5 months (95% CI 9.5—not reached) for the pts with TRK fusion cancer. The proportional hazards ratio comparing pts with TRK fusion vs. WT-TRK cancer was 1.436 (95% CI 0.612-3.373). Conclusions: Pts with TRK fusion cancer had lower co-occurrence of other oncogenic biomarkers but had higher frequencies of MSI-high and TMB-high vs. pts with WT-TRK cancer. While no clear differences in OS were seen, there was a trend to shorter OS for pts with TRK fusion cancer. Further study allowing for inclusion of additional prognostic factors is needed to confirm the prognostic value of NTRK gene fusions. Citation Format: Lyudmila Bazhenova, Xiaolong Jiao, Andrew Lokker, Jeremy Snider, Emily Castellanos, Shivani Nanda, Virginia Fisher, Jihong Zong, Karen Keating, Marc Fellous. Cancers with NTRK gene fusions: Molecular characteristics and prognosis [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 09.

Systemic therapy for metastatic salivary gland tumors—challenges and novel concepts

SummarySalivary gland cancers (SGC) are a rare and heterogeneous group of malignancies. Most frequently tumors arise in the parotid gland. The most common histologic subtypes are adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma (MEC). Rare subtypes include salivary ductal carcinoma (SDC), mammary analogue secretory carcinoma (MASC) and adenocarcinoma not other specified (AC NOS). For locally advanced or metastatic disease, chemotherapy has been the mainstay of therapy. The course of disease differs markedly between the subtypes, especially ACC usually presents as slowly progressing disease. Due to the rarity of these tumors only small phase I/II studies exist, which report efficacy of cytotoxic regimens in advanced SGC. However, due to advances in the understanding of tumor biology and molecular testing, drugable genetic changes like androgen receptor (AR) status, HER2/neu overexpression and neurotrophic tyrosine receptor kinase (NTRK) gene fusion have evolved as potential therapy targets in subsets of SGC. Consequently therapy with androgen receptor blockade (ARB) can be offered to patients with AR expressing tumors. Anti-HER2 therapy with trastzumab is an option for the treatment of tumors with overexpression of HER2/neu and finally NTRAK inhibitors can be used for tumors harboring a NTRK gene fusion. Taken together, due to the small number of patients, data from large phase III studies for the treatment of SGC are missing. However, promising targeted therapy approaches have been recently undertaken.

NTRK fusions in osteosarcoma are rare and non-functional events.

Neurotrophic tyrosine receptor kinase (NTRK) fusions are promising molecular targets that have been described in a broad range of malignant tumours. Fusions commonly lead to the expression of chimeric proteins with constitutive tyrosine kinase activation that drives tumorigenesis. Despite a low prevalence among most solid tumours (<1%), the first encouraging results with pan‐NTRK tyrosine kinase inhibitors (TKIs) such as larotrectinib or entrectinib stimulated the search for eligible patients. Here, we report the first three cases of osteosarcoma harbouring NTRK fusions, among 113 patients sequenced. It is also the first report on NTRK fusions within a tumour type characterised by highly rearranged genomes and abundant passenger mutations. Whereas the presence of NTRK gene fusions in many tumours is considered to be one of the main driver events for tumour progression, the three chimeric transcripts described here appear non‐functional and likely represent randomly occurring passenger alterations. Particularly in tumours with complex karyotypes, it may therefore be advisable to specifically investigate the fusion transcripts for functional impact before considering targeted treatment approaches using pan‐NTRK TKIs.

A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors.

Introduction:The research objective was to systematically review evidence on neurotrophic tyrosine receptor kinase (NTRK) gene fusion frequency in solid tumors.Methods:Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review (SLR) was conducted of studies published from January 1987 to 2 January 2020. Selected studies were appraised for use in meta-analysis, with frequency reported as a point estimate with confidence intervals, to estimate NTRK gene fusion tumor incidence and prevalence.Results:The SLR identified 222 studies from North America (n = 122), Europe (n = 33), Asia (n = 41), Brazil (n = 5), Australia (n = 2), and multi-continental (n = 19) reporting NTRK gene fusion frequencies across 101 histologies. Studies were prospective (n = 43) and retrospective (n = 179). Testing methods involved DNA (n = 93), RNA (n = 72), combined DNA/RNA (n = 48), protein [immunohistochemistry (IHC), n = 5], and unreported (n = 5). Sample sizes ranged from 1 to 66,871. Of the 222 studies, 107 were suitable for meta-analysis. Highest NTRK gene fusion frequencies were reported in rare cancers: infantile/congenital fibrosarcoma (90.56%, 95% CI 67.42–100.00), secretory breast cancer (92.87%, 95% CI 72.62–100.00), and congenital mesoblastic nephroma (21.52%, 95% CI 13.06–32.20). Lower frequencies were reported in non-small cell lung cancer (0.17%, 95% CI 0.09–0.25), colorectal adenocarcinoma (0.26%, 95% CI 0.15–0.36), cutaneous melanoma (0.31%, 95% CI 0.07–0.55), and non-secretory breast carcinoma (0.60%, 95% CI 0.00–1.50). Reported frequency was ~0% for some cancers: mesothelioma, renal cell carcinoma, prostate cancer, and bone sarcoma. Estimated global overall NTRK gene fusion tumour incidence and 5-year prevalence in 2018 was 0.52 and 1.52 per 100,000 persons, respectively.Conclusion:This research confirms the rarity and varying frequency of NTRK gene fusion across tumor types. Limitations included relatively low historic NTRK gene fusion testing and reporting, limited study samples for some cancers, and suboptimal molecular testing methods. In this rapidly developing area, gold-standard testing methods and companion diagnostics are needed to capture all NTRK gene fusions.

Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor for the treatment of TRK fusion cancer

ABSTRACTIntroduction: Detecting oncogenic drivers across multiple cancers has brought about a shift toward a more targeted therapeutic approach. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are genomic rearrangements containing the kinase domain of one of three tropomyosin receptor kinases (TRK) and a dimerization domain contributed by another gene, generating fusion proteins, which are oncogenic drivers, targetable with TRK inhibitors. Larotrectinib is a first-in-class TRK inhibitor, granted accelerated FDA approval for treating TRK fusion cancer. This breakthrough indication across cancer subtypes and ages, from infancy through adulthood, highlights the need to understand the heterogeneous patient population and cancer types studied in larotrectinib clinical trials.Areas covered: We provide a narrative review of preclinical, pharmacokinetic, efficacy, and safety data for larotrectinib from three clinical trials that led to regulatory approval.Expert opinion: Larotrectinib elicits impressive responses in most patients with TRK fusion cancer, regardless of tumor type and age. Treatment is well tolerated with a low rate of treatment-emergent grade 3–4 adverse events, dose reductions and discontinuations due to adverse events, and recent findings indicate patient-reported improvement in quality of life. This highlights the importance of early testing for NTRK gene fusions in cancers that may harbor them, even if rare.

PCN107 BUDGET IMPACT ANALYSIS OF LAROTRECTINIB FOR 8 TUMORS IN THE UNITED STATES

Larotrectinib is an oral tropomyosin receptor kinase (TRK) inhibitor indicated for cancers where the tumor expresses neurotrophic tyrosine receptor kinase (NTRK) gene fusions. We assessed potential budget impact of the introduction of larotrectinib. In accordance with the expected pan-tumor indication, we assessed the financial implications of covering larotrectinib across 8 tumors: colorectal, non-small cell lung, melanoma, thyroid, gastrointestinal stromal tumor, infantile fibrosarcoma, soft tissue sarcoma, and salivary gland cancer. We created a budget impact model with a flexible time horizon. The model framework centralizes parameter control while separately modeling the available treatments, dosing, and market share for each of the 8 tumor types. The base case assumed a commercial U.S. health plan of 1,000,000 enrollees. The treated population for each tumor type was estimated from SEER, TRK fusion testing rate assumptions, fusion mutation prevalence, and treatment uptake assumptions. The budget impact was calculated as total and per member per month (PMPM) cost. Scenario analyses were performed in order to approximate the uncertainty in the base case results and identify likely financial determinants. We estimated that less than one patient would be treated with larotrectinib across the eight tumor types in the first year after accounting for the frequency of NTRK gene fusion in each tumor type. The total costs in year 1 without larotrectinib were $41,300 compared to $68,000 with the first year of larotrectinib uptake, an increase of $26,700 (less than $0.001 PMPM). Over three years, we estimated 1 patient was treated with larotrectinib, a PMPM increase of $0.01. The increase in costs was due proportionally to increased costs of genetic testing and increased drug costs. These results were most sensitive to the parameters that define the treated population. Adding larotrectinib is likely to have minimal additional costs when added to a health plan formulary.