Tropomyosin Receptor Kinase Inhibitors for the Treatment of TRK Fusion Cancer

Laetsch, Theodore W.; Hong, David S.

doi:10.1158/1078-0432.ccr-21-0465

Cited by 39 publications

(35 citation statements)

References 60 publications

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Section: Discussionmentioning

confidence: 99%

“…Next-generation TRK inhibitors with activity against TRK kinase domain resistance mutations are in clinical development. 8,29 Off-target resistance mechanisms involve bypass signaling activation because of genomic alterations in other oncogenic drivers, and these alterations may often be targetable with existing agents. 30 In summary, the highly selective TRK inhibitor larotrectinib is active and well tolerated in patients with TRK fusion-positive lung cancers, including those with CNS metastases.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion–Positive Lung Cancers

Drilon

Tan

Lassen

et al. 2022

JCO Precision Oncology

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PURPOSE Larotrectinib is a highly selective and CNS-active tropomyosin receptor kinase (TRK) inhibitor that has demonstrated efficacy across TRK fusion–positive cancers, regardless of the tumor type. The aim of this study was to assess the efficacy and safety of larotrectinib in patients with TRK fusion–positive lung cancers. MATERIALS AND METHODS Data from two global, multicenter, registrational clinical trials of patients treated with larotrectinib were analyzed: a phase II adult and young adult basket trial ( NCT02576431 ) and a phase I adult trial ( NCT02122913 ). The primary end point was objective response rate (ORR). RESULTS By July 20, 2020, 20 patients with TRK fusion–positive lung cancer had been treated. The ORR by investigator assessment among 15 evaluable patients was 73% (95% CI, 45 to 92); one (7%) patient had a complete response, 10 (67%) had a partial response, three (20%) had stable disease, and one (7%) had progressive disease as best response. The median duration of response, progression-free survival, and overall survival were 33.9 months (95% CI, 5.6 to 33.9), 35.4 months (95% CI, 5.3 to 35.4), and 40.7 months (95% CI, 17.2 to not estimable), respectively. Among patients with baseline CNS metastases, the ORR was 63% (95% CI, 25 to 91). Adverse events were mainly grade 1 or 2. CONCLUSION Larotrectinib is highly active with rapid and durable responses, extended survival benefit, and a favorable long-term safety profile in patients with advanced lung cancer harboring NTRK gene fusions, including those with CNS metastases. These findings support routine testing for NTRK fusions in patients with lung cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion–Positive Lung Cancers

Drilon

Tan

Lassen

et al. 2022

JCO Precision Oncology

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“…Similarly, a high tumor mutation burden can be utilized as an agnostic marker for the administration of immune checkpoint inhibitors [84]. NTRK1/2/3 gene rearrangements, which are found at a reasonable frequency in pediatric tumors but are exceptionally rare in adults, are associated with the tumor's responsiveness to entrectinib or larotrectinib [105][106][107][108]. ALK, ROS1 and RET rearrangements, although not formally classified as agnostic markers, occur in multiple tumor types and render sensitivity to appropriate inhibitors [63,[109][110][111][112].…”

Section: Agnostic Versus Tissue-specific Targetsmentioning

confidence: 99%

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

Aleksakhina

Imyanitov

2021

IJMS

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The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 amplifications, ALK translocations or MET exon 14 skipping mutations, cause overproduction of the entire protein or its kinase domain. There are multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair. Treatment planning for non-small cell lung cancer requires testing for EGFR, ALK, ROS1, BRAF, MET, RET and KRAS gene alterations. Colorectal cancer patients need to undergo KRAS, NRAS, BRAF, HER2 and microsatellite instability analysis. The genomic examination of breast cancer includes testing for HER2 amplification and PIK3CA activation. Melanomas are currently subjected to BRAF and, in some instances, KIT genetic analysis. Predictive DNA assays have also been developed for thyroid cancers, cholangiocarcinomas and urinary bladder tumors. There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients.

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“…Chromosomal rearrangement of neurotrophin receptor tyrosine kinase genes (NTRK1, NTRK2, NTRK3) encoding tropomyosin receptor tyrosine kinases (TRKA, TRKB, TRKC) create oncogenic fusion proteins in a range of cancers (1)(2)(3). Patients harboring these gene fusions have high response rates to treatment with the first-generation TRK tyrosine kinase inhibitors (TKI) larotrectinib and entrectinib (Figure 1A) (4). Larotrectinib received FDA approval for treatment of patients with solid tumors harboring NTRK gene fusions and has a 79% overall response rate, a 35.2 month median duration of response, and a 16% complete response rate in a pooled analysis of 159 patients with solid tumors (5).…”

Section: Introductionmentioning

confidence: 99%

“…Clinical studies of entrectinib report a 57% overall response rate, 10.4 month median duration of response, and 7% complete response rate in 54 patients with NTRK+ solid tumors (6). The effectiveness of these agents is often limited by emergence of drug resistance (3,4) from mutations in distinct regions of the active site of the TRK kinase domain (solvent-front region, SFM; gatekeeper residue, GKM; activation loop, xDFG) (1,4,7-10) (Figure 1B). In addition, emergence of compound mutations (multiple mutations in an active site) are possible based on clinical experience with therapies targeting related ABL, ALK, RET, and ROS1 fusion protein-dependent cancers (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations

Murray¹,

Rogers²,

Zhai³

et al. 2021

Molecular Cancer Therapeutics

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NTRK chromosomal rearrangements yield oncogenic TRK fusion proteins that are sensitive to TRK inhibitors (larotrectinib, entrectinib) but often mutate, limiting the durability of response for NTRK+ patients. Next-generation inhibitors with compact macrocyclic structures (repotrectinib, selitrectinib) were designed to avoid resistance mutations. Head-to-head potency comparisons of TRK inhibitors and molecular characterization of binding interactions are incomplete obscuring a detailed understanding of how molecular characteristics translate to potency. Larotrectinib, entrectinib, selitrectinib, and repotrectinib were characterized using cellular models of wild-type TRKA/B/C fusions and resistance mutant variants with a subset evaluated in xenograft tumor models. Crystal structures were determined for repotrectinib bound to TRKA (wild-type, solvent front mutant). TKI-naïve and pretreated case studies are presented. Repotrectinib was the most potent inhibitor of wild-type TRKA/B/C fusions and was more potent than selitrectinib against all tested resistance mutations, underscoring the importance of distinct features of the macrocycle structures. Co-crystal structures of repotrectinib with wild-type TRKA and the TRKA G595R SFM variant elucidated how differences in macrocyclic inhibitor structure, binding orientation, and conformational flexibility affect potency and mutant selectivity. The SFM crystal structure revealed an unexpected intramolecular arginine sidechain interaction. Repotrectinib caused tumor regression in LMNA-NTRK1 xenograft models harboring GKM, SFM, xDFG, and GKM+SFM compound mutations. Durable responses were observed in TKI-naïve and -pretreated patients with NTRK+ cancers treated with repotrectinib (NCT03093116). This comprehensive analysis of first-and second-generation TRK inhibitors informs the clinical utility, structural determinants of inhibitor potency, and design of new generations of macrocyclic inhibitors.

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Tropomyosin Receptor Kinase Inhibitors for the Treatment of TRK Fusion Cancer

Cited by 39 publications

References 60 publications

Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion–Positive Lung Cancers

Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion–Positive Lung Cancers

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations

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