TRK Fusion-positive Cancers Research Articles

Economic Evaluation of a Tumour-Agnostic Therapy: Dutch Economic Value of Larotrectinib in TRK Fusion-Positive Cancers.

BackgroundLarotrectinib is the first tumour-agnostic therapy that has been approved by the European Medicines Agency. Tumour-agnostic therapies are indicated for a multitude of tumour types. The economic models supporting reimbursement submissions of tumour-agnostic therapies are complex because of the multitude of indications per model.ObjectiveThe objective of this paper was to evaluate the cost effectiveness of larotrectinib compared with standard of care in patients with cancer with tropomyosin receptor kinase fusion-positive tumour types in the Netherlands.MethodsA previously constructed cost-effectiveness model with a partitioned survival approach was adapted to the Dutch setting, simulating costs and effects of treatment in patients with tropomyosin receptor kinase fusion-positive cancer. The cost-effectiveness model conducts a naïve comparison of larotrectinib to a weighted comparator standard-of-care arm. Dutch specific resource use and costs were implemented and inflated to reflect 2019 euros. The analysis includes a lifetime horizon and a societal perspective.ResultsLarotrectinib versus Dutch standard of care resulted in 5.61 incremental (QALYs) and €232,260 incremental costs, leading to an incremental cost-effectivenes ratio of €41,424/QALY. The probabilistic sensitivity analysis reveals a 88% chance of larotrectinib being cost effective compared with the pooled comparator standard-of-care arm at the applicable €80,000/QALY willingness-to-pay threshold in the Netherlands.ConclusionsThe incremental cost-effectivenes ratio was well below the applicable threshold for diseases with a high burden of disease in the Netherlands (€80,000). At this threshold, larotrectinib was estimated to be a cost-effective treatment for patients with tropomyosin receptor kinase fusion-positive cancer compared with current standard of care in the Netherlands.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40258-022-00740-1.

TRK inhibitor activity and resistance in TRK fusion-positive cancers in adults

NTRK fusions drive oncogenesis in a variety of adult cancers. The approval of the first-generation TRK inhibitors, larotrectinib and entrectinib, for any cancer with an NTRK fusion represented a focal point in tumor-agnostic drug development. These agents achieve high response rates and durable disease control, and display intracranial activity. The use of these agents has resulted in a deeper understanding of the clinical consequences of TRK inhibition. These on-target side effects include dizziness, weight gain, and withdrawal pain. The study of TRK inhibitor resistance led to the development of next generation drugs, such as selitrectinib, repotrectinib, taletrectinib, and other agents that maintain disease control against selected acquired kinase domain mutations. This review discusses the clinical efficacy of TRK inhibitors, their safety profiles, and resistance mechanisms with a focus on data in adult cancers.

Characterization of KRC-108 as a TrkA Kinase Inhibitor with Anti-Tumor Effects.

Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion. KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited anti-tumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.

TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors.

On-target resistance to next-generation TRK inhibitors in TRK fusion-positive cancers is largely uncharacterized. In patients with these tumors, we found that TRK xDFG mutations confer resistance to type I next-generation TRK inhibitors designed to maintain potency against several kinase domain mutations. Computational modeling and biochemical assays showed that TRKAG667 and TRKCG696 xDFG substitutions reduce drug binding by generating steric hindrance. Concurrently, these mutations stabilize the inactive (DFG-out) conformations of the kinases, thus sensitizing these kinases to type II TRK inhibitors. Consistently, type II inhibitors impede the growth and TRK-mediated signaling of xDFG-mutant isogenic and patient-derived models. Collectively, these data demonstrate that adaptive conformational resistance can be abrogated by shifting kinase engagement modes. Given the prior identification of paralogous xDFG resistance mutations in other oncogene-addicted cancers, these findings provide insights into rational type II drug design by leveraging inhibitor class affinity switching to address recalcitrant resistant alterations. SIGNIFICANCE: In TRK fusion-positive cancers, TRK xDFG substitutions represent a shared liability for type I TRK inhibitors. In contrast, they represent a potential biomarker of type II TRK inhibitor activity. As all currently available type II agents are multikinase inhibitors, rational drug design should focus on selective type II inhibitor creation.This article is highlighted in the In This Issue feature, p. 1.

In This Issue

In This Issue

Abstract 3087: FCN-098, a novel second-generation TRK inhibitor, overcomes TRK resistance mutations in vitro and in vivo

Abstract Tropomyosin receptor kinases (TRK or NTRK) are the transmembrane tyrosine kinases activated by soluble growth factors named neurotrophins (NT). TRK family includes three different members, namely TRKA, TRKB and TRKC. Extracellular recognition of NT to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signal transduction pathways via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRKs are expressed primarily in neuronal tissues and regulate differentiation and survival of neuronal cells. Alteration of TRK pathway caused by gene fusion of TRK is frequently associated with the poor prognosis of a wide range of solid malignancies, such as neuroblastoma, breast cancer, pancreatic cancer, melanoma, thyroid cancer, glioblastoma, colorectal cancer, sarcomas, cholangiocarcinoma, and non-small cell lung cancer. The efficacy of TRK inhibition in TRK fusion-positive cancers has been demonstrated by the high response rate and lasting effect of the first-generation TRK inhibitors larotrectinib and entrectinib. However, acquired resistance mutations of TRK, such as solvent front mutations, gatekeeper mutations and DFG motif mutations, often emerge and abrogate the inhibitory effect of first-generation inhibitors. Thus, developing novel TRK inhibitors that can effectively overcome resistance mutations can provide great clinical benefits to patients. Here we introduce FCN-098, a potent second-generation TRK inhibitor. FCN-098 demonstrated marked kinase inhibition activity against wild-type (WT) and mutant TRK with IC50 at sub-nano or single nanomolar range. FCN-098 significantly and dose-dependently inhibited phosphorylation of TRK and its downstream effector ERK in TRK fusion-positive KM12 human colon cancer cells and BaF3 cells ectopically overexpressing WT or mutant TRK fusions. FCN-098 potently inhibited proliferation of KM12 cells and BaF3 cells overexpressing WT or various mutant TRK fusions while sparing TRK-negative cell lines. Consistent with in vitro results, FCN-098 showed remarkable anti-tumor activity in xenograft models driven by WT or mutant TRK fusions in a dose-dependent manner. In particular, the anti-tumor activity of FCN-098 was superior to another second-generation TRK inhibitor LOXO-195 at the same dose in xenografts driven by TPM3-TRKA G595R or ETV6-TRKC G623R mutation, and exhibited comparable potency to LOXO-195 in LMNA-TRKA G667C-driven xenografts. In non-clinical studies, FCN-098 exhibited excellent pharmacokinetic (PK) and safety properties, demonstrating longer T1/2 in both dogs and rats along with higher Cmax and larger dose-normalized AUC in dogs compared to LOXO-195. Overall, FCN-098 overcomes TRK resistance mutations in vitro and in vivo and exhibits favorable PK and safety profiles. FCN-098 has the potential to become an effective and safe therapeutic choice for a wide range of solid tumors harboring WT or mutant TRK fusions. Citation Format: Shu Lin, Tongshuang Li, Xianlong Wang, Lijun Yang, Zhifang Chen, Yue Rong, Xingdong Zhao, Yanxin Liu, Zongyao Zou, Min Lin, Yuwei Gao, Jiashu Zhou, Weibo Wang. FCN-098, a novel second-generation TRK inhibitor, overcomes TRK resistance mutations in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3087.

Abstract 38: Large-scale study of NTRK fusions in Chinese solid tumors and using next generation sequencing: A multicenter study

Abstract Background: NTRK gene fusions involving either NTRK1, NTRK2 or NTRK3 are oncogenic drivers of various solid tumor types but generally at a low frequency. TRK inhibitors such as LOXO-101, entrectinib, X396, AB-106, TL118 had remarkable and durable antitumor activities in patients (pts) with TRK fusion-positive cancers, regardless of age or tumor type. We assessed the frequency of NTRK fusions across 14, 491 advanced cancers to reveal the landscape in a wide variety of subtypes. Methods: A multicenter study in China was initiated from July 2013, and advanced cancer patients have been enrolled as of September 2018. We analyzed data from 14, 491 clinical advanced cancer cases, each of which had results from next-generation sequencing (NGS)-based 381 genes panel assay, analogous to the index patient. Results: Of this entire cohort [6837 lung cancer (47.18%), 1894 breast cancer (13.07%), 1325 colorectal cancer (9.14%), 312 soft tissue sarcoma (2.15%), 260 head and neck cancer (1.79%) and 1804 others (12.45%)], 40 patients were identified with NTRK fusions, including TPM3-NTRK1, LMNA-NTRK1, IRF2BP2-NTRK1, TPR-NTRK1, SQSTM1-NTRK1, C1orf111-NTRK1, NTRK1-CUL3, LIPI-NTRK1, NTRK1-C1orf61, TARDBP-NTRK1, LOC643387-NTRK1, NFASC-NTRK1, RFWD2-NTRK1, MSN-NTRK2, ATL2-NTRK2, AGTPBP1-NTRK2, ZCCHC7-NTRK2, CALR-NTRK2, ESRP1-NTRK2, ETV6-NTRK3. NTRK fusions were seen in 0.26% (18/6837) of lung cancer [C1orf111-NTRK1+TPM3-NTRK1(1), TPR-NTRK1(1), TPM3-NTRK1(2), SQSTM1-NTRK1+NTRK1-CUL3(1), LIPI-NTRK1(1), NTRK1-C1orf61(1), LMNA-NTRK1(1), MSN-NTRK2(1), TARDBP-NTRK1+LOC643387-NTRK1(1), IRF2BP2-NTRK1(1), ATL2-NTRK2 (1), NFASC-NTRK1(1), AGTPBP1-NTRK2(1), RFWD2-NTRK1(1), ZCCHC7-NTRK2(1), CALR-NTRK2(1) and ESRP1-NTRK2]; 0.21%(4/1894) of breast cancer [ETV6-NTRK3(4)]; 0.37%(5/1325) of colorectal cancer [TPM3-NTRK1(1), ETV6-NTRK3(4)]; 3.53%(11/312) of soft tissue sarcoma [LMNA-NTRK1(3), TPM3-NTRK1(1), ETV6-NTRK3(7)]; 0.38%(1/260) of head and neck cancer [ETV6-NTRK3(1)] and 0.05%(1/1804) of others [ETV6-NTRK3(1)]. Conclusion: NTRK fusions are a rare molecular subtype in Chinese solid tumors. The NTRK gene fusions more commonly occurred in NSCLC (0.3%), CRC (0.4%) and BC (0.2%), and may occur without other targetable alterations such as EGFR, ALK, ROS1. The clinical evidence for responsiveness of NTRK fusions driven solid tumors provides an opportunity to personalize treatments and improve clinical outcomes for patients (pts). Citation Format: Wen-xian Wang, Chun-wei Xu, Lei Lei, Xiao-jia Wang, You-cai Zhu, Yong Fang, Xiu-yu Cai, Rong-bo Lin, Li Lin, Hong Wang, Mei-yu Fang, Yin-bin Zhang, Shi-jie Lan, Xin Cai, Xin Liu, Xing-xiang Pu, Zong-yang Yu, Bing Wan, Jin-luan Li, Xian-bin Liang, Li-ping Wang, Wu Zhuang, Zi-yan Yang, Gang Chen, Tang-feng Lv, Yong Song. Large-scale study of NTRK fusions in Chinese solid tumors and using next generation sequencing: A multicenter study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 38.

Abstract 16: Landscape and outcome of TRK fusion-positive Cancers

Abstract TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion-positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, clinical outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion-positive cancers. Utilizing a center-wide screening program involving more than 26,000 prospectively sequenced patients, genomic and clinical data from all cases with identified TRK fusions were extracted. An integrated analysis was performed of genomic, therapeutic, and phenomic outcomes. In total, we identified 76 cases with confirmed TRK fusions (0.27% overall prevalence) involving 48 unique rearrangements and 17 distinct cancer types. The presence of a TRK fusion was associated with depletion of concurrent oncogenic drivers (p=4.4E-7) and lower tumor mutation burden (p=4.2E-9), with the exception of colorectal cancer where TRK fusions co-occur with microsatellite instability (MSI-H). Longitudinal profiling in a subset of patients indicated that TRK fusions were present in all sampled timepoints in 82% (14/17) of cases. Progression-free survival on first-line therapy, excluding TRK inhibitors, administered for advanced disease was 9.6 months (95% CI: 4.8-13.2). The best ORR achieved with chemotherapy containing-regimens across all lines of therapy was 63% (95% CI: 41-81). Among 12 patients treated with checkpoint inhibitors, the only response observed was in an MSI-H colorectal patient. TRK fusion-positive cancers can respond to alternative standards of care, although efficacy of immunotherapy in the absence of other predictive biomarkers (MSI-H) appears limited. TRK fusions are present in tumors with simple genomes lacking in concurrent drivers that may partially explain the tumor-agnostic efficacy of TRK inhibitors. Citation Format: Ezra Y. Rosen, Debra A. Goldman, Jaclyn F. Hechtman, Ryma Benayed, Alison M. Schram, Emiliano Cocco, Sophie Shifman, Yixiao Gong, Ritika Kundra, James P. Solomon, Alberto Bardelli, Maurizio Scaltriti, Alexander Drilon, Alexia Iasonos, Barry S. Taylor, David M. Hyman. Landscape and outcome of TRK fusion-positive Cancers [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 16.

TRK fusion positive cancers: From first clinical data of a TRK inhibitor to future directions.

Genetic alterations of neurotrophic tropomyosin or tyrosine receptor kinase (NTRK) 1/2/3 genes generate TRK fusion proteins have been reported in a variety of adult and child cancers from diverse cell/tissue lineages. Larotrectinib, a tumour-agnostic TRK inhibitor, has shown remarkable efficacy in a novel "basket" study which has enrolled patients from infants to elderly with different TRK fusion-positive cancers. In this review, we focus on the challenges and expectations on the development of "tumour-agnostic" targeted therapies in rare malignancies.

TRK Fusions Are Enriched in Cancers with Uncommon Histologies and the Absence of Canonical Driver Mutations.

TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion-positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion-positive cancers. Utilizing a center-wide screening program involving more than 26,000 prospectively sequenced patients, genomic and clinical data from all cases with TRK fusions were extracted. An integrated analysis was performed of genomic, therapeutic, and phenomic outcomes. We identified 76 cases with confirmed TRK fusions (0.28% overall prevalence) involving 48 unique rearrangements and 17 cancer types. The presence of a TRK fusion was associated with depletion of concurrent oncogenic drivers (P < 0.001) and lower tumor mutation burden (P < 0.001), with the exception of colorectal cancer where TRK fusions cooccur with microsatellite instability (MSI-H). Longitudinal profiling in a subset of patients indicated that TRK fusions were present in all sampled timepoints in 82% (14/17) of cases. Progression-free survival on first-line therapy, excluding TRK inhibitors, administered for advanced disease was 9.6 months [95% confidence interval (CI), 4.8-13.2]. The best overall response rate achieved with chemotherapy containing-regimens across all lines of therapy was 63% (95% CI, 41-81). Among 12 patients treated with checkpoint inhibitors, a patient with MSI-H colorectal cancer had the only observed response. TRK fusion-positive cancers can respond to alternative standards of care, although efficacy of immunotherapy in the absence of other predictive biomarkers (MSI-H) appears limited. TRK fusions are present in tumors with simple genomes lacking in concurrent drivers that may partially explain the tumor-agnostic efficacy of TRK inhibitors.

TRK inhibitors in TRK fusion-positive cancers.

TRK fusions are oncogenic drivers of various adult and paediatric cancers. The first-generation TRK inhibitors, larotrectinib and entrectinib, were granted landmark, tumour-agnostic regulatory approvals for the treatment of these cancers in 2018 and 2019, respectively. Brisk and durable responses are achieved with these drugs in patients, including those with locally advanced or metastatic disease. In addition, intracranial activity has been observed with both agents in TRK fusion-positive solid tumours with brain metastases and primary brain tumours. While resistance to first-generation TRK inhibition can eventually occur, next-generation agents such as selitrectinib (BAY 2731954, LOXO-195) and repotrectinib were designed to address on-target resistance, which is mediated by emergent kinase domain mutations, such as those that result in substitutions at solvent front or gatekeeper residues. These next-generation drugs are currently available in the clinic and proof-of-concept responses have been reported. This underscores the utility of sequential TRK inhibitor use in select patients, a paradigm that parallels the use of targeted therapies in other oncogenic driver-positive cancers, such as ALK fusion-positive lung cancers. While TRK inhibitors have a favourable overall safety profile, select on-target adverse events, including weight gain, dizziness/ataxia and paraesthesias, are occasionally observed and should be monitored in the clinic. These side-effects are likely consequences of the inhibition of the TRK pathway that is involved in the development and maintenance of the nervous system.

PL01.01 Tumor-Agnostic Biologically Driven Treatments: An Endless Dream?

PL01.01 Tumor-Agnostic Biologically Driven Treatments: An Endless Dream?

Abstract LB-118: Resistance to TRK inhibition mediated by convergent MAP kinase pathway activation

Abstract Background: TRK inhibition is now standard of care for advanced pediatric and adult patients (pts) with TRK fusion solid tumors, regardless of origin. To date, TRK kinase domain mutations are the only known resistance mechanism, and next-generation TRK inhibitors active against these mutations such as LOXO-195 are being developed. We reasoned some pts will develop TRK-independent resistance and hypothesized that these pts will require unique therapeutic approaches. Methods: Paired tumor biopsies and serial cell-free DNA (cfDNA) prospectively collected from pts with TRK fusion-positive cancers treated with first- and next-generation TRK inhibitors before treatment and at progression were sequenced. In parallel, pt-derived and engineered models were analyzed. Results: Alterations involving upstream non-TRK receptor kinases and downstream MAPK pathway members were initially identified in tumors from 3 TRK fusion-positive gastrointestinal (GI) cancer pts who developed resistance to TRK inhibitors. Pt 1 with CTRC-NTRK1 pancreatic cancer developed temporally distinct emergent BRAF V600E and KRAS G12D mutations. Pt 2 with LMNA-NTRK1 colorectal cancer developed temporally distinct KRAS G12A and G12D mutations. Pt 3 with PLEKHA6-NTRK1 cholangiocarcinoma developed focal MET amplification. Phenocopying these clinical observations, pt-derived xenografts and primary cell lines developed BRAF and KRAS mutations following chronic TRK inhibition. Consistently, ectopic expression of these alterations conferred resistance to TRK inhibitors. Given that all 3 index pts had GI cancers, we expanded serial cfDNA sequencing to 5 additional TRK fusion-positive GI disease, identifying 3 with emergent MAPK alterations at progression, bringing the overall frequency of acquired MAPK alterations in GI cancers analyzed to 75% (6/8). To further evaluate whether these emergent alterations induced functional dependence on ERK signaling, pts 1-3 were treated with agents targeting these emergent alterations (dabrafenib + trametinib, LOXO-195 + trametinib, and LOXO-195 + crizotinib, respectively). Pt 1 achieved transient tumor regression, followed by outgrowth of KRAS-mutant disease. Pt 3 achieved a 4.5 months tumor regression. Sequencing at progression in pt 3 identified multiple acquired MET point mutations known to interfere with crizotinib binding. Conclusions: These data suggest that a subset of TRK fusion-positive cancers will develop off-target mechanisms of resistance to TRK inhibition. Relative to other TRK fusion-positive tumors, GI cancers may have a higher propensity for developing these bypass alterations that demonstrate remarkable convergence on ERK signaling. A portion of these mechanisms may be managed with simultaneous targeting of the TRK and MAPK pathways, although additional modeling is required to determine if upfront treatment would confer more durable responses. Citation Format: Emiliano Cocco, Amanda Kulick, Sandra Misale, Rona Yaeger, Pedram Razavi, Helen H. Won, Ryan Ptashkin, Jaclyn F. Hechtman, Eneda Toska, James Cownie, Romel Somwar, Sophie Shifman, Marissa Mattar, S Duygu Selçuklu, Aliaksandra Samoila, Sean Guzman, Brian B. Tuch, Kevin Ebata, Elisa de Stanchina, Rebecca J. Nagy, Richard B. Lanman, Michael F. Berger, Marc Ladanyi, David M. Hyman, Alexander Drilon, Maurizio Scaltriti, Alison M. Schram. Resistance to TRK inhibition mediated by convergent MAP kinase pathway activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-118.

TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors

On-target resistance to next-generation kinase inhibitors, drugs specifically designed to maintain potency in the setting of kinase domain mutations, remains poorly characterized. Having identified that xDFG (TRKA G667) mutations confer second-generation TRK inhibitor resistance in patients with TRK fusion-positive cancers, we used computational modeling and biochemical assays to study how these affect drug binding. We found that xDFG mutations stabilize the inactive kinase conformation, hampering the binding of type I second-generation TRK inhibitors, while increasing the affinity for type II multikinase inhibitors. Type II drugs consistently inhibit the growth and TRK-mediated signaling of isogenic and patient-derived models harboring xDFG mutations. Collectively these data demonstrate that TRK xDFG substitutions trigger conformational changes that favor type II binding mechanisms. Given prior identification of paralogous xDFG resistance mutations in other oncogene addicted cancers, these findings provide insight into rational drug design to address these recalcitrant resistant alterations by leveraging inhibitor class affinity switching.

75P - The landscape of NTRK fusions in Chinese patients with solid tumor

Background: NTRK gene fusions resulting in the elevated expression of TRK kinases were discovered in a wide variety of tumor types but generally at a low frequency. TRK inhibitors such as LOXO-101 and entrectinib had remarkable and durable antitumor activities in patients (pts) with TRK fusion-positive cancers, regardless of age or tumor type. Methods: FFPE tumor samples of over 3700 Chinese solid tumor pts were collected for NGS-based assay. We measured the gene fusions, mutations, and copy number alterations in tumor tissue against matched blood. Pan-Trk IHC testing was performed on five NTRK1 fusions. Results: 12 pts were idendified as NTRK fusion positive, which accounted to approximately 0.3% of the Chinese solid tumor pts in our cohort. Seven out of 12 pts harbored NTRK1 fusions with 6 partners, and the remaining ones were NTRK3 fusions with 2 partners. The half fusions with novel partner genes or breakpoints were defined as likely fusions. The tumor types of pts with NTRK fusions included NSCLC, colorectal cancer (CRC), prostate cancer and fibrosarcoma. NTRK fusions were more likely t occur in NSCLC and CRC, which accouted for 0.3% and 1.4%, respectively. Three predicted likely fusions and two known fusions were selected to perform pan-Trk IHC assay, and four were IHC positive. One known TPR-NTRK1 fusion not detected by IHC, which highlighted the necessity to use NGS to detect NTRK fusions due to higher sensitivity and capability. NTRK fusions were not always mutually exclusive with driver mutations. Three lung cancer pts with NTRK fusions also harbored EGFR-sensitive mutations.Table: 75PGene fusionCancer typeIHCPathogenicNTRK1TPM3 exon10-NTRK1 exon8Colorectal cancerPositiveLikelyIRF2BP2 exon1-NTRK1 exon8Prostate cancerPositiveLikelyPRDX1 exon5-NTRK1 exon12Lung adenocarcinomaPositiveLikelyLMNA exon2-NTRK1 exon11FibrosarcomaPositiveKnownTPR exon21-NTRK1 exon 9Lung adenocarcinomaNegativeKnownTPM3 exon10-NTRK1 exon8Colorectal cancerNALikelyAMOTL2 exon6-NTRK1 exon12Lung adenocarcinomaNALikelyNTRK3ETV6 exon5 -NTRK3 exon15Colorectal cancerNAKnownETV6 exon5 -NTRK3 exon15Colorectal cancerNAKnownETV6 exon5 -NTRK3 exon15Squamous cell lung cancerNAKnownETV6 exon4 -NTRK3 exon14Small cell lung cancerNAKnownAKAP13 exon3-NTRK3 exon14Lung adenocarcinomaNALikely Open table in a new tab Conclusions: This study revealed NTRK fuisons in approximately 0.3% of Chinese solid tumor pts for the first time. The NTRK gene fusions more commonly occurred in NSCLC (0.3%) and CRC (1.4%), but may occur with other targetable alterations such as EGFR-activating mutations. NGS panel sequencing showed the advantage of detecting NTRK fusion and providing structure information of partners which could potentially guide more precise treatment options. Legal entity responsible for the study: OrigiMed. Funding: Has not received any funding. Disclosure: R. Ma, D. Chen, H. Chen, X. Dong, W. Wang, M. Yao: Employee: OrigiMed. All other authors have declared no conflicts of interest.

Abstract PR07: A pediatric phase 1 study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family: An updated analysis

Abstract Background: NTRK gene fusions occur in a broad range of pediatric and adult malignancies at low frequencies, but are present in the vast majority of infantile fibrosarcomas. Larotrectinib is the first selective small-molecule inhibitor of TRKA, B, and C in clinical development. Larotrectinib has demonstrated a high response rate and a favorable safety profile in children and adults with TRK-fusion positive cancers. Here we report an updated analysis from the pediatric phase 1 study of larotrectinib. Methods: This multicenter, rolling 6 phase 1 study enrolled pediatric patients with refractory solid or CNS tumors. Patients with locally advanced infantile fibrosarcoma who would require disfiguring surgery or limb amputation to achieve a complete surgical resection were also eligible. Measurable or evaluable disease by RECIST v1.1/RANO was required. Patients were dosed orally BID on a continuous 28-day schedule either by capsule or oral solution. Pharmacokinetic (PK)-directed intra-subject dose escalation was permitted, with exposures targeting the adult recommended phase 2 dose (RP2D) of 100 mg BID. The primary objective was to define the maximum tolerated dose (MTD) / RP2D; secondary objectives included pharmacokinetics (PK) and efficacy using RECIST v1.1/RANO. Results: As of July 17, 2017, 24 patients (17 with TRK fusions, 7 without TRK fusions) with a median age of 4.5 years (range 1 month-18 years) were enrolled. Patients had diverse TRK fusions (9 NTRK1, 1 NTRK2, and 7 NTRK3) in heterogeneous tumor diagnoses (8 infantile fibrosarcoma (IFS), 7 other sarcoma, and 2 papillary thyroid cancer). Patients were treated on 3 dose levels: 100 mg BID (DL1, n=4) and 150 mg BID (DL2, n=11) adult equivalent doses by SimCyp modeling, and 100 mg/m2/dose BID with a cap of 100 mg/dose (DL3, n=9). The RP2D was determined to be 100 mg/m2 (capped at 100 mg) BID based on PK, safety and efficacy. No MTD was defined. The most common AEs attributed to larotrectinib were increased AST, vomiting, and neutropenia. No grade 4/5 AEs were attributed to larotrectinib. Both capsule and solution formulations delivered similar dose-dependent PK. AUC0-24 at the RP2D was comparable to the adult RP2D across the pediatric age spectrum (&amp;lt;2, 2-11, and 12-18 years). No responses were seen in patients (n=7) without TRK fusions (all had PD as best response). Among patients with TRK fusions and measureable disease by RECIST (n=15), the investigator-assessed confirmed objective response rate was 93% (67% PR, 27% CR). 1 patient (7%) had SD with tumor shrinkage. All patients with TRK fusions (n=17) had a reduction in tumor burden regardless of histology or specific TRK fusion. With median follow-up of 6.5 (range 1.5+ to 12.5+) months, 14 patients with TRK fusions remain on treatment. Three patients have discontinued therapy, including two patients with responses that led to surgical resection; both had negative margins (R0 surgery) and one had a pathologic complete response. These patients remain on study and off larotrectinib without recurrence. Only one case of acquired resistance has been observed, which involved a TRKC G623R mutation. Conclusions: Larotrectinib demonstrated broad histology-independent efficacy in pediatric patients harboring TRK fusions and a favorable tolerability profile. A pediatric RP2D of 100 mg/m2/dose BID with a cap of 100 mg/dose has been defined. Blinded central review of responses and a minimum of 6 months of follow-up for all patients will be presented. Citation Format: Brian Turpin, Catherine M. Albert, Leo Mascarenhas, Noah Federman, Ramamoorthy Nagasubramanian, Mark Reynolds, Steven Smith, Scott Cruickshank, Michael C. Cox, Alberto S. Pappo, Douglas S. Hawkins, Steven G. DuBois, Theodore W. Laetsch. A pediatric phase 1 study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family: An updated analysis [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr PR07.

Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers

Unlike many conventional cancers with preferential patterns of oncogenic genetic alterations, TRK fusions resulting from NTRK1/2/3 genetic alterations drive oncogenic transformations in more than 20 different malignancies over diverse tissue/cell lineages, in both children and adults. A recent “basket” study of larotrectinib, a TRK inhibitor, has demonstrated significant efficacy in TRK fusion-positive tumors of all types from infants to the elderly. Here, we discuss the larotrectinib study and perspectives and challenges in developing “tumor-agnostic” targeted therapies in rare tumors.

Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study

Gene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had shown activity in preclinical models and in adults with tumours harbouring TRK fusions. This study aimed to assess the safety of larotrectinib in paediatric patients. This multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion status; had a Karnofsky (≥16 years of age) or Lansky (<16 years of age) performance status score of 50 or more, adequate organ function, and full recovery from the acute toxic effects of all previous anticancer therapy. Following a protocol amendment on Sept 12, 2016, patients with locally advanced infantile fibrosarcoma who would require disfiguring surgery to achieve a complete surgical resection were also eligible. Patients were enrolled to three dose cohorts according to a rolling six design. Larotrectinib was administered orally (capsule or liquid formulation), twice daily, on a continuous 28-day schedule, in increasing doses adjusted for age and bodyweight. The primary endpoint of the phase 1 dose escalation component was the safety of larotrectinib, including dose-limiting toxicity. All patients who received at least one dose of larotrectinib were included in the safety analyses. Reported here are results of the phase 1 dose escalation cohort. Phase 1 follow-up and phase 2 are ongoing. This trial is registered with ClinicalTrials.gov, number NCT02637687. Between Dec 21, 2015, and April 13, 2017, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) with a median age of 4·5 years (IQR 1·3-13·3) were enrolled to three dose cohorts: cohorts 1 and 2 were assigned doses on the basis of both age and bodyweight predicted by use of SimCyp modelling to achieve an area under the curve equivalent to the adult doses of 100 mg twice daily (cohort 1) and 150 mg twice daily (cohort 2); and cohort 3 was assigned to receive a dose of 100 mg/m2 twice daily (maximum 100 mg per dose), regardless of age, equating to a maximum of 173% of the recommended adult phase 2 dose. Among enrolled patients harbouring TRK fusion-positive cancers, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. Adverse events were predominantly grade 1 or 2 (occurring in 21 [88%] of 24 patients); the most common larotrectinib-related adverse events of all grades were increased alanine and aspartate aminotransferase (ten [42%] of 24 each), leucopenia (five [21%] of 24), decreased neutrophil count (five [21%] of 24), and vomiting (five [21%] of 24). Grade 3 alanine aminotransferase elevation was the only dose-limiting toxicity and occurred in one patient without a TRK fusion and with progressive disease. No grade 4 or 5 treatment-related adverse events were observed. Two larotrectinib-related serious adverse events were observed: grade 3 nausea and grade 3 ejection fraction decrease during the 28-day follow-up after discontinuing larotrectinib and while on anthracyclines. The maximum tolerated dose was not reached, and 100 mg/m2 (maximum of 100 mg per dose) was established as the recommended phase 2 dose. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response as per Response Evaluation Criteria In Solid Tumors version 1.1; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. The TRK inhibitor larotrectinib was well tolerated in paediatric patients and showed encouraging antitumour activity in all patients with TRK fusion-positive tumours. The recommended phase 2 dose was defined as 100mg/m2 (maximum 100 mg per dose) for infants, children, and adolescents, regardless of age. Loxo Oncology Inc.