taletrectinib (AB-106)

The procedure was then applied to quantify taletrectinib in beagle dog plasma after oral and intravenous doses and achieved success. The obtained pharmacokinetic parameters indicated high bioavailability of taletrectinib (>85 %) and extensive tissue distribution (>40 L/kg).

P3, N=138, Not yet recruiting, AnHeart Therapeutics Inc.

Using Ba/F3 and NIH3T3 cell models, CRISPR/Cas9-edited isogenic wildtype and mutant patient-derived cell lines, and in vivo tumor growth studies, we compared type I TKIs (crizotinib, entrectinib, taletrectinib, lorlatinib, and repotrectinib) to type II TKIs (cabozantinib and merestinib) and the type I FLT3 inhibitor gilteritinib...While cabozantinib effectively inhibits ROS1 L2086F, its multi-kinase inhibitor nature highlights the need for more selective and better-tolerated TKIs to overcome kinase-intrinsic resistance. Gilteritinib may offer an alternative for targeting ROS1 L2086F with distinct off-target toxicities, but further studies are required to fully evaluate its potential in this setting.

The anti-tumour efficacy of SIAIS039 surpasses two approved drugs, crizotinib and entrectinib, and matches that of the top inhibitors, including lorlatinib and taletrectinib. In addition, 039 exhibited excellent oral bioavailability in a mouse xenograft model, highlighting its potential for clinical application. In conclusion, our study presents a promising and novel therapeutic strategy for ROS1 fusion-positive NSCLC by targeting ROS1 fusion oncoproteins for degradation, laying the foundation for the development of further PROTAC and offering hope for patients with ROS1 fusion-positive NSCLC.

No abstract available

Taletrectinib continues to show high and durable overall responses, prolonged PFS, robust activity against intracranial lesions and acquired resistance mutations including G2032R, and a favorable safety profile with a low incidence of neurologic TEAEs.

P2, N=61, Not yet recruiting, Megan Kruse, MD | Initiation date: Apr 2024 --> Oct 2024

P2, N=224, Recruiting, AnHeart Therapeutics Inc. | N=154 --> 224

P2, N=61, Not yet recruiting, Megan Kruse, MD

While crizotinib and entrectinib have been approved to treat ROS1 fusion-positive (ROS1+) non-small-cell lung cancer (NSCLC), unmet needs remain. Taltrectinib has the potential to improve PFS based on its greater potency against ROS1+ tumors and high CNS penetration. By selectively inhibiting ROS1 wild-type and its resistant mutations over TRKB, taltrectinib has a better safety profile with minimal CNS-related AEs compared to other ROS1+ inhibitors.

"AnHeart Therapeutics...and Foundation Medicine, Inc., today announced the companies have entered a strategic collaboration for the development and regulatory approval of Foundation Medicine’s tissue-based and liquid-based comprehensive genomic profiling tests, FoundationOne^®CDx and FoundationOne^®Liquid CDx, as companion diagnostics for AnHeart’s investigational next-generation ROS1 inhibitor, taletrectinib, in the United States....Taletrectinib is a potential best-in-class ROS1 inhibitor being evaluated for the treatment of patients with advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC), an underserved group of lung cancer patients in need of new options."

Despite ROS1 fusion positive (ROS1+) NSCLC accounting approximately 1-2% of NSCLC, there is a dizzying list of ROS1 tyrosine kinase inhibitor (TKIs) being developed in addition to two approved ROS1 TKIs, crizotinib and entrectinib...Additionally, the less known central β-sheet 6 (Cβ6) mutation ROS1 L2086F confer resistances to next-generation ROS1 TKIs (taletrectinib, lorlatinib, potentially NVL-520) that can be overcome by cabozantinib as documented in published patient reports and may potentially by certain L-shaped Type I ROS1 TKIs including gilteritinib which is approved as a FLT3 inhibitor for AML. Future clinical trials should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that can target Cβ6 mutation.

P2, N=173, Active, not recruiting, AnHeart Therapeutics Inc. | Recruiting --> Active, not recruiting | N=106 --> 173

No treatment-related AE (TRAE) led to discontinuation or death; 24% of pts had a TRAE leading to dose reduction. Conclusions In this ongoing global pivotal phase 2 study, taletrectinib demonstrated robust and consistent clinical activity with TRUST-I, including high response rates and a tolerable safety profile in both TKI-naive and TKI-pretreated pts with ROS1+ NSCLC.

Crizotinib and entrectinib have been approved to treat ROS1 fusion-positive (ROS1) non-small-cell lung cancer. Secondary end points include duration of response, progression-free survival, overall survival and safety. This trial is enrolling patients in North America, Europe and Asia.

CRZ, crizotinib; DCR, disease control rate; NE, not evaluable; ORR, overall response rate; PFS, progression-free survival; TKI, tyrosine kinase inhibitor. Conclusions With additional follow-up, taletrectinib continued to demonstrate meaningful efficacy outcomes including high response rates, prolonged PFS, robust intracranial activity, activity against G2032R, and tolerable safety with low incidence of neurological AEs.

"Guardant Health Inc...announced today a strategic collaboration on the development, regulatory approval and commercialization of the Guardant360^® CDx and Guardant360 TissueNext™ assays as companion diagnostics for taletrectinib in the United States and European Union....The collaboration will focus on the use of the Guardant tests for comprehensive genomic profiling to identify patients with the specific tumor mutations that are targeted by taletrectinib."

On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. In addition, ADK-VR2 tumor growth was significantly reduced but not eradicated by crizotinib treatment. The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies.

On the contrary, the treatment with other TKIs, such as entrectinib and DS-6051b, did not result in cell growth inhibition. Lorlatinib showed dramatically different efficacy, depending on the cell culture conditions...Additionally, the crizotinib-resistant clone ADK-VR2 AG143 showed a slower growth in vivo, compared to ADK-VR2; suggesting a role for crizotinib in modulation of stemness and growth. Conclusion The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies.

The study consists of four cohorts: cohort 1: systemic chemotherapy naïve or ≤ one prior line and ROS1 TKI naïve NSCLC (N = 53); cohort 2: previously treated with one ROS1 TKI (crizotinib or entrectinib) and with progression who are either chemotherapy naïve or ≤ one line of platinum and/or pemetrexed based therapy for NSCLC (N = 46); cohort 3: ≤ 2 prior ROS1 TKIs and with progression who are either chemotherapy naïve or ≤ 2 lines of platinum and/or pemetrexed based therapy for NSCLC (N = 10); and cohort 4: systemic chemotherapy naïve or ≤ 2 prior lines of chemotherapy, but ROS1-TKI naïve ROS1 positive solid tumor other than NSCLC (N = 10). This study is currently recruiting in Japan, Republic of Korea, and USA. Additional accrual is planned in Canada, China, and European Union.

Taletrectinib demonstrated meaningful clinical efficacy in both TKI-naïve and crizotinib-pretreated ROS1 positive NSCLC patients. In particular, taletrectinib showed clinical effectiveness in patients with ROS1 secondary G2032 mutations and patients with brain metastasis. Taletrectinib was well tolerated in this patient population.

The study consists of four cohorts: cohort 1: systemic chemotherapy naïve or ≤ one prior line and ROS1 TKI naïve NSCLC (N=53); cohort 2: previously treated with one ROS1 TKI (crizotinib or entrectinib) and with progression who are either chemotherapy naïve or ≤ one line of platinum and/or pemetrexed based therapy for NSCLC (N=46); cohort 3: ≤ 2 prior ROS1 TKIs and with progression who are either chemotherapy naïve or ≤ 2 lines of platinum and/or pemetrexed based therapy for NSCLC (N=10); and cohort 4: systemic chemotherapy naïve or ≤ 2 prior lines of chemotherapy, but ROS1-TKI naïve ROS1-positive solid tumor other than NSCLC ( N=10). This study is currently recruiting in Japan, Republic of Korea, and USA. Additional accrual is planned in Canada, China, and European Union.

P2, N=119, Recruiting, AnHeart Therapeutics Inc. | Not yet recruiting --> Recruiting | Initiation date: Jun 2021 --> Sep 2021

The first-generation TRK inhibitors, larotrectinib and entrectinib, have demonstrated clinically meaningful antitumor activity in TRK fusion-positive cancers in a tumor-agnostic fashion and should be considered first-line therapeutic options for TRK fusion-positive lung cancers. Next-generation TRK inhibitors, such as selitrectinib, repotrectinib, and taletrectinib, are available on ongoing clinical trials and address on-target resistance. This review will focus on NTRK fusions and TRK-directed targeted therapy specifically in the context of lung cancer.

Grade 3 or higher adverse events were alanine transaminase elevations (18.2%), aspartate transaminase (9.1%), and diarrhea (4.5%). Taletrectinib (AB106/DS6051b) has a meaningful clinical activity in patients with advanced ROS1+ NSCLC who are ROS1 TKI-naive or crizotinib-refractory and a manageable safety profile.

P2, N=40, Recruiting, AnHeart Therapeutics Inc. | Not yet recruiting --> Recruiting

P2, N=119, Not yet recruiting, AnHeart Therapeutics Inc.

P2, N=106, Recruiting, AnHeart Therapeutics Inc. | Trial primary completion date: Dec 2022 --> Dec 2023

P2, N=40, Not yet recruiting, AnHeart Therapeutics Inc. | Trial completion date: Dec 2024 --> Dec 2026 | Initiation date: Mar 2021 --> Jun 2021 | Trial primary completion date: Apr 2022 --> Apr 2024

The ROS1 TKI naïve or crizotinib pre-treated NSCLC patients with ROS1 fusion were treated with taletrectinib 400 or 600 mg QD . Taletrectinib demonstrated promising clinical activity with high ORR and good tolerability in ROS1 fusion positive NSCLC patients . The safety and PK profiles following taletrectinib treatment was generally consistent with the phase I trials.

P2, N=40, Not yet recruiting, AnHeart Therapeutics Inc. | Initiation date: Dec 2020 --> Mar 2021

P2, N=106, Recruiting, AnHeart Therapeutics Inc. | Not yet recruiting --> Recruiting | Trial primary completion date: Sep 2022 --> Dec 2022

P1, N=46, Completed, AnHeart Therapeutics Inc. | Active, not recruiting --> Completed | N=70 --> 46

We describe cases of advanced ROS1-rearranged lung cancer receiving crizotinib, entrectinib, and/or lorlatinib in first and later line treatment settings to dissect the current state of evidence supporting management decisions for these patients. The next generation ROS1 TKIs (repotrectinib and DS-6051b), owing to their broad activity against kinase mutations including ROS1-G2032R in preclinical studies, hold promise to transform the current treatment paradigm and permit even further gains with regards to long-term outcomes in this subset of patients.

Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in crizotinib-refractory ROS1+ NSCLC patients.

P2, N=106, Not yet recruiting, AnHeart Therapeutics Inc.

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. 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).