Reference Detail

Ref Type

Journal Article

PMID

(31217479)

Authors

Lin CC, Arkenau HT, Lu S, Sachdev J, de Castro Carpeño J, Mita M, Dziadziuszko R, Su WC, Bobilev D, Hughes L, Chan J, Zhang ZY, Weiss GJ

Title

A phase 1, open-label, dose-escalation trial of oral TSR-011 in patients with advanced solid tumours and lymphomas.

Journal	Vol	Issue	Date	Pages	Journal Short Title
British journal of cancer	121	2	2019 07	131-138	Br J Cancer

URL

Abstract Text

Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in non-small-cell lung cancer (NSCLC). TSR-011 is a dual ALK and tropomyosin-related kinase (TRK) inhibitor, active against ALK inhibitor resistant tumours in preclinical studies. Here, we report the safety, tolerability and recommended phase 2 dose (RP2D) of TSR-011 in patients with relapsed or refractory ALK- and TRK-positive advanced cancers.In this sequential, open-label, phase 1 trial (NCT02048488), patients received doses of 30 mg, escalated to 480 mg every 24 hours (Q24h), followed by an expansion cohort of patients with ALK-positive cancers. The primary objective was to evaluate safety and tolerability. Secondary objectives included pharmacokinetics.TSR-011 320- and 480-mg Q24h doses exceeded the maximum tolerated dose. At the RP2D of 40 mg every 8 hours (Q8h), the most common grade 3-4 treatment-emergent adverse events occurred in 3.2-6.5% of patients. Of 14 ALK inhibitor-naive patients with ALK-positive NSCLC, 6 experienced partial responses and 8 had stable disease.At the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued.NCT02048488.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Belizatinib	Belizatinib	6	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Belizatinib		TSR-011	ALK Inhibitor 32 Trk Receptor Inhibitor (Pan) 32	Belizatinib (TSR-011) binds to ALK and TRK kinases and inhibits downstream signaling, which may result in decreased proliferation of ALK/TRK expressing tumor cells (PMID: 26753004, PMID: 31217479).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK amp	lung non-small cell carcinoma	no benefit	Belizatinib	Phase I	Actionable	In a Phase I trial, treatment with Belizatinib (TSR-011) in ALK inhibitor-naive non-small cell lung cancer patients (n=14) harboring either an ALK mutation, ALK amplification, or an ALK rearrangement resulted in a partial response in 6 patients and stable disease in 8 patients, however, it was determined that the drug resulted in limited efficacy and development of the drug was discontinued (PMID: 31217479; NCT02048488).	31217479
ALK rearrange	lung non-small cell carcinoma	no benefit	Belizatinib	Phase I	Actionable	In a Phase I trial, treatment with Belizatinib (TSR-011) in ALK inhibitor-naive non-small cell lung cancer patients (n=14) harboring either an ALK mutation, ALK amplification, or an ALK rearrangement resulted in a partial response in 6 patients and stable disease in 8 patients, however, it was determined that the drug resulted in limited efficacy and development of the drug was discontinued (PMID: 31217479; NCT02048488).	31217479
ALK R1275Q	neuroblastoma	no benefit	Belizatinib	Case Reports/Case Series	Actionable	In a Phase I trial, a neuroblastoma patient harboring ALK R1275Q did not respond to treatment with Belizatinib (TSR-011) (PMID: 31217479; NCT02048488).	31217479
ALK mutant	lung non-small cell carcinoma	no benefit	Belizatinib	Phase I	Actionable	In a Phase I trial, treatment with Belizatinib (TSR-011) in ALK inhibitor-naive non-small cell lung cancer patients (n=14) harboring either an ALK mutation, ALK amplification, or an ALK rearrangement resulted in a partial response in 6 patients and stable disease in 8 patients, however, it was determined that the drug resulted in limited efficacy and development of the drug was discontinued (PMID: 31217479; NCT02048488).	31217479