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Herbert H. Loong
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OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Christine Lee Hann, Makoto Nishio
- Coordinates: 9/08/2019, 13:30 - 15:00, Hilton Head (1978)
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OA03.08 - Discussant - OA03.05, OA03.06, OA03.07 (Now Available) (ID 3729)
13:30 - 15:00 | Presenting Author(s): Herbert H. Loong
- Abstract
- Presentation
Abstract not provided
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-20 - ATORG-003: Dacomitinib With or Without Dose Titration as First-Line Therapy for Metastatic EGFR Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 67)
10:15 - 18:15 | Author(s): Herbert H. Loong
- Abstract
Background
Dacomitinib is a second generation EGFR tyrosine kinase inhibitor (TKI) with irreversible pan-HER inhibitory activity. In the phase III ARCHER 1050 trial, median PFS was improved from 9.2 months to 14.7 months in the gefitinib and dacomitinib groups respectively. Significantly, median overall survival (OS) was also improved from 26.8 months to 34.1 months. However, dacomitinib commenced at 45 mg orally daily was associated with increased toxicity, higher rates of dose reductions and treatment discontinuation. Despite this, post-hoc analysis revealed the efficacy of dacomitinib (PFS and OS) was similar in dose-reduced patients and the overall study population. This investigator-initiated trial aims to evaluate an alternative dose titration strategy to improve the safety and tolerability of dacomitinib while maintaining treatment efficacy. The trial is being conducted by the Asian Thoracic Oncology Research Group (ATORG) – a co-operative lung cancer trials group in Asia.
Method
ATORG-003 is a multi-national, multi-centre, single-arm, open-label, phase 2 clinical trial of dacomitinib in newly diagnosed stage IIIB/IV or recurrent EGFR mutant (exon 19 deletion or L858R mutation) NSCLC patients. Importantly, subjects with asymptomatic central nervous system (CNS) metastases will be eligible. Patients will be administered dacomitinib 30 mg orally daily for one cycle (4 weeks), after which subjects with <G1 toxicity attributable to dacomitinib may escalate to 45 mg with shared investigator and patient decision. Dose reductions to 30 or 15 mg daily will be permitted. The primary objective is to evaluate PFS rate at 12 months. Key secondary objectives include OS, objective response rate (ORR), time to treatment failure (TTF) and intracranial objective response rate (iORR). Exploratory objectives include evaluation of dacomitinib resistance mechanism(s) using next-generation sequencing (NGS) on tissue and plasma circulating tumour DNA (ctDNA). Across 15 sites in six Asian countries (Hong Kong, Korea, Malaysia, Singapore, Taiwan, Thailand), a planned 118 subjects will be enrolled. Primary analysis will be conducted on subjects without CNS metastases only, with 94 subjects required to achieve a one-sided significance level of 5% and 90% power to detect a 15% improvement in 12 month PFS rate for dacomitinib versus historical control for gefitinib (i.e. 55% versus 40%) using the intent-to-treat (ITT) analysis population. Enrollment is due to begin in July 2019.
Result
Section not applicable.
Conclusion
Section not applicable.
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PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)
- Event: WCLC 2019
- Type: Plenary Session
- Track:
- Presentations: 1
- Now Available
- Moderators:Giorgio Vittorio Scagliotti, Ramon Rami-Porta
- Coordinates: 9/09/2019, 08:00 - 10:15, Barcelona (2005)
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PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)
08:00 - 10:15 | Author(s): Herbert H. Loong
- Abstract
- Presentation
Background
No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.
Method
This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.
Result
As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.
Conclusion
Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.
The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.
LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.
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