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Shao Weng Daniel Tan
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OA07 - Precision Medicine Involves Biology and Patients (ID 132)
- Event: WCLC 2019
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Silvia Novello, Fabrice Barlesi
- Coordinates: 9/09/2019, 11:00 - 12:30, Copenhagen (1980)
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OA07.09 - Daniel C. Idhe Lectureship Award for Medical Oncology (Now Available) (ID 3904)
11:00 - 12:30 | Presenting Author(s): Shao Weng Daniel Tan
- Abstract
- Presentation
Abstract not provided
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-11 - ALKternate: A Proof of Concept Study in ALK-Rearranged NSCLC Alternating Lorlatinib with Crizotinib After Disease Progression (Now Available) (ID 2043)
10:15 - 18:15 | Author(s): Shao Weng Daniel Tan
- Abstract
Background
Standard frontline therapy for patients with advanced ALK-NSCLC has rapidly evolved to 2nd generation ALK TKIs based on superior survival. Regardless, resistance to treatment is inevitable. Most will receive multiple lines of TKIs +/- chemotherapy before eventually dying from the disease.
Lorlatinib is a 3rd generation ALK TKI active against a broad range of acquired ALK kinase domain (KD) resistance mutations. A recent report demonstrated re-sensitisation to crizotinib by the lorlatinib ALK resistance mutation L1198F. Increased knowledge of resistance mechanisms is key to overcoming and preventing its emergence.
Based on knowledge of the varying patterns of resistance to different ALK TKIs, ALKternate will test the hypothesis that treatment with alternating TKIs will re-equilibrate the selection pressure for enrichment of resistant clones. This hypothesis has been tested preclinically in accompanying abstracts #2072 and #2074.
Method
ALKternate is a proof of concept open label multi-centre translational study alternating lorlatinib (100mg OD) with crizotinib (250mg BD) (Figure 1. including eligibility).
The aim is to identify whether this fixed alternating schedule of ALK TKI is: safe; feasible and active, resulting in prolonged systemic and intracranial disease control via delaying the emergence of ALK TKI resistance. A secondary aim is to investigate whether plasma ALK-dependent and independent resistance profiles can be used to monitor therapy effectiveness.
The primary outcome measure is time to treatment failure (TTTF) with alternating therapy. Secondary end points include best OR, PK analysis, PFS, DCR (systemic and CNS) after lorlatinib induction and the first cycle of alternating therapy, OS, toxicity, PROs and QOL measures. Plasma ctDNA and proteomic biomarkers will be analysed.
Enrolled patients must demonstrate disease control after induction lorlatinib to continue alternating therapy. Imaging occurs more frequently initially (Figure 1.), before 12 weekly after two alternating cycles in those with disease control.
Status: Trial in Progress. Enrollment began Q3 2019, ethics approval NSLHD ETH00389.
Figure 1. ALKternate trial schema
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): Shao Weng Daniel Tan
- 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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