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Scott Cruickshank
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OA12 - Novel Therapies in MET, RET and BRAF (ID 921)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 106
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OA12.07 - Clinical Activity of LOXO-292, a Highly Selective RET Inhibitor, in Patients with RET Fusion+ Non-Small Cell Lung Cancer (ID 13922)
16:20 - 16:30 | Author(s): Scott Cruickshank
- Abstract
- Presentation
Background
RET kinase gene fusions are actionable drivers that occur in ~2% of non-small cell lung cancers (NSCLC). However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET fusion+ NSCLC patients has been limited. LOXO-292 is a highly selective RET inhibitor, with preclinical activity against diverse RET fusions, potential acquired resistance mutations, and against brain metastases.
a9ded1e5ce5d75814730bb4caaf49419 Method
LIBRETTO-001 is a multicenter global phase 1/2 study (26 sites, 9 countries) enrolling patients w/ advanced solid tumors (NCT03157128) including RET fusion+ NSCLC. Patients are dosed orally in 28-day cycles with dose escalation following a 3+3 design. The primary endpoint is MTD/recommended dose determination. Secondary endpoints include safety, overall response rate (ORR, RECIST 1.1) and duration of response (DoR). Initial data were presented at the ASCO 2018 Annual Meeting.
4c3880bb027f159e801041b1021e88e8 Result
As of 02-April 18, 82 solid tumor patients (including 38 RET fusion+ NSCLC) were treated at 8 doses (20 mg QD-240 mg BID). The MTD was not reached. AEs (≥10% of patients) were fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%), and dyspnea (11%); most were grade 1-2. 2 TEAEs ≥ grade 3 were attributed to LOXO-292 (Gr3 tumor lysis syndrome, Gr3 increased ALT). Of the 38 RET fusion+ NSCLC pts, 30 had at least 1 post-baseline assessment or discontinued LOXO-292 prior to such assessment. 26 of 30 patients (87%) had >20% radiographic tumor reduction (range: -21 to -72%). The ORR was 77% (23/30, 3 responses pending confirmation) with a confirmed ORR of 74% (20/27, excluding 3 patients with unconfirmed responses). The response rate was similar regardless of prior MKI treatment (12/15 MKI-naïve, 11/15 MKI pretreated). Responses occurred independent of upstream fusion partner when known (13/16 KIF5B vs 9/11 other) and included patients w/ baseline brain metastases. Most patients remained on treatment (33/38), including all responders. The median DoR was not reached (longest response was the first responder: >10+ months). Rapid plasma clearance of RET variants was observed, with complete clearance by day 15 in 10 of 17 (59%) NSCLC patients with assessable baseline and day 15 ctDNA.
8eea62084ca7e541d918e823422bd82e Conclusion
LOXO-292 was well-tolerated and had marked antitumor activity in RET-fusion+ NSCLC patients, including those w/ resistance to prior MKIs and brain metastases. Phase 2 cohorts are now open globally (160 mg BID). Updated safety and efficacy data as of 19 Jul 2018 will be presented.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-40 - Rapid, Robust and Durable Responses to Larotrectinib in Patients with TRK Fusion Non-Small Cell Lung Cancer (ID 14528)
16:45 - 18:00 | Author(s): Scott Cruickshank
- Abstract
Background
Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic independent of tumor lineage and are widely distributed across cancers. NTRK gene fusions were first reported in lung cancer in 2013 (Vaishnavi et al Nat Med 2013). Larotrectinib is a potent and highly selective oral tropomyosin receptor kinase (TRK) inhibitor in clinical development. Initial data of treatment of 55 patients with TRK fusion cancer resulted in an investigator-assessed objective response rate of 80%, and 71% of patients still in response at one year (Drilon et al., NEJM 2018). We report here on the safety and efficacy of larotrectinib in 4 patients with NSCLC from the 55 patient dataset.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with previously treated lung adenocarcinoma were treated under clinical trial and enrolled based on a molecular report of NTRK gene fusion from a CLIA-certified lab. Larotrectinib was administered at 100 mg BID until disease progression or lack of clinical benefit. Tumors were assessed by investigators every 8 weeks using RECIST v1.1 criteria.
4c3880bb027f159e801041b1021e88e8 Result
As of July 17, 2017, four patients with adenocarcinoma of the lung who had progressed after 1 or more lines of platinum-based chemotherapy for advanced disease were enrolled. Three patients harbored an NTRK1 fusion and one an NTRK3 fusion. Three of 4 patients had a partial response or complete response confirmed on a subsequent scan. One patient with a possible brain metastasis demonstrated regression of mass on MRI. Responses were rapid and robust, with a time to response ranging between 49 and 56 days. At the time of analysis, 3 patients continued to have an ongoing response ranging between 5.7 and 12 months. The other patient had stable disease and progressed outside of the CNS after 300 days of treatment and continued on larotrectinib for clinical benefit. Larotrectinib was well tolerated, with 3 of 4 patients having grade 1 events only.
8eea62084ca7e541d918e823422bd82e Conclusion
Larotrectinib treatment resulted in rapid and durable responses and had a well tolerated adverse event profile with no CNS progressive events in patients with previously treated lung cancer harboring NTRK gene fusions. These results strongly support the inclusion of NTRK gene fusions as part of routine testing for patients with lung cancer.
6f8b794f3246b0c1e1780bb4d4d5dc53
