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Geoffrey R. Oxnard
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MA16 - Novel Mechanisms for Molecular Profiling (ID 917)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 203 BD
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MA16.03 - Discussant - MA 16.01, MA 16.02 (ID 14645)
13:40 - 13:55 | Presenting Author(s): Geoffrey R. Oxnard
- Abstract
- Presentation
Abstract not provided
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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 | Presenting Author(s): Geoffrey R. Oxnard
- 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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P1.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 948)
- 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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P1.16-47 - Adjuvant Targeted Therapy Following Standard Adjuvant Therapy for Resected NSCLC: An Initial Report from ALCHEMIST (Alliance A151216) (ID 12828)
16:45 - 18:00 | Presenting Author(s): Geoffrey R. Oxnard
- Abstract
Background
The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) was launched in 2014 across the National Clinical Trials Network (NCTN) of the National Cancer Institute (NCI). This trial platform aims to enroll up to 8300 patients with resected high-risk non-small cell lung cancer (NSCLC) to facilitate enrollment to adjuvant targeted therapy trials following completion of standard adjuvant therapy, and to collect biospecimens for clinical and investigational genomics. On 5/1/2016, the study was expanded to include squamous NSCLC and PDL1 testing to facilitate enrollment to a new immunotherapy study.
a9ded1e5ce5d75814730bb4caaf49419 Method
Eligible patients have completely resected NSCLC, stage IB (>4cm) to IIIA by AJCC 7. Eligibility window extends 75-285 days post-op depending upon receipt of adjuvant chemotherapy and/or radiation. Molecular testing of EGFR, ALK, PDL1 is performed centrally (depending on the histology and testing results) and results are returned to sites within 7-21 days. FFPE tissue and blood are collected by the NCI for genomic analysis. Appropriate patients may then enroll to one of three therapeutic trials studying single agent adjuvant targeted therapy (erlotinib NCT02193282, crizotinib NCT02201992, or nivolumab NCT02595944) versus observation.
4c3880bb027f159e801041b1021e88e8 Result
As of March 19, 2018, 2945 patients have been enrolled from 575 sites within the US, with a median enrollment of 98/month (range: 71-133) in 2017. Central molecular testing was completed in 83%-92% of appropriate patients: EGFR L858R/19del was detected in 395 of 2468 patients (16.0%), ALK FISH was positive in 106 of 2458 patients (4.3%), and PDL1 IHC was >1% in 902 of 1464 patients (61.6%). Adequate tissue and blood for whole exome sequencing (WES) was collected on 1928 patients (65.5%), and enrollment plasma (added January 2017) has been collected on 885 patients (30.1%). Of 1960 patients deemed to be eligible for the adjuvant treatment trials with sufficient follow-up, 560 (28.6%) were enrolled; those enrolled were younger (p=0.01) and had higher N stage (<0.01) than those not enrolled. The primary reason for eligible patients not enrolling to treatment trials was lack of interest in further adjuvant therapy (53%).
8eea62084ca7e541d918e823422bd82e Conclusion
ALCHEMIST has achieved an enrollment of ~100 patients/month with resected high-risk NSCLC. This initial report demonstrates the feasibility of central molecular testing for enrollment to adjuvant targeted therapies. Efforts are ongoing to plan clinically-informed genomic analyses of tumor and plasma, as well as the planning of new treatment arms that leverage this ongoing trial platform.
Support: U10CA180821, U10CA180882, U10CA180820, U10CA180868, U10CA180888; ClinicalTrials.gov Identifier: NCT02194738
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P3.04 - Immunooncology (Not CME Accredited Session) (ID 970)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.04-02 - Early Plasma ctDNA Response Anticipates Clinical Response to First-Line Immunotherapy in Advanced NSCLC (ID 14240)
12:00 - 13:30 | Author(s): Geoffrey R. Oxnard
- Abstract
Background
Shedding of circulating tumor DNA (ctDNA) into plasma can be an independent prognostic indicator in lung cancer, and changes in plasma ctDNA levels correlate with response to targeted therapy. We hypothesized that serial assessment of plasma ctDNA by next generation sequencing (NGS) would enable early detection of response to immunotherapy in NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with advanced NSCLC who received first-line treatment with pembrolizumab alone or in combination with platinum doublet chemotherapy at the Dana-Farber Cancer Institute were enrolled in this study. Plasma collected from patients prior to starting therapy and again at 3 and 3 weeks after starting therapy was analyzed by NGS using enhanced tagged-amplicon sequencing of hotspots and coding regions from 36 genes (InVisionSeq). The trends of the ctDNA allele frequency were correlated with radiographic responses to therapy.
4c3880bb027f159e801041b1021e88e8 Result
Serial plasma samples were collected on 21 patients with the following characteristics: 67% female, median age 62, 90% adenocarcinoma, 10% squamous cell carcinoma. Pembrolizumab was administered as monotherapy to 18 (86%) patients and in combination with platinum/pemetrexed in 3 (14%) patients for a median of 6 cycles. Among the 8 (38%) patients with no detectable ctDNA at baseline, 5 patients who maintained no detectable ctDNA during serial analyses responded to treatment, and 3 patients with emergence of ctDNA within the first 6 weeks of treatment initiation experienced progressive disease. In the 13 (62%) patients with detectable ctDNA at baseline, radiographic responses were preceded by earlier changes in ctDNA allele frequency. Six of 7 patients with >50% decreases in ctDNA allele fraction responded to treatment while 4 of 6 patients with progressive disease had increases in ctDNA within 6 weeks.
8eea62084ca7e541d918e823422bd82e Conclusion
In advanced NSCLC treated with first-line immunotherapy, rapid decreases and clearance of ctDNA correlated with clinical benefit, while increasing or newly detectable ctDNA was a harbinger of progressive disease. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.
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