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Kadoaki Ohashi
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OA02 - A New Vision of Targets and Strategies (ID 120)
- Event: WCLC 2019
- Type: Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Frank Griesinger, Luis Paz-Ares
- Coordinates: 9/08/2019, 10:30 - 12:00, Seoul (2007)
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OA02.01 - Alectinib in Previously Treated RET-Rearranged Advanced Non-Small-Cell Lung Cancer: A Phase 1/2 Trial (ALL-RET) (Now Available) (ID 1651)
10:30 - 12:00 | Author(s): Kadoaki Ohashi
- Abstract
- Presentation
Background
RET rearrangements occur in 1–2% of non-small cell lung cancers (NSCLCs). Alectinib (300 mg twice daily) has been approved for the treatment of ALK-rearranged NSCLC in Japan; it also has a high activity against RET in vitro. A global trial (ALEX study) showed the efficacy and safety of alectinib (600 mg twice daily) in ALK-rearranged NSCLC patients. We conducted a phase 1/2 study of alectinib to establish the recommended dose (RD) and examined its activity in RET-rearranged Japanese NSCLC patients.
Method
This study was a single-arm, open-label, multi-institutional phase 1/2 trial. RET-rearranged NSCLC patients treated with at least one regimen of chemotherapy were recruited. RET rearrangements were screened using LC-SCRUM-Japan, a nationwide genomic screening network. In phase 1, alectinib (600 or 450 mg twice daily) was administered, following a 3 + 3 design. The primary endpoint was safety. During phase 2, alectinib at the RD defined in phase 1 was administered. The primary endpoint was the objective response rate in RET inhibitor-naïve patients.
Result
Between March 8, 2016 and January 29, 2018, 35 patients were enrolled, and 34 patients were administered alectinib. KIF5B-RET was the most common fusion gene (22 cases [63%]), and the CCDC6-RET fusion was identified in 8 cases. The remaining 5 cases were not distinguishable. In cohort 1 (600 mg twice daily), we observed 5 DLTs (grade 3 rash, increased aspartate aminotransferase, erythema multiforme, thromboembolic event, and increased CPK) in 3 of 6 patients. In accordance with the protocol, we moved to cohort 2 (450 mg twice daily) and observed no DLTs in 3 patients. Additionally, pharmacokinetic analysis indicated that the mean exposure (AUC0–10) of 600 mg twice daily was higher than that previously reported in AF-002JG trial (global phase 1 study). Therefore, we determined 450 mg twice daily as the RD for phase 2. Twenty-five RET inhibitor-naïve patients were treated with the RD, of whom 1 achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%) as determined by central review. The median progression-free survival was 3.4 months (95% CI 2.0-5.4), and the median overall survival was 19.0 months (5.4-NE). We observed grade 3 neutropenia, pneumonitis, diarrhea, hyponatremia, increased CPK and blood bilirubin (4%) in patients treated with 450 mg alectinib twice daily; no grade 4 adverse events were observed.
Conclusion
Alectinib had limited activity in patients with RET-rearranged NSCLC. Further investigation of new targeted therapeutics is required to improve outcomes for these patients.
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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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OA07.03 - Clinical Outcome of Non-Small Cell Lung Cancer with EGFR/HER2 Exon 20 Insertions Identified in the LC-SCRUM-Japan (Now Available) (ID 629)
11:00 - 12:30 | Author(s): Kadoaki Ohashi
- Abstract
- Presentation
Background
In-frame insertions in exon 20 (Ex20ins) of EGFR/HER2 occur in 2-5 % of non-small cell lung cancer (NSCLC). There is no approved targeted therapy for patients with these mutations. Historical control data would be valuable for the development of novel targeted therapies for these rare cancers.
Method
A nationwide genome screening project in Japan (LC-SCRUM-Japan) has been established for the development of molecular-targeted therapies for lung cancers. In this project, 161 cancer-related genes have been analyzed by a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. The therapeutic efficacy and survival of the patients with non-squamous (non-sq) NSCLC harboring EGFR/HER2 Ex20ins were evaluated using a large-scale clinico-genomic database in the LC-SCRUM-Japan.
Result
A total of 3441 advanced non-sq NSCLC patients were successfully analyzed from 2015 to 2018. EGFR Ex20ins were detected in 73 patients (2%; M766_A767insASV/A767_S768insSVD/H773_V774insH/D770_N771insNPH/N771_P772insPH/others=22/17/5/4/4/21) and HER2 Ex20ins were detected in 128 patients (4%; A775_G776insYVMA/G776delinsVC/P780_Y781insGSP/others=95/16/10/7). The median age of the patients was 62 (range, 33-90) years. Eighty-one patients (40%) were male and 114 (57%) were never smoker. Two-hundred patients (99%) were diagnosed as adenocarcinoma and 1 as adenosquamous-cell carcinoma. Based on our database, the median overall survivals in patients with EGFR Ex20ins were 22.4 (95%CI, 15.3-36.8) months, and those with HER2 Ex20ins were 18.8 (13.6-30.3) months. In the patients with EGFR/HER2 Ex20ins, the objective response rate (ORR) and median progression-free survivals (mPFS) of 1st-line platinum-containing chemotherapies were 32% and 6.0 (5.7-7.0) months, respectively. The ORR and mPFS of docetaxel with or without ramucirumab were 26% and 5.1 (3.8-5.9) months, respectively. The ORR and mPFS of PD-1 inhibitor were 0% and 2.0 (1.6-2.6) months, respectively. No significant difference in the therapeutic efficacy of these drugs was observed between the patients with EGFR Ex20ins and HER2 Ex20ins. In 19 patients with EGFR Ex20ins treated with 1st/2nd generation EGFR-TKIs, the ORR was 5% (a M766_A767insASV-positive tumor responded to afatinib) and the mPFS was 2.1 (1.3-4.2) months.
Conclusion
The patients with EGFR/HER2 Ex20ins-positive NSCLC showed poor responses to PD-1 inhibitors and 1st/2nd generation EGFR-TKIs. These historical data are highly informative in evaluating the efficacy of novel targeted therapies for EGFR/HER2 Ex20ins-positive NSCLC.
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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): Kadoaki Ohashi
- 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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