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R.C. Doebele
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA07.12 - Discussant for MA07.09, MA07.10, MA07.11 (ID 7046)
12:18 - 12:30 | Author(s): R.C. Doebele
- Abstract
- Presentation
Abstract not provided
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)
14:26 - 14:32 | Author(s): R.C. Doebele
- Abstract
- Presentation
Background:
GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.
Methods:
A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).
Results:
165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.
Conclusion:
RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-057 - Clinical Utility of ctDNA for Detecting ALK Fusions and Resistance Events in NSCLC: Analysis of a Laboratory Cohort (ID 6247)
14:30 - 14:30 | Author(s): R.C. Doebele
- Abstract
Background:
Advanced NSCLC patients whose tumors harbor ALK fusions benefit from first line treatment with ALK inhibitors (ALKi). However, insufficient tissue for testing (QNS) occurs ~25% of the time. Patients treated with ALKi ultimately progress. Historically, identification of the resistance mechanism/s required repeat tumor biopsy. Circulating tumor DNA (ctDNA) may provide a non-invasive way to identify ALK fusions and actionable resistance mechanisms without a repeat biopsy.
Methods:
The Guardant360 (G360) de-identified database of NSCLC cases was queried to identify 57 patients (2/2015-6/2016) with 58 ctDNA-detected ALK fusions. G360 is a CLIA-laboratory ctDNA test that detects point mutations in 70 genes and select amplifications, fusions and indels. Available records were reviewed to characterize patients at baseline and at progression.
Results:
Identified fusion partners included EML4 (n=51, 88%), STRN (7%), KLC1 (3%), KIF5B (2%). Thirty patients had no history of targeted therapy (new diagnosis or no prior genotyping, “cohort 1”); 23 patients were drawn at ALKi progression (“cohort 2”). In 6 samples, the patients’ clinical status was unknown. Three additional cases had ALK resistance mutations (F1174C, F1269A/I1171T, D1203N) detected in ctDNA but no fusion detected; historical tissue testing was ALK+. Conversely, in cohort 1, 10 (33%) were tissue QNS (7) or tissue ALK negative (3) while 4 (13%) were tissue ALK+ and 16 (54%) had unknown tissue status. As expected, no documented or putative resistance mechanisms were identified in cohort 1, although TP53 mutations were identified in 43%. Among 18 patients progressing on an ALKi, 7 (39%) contained 1 (4 patients), 2 (1 patient) or 3 (2 patients) ALK resistance point mutations (F1174C/V: 3 occurrences; G1202R: 3; L1196M: 3; G1128A: 1; L1189F: 1; I1171T: 1). Additional events co-occurring in the resistance cohort included 1 each of: BRAF[V600E], MET[E14skip], KRAS[G12], KRAS[G13], HRAS[Q61], EGFR[E330K], KIT[amp], BRAF[amp]. 5 EGFR-mutant NSCLC cases at progression harbored ALK fusions (4 STRN, 2 EML4; 1 patient had both) representing 1% of all EGFR-mutant progressing NSCLC cases in the G360 database. Four of these patients also harbored EGFR[T790M], but the presence of an ALK fusion may represent further subclonal evolution following the selective pressure of an EGFR inhibitor.
Conclusion:
These results add to the growing body of literature demonstrating that comprehensive ctDNA assays provide a non-invasive means of detecting targetable alterations in the first line when tissue is QNS as well as detecting known and novel resistance mechanisms that may inform treatment decisions at progression.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-007 - A Phase 1/2 Trial of the Oral EGFR/HER2 Inhibitor AP32788 in Non–Small Cell Lung Cancer (NSCLC) (ID 5047)
14:30 - 14:30 | Author(s): R.C. Doebele
- Abstract
Background:
Approximately 4%–9% of EGFR-mutated NSCLC tumors have EGFR exon 20 insertion mutations, and no targeted treatment options are currently approved for patients with these mutations. In addition, approximately 2%–4% of patients with NSCLC have HER2 mutations, the majority of which are exon 20 insertion mutations. The irreversible EGFR/HER2 inhibitor AP32788 was designed to selectively inhibit EGFR or HER2 kinases with EGFR/HER2 exon 20 mutations. In preclinical studies, investigational agent AP32788 had potent inhibitory activity against all EGFR and HER2 mutants tested, including exon 20 insertion mutants, while sparing wild-type EGFR.
Methods:
This phase 1/2 trial is a first-in-human, open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of orally administered AP32788 (NCT02716116). The study will be conducted in 2 parts: a dose-escalation phase with a 3+3 design and an expansion phase of 4 histologically and molecularly defined cohorts after the recommended phase 2 dose (RP2D) is determined. Patients (≥18 years) must have locally advanced or metastatic NSCLC. In phase 1, the dose-escalation phase, patients refractory to standard available therapies will be enrolled. The primary endpoint of phase 1 is identification of the RP2D of AP32788. Secondary endpoints include safety, dose-limiting toxicities, maximum tolerated dose, and plasma pharmacokinetics. Expected phase 1 enrollment is 20–30 patients. In phase 2, the expansion phase, 4 cohorts will be enrolled, patients with: 1. EGFR exon 20 activating insertions, without active, measurable CNS metastases; 2. HER2 exon 20 activating insertions or point mutations, without active, measurable CNS metastases; 3. EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases; 4. other targets against which AP32788 has demonstrated preclinical activity (eg, EGFR exon 19 deletions or exon 21 substitutions [with/without the T790M mutation] and other uncommon activating mutations in EGFR). The primary endpoint of phase 2 is investigator-assessed objective response rate (ORR) per RECIST v1.1 for all expansion cohorts except Expansion Cohort 3, for which the primary endpoint is intracranial ORR. Phase 2 secondary endpoints include safety, pharmacokinetics, and additional efficacy assessments (ORR per independent review committee, best overall response, best target lesion response, duration of response, disease control rate, progression-free survival, and overall survival; for Expansion Cohort 3: duration of intracranial response and intracranial progression-free survival). Expected phase 2 enrollment is 80 patients (total). The first patient was enrolled in phase 1 in June 2016.
Results:
Section not applicable.
Conclusion:
Section not applicable.
