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C. Lin
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.06 - Activity of AUY922 in NSCLC Patients With EGFR Exon 20 Insertions (ID 1744)
19:00 - 19:05 | Author(s): C. Lin
- Abstract
- Presentation
Background:
EGFR exon 20 insertions (ins20) represent a rare subtype (4%) of EGFR mutations and are refractory to EGFR-specific tyrosine kinase inhibitors (TKIs). No effective targeted therapies exist for patients (pts) with ins20; median PFS on the irreversible EGFR TKI Afatinib is 2.8 months (mos). Based on a durable RECIST partial response (PR) to AUY922, a Heat Shock Protein 90 (Hsp90) inhibitor, observed in an EGFR ins20 patient in a previous study (NCT01124864), we designed a phase II investigator-initiated trial to assess the activity of AUY922 in NSCLC pts with EGFR ins20. Since pts with these mutations are rare, we identified other international investigators who have treated ins20 patients with AUY922. Here, we present the results of a pooled international experience of 21 patients with EGFR ins20 treated with AUY922 in the United States, Taiwan and the Netherlands.
Methods:
A total of 21 patients with EGFR in20 are included in this analysis. 14 were treated on a single-arm, multi-center, open-label study of AUY922 in advanced NSCLC pts with EGFR ins20 mutations in the US (NCT01854034). Five were treated on a multicenter Taiwanese trial of AUY922 across a variety of molecular NSCLC subtypes (NCT01922583) and two were treated on a compassionate-use basis in the Netherlands. The starting dose of AUY922 was 70mg/m2 IV weekly for all patients.
Results:
21 pts, including 14 females and 7 males, average age 55 (range, 27-75) were included in this analysis. The median number of prior therapies was 2 (range, 1-6.) 6 pts received a prior EGFR TKI; none responded to TKI monotherapy. The most common AUY922-related toxicities were grade 1-2 visual changes (18/21; 86%) diarrhea (18/21; 86%) and fatigue (15/21; 71%). The only treatment-related grade 3 toxicities was hypertension (2/21; 1%) and AST elevation (1/21; 0.5%). There was one death on study, related to pre-existing comorbidity/unrelated to AUY922. Among the 21 patients treated, 5 achieved a partial response by RECIST 1.1 (ORR 24%) (Figure 1.) The median PFS estimate is 3.9 mos (95% CI, 2.9 to 10.7.) 6 patients remain on treatment at the time of abstract submission. Updated results and correlation with specific ins20 mutations will be presented. Figure 1
Conclusion:
This international experience suggests that AUY922 may be an active therapy for advanced NSCLC pts with EGFR ins20 mutations with an ORR 24% and median PFS 3.9 mo. AUY922 is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of AUY922 in this population is warranted.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-100 - Phase Ib Trial of Afatinib and BI 836845 in Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1767)
09:30 - 09:30 | Author(s): C. Lin
- Abstract
Background:
Patients harboring epidermal growth factor receptor (EGFR)-mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) invariably develop acquired resistance (AR). The mechanisms of AR are unknown in 30–40% of patients. In pre-clinical studies, insulin-like growth factor (IGF) signaling has been implicated in AR to EGFR TKIs in the absence of other known mechanisms including T790M mutation. It is hypothesized that an EGFR TKI combined with an IGF inhibitor can overcome this resistance. BI 836845 is a fully human, affinity-optimized, IGF ligand-neutralizing antibody. BI 836845 binds to IGF-1 and IGF-2 and neutralizes growth-promoting signaling. Preliminary results from two Phase I studies have shown a tolerable safety profile. This trial was designed to evaluate the safety and anti-tumor activity of BI 836845 combined with afatinib in patients with EGFR-mutated NSCLC progressing following prior treatment with reversible or irreversible EGFR TKIs.
Methods:
This is an open-label, dose-escalation trial in Korea, Taiwan and Singapore (NCT02191891; Study 1280.16) consisting of a dose confirmation part (Part A) followed by an expansion part (Part B). Eligible patients are aged ≥18 years with advanced and/or metastatic NSCLC progressing during continuous treatment with single-agent EGFR TKI ≤30 days immediately prior to study treatment, with documented presence of an activating EGFR mutation and lacking an EGFR T790M mutation (confirmed by central testing in Part B). Patients with prior afatinib treatment at a dose below the assigned dose level (Part A only) or <30 mg/day (Parts A and B), or disease progression on an insufficient dose of EGFR TKI immediately prior to study in the investigator’s opinion, or >2 (Part A) or >1 (Part B) prior EGFR TKI treatment regimens for relapsed or metastatic NSCLC are excluded. Part A follows a 3+3 design to determine the MTD and/or recommended Phase 2 dose (RP2D) of BI 836845 combined with afatinib (starting dose: BI 836845 1000 mg/week intravenous infusion over 60 minutes plus oral afatinib 30 mg/day administered in 4-week courses). Patients receive continuous treatment until disease progression, intolerable adverse events (AEs), consent withdrawal or non-compliance with the study protocol. Patients are entered sequentially into escalating/de-escalating dose tiers to determine the MTD based on the occurrence of dose-limiting toxicities (DLTs) during Course 1 (3–6 patients per cohort); 6 additional patients will be enrolled in an extension cohort at the R2PD. Part B consists of two separate expansion cohorts of patients previously treated with irreversible EGFR TKIs (e.g. afatinib, dacomitinib; Cohort 1) and those previously treated with reversible EGFR TKIs (gefitinib or erlotinib; Cohort 2). In each cohort, 18 patients will be treated with the RP2D determined in Part A. Primary endpoints are the MTD and DLTs during Course 1 (Part A) and the objective response assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Part B). Secondary endpoints include disease control, time to objective response, duration of objective response, and pharmacokinetic parameters. AEs are evaluated according to Common Terminology Criteria for AEs (CTCAE) v4.03. All analyses will be descriptive and exploratory.
Results:
Not applicable.
Conclusion:
Not applicable.
