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Gee-Chen Chang
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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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MA 12.02 - Phase I/II Study of S49076, a MET/AXL/FGFR Inhibitor, Combined with Gefitinib in NSCLC Patients Progressing on EGFR TKI (ID 7974)
11:05 - 11:10 | Presenting Author(s): Gee-Chen Chang
- Abstract
- Presentation
Background:
S49076 is a potent ATP-competitive TKI that targets MET, AXL and FGFR1/2/3 at clinically relevant doses. Preclinical data showed that combination of S49076 with 1[st] generation EGFR-TKI can overcome acquired resistance to EGFR inhibition in a NSCLC EGFR-mutated MET-amplified cell model. Here we report interim phase I data from NSCLC patients treated with S49076 in combination with gefitinib to overcome acquired non-EGFR-T790M-mediated resistance to EGFR TKI (1[st]/2[nd] generation).
Method:
This is a phase I dose-finding study of S49076 combination with a standard dose of gefitinib using a modified Bayesian Continual Reassessment Method with S49076 doses of 500 and 600mg. Both agents are administered orally once daily. The primary objective is to determine the safety profile of the combination and the recommended phase 2 dose (RP2D) based on safety assessments. Patients are selected according to tumor status; they carried an activating-EGFR mutation without secondary T790M mutation and with at least one of the following dysregulations: MET IHC3+, MET FISH 2+/3+, or AXL IHC 2+/3+.
Result:
In June 2017, molecular screening was performed in 48 EGFR/T790M-negative tumor samples to assess MET and AXL dysregulation. 17/48 met the molecular eligibility criteria: 12/17 with MET overexpression/amplification; 4/17 with both MET overexpression/amplification and AXL overexpression; and 1/17 with AXL overexpression. As regards S49076 dose levels, 4 patients were included at 500 mg and 4 at 600 mg. Five patients discontinued treatment: 4 disease progression and 1 consent withdrawal. The most frequent related AEs (≥2 patients) were asthenia (n=5), diarrhea, nausea and paronychia (n=4 each), ASAT/ALAT increase, anemia, and yellow skin (n=3 each), peripheral edema, stomatitis, blood creatinine increase, vomiting, hypoalbuminemia, and decreased appetite (n=2 each); most were grade 1-2. A DLT occurred in 1 patient at 600mg (grade 3 stomatitis). The other severe related AEs included grade 3 ALAT increase, asthenia, and neutrophil count decrease. Concomitant intake of gefitinib did not appear to modify the S49076 PK profile as compared to previous data. The best overall response rate were partial response (PR, 1/8), stable disease (SD, 6/8), and progressive disease (1/8), including 3 patients with PR/SD ≥6 months.
Conclusion:
According to preliminary data, the frequency of MET and AXL dysregulations is consistent with the literature. Combination of S49076 and gefitinib is well tolerated and safety data are consistent with the overall safety profile of each drug. The phase II part of this study will start once the RP2D is defined to evaluate the anti-tumour activity of the combination.
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P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.03-050 - Clinical Consequences, Quality of Life, and Management of Neutropenic NSCLC Patients in the REVEL Trial (ID 8279)
09:30 - 09:30 | Author(s): Gee-Chen Chang
- Abstract
Background:
Ramucirumab is a human IgG1 monoclonal antibody antagonist of VEGFR-2 approved as a post-platinum progression therapy in non-small cell lung cancer (NSCLC). Chemotherapy-induced neutropenia is a major risk during cancer treatment and can be potentially dose-limiting, as well as play a significant role in infection-related morbidity and mortality. In the REVEL phase 3 global, placebo-controlled study of Stage IV NSCLC patients (NCT01168973), ramucirumab plus docetaxel treatment improved patient survival versus docetaxel monotherapy independent of histology; however, all grade and high-grade (Grade ≥3) neutropenia was numerically increased with ramucirumab versus placebo (Table 1). A post-hoc analysis was performed on the REVEL data to characterize neutropenia: clinical consequences, quality of life (QoL), and clinical management.
Method:
The duration of neutropenia, as well as the course and incidence of complications and their severity and related consequences associated with neutropenia were summarized. Time to deterioration in ECOG performance status (PS) was analyzed using Kaplan-Meier method, and stratified hazard ratios and 95% confidence intervals (CI, Wald) were estimated for average symptom burden index and lung cancer symptom scale items using Cox model. Clinical management summary data will be presented at the meeting.
Result:
Neutropenia events from the REVEL trial are summarized in terms of duration, course, incidence of complications, severity and resolution status in Table 1. All-grade neutropenia risk ratio is 1.197 (95% CI 1.072, 1.338) and Grade ≥3 is 1.226 (95% CI 1.081, 1.390). Figure 1
Conclusion:
Despite numerically increased rates of neutropenia observed in the ramucirumab plus docetaxel arm of the REVEL trial, the clinical consequences (resolution) of neutropenia, rate of hospitalization, and duration/incidence of Grade ≥3 infection were similar to placebo. In addition, the quality of life results do not indicate any significant differences between placebo and ramucirumab. Therefore, neutropenia in the NSCLC population is considered to be manageable during ramucirumab treatment.
