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F. Ciardiello
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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 | Author(s): F. Ciardiello
- 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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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-052 - Patient-Reported Outcomes (PROs) in OAK: A Phase III Study of Atezolizumab vs Docetaxel in Non-Small-Cell Lung Cancer (NSCLC) (ID 9903)
09:30 - 09:30 | Author(s): F. Ciardiello
- Abstract
Background:
The phase III OAK study in NSCLC (NCT02008227) demonstrated prolonged overall survival with atezolizumab (an anti-programmed death-ligand 1 antibody) versus docetaxel (median 13.8 vs 9.6 months; HR:0.73, 95% CI 0.62–0.87; p=0.0003). PROs were collected to support documentation of clinical benefit. We report data regarding symptom burden, functioning, and health-related quality of life (HRQoL).
Method:
Patients (n=850) with squamous/non-squamous, previously treated NSCLC, ≥18 years, with measurable disease (RECIST), and ECOG PS 0–1 were randomized to receive atezolizumab 1200mg or docetaxel 75mg/m[2] q3w. PROs were collected using two questionnaires: EORTC QLQ-C30 and its lung module, QLQ-LC13. Analyses included time-to-confirmed-deterioration (TTD) in lung cancer symptoms, physical and role function, HRQoL, longitudinal analyses of mean scores change from baseline to Cycles 5 and 6, proportion of patients with clinically meaningful worsening (≥10-point change from baseline) by Cycles 5 and 6.
Result:
High completion rates were observed throughout treatment (>80% for most cycles). Atezolizumab delayed TTD in physical (HR:0.75, 95% CI 0.58–0.98) and role function (HR:0.79, 95% CI 0.62–1.00). Prolonged TTD in chest pain (HR:0.71, 95% CI 0.49–1.05) was observed with atezolizumab; no differences in TTD were seen for other lung cancer symptoms and HRQoL. Longitudinal analyses demonstrated average changes from baseline in favor of atezolizumab for lung cancer symptoms (Cycle 6: dyspnea, fatigue), domains of functioning (Cycle 6: physical function, social function), HRQoL (Cycle 5); see Table. Fewer atezolizumab-treated patients experienced clinically meaningful worsening in possible treatment-related symptoms during treatment (Cycle 6: diarrhea [OR:0.51, p<0.0001], sore mouth [OR:0.40, p<0.0001], dysphagia [OR:0.61; p=0.0052], peripheral neuropathy [OR:0.50, p<0.0001], alopecia [OR:0.02; p<0.0001]).
Conclusion:
In OAK, atezolizumab delayed the time until NSCLC patients experience limitations in physical and role functioning versus docetaxel. Patient-reported data indicate atezolizumab maintained/improved lung cancer symptom burden and HRQoL compared with baseline, while demonstrating improved tolerability, versus docetaxel.By Cycle 5 By Cycle 6 LS means difference between treatment arms (average change from baseline) P value LS means difference between treatment arms (average change from baseline) P value EORTC QLQ-C30 Global Health Status and Function Scales (positive values indicate greater improvement with atezolizumab over docetaxel) Global Health Status 4.32* p=0.0151 3.08 p=0.1257 Physical Function 3.33* p=0.0290 6.64* p<0.0001 Role Function 2.93 p=0.1959 4.72 p=0.0542 Emotional Function 2.66 p=0.1110 1.92 p=0.2868 Cognitive Function -0.67 p=0.6790 -1.08 p=0.5309 Social Function 3.25 p=0.1159 4.68* p=0.0319 EORTC QLQ-C30 Symptom Scales (negative values indicate greater improvement with atezolizumab over docetaxel) Fatigue -6.27* p=0.0015 -7.66* p=0.0003 Nausea/Vomiting -0.37 p=0.7824 -0.18 p=0.9040 Pain 1.44 p=0.5132 -1.67 p=0.4727 Dyspnea -4.70* p=0.0317 -5.92* p=0.0138 Insomnia 3.50 p=0.1675 0.83 p=0.7564 Appetite Loss -2.94 p=0.1994 -4.49 p=0.0586 Constipation -0.31 p=0.8772 -0.33 p=0.8816 Diarrhea -3.14* p=0.0482 -2.05 p=0.1748 EORTC QLQ-LC13 Symptom Scales (negative values indicate greater improvement with atezolizumab over docetaxel) Dyspnea -1.66 p=0.3146 -4.80* p=0.0140 Coughing -2.60 p=0.2572 -1.38 p=0.5772 Sore Mouth -7.29* p<0.0001 -9.23* p<0.0001 Dysphagia -0.08 p=0.9595 -2.01 p=0.1575 Peripheral Neuropathy -12.98* p<0.0001 -15.71* p<0.0001 Hemoptysis -0.24 p=0.7365 -0.91 p=0.2080 Alopecia -50.59* p<0.0001 -47.04* p<0.0001 Chest Pain -0.91 p=0.6064 -0.58 p=0.7779 Arm/Shoulder Pain -2.27 p=0.3177 -0.58 p=0.8109 Pain in Other Parts 0.94 p=0.7197 -1.05 p=0.7034 *Values that are significantly in favor of atezolizumab versus docetaxel
