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M. Domine
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MINI 38 - Biology and Prognosis (ID 167)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:R. Tsuchiya, M. Wynes
- Coordinates: 9/09/2015, 18:30 - 20:00, 702+704+706
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MINI38.06 - FP1039/GSK3052230 with Chemotherapy in Patients with Fibroblast Growth Factor (FGF) Pathway Deregulated Squamous NSCLC or MPM (ID 2879)
19:00 - 19:05 | Author(s): M. Domine
- Abstract
- Presentation
Background:
GSK3052230/FP1039 is a soluble fusion protein with the ECD of FGFR1c linked to the hinge and Fc regions of human IgG1 and acts as a ligand trap by sequestering FGFs involved in tumor growth and angiogenesis. In contrast to small molecule FGFR kinase inhibitors, GSK3052230 spares the hormonal FGF ligands, namely FGF19, 21 and 23. GSK3052230 combined with chemotherapy was efficacious in xenograft models of FGFR1-amplified NSCLC and malignant pleural mesothelioma (MPM) with FGF2 mRNA overexpression. A phase I monotherapy study determined 20mg/kg weekly as the maximum feasible dose (MFD) achieving the desired blood concentration, with no maximum tolerated dose (MTD) reached.
Methods:
This study (NCT01868022 funded by GSK) will evaluate the safety and efficacy of GSK3052230 weekly infusion in combination with paclitaxel + carboplatin in previously untreated FGFR1 amplified metastatic sqNSCLC (Arm A), in combination with docetaxel in FGFR1 amplified metastatic sqNSCLC that has progressed after at least 1 line of chemotherapy (Arm B), or in combination with pemetrexed + cisplatin in patients with untreated and unresectable MPM (Arm C). Each arm involves a dose escalation phase utilizing the 3+3 design, followed by an expansion phase up to 30 patients (pts). Key endpoints include the MTD/MFD of GSK3052230 with chemotherapy, safety, response rates and duration.
Results:
Thirty-four pts have been dosed with GSK3052230 at dose levels ranging from 5mg/kg to 20mg/kg in combination with chemotherapy across three Arms, n=15 (A), n=6 (B) and n=13 (C). Baseline characteristics: males/females 29/5; mean age 68.5 years; ECOG PS 0 (n=20), 1 (n=13), 2 (n=1). Most common AEs were: Arm A: asthenia, neutropenia; Arm B: neutropenia, diarrhea, rash; Arm C: decreased appetite, nausea, infusion reaction. Infusion reactions were seen in 8/34 (24%) pts (n=3 Grade (Gr)1, n=3 Gr2, n=2 Gr3). Serious AEs included: Arm A- neutropenia (n=4), fatigue (n=1), asthenia (n=1), fever (n=1), respiratory infection (n=1); Arm B- neutropenia (n=1), abdominal pain (n=1); Arm C-bowel perforation/ischemia (n=1), infusion reaction (n=1), elevated creatinine (n=1). No DLTs have been observed in sqNSCLC pts (Arms A and B). Three DLTs were reported in mesothelioma pts (Arm C 20mg/kg): Gr5 bowel perforation/ischemia, Gr4 elevated creatinine levels and Gr3 infusion reaction. MFD for Arm A is determined at 20mg/kg. Dose escalation is ongoing for Arms B and C. Preliminary PK results revealed no drug-drug interactions. At time of data-cutoff, 10 PR were observed among 23 patients evaluable for efficacy (ORR = 43%) and a clinical benefit rate of 78% with two ongoing subjects on study >300 days. Preliminary efficacy is as follows: Arm A (6 PR, 2 SD, 1 PD, 6= not-yet-evaluable (NE)), Arm B (4 SD, 1 PD, 1 NE), and Arm C (3 PR, 3 SD, 3 PD, 4 NE).
Conclusion:
GSK3052230 is in general well tolerated in combination with chemotherapy. The MFD for GSK3052230 is 20mg/kg in combination with paclitaxel + carboplatin in first line sqNSCLC patients. Toxicities typically associated with small-molecule FGFR inhibitors, namely hyperphosphatemia and retinal, nail, and skin changes, were not observed. The initial activity and safety profile of GSK3052230 warrant further study.
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-075 - Phase III, Randomized, Double-Blind Trial of Bavituximab Plus Docetaxel in Previously Treated Stage IIIb/IV Non-Squamous NSCLC (SUNRISE) (ID 1581)
09:30 - 09:30 | Author(s): M. Domine
- Abstract
Background:
Exposed phosphatidylserine (PS) in the tumor microenvironment is highly immunosuppressive. PS binding to PS receptors on myeloid derived suppressor cells (MDSC) and M2 macrophages leads to production of anti-inflammatory cytokines such as TGF-β and IL-10. Bavituximab, a first-in-class PS-targeting monoclonal antibody, counters these effects, resulting in production of pro-inflammatory cytokines such as TNF-α and IL-12, maturation of dendritic cells and induction of tumor specific cytotoxic T lymphocyte (CTL) immunity. Docetaxel has also been shown to suppress MDSCs while increasing tumor antigens and T-cell mediated cytotoxicity, thereby enhancing bavituximab’s immunomodulatory effects. In a prior double-blind Phase II trial in 2nd line non-squamous non-small cell lung cancer, bavituximab 3 mg/kg plus docetaxel was well-tolerated and demonstrated 60% improvement (11.7 vs 7.3 month) in median overall survival (OS) compared to control.
Methods:
SUNRISE is a Phase III, double-blind trial where patients with previously treated Stage IIIb/IV non-squamous, non-small cell lung cancer are randomized in a 1:1 ratio to receive up to six 21-day cycles of docetaxel in combination with either weekly 3 mg/kg bavituximab or placebo, followed by maintenance with weekly bavituximab or placebo until progression or toxicity. Patients will be stratified by region (North America, Europe, or Rest of World), disease stage (IIIb or IV), and previous maintenance/targeted therapy (yes or no). This trial was initiated in December 2013 and accrual of 582 patients across 160+ sites in 14 countries is planned over 24 months. The primary endpoint is OS and two interim analyses are planned. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR) and safety. Radiographic tumor response is centrally assessed every two cycles during combination therapy and every nine weeks during maintenance. Exploratory analysis will include the assessment of changes in circulating immune cells and cytokines to better understand the immunotherapeutic mechanism.
Results:
Trial in progress
Conclusion:
Trial in progress
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P1.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 212)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.03-008 - Weekly Carboplatin/Gemcitabine + Concurrent Thoracic RT Followed by Consolidation Carboplatin/Gemcitabine for Inoperable Stage III NSCLC (ID 994)
09:30 - 09:30 | Author(s): M. Domine
- Abstract
Background:
Concurrent chemo and radiotherapy (CT- RT) is standard of care for inoperable stage IIIA/B non-small cell lung cancer (NSCLC). Optimal regimen and schedule of concurrent CT- RT remain undefined. This phase II trial evaluated carboplatin –gemcitabine + concurrent RT followed by consolidation carboplatin – gemcitabine
Methods:
Treatment schedule during CT-RT phase: weekly carboplatin (AUC 2) + gemcitabine (200mg/m2) for 6 weeks + concurrent RT (60 Gy). CT consolidation phase: carboplatin (AUC 3) gemcitabine (2500 mg/m2) every two weeks for 3 cycles. Primary endpoint was security and secondary response rate, time to progression (TTP) and overall survival (OS)
Results:
24 patients were enrolled: Sex 18 male, 6 female. Histology: 12 adenocarcinoma, 8 squamous, 4 undifferentiated large cell carcinoma. Stage: IIIB: 20, IIIA: 4. ECOG 0-1: 23, ECOG 2: 1. All the patients completed concurrent CT-RT and 22 consolidation CT. Toxicity: CT- RT phase: No grade 4 toxicity was observed. Grade 3: Neutropenia 0, anemia 4.1%, thrombocytopenia 12.5%, esophagitis 16.6%. CT consolidation phase: Grade 3-4 toxicity: Neutropenia 16.6%, Anemia 21%, Thrombocytopenia 16.6% of the patients. 3 patients required red blood cell transfusion and 1 patient died for febrile neutropenia grade 4 during consolidation. Efficacy: Response Rate: 75% (Partial: 50% Complete: 22%), Stable disease 21% Progression 4%. Median TTP: 11 months (95% CI 7-17) and median OS: 18 months (95% CI 16.2- 20.5)
Conclusion:
Concurrent carboplatin – gemcitabine with thoracic RT is feasible with a favorable profile showing less hematologic toxicity and esophagitis than other CT-RT regimens. CT consolidation showed severe hematological toxicity. This regimen is active and could be a good option to combine with concurrent RT.
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-015 - Malignant Pleural Mesothelioma: Observational and Retrospective Analysis of Spanish Database (BEMME). The Spanish Lung Cancer Group (SLCG) (ID 2355)
09:30 - 09:30 | Author(s): M. Domine
- Abstract
Background:
Malignant Pleural Mesothelioma (MPM) is a rare but aggressive malignancy of the pleura, with a strong causal link to asbestos exposure. Although in Spain asbestos was banned in 2002, it is estimated that occupationally related deaths due to MPM will continue to occur until 2040. BEMME (Base Epidemiológica Mesotelioma Maligno en España) is an observational and retrospective study sponsored by the Spanish Lung Cancer Group that aimed to characterize the patient’s and tumour’s features as well as the treatment modalities of patients diagnosed with mesothelioma in Spain.
Methods:
Clinical records of patients with malignant pleural and peritoneal mesothelioma were retrospectively reviewed to collect epidemiological data, diagnostic tests, treatment modalities and survival data into an electronic and anonymous database. Thirty-five Spanish hospitals participated in the project and 570 mesothelioma patients were included in the BEMME database. Here we present a descriptive analysis of MPM patients based upon these data.
Results:
From January 2008 to December 2013, 538 patients (p) had MPM. Most patients were males (77%) and 74% of patients were ≥ 60 years (60-70y: 33%, >70y: 41%). Most patients (49%) had a performance status 1 at diagnosis. Only 32% of patients were recorded as positive for asbestos exposure and 77% of patients were never-smokers. Dyspnoea (35%) and thoracic pain (26%) were reported as the most frequent symptoms at diagnosis. Epithelioid was the most frequent histological subtype (63%), followed by sarcomatoid (12%), biphasic (8%) and not specified (17%). Disease stages at diagnosis were: stage I, 7%; stage II, 9%; stage III, 17%; stage IV, 45%; not specified, 22%. Surgery was performed in 41p: extrapleural neumonectomy 16p, extended pleurectomy 15p and partial pleurectomy 10p. Palliative pleurodesis was performed in 22% of patients. A total of 70% of patients received chemotherapy (55% palliative, 11 neoadjuvant and 6% adjuvant). The median overall survival (OS) for all patients was 13.2 months (95% CI 12.2 – 15.2). There were no statistically significant differences in OS according to age, gender and asbestos exposure. In the univariate analysis, higher stage (III-IV vs. I-II, p=0.0003) and non-epithelioid subtype (non-epithelioid vs. epithelioid, p=0.00001) were significantly associated with shorter OS.
Conclusion:
In Spain, most MPM patients are diagnosed at advanced stages and are treated with palliative modalities: mainly chemotherapy and pleurodesis. Stage and histologic subtype were prognostic factors for survival. BEMME database is a helpful tool to describe the therapeutic strategies employed in MPM patients in Spain.
