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Mark David Vincent
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-91 - A Phase I Study of Fixed Dose Vinorelbine and Escalating Doses of Ifosfamide in First-Line Advanced Non-Small Cell Lung Cancer (ID 14266)
16:45 - 18:00 | Author(s): Mark David Vincent
- Abstract
Background
Platinum doublet chemotherapy is generally the backbone treatment of advanced NSCLC (aNSCLC), although toxicity and limited benefit necessitated the need for investigation of alternatives. We examined vinorelbine and ifosfamide combination chemotherapy as a possible alternative in first-line aNSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
31 patients were enrolled and treated between January 2004 and July 2006. Vinorelbine (25 mg/m2) and escalating doses of ifosfamide were given on days 1 and 8 q21 days. The starting dose of ifosfamide was 2.0 g/m2. If ≤1/6 patients experienced dose-limiting toxicities (DLT) in cycle 1, the next cohort was recruited and given an additional 0.25 g/m2 of ifosfamide. If ³ 2/6 patients within a cohort experienced DLT, recruitment was halted, and previous cohort’s dose was determined to be ideal for phase II study. DLT were defined as grade 4 hematologic or grades 3 or 4 non-hematologic toxicities.
4c3880bb027f159e801041b1021e88e8 Result
The ideal phase II ifosfamide dose was determined to be 2.0 g/m2. Median PFS and OS were 5.5 and 9.2 months, respectively. The ORR was 12.9% and the 1-year OS was 21%, both lower than historical reports of platinum doublet efficacy and even vinorelbine monotherapy at 30 mg/m2. Six “excellent responders” were identified who survived between 20 and 45 months. DLT were experienced by 58% of patients. DLT were largely hematologic, but higher doses of ifosfamide produced non-hematologic toxicities.
8eea62084ca7e541d918e823422bd82e Conclusion
There was no significant evidence that vinorelbine and ifosfamide combination could provide an alternative to platinum doublet chemotherapy based on inferior efficacy and the high rate of DLT. The 6 “excellent responders” may be explained by chance or secondary to subsequent treatment with erlotinib while harbouring occult EGFR mutations. Further study may be relevant to examine synergy between vinorelbine or ifosfamide with modern targeted therapies.
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P1.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 948)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.16-04 - Outcomes of Patients < 70 or ≥70 Years of Age in PACIFIC (ID 13012)
16:45 - 18:00 | Author(s): Mark David Vincent
- Abstract
Background
In the Phase 3 PACIFIC study of durvalumab versus placebo in patients with stage III, unresectable NSCLC without progression after concurrent chemoradiotherapy (cCRT), the co-primary endpoint PFS was significantly longer with durvalumab (stratified HR 0.52, 95% CI, 0.42–0.65; P<0.0001). In a prespecified analysis, PFS benefit with durvalumab was observed regardless of a 65-year age cutoff. However, median age at NSCLC diagnosis is 70 (CA Cancer J Clin, 2014). We therefore performed subgroup analyses to explore outcomes using a 70-year age cutoff.
a9ded1e5ce5d75814730bb4caaf49419 Method
PACIFIC (NCT02125461) was a Phase 3, randomized, double-blind, all-comers study of patients with WHO PS 0/1 who did not progress following ≥2 cycles of platinum-based cCRT. Patients were stratified by age, sex, and smoking history and randomized (2:1) 1–42 days after cCRT to receive durvalumab 10 mg/kg IV Q2W or placebo up to 12 months. Co-primary endpoints were PFS (BICR, RECIST v1.1) and OS (not available). Secondary endpoints included ORR, time to death/distant metastasis (TTDM), and safety. Between-treatment endpoint comparisons were performed for patients <70 and ≥70 years.
4c3880bb027f159e801041b1021e88e8 Result
As of Feb 13, 2017, 713 patients were randomized; 78% and 22% were <70 and ≥70 years, respectively. Baseline patient and tumor characteristics were generally well balanced across subgroups. However, patients ≥70 were more likely to be male, have PS 1, and, within the placebo arm, to be Asian. Older patients more commonly received carboplatin-based CT than younger patients. Durvalumab demonstrated PFS benefit compared with placebo, regardless if patients were <70 years (median 16.9 vs 5.6 months, HR=0.53, 95% CI: 0.42–0.67) or ≥70 years (median 12.3 vs 6.1 months, HR=0.62, 95% CI: 0.41–0.95). Durvalumab improved TTDM (<70 years: HR=0.53, 95% CI: 0.39–0.71; ≥70 years: HR=0.66, 95% CI: 0.39–1.13) and ORR (<70 years: 27.6% vs 15.4%; ≥70 years: 31.9% vs 17.6%) regardless of age. Younger patients on durvalumab received treatment longer (median total duration 45.5 vs 36.0 weeks). Regardless of treatment, older patients discontinued more due to AEs (durvalumab: 22.0% vs 13.7%; placebo: 16.1% vs 7.8%) and had more grade 5 AEs (durvalumab: 10.9% vs 2.7%; placebo: 9.1% vs. 4.5%). Among patients receiving durvalumab, older patients experienced more all-cause SAEs (42.6% vs 24.9%) and grade 3/4 AEs (41.6% vs 29.4%) but fewer AESIs (56.4% vs 67.9%) than younger patients.
8eea62084ca7e541d918e823422bd82e Conclusion
Patients achieved clinical benefit with durvalumab regardless of age. Increased AEs/SAEs observed in older patients across treatments may reflect age/cCRT related morbidity.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.01-27 - Characterization and Sensitization of Non-Small Cell Lung Cancer Cell Line Variants Selected for Resistance to Osimertinib (ID 12145)
12:00 - 13:30 | Author(s): Mark David Vincent
- Abstract
Background
Many non-small cell lung cancers (NSCLC) are oncogenically driven by mutant epidermal growth factor receptor (EGFR). EGFR tyrosine kinase inhibitors (TKIs) are commonly used as first-line treatments against such tumours, but NSCLC tumours recur with novel EGFR mutation(s) (often a T790M mutation in exon 20) that confers resistance to these drugs [Ther Adv Respir Dis 10(6): 549-565, 2016]. Third generation EGFR TKIs (e.g., osimertinib) have been designed that are highly active against both T790M EGFR and the original oncogenic EGFR lacking the T790M mutation. Clinical resistance to third generation TKIs has been observed, but model systems in which to study the mechanisms of resistance are few. The human NSCLC cell line H1650 has the EGFR-activating mutation del E746-A750. The human NSCLC line H1975, derived from an EGFR-TKI-resistant tumor, contains EGFR-activating mutation L858R as well as resistance-conferring T790M. To explore mechanisms mediating resistance to third generation TKIs, we selected variants of the H1650 and H1975 cell lines for resistance to osimertinib to create models in which mechanisms of resistance can be characterized and tested for potential methods to overcome that resistance.
a9ded1e5ce5d75814730bb4caaf49419 Method
Cells were exposed continuously to a single concentration of osimertinib, in some cases with the inclusion of verapamil to avoid possible selection of multidrug-resistant cells. After 4 weeks, with weekly changes of drug-medium, clonal cell lines were selected from H1650 cultured in the presence of 25 or 50 µM osimertinib plus 10 µM verapamil, and selected from H1975 cultured in 6 or 10 µM osimertinib alone or 5 µM osimertinib plus 10 µM verapamil.
4c3880bb027f159e801041b1021e88e8 Result
The H1650 osimertinib-resistant cell lines (H1650/osi-25a/VPL and H1650/osi-50a/VPL) are 1.6- to 1.8-fold resistant to osimertinib. The H1975 osimertinib-resistant cell lines (H1975/osi-6b, osi-10c, and osi-5b/VPL) were, respectively, 90-, 95-, and 38-fold resistant to osimertinib. None of the cell lines was cross-resistant to imatinib. The compound 2-(benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline (IBR2) is an inhibitor of the DNA repair protein RAD51 and enhances cytotoxicity of EGFR inhibitors against numerous cell lines (Ferguson et al., JPET 2018, doi.org/10.1124/jpet.117.241661). IBR2 decreased osimertinib-resistance by up to 80% in the H1650- and H1975-derived osimertinib-resistant cell lines. Further analyses of the resistant cell lines are being undertaken.
8eea62084ca7e541d918e823422bd82e Conclusion
The H1650 and H1975 osimertinib-resistant cell lines are a valuable resource in which to test methods to circumvent resistance to third generation EGFR TKIs.
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P3.04 - Immunooncology (Not CME Accredited Session) (ID 970)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.04-19 - Do Advanced Lung Cancer Patients Derive Similar Survival Benefits from Immunotherapy? A Systematic Review and Meta-Analysis (ID 12649)
12:00 - 13:30 | Author(s): Mark David Vincent
- Abstract
Background
Checkpoint inhibitors targeting the programmed death-1 (PD-1)/PD-ligand 1 (L1) pathway have become a standard treatment in advanced non-small cell lung cancer (NSCLC) in the first and second line setting. Yet, subgroup analyses from randomized trials have shown inconsistent results regarding survival benefit in elderly patients (> 65 years old), never-smokers and patients with PD-L1 (-) expressing tumors (<1%). We conducted a systematic review and meta-analysis to assess the efficacy of checkpoint inhibitors in these pre-defined subgroups of patients.
a9ded1e5ce5d75814730bb4caaf49419 Method
The electronic databases PubMed and EMBASE, were searched for relevant randomized trials between January 2005 and December 2017. Pooled hazard ratios (HR) for overall survival (OS) and progression free survival (PFS) were meta-analyzed using the generic inverse variance method. To account for between-studies heterogeneity, random-effect models were used to compute pooled estimates. Subgroup analyses compared patients treated in the first versus second line setting.
4c3880bb027f159e801041b1021e88e8 Result
Seven studies were included. Compared to chemotherapy, a significant reduction in the risk of death was seen with the use of checkpoint inhibitors in the second line independent of PD-L1 expression (4 studies, 2,364 participants, HR=0.79, 95%CI 0.66-0.96 and HR=0.66, 95%CI 0.57-0.78 in PD-L1 (–) and (+) patients respectively). Yet, a PFS benefit was only seen in patients with PD-L1 (+) tumors (2 studies, 852 participants, HR=0.69, 95%CI 0.55-0.88). Similarly, an OS benefit was seen in patients independent of age (5 studies, 3,651 participants, HR=0.77, 95%CI 0.64-0.92 and HR=0.75, 95%CI 0.6-0.94 in elderly and non-elderly patients respectively). Conversely, an OS benefit was only seen in ever-smokers (5 studies, 2,905 participants, HR=0.76, 95%CI 0.63-0.92 in ever-smokers and HR=0.83, 95%CI 0.64-1.08 in never-smokers) and a detrimental effect on PFS in never-smokers (3 studies, 1,426 participants, HR=1.68, 95%CI 1.07-2.63). In subgroup analyses, with the use of checkpoint inhibitors, elderly patients derived an OS benefit only in the second line setting (HR=0.69, 95%CI 0.59-0.81). Furthermore, never-smokers had no OS benefit in the first or second line (HR=1.02, 95%CI 0.54-1.93 and HR=0.79, 95%CI 0.59-1.07 respectively) and worse PFS particularly in the first line (HR=2.3, 95%CI 1.23-4.3).
8eea62084ca7e541d918e823422bd82e Conclusion
In the second line setting, patients with advanced NSCLC derive a survival benefit from checkpoint inhibitors independent of tumor PD-L1 expression and age. However, never-smokers do not benefit from these drugs particularly in the first line. Caution should be exercised when offering checkpoint inhibitors to elderly patients with advanced NSCLC in the first line and further research is needed to define their role in never-smokers.
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