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N. Steele
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MA 19 - Mesothelioma: Bench to Bedside (ID 680)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:Dean A Fennell, Hedy Lee Kindler
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 315
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MA 19.03 - Nintedanib + Pemetrexed/Cisplatin in Malignant Pleural Mesothelioma (MPM): Phase II Biomarker Data from the LUME‑Meso Study (ID 8111)
11:10 - 11:15 | Author(s): N. Steele
- Abstract
- Presentation
Background:
Nintedanib is a triple angiokinase inhibitor. LUME-Meso (NCT01907100) is a randomised, Phase II/III study of ≤6 cycles of nintedanib+pemetrexed/cisplatin versus placebo+pemetrexed/cisplatin, followed by nintedanib or placebo maintenance, in chemo-naïve patients with MPM. In Phase II results, nintedanib+pemetrexed/cisplatin improved progression-free survival (PFS) versus control (hazard ratio [HR]=0.54; p=0.010), with a trend for prolonged overall survival (OS; HR=0.77; p=0.319). Benefit was most pronounced in patients with epithelioid tumours. Since no pharmacodynamic/predictive biomarkers are validated for anti-angiogenic therapies, exploratory analyses were conducted to investigate potential associations of plasma-derived angiogenic factors and genomic markers with treatment outcome in the LUME-Meso Phase II epithelioid population.
Method:
Blood samples were collected at baseline and, for patients receiving maintenance, at monotherapy Cycle 3 (C3mono) and end of monotherapy (EoTmono). Analyses focused on 58 angiogenic factors (Human AngiogenesisMAP[®] panel, Myriad RBM) and single-nucleotide polymorphisms (SNPs) in genes implicated in mesothelioma and/or associated with response to anti-angiogenic therapies in other tumour types (VEGFR1, VEGFR3 and mesothelin). Associations of biomarkers with treatment effect were evaluated by Cox regression and tested for interaction with false discovery rate (FDR) adjustment. Adjusted mean changes in angiogenic factor levels were compared between arms by ANCOVA. Analyses were exploratory, limited by small sample size, and considered hypothesis generating.
Result:
Of 77 patients with epithelioid tumours, angiogenic factor and genomic data were available for 71 and 67 patients, respectively. PFS/OS benefit of nintedanib appeared potentially more pronounced in patients with baseline plasma endoglin level below the median. There were possible weak associations between major homozygous genotypes for two VEGFR3 SNPs (rs307821 G/G and rs307826 A/A), and OS benefit and between VEGFR1 SNP rs9582036 A/A genotype and PFS benefit. Biomarker treatment associations were limited by small subgroup size, especially for low-frequency SNPs, and interaction tests were not significant after FDR adjustment. Regarding pharmacodynamic effects, adjusted mean change in interleukin-8 levels with nintedanib was greater from baseline to C3mono and lower from C3mono until EoTmono, compared with placebo. Nintedanib showed lower adjusted mean changes versus placebo for VEGFR2 from baseline to C3mono, and for VEGFR2 and VEGFR3 from baseline to EoTmono.
Conclusion:
These analyses represent the first biomarker results for nintedanib-treated MPM. While there seemed to be signals for greater PFS and OS improvement in patients with low plasma endoglin and major homozygous VEGFR1/3 genotypes, no biomarkers showed clear significant association with treatment benefit. These findings warrant further evaluation in the Phase III study.
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P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.04-013a - CONFIRM: A Phase III Randomized Trial to Evaluate the Efficacy of Nivolumab versus Placebo in Relapsed Mesothelioma (ID 8542)
09:30 - 09:30 | Author(s): N. Steele
- Abstract
Background:
Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Despite a significant number of clinical studies in the second line setting, no randomized study has been positive. Early promising signals of activity relating to both PD-L1 and PD-1 targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint, and support the development of a randomized phase III trial to evaluate the efficacy of nivolumab. CONFIRM is the first ever placebo controlled, randomized phase III trial of a PD-1/PD-L1 immune checkpoint inhibitor in mesothelioma.
Method:
The primary objective is to determine whether nivolumab increases overall survival (OS) in relapsed mesothelioma. Secondary objectives are to determine whether nivolumab a) increases progression-free survival, b) increases response rate, c) has good safety/tolerability, and d) results in acceptable patient quality of life and cost per quality adjusted life year. A translational study will be undertaken to determine the correlation between OS and i) PD-L1 expression, ii) mutational burden (estimated by genome-wide analysis of copy number alterations), iii) immunotranscriptomic profile. Developed by researchers at the Universities of Leicester and Southampton on behalf of the UK NCRI Lung Clinical Studies Group the trial is co-ordinated by the Cancer Research UK Southampton Clinical Trials Unit in the UK, within the Centre of Cancer Immunotherapy. The trial will recruit 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy, from UK sites between March 2017 and 2021. We are also investigating opening recruitment to international sites. Patients will be randomized 2:1 (treatment: control), stratified according to epithelioid vs. non-epithelioid and center, to receive 240mg nivolumab (anti PD-1 antibody) monotherapy or saline placebo as a 30-minute intravenous infusion. Allocation will be double-blind. Treatment will be on day one of each 14-day cycle, until disease progression for a maximum of 12 months. Trial follow up will continue for 6 months after the last participant has progressed, or completed or discontinued treatment. The trial is powered (80%, with 2-sided 4% significance level) to detect a hazard ratio of 0.7 using an adjusted Cox regression model (time-to-event) and will be analyzed using intention-to-treat. This trial is funded by Cancer Research UK (C16728/A21400) and Bristol Myers Squibb (CA 209-841). Trial registrations: NCT03063450 and ISRCTN79814141.
Result:
Section not applicable
Conclusion:
Section not applicable
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P3.15 - SCLC/Neuroendocrine Tumors (ID 731)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.15-003 - Second Line Chemotherapy in SCLC: The West of Scotland Experience (ID 8057)
09:30 - 09:30 | Author(s): N. Steele
- Abstract
Background:
SCLC has a high response rate to first line chemotherapy but this is often short lived. Patients who relapse six months after first line chemotherapy can be retreated with platinum +/- etoposide and patients that relapse early are treated with CAV (cyclophosphamide, doxorubicin and vincristine), Topotecan or best supportive care (BSC). There have been no clinical trials comparing oral Topotecan with iv CAV.
Method:
A retrospective case note review was undertaken of 296 SCLC patients who received second line chemotherapy for recurrent SCLC in the West of Scotland. Results were analysed using STATA version 14.
Result:
SCLC patients that relapsed after first line platinum-based chemotherapy received CAV (n=161), platinum +/-etoposide (n=61), oral topotecan (n=67) and 7 patients received other cytotoxic agents. Median survival for patients who received CAV was 5.1 months (CI 4.1 – 5.7), 6.3 months (CI 5.2-8.6) for platinum/etoposide and 3.0 months (CI 1.9-3.6) for Topotecan. As expected platinum +/- etoposide was superior to CAV (Log rank p = 0.016) and Topotecan (p <0.0001), as these patients had demonstrated platinum sensitivity. CAV appeared superior to Topotecan (p = 0.001) and was better tolerated. 79% of Topotecan patients required a dose reduction versus 29% of CAV patients. 16% of Topotecan, 8% of CAV and no platinum +/- etoposide patients died within 30 days of receiving chemotherapy. 39% of Topotecan and 19% of CAV patients experienced either neutropenic sepsis or myelosuppression requiring a dose reduction or dose delay. There was no difference in time to progression after first line chemotherapy in the CAV and Topotecan populations. Figure 1
Conclusion:
In this West of Scotland retrospective data collection, patients treated with oral Topotecan appear to have a lower median overall survival and experienced more toxicity than those receiving iv CAV.
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P3.15-005 - Third Line Chemotherapy in SCLC: The West of Scotland Experience (ID 8058)
09:30 - 09:30 | Author(s): N. Steele
- Abstract
Background:
Scotland has one of the highest incidences of SCLC globally (cancerresearchuk.org). Lung cancer is the leading cause of cancer related deaths in the UK (cancerresearchuk.org), with SCLC having a worse prognosis than NSCLC and fewer treatment options. Initially, SCLC has a high response rate to first line chemotherapy but rapidly becomes resistant to chemotherapy. There is little evidence to support and guide third line chemotherapy regimens. A West of Scotland (WoS) retrospective database (2007 to 2013) has been developed to gain useful insights into this aggressive disease to improve patient outcomes.
Method:
A retrospective case note review was undertaken of 1325 SCLC patients from the WoS. 58 patients were identified as receiving third line chemotherapy. Information was collected regarding radiological staging, performance status (PS), treatment history, time to progression and survival. Results were analysed using STATA version 14.
Result:
17% of SCLC patients in this WoS database received no chemotherapy, 60% one line (n= 801), 22% (n= 296) two lines, 4% (n=58) three lines and 0.004% (n= 6) four lines of chemotherapy. Of the 58 patients that received third line chemotherapy 28 had Topotecan, 17 CAV, 7 platinum +/- etoposide and 6 included a variety of other cytotoxics. For all patients receiving third line chemotherapy the median survival was 4.7 months (CI 4.1-5.3) and progression free survival was 3.0 months (CI 2.5 – 3.6). Median survival was 3.5 months (CI 2.6- 5.6) for Topotecan, 4.1 months (CI 2.7-5.0) for CAV and 9.0 months (CI 1.8-12.2) for platinum +/ etoposide. 32 (55%) patients received 3 different regimens for each line of chemotherapy, 25 patients (43%) received a platinum-based chemotherapy regimen twice and 1 patient received a platinum based regimen all three lines of chemotherapy. Only 2 patients received a clinical trial novel treatment for their third line therapy.
Conclusion:
SCLC continues to have a poor prognosis with few patients receiving three lines of chemotherapy. The patients that maintain some sensitivity to platinum based chemotherapy tend to have a marginally better response to third line therapy. Clincial trial opportunities for this group of patients were limited. Patients should be enrolled in clinical trials wherever possible.
