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Alex Adjei
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OA 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 8
- Moderators:Alex Adjei, Eun Kyung Cho
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 311 + 312
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OA 14.01 - The Impact of Measurement Variability on Response Categorization in Oncology Trials (ID 9986)
11:00 - 11:10 | Presenting Author(s): Soon Ho Yoon | Author(s): J. Yoon, S. Hahn, Jin Mo Goo, D. Kim
- Abstract
- Presentation
Background:
Radiologic assessments of the baseline and post-treatment tumor burden are subject to measurement variability, but the impact of this variability on response categorization and the resulting overall response rate (ORR) in a specific trial has been practically unpredictable.
Method:
We built up a hierarchical model of measurement variability using a clinical trial dataset of CT scans. Simulations were then performed using the model 1) to establish the behaviour of differences between the first and the hypothetical second assessments of percent change of tumor burden in various scenarios, 2) to elaborate on the probabilistic nature of decisions about categorization, and 3) to estimate the variation in the ORR due to measurement variability.
Result:
The extent of the discrepancies between assessments of the percent change depended on the baseline burden. Smaller differences were associated with larger shrinkage of tumor burdens. The simulated probability for a specific categorization (-30% or 20%) to result from reassessment had a sigmoid shape depending on the percent change in the first set of readings, inflecting at the cutoff point for the categorization. In 3 virtual trials having the same baseline burden and the same ORR of 50%, the presence of fewer percent changes around the cutoff in a trial resulted in a more reproducible ORR (95% central range, 35%-65% vs. 40%-60% vs. 45%-60%). Figure 1
Conclusion:
Since determinations of partial response or progression are probabilistic outcomes due to measurement variability, quantification of the variation in the ORR by potential measurement variability is essential and will help inform decisions made on the basis of trial data.
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OA 14.02 - Rethinking Progression-Free Survival (PFS) as a Clinical Trials Surrogate for Overall Survival (OS) (ID 10276)
11:10 - 11:20 | Presenting Author(s): David James Stewart | Author(s): D. Bosse, A. Ocana, Glenwood Goss, D. Jonker
- Abstract
- Presentation
Background:
►►OS assessment requires high follow-up times and patient numbers and is impacted by crossover (CO). OS hazard ratios (HRs) are generally inferior to PS HRs due to impact of post-progression survival (PPS) and CO. Some authors propose that absolute OS gains (ΔOS) should be similar to those in PFS (ΔPFS). Hence, ΔPFS might be a useful OS surrogate (Clin Cancer Res 2013;19:2646; Ann Oncol 2016;27:373).
Method:
To assess this further, we reviewed Journal of Clinical Oncology and New England Journal of Medicine 01/01/2012-06/12/2017 for randomized drug trials in incurable solid tumors. We extracted data for PFS and OS medians and HRs, calculated ΔPFS and ΔOS (experimental medians minus control medians), and did paired comparisons between 2-6 different arms in each study (245 comparisons across 201 trials).
Result:
Mean ΔOS across studies (1.03 months) was similar to mean ΔPFS (1.06 months) (n=201 evaluable, p=0.88). ΔOS correlated with ΔPFS (r=0.50, p<0.0001). With CO in <20% of patients or unstated %CO (n=144), mean ΔOS and ΔPFS were 0.93 and 0.92 months, respectively. With CO in >20% of patients (n=57), mean ΔOS and ΔPFS were 1.29 and 1.41 months, while with CO>50% (n=20), they were 1.4 and 1.9 months. OS HRs (mean=0.92) were inferior to PFS HRs (mean=0.82, n=196, p<0.0001), although OS and PFS HRs correlated with each other (r=0.64, p<0.0001). With CO<20% or unstated (n=135), mean OS and PFS HRs were 0.93 and 0.83, while with CO>20% (n=61), they were 0.90 and 0.80, and with CO>50% (n=20), they were 0.94 and 0.71.
Conclusion:
OS HRs were inferior to PFS HRs, probably due to PPS, competing causes of death and CO. The better mean gains and HRs in high vs low CO trials may be due to more frequently allowing CO in trials with more effective therapies. This increases risk of false-negative OS results with effective therapies if CO is permitted, but it is potentially unethical to withhold CO of effective therapies. With PFS, clinically insignificant gains may be statistically significant. Since ΔOS and ΔPFS are similar, an alternate approach would be a primary study outcome requiring PFS HR to be statistically significant and ΔPFS 95% CIs in a range considered clinically relevant for OS gains. To better understand the limitations of this approach, we are analyzing examples with minimal OS gains despite ΔPFS>2 months and examples of ΔOS>2 months but no gain in PFS, and have formulated a potential biological/statistical explanation for the latter.
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OA 14.03 - Ontario's Bundled Payment System for Systemic Therapy Supports Lung Cancer Trials (ID 9636)
11:20 - 11:30 | Presenting Author(s): William Kenneth Evans | Author(s): T. Kais-Prial, R. Fung, L. Forbes
- Abstract
- Presentation
Background:
Clinical trials (CTs) are recognized as a key component of a quality cancer care system. When funding for systemic therapy (ST) services in Ontario transitioned in 2014/15 from a one-time payment for new cases to bundled payments for specific evidence-informed regimens, stakeholders expressed concern that the funding model could exclude patients from participation in CTs as treatment facilities would only receive funding when evidence-informed regimens were used.
Method:
A CT policy was implemented to enable public funding through the ST funding model for older and inexpensive drugs and their administration within randomized CTs at the level of the standard of care. Non-randomized CTs were to be funded at the level of best supportive care or other appropriate funding level. New and expensive drugs in a CT could be funded through a separate provincial drug reimbursement program if used according to public funding criteria with administration costs covered by the ST funding model. Each new CT is now assessed to determine the level of public funding possible. The funding model can now capture data on phase of trial, disease type, treatment regimen, trial purpose (adjuvant, palliative) and patient accrual by treatment facility
Result:
During 2015/16 and 2016/17, 43 and 44 lung CTs, respectively, were assessed and activated in Ontario. Trial accrual increased by 33% (from 311 to 413 patients) over the two years since the introduction of the funding model. Accrual varied by facility. In 2016/17, it ranged from a low of 0.25% to 37.5% of the new lung cancer (LC) patients seen at individual facilities. For the five largest cancer centres in Ontario, the percentage of patients recruited ranged from 5% to 18.3% and total accruals from these centres (n=257) comprised 63% of provincial LC trial recruitment. Five immuno-oncology trials accrued 183 patients and made up 44% of total LC trial accruals. Public funding through the ST funding model amounted to $415,000 in 2015/16 and increased to $815,000 in 2016/17.
Conclusion:
The new bundled payment system for ST and the CT policy have enabled public funding to support lung CTs. The ST funding model has facilitated the capture of CT data and trends not previously available for LC and other tumours. The new provincial CT policy and payment system do not appear to have negatively impacted participation in lung cancer CTs. The variance in trial accrual between centres warrants further study.
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OA 14.04 - Discussant - OA 14.01, OA 14.02, OA 14.03 (ID 10777)
11:30 - 11:45 | Presenting Author(s): George R. Simon
- Abstract
- Presentation
Abstract not provided
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OA 14.05 - Phase 2 Basket Trial of Ado-Trastuzumab Emtansine in Patients with HER2 Mutant or Amplified Lung Cancers (ID 10368)
11:45 - 11:55 | Presenting Author(s): Bob T. Li | Author(s): R. Shen, D. Buonocore, Z.T. Olah, A. Ni, M.S. Ginsberg, G. Ulaner, W. Weber, Dana W.Y. Tsui, M. Offin, H.H. Won, Marc Ladanyi, Gregory J Riely, D.B. Solit, D.M. Hyman, Charles M Rudin, M.F. Berger, J. Baselga, M. Scaltriti, Maria E Arcila, Mark G Kris
- Abstract
- Presentation
Background:
Human epidermal growth factor receptor 2 (HER2, ERBB2) mutation and amplification each occurs in 2% of lung cancers, resulting in receptor dimerization and oncogenic signaling with in vitro sensitivity to trastuzumab. Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate linking trastuzumab with the anti-microtubule agent emtansine.
Method:
Patients with advanced HER2 mutant or amplified lung cancers were enrolled into separate cohorts in a basket trial of ado-trastuzumab emtansine, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1. A separate cohort included patients with HER2 mutant lung cancers assessed using PERCIST, with pre-treatment 89Zr-trastuzumab PET as correlative imaging. A Simon two stage optimal design was used with type I error rate under 2.7% (and a family wise error rate across baskets under 10%), power of 89%, H0 10%, H1 40%. Other endpoints include progression-free survival (PFS) and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing (NGS), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).
Result:
A total of 33 patients were identified by NGS and enrolled. The first HER2 mutant cohort completed accrual of 18 patients with ORR of 44% (8/18 confirmed, 95% CI 22-69%), rejecting null hypothesis. The median PFS was 4 months, and median PFS for responders was 6 months (range 4-11 months). The PERCIST measured HER2 mutant cohort accrued 9 patients, there were 2 confirmed partial responses (PR) in 5 patients evaluated. The HER2 amplified cohort accrued 6 patients, with 3 confirmed PR observed including 1 with concurrent EGFR sensitizing mutation and resistance to erlotinib. Toxicities included grade 1 or 2 including infusion reaction, thrombocytopenia and transaminitis, there were no treatment related deaths. Of the 27 patients in the HER2 mutant cohorts, there were 18 (67%) exon 20 insertions and 9 (33%) point mutations; responders were seen across mutation subtypes (A775_G776insYVMA, G776delinsVC, V659E, S310F, L755P). Concurrent HER2 amplification was observed in 4 of 27 patients by either NGS or FISH. IHC ranged from 0 to 3+ and did not predict response. Of the 6 patients in the HER2 amplified cohort, 2 had concurrent HER2 mutation and 1 had concurrent EGFR L858R mutation.
Conclusion:
Ado-trastuzumab emtansine is active and well tolerated in patients with advanced HER2 mutant or amplified lung cancers as identified by NGS. While cohort expansion is ongoing, this study has met its primary endpoint in patients with HER2 activating mutations. Further development is warranted.
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OA 14.06 - Entrectinib in Patients with Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC) (ID 8564)
11:55 - 12:05 | Presenting Author(s): Myung-Ju Ahn | Author(s): Byoung Chul Cho, S. Siena, Alexander Drilon, F. De Braud, Matthew G Krebs, T. John, C. Karapetis, A.D. Johnson, E. Chow-Maneval, P.S. Multani, Robert C. Doebele
- Abstract
- Presentation
Background:
Entrectinib is a potent, investigational, CNS-active, oral inhibitor of ROS1 with a biochemical IC~50~ (0.2 nM) ~30 times more potent than crizotinib, the only agent approved for the treatment of ROS1-positive NSCLC. Previously, we reported an objective response rate of 85% in 13 ROS1 inhibitor-naïve NSCLC patients who were treated in Phase 1 studies (Drilon and Siena et al, Cancer Discov 2017), including 2 of 3 (67%) patients with CNS disease. Responses were durable, with 1 patient remaining on study for more than 3 years. Entrectinib was well tolerated, with predominantly Grades 1 or 2 adverse events that were reversible with dose modification.
Method:
Patients with ROS1 inhibitor-naïve NSCLC were enrolled across Phase 1 and 2 studies of entrectinib. Patients were screened for ROS1 gene fusions either locally or centrally at Ignyta’s diagnostic laboratory using next generation sequencing. Entrectinib was administered orally at 600 mg once-daily in 4-week cycles. Safety was assessed by monitoring adverse events, laboratory tests, and clinic visits. Tumor assessments were performed at the end of Cycle 1 and every 8 weeks thereafter. All scans were read locally (INV) and by blinded independent central review (BICR) using RECIST v1.1. INV results will be presented except where noted.
Result:
As of 24 May 2017, a total of 32 patients were evaluable for response (median age 52 years, 72% female). At a median follow-up of 12 months, objective responses were observed in 24 of 32 (75% [95% CI: 56.6, 88.5]; 3 complete responses) patients, including 7 of 11 (64% [95% CI: 30.8, 89.1]) patients with CNS disease at baseline. Five of 7 patients with evaluable CNS lesions by BICR experienced confirmed RECIST intracranial responses, for a CNS response rate of 71% (95% CI: 29.0, 96.3). With 19 (59%) patients remaining on study, the median duration of response was 17.2 months (95% CI: 6.5, 36.0) and progression-free survival was 19.1 months (95% CI: 6.5, 36.6). The most common (>15%) treatment-related adverse events were fatigue/asthenia (34%), dysgeusia (34%), dizziness (24%), weight increase (21%), paresthesia (19%), nausea (18%), constipation (18%), and diarrhea (16%). All data will be updated at the time of presentation.
Conclusion:
Entrectinib is well tolerated and has shown promising antitumor activity in ROS1 inhibitor-naïve NSCLC, including patients with CNS disease. Patients with ROS1+ NSCLC and other tumor types continue to be enrolled in STARTRK-2 (NCT02568267) in order to support a potential regulatory filing for entrectinib in this population.
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OA 14.07 - Progress in Lung Squamous Cell Carcinoma from the Lung-MAP Master Protocol (S1400) Sub-Studies S1400A, S1400B, S1400C and S1400D (ID 9593)
12:05 - 12:15 | Presenting Author(s): Roy S. Herbst | Author(s): Mary Redman, David R. Gandara, Fred R. Hirsch, Philip Christopher Mack, Hossein Borghaei, Corey J Langer, J. Wade, J.A. Engelman, Martin Edelman, K. Albain, Primo Lara, C. Aggarwal, M.A. Socinski, Scott N. Gettinger, Lyudmila Bazhenova, S.N. Waqar, Francisco Robert, G.J. Kiefer, Jeffrey Bradley, Jeffrey Crawford, E. McGary, N.M. Rafique, D. Petro, P.C. Hoffman, Y. Zhou, J. Miao, K. Griffin, S. McDonough, C. Miwa, S. Malik, V.A. Miller, E.V. Sigal, S. Adam, C.D. Blanke, Karen Kelly, Vassiliki A Papadimitrakopoulou
- Abstract
- Presentation
Background:
Lung-MAP (S1400) is a master umbrella protocol designed to establish genomic screening for previously treated squamous cell lung cancer patients (SqCCA), and independently evaluate targeted therapies with matching biomarkers and alternative therapies (designated non-match therapy) in patients without putative markers. The protocol opened June 16, 2014 with four biomarker-driven sub-studies and one non-match sub-study.
Method:
Eligibility stipulated advanced SqCCA, progressing after at least one prior platinum-based chemotherapy, PS 0–2, and EGFR/ALK wild-type. Tumor samples were required and analyzed for gene alterations by FoundationOne NGS assay (Foundation Medicine). The original biomarker and non-match studies were: S1400B evaluating taselisib for PI3K mutations, S1400C evaluating palbociclib for cell cycle gene alterations (CCGA), S1400D evaluating AZD4547 for FGFR mutations, S1400E evaluating rilotumumab and erlotinib for c-MET positive tumors, and S1400A evaluating durvalumab in patients with no matching biomarkers. The original design included randomization to a control arm, but was amended to a single-arm phase 2 design. The primary endpoint for each modified sub-study was response.
Result:
As of June 16, 2017 all original sub-studies have been closed to accrual; 1298 patients registered to the screening component of the trial and 486 patients have registered to a sub-study. Two new sub-studies have been launched and are currently accruing. Details of the completed sub-studies are included in the table.Sub-study Final Accrual Biomarker prevalence/% of sub-study registrations Closure Date Response to investigational therapy N (%) Status S1400A (non-match) Total: 116 Durvalumab: 78 Docetaxel: 38 NA/59% 12/18/15 Docetaxel arm closed: 4/22/15 11 (16%) Administratively closed to enable activation of new non-match study. S1400B PI3K Total: 39 taselisib: 31 Docetaxel: 8 8%/9% 12/12/16 Docetaxel arm closed: 12/18/15 1 (4%) Closed at interim futility analysis. S1400C (CCGA+) Total: 54 Palbociclib: 37 Docetaxel: 17 19%/15% 09/01/16 Docetaxel arm closed: 12/18/15 2 (6%) Closed at interim futility analysis. S1400D (FGFR+) Total: 45 AZD4547: 35 Docetaxel: 10 16%/12% 10/31/16 Docetaxel arm closed: 12/18/15 2 (7%) Closed at interim futility analysis. S1400E (MET+) Total: 9 R+E: 4 E: 5 N/A (closed too early) 11/26/2014 N/A Closed d/t discontinuation of development of rilotumumab
Conclusion:
Lung-MAP as a master genomic screening protocol has demonstrated feasibility with respect to accrual and evaluation of targeted therapies in lower prevalence patient populations. This dynamic, centralized, single-IRB platform is well positioned to efficiently assess multiple novel therapeutics for advanced SqCCA patients.
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OA 14.08 - Discussant - OA 14.05, OA 14.06, OA 14.07 (ID 10778)
12:15 - 12:30 | Presenting Author(s): Fiona Blackhall
- Abstract
- Presentation
Abstract not provided
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Author of
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MA 01 - SCLC: Research Perspectives (ID 650)
- Event: WCLC 2017
- Type: Mini Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:John V Heymach, Eun Kyung Cho
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 503
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MA 01.06 - A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Chemotherapy-Resistant Small Cell Lung Cancer (ID 10255)
11:35 - 11:40 | Author(s): Alex Adjei
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) has poor prognosis and systemic chemotherapy is the standard treatment. Irinotecan is a topoisomerase-I inhibitor that has been used in treating SCLC. Etirinotecan pegol (NKTR-102) is a polyethylene glycol conjugate of irinotecan uniquely designed for prolonged tumor cell exposure by using the polymer conjugate technology. This is a single arm phase II study to evaluate single agent etirinotecan pegol in patients with relapsed SCLC (NCT01876446). In WCLC 2016 we reported its promising activity with an acceptable toxicity profile in treatment of chemotherapy-sensitive SCLC. Here we report the results in chemotherapy-resistant SCLC.
Method:
A total of 38 patients who have received only one prior systemic therapy for SCLC were enrolled. There were 2 patient cohorts: those progressing on first-line chemotherapy <3 months after completion of treatment (Group A: chemotherapy-resistant, N=20) and those progressing on first-line chemotherapy ≥3 months after completion of treatment (Group B: chemotherapy-sensitive, N=18). Etirinotecan pegol was administered at 145 mg/m[2] IV once every 3 weeks. Cycles were repeated every 21 days until disease progression, unacceptable toxicity, or withdrawal from study. The primary endpoint was the 18-week progression free survival (PFS) rate. The secondary endpoints were objective response rate (ORR), duration of response (DOR), overall survival (OS) and toxicity. A single-stage design was used to assess the primary endpoint separately for each patient group.
Result:
Group A has completed targeted enrollment of 20 patients and the results are presented here. Median age was 60.4 (46.1-74.8) years, with 50% male and ECOG PS 0 (9/20) or 1 (11/20). Prior chemotherapy included cisplatin/etoposide (25%) or carboplatin/etoposide (70%). Patients received a median of 2 (1-10) cycles of etirinotecan pegol, with dose reduction in 15%. PFS rate at week 18 was 35% (7/20, 95% Confidence Interval (CI): 16-55%). ORR was 20% (4/20), all of which were partial response. Another 30% (6/20) of patients had stable disease. Median DOR was 4.8 (1.6-10.5) months. Median PFS was 9.4 (95% CI: 5.8, 21.6) weeks, and OS was 8.1 (95% CI: 2.9, 11.9) months. The most common treatment-related adverse events (AEs) of any grade were diarrhea (50%), fatigue (35%), weight loss (35%), nausea (30%), and vomiting (30%). The most common AEs ≥grade 3 were diarrhea, leukopenia and neutropenia (2 cases each, all grade 3).
Conclusion:
Etirinotecan pegol has demonstrated promising activity with an acceptable toxicity profile and a convenient schedule in treatment of patients with chemotherapy-resistant relapsed SCLC and therefore warrants further investigation.
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MA 18 - Global Tobacco Control and Epidemiology II (ID 676)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
- Presentations: 1
- Moderators:H. Kawai, Christian Klaus Manegold
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 511 + 512
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MA 18.09 - Enrollment of Minorities, the Elderly, and Women in Lung Cancer Clinical Trials (ID 8406)
16:35 - 16:40 | Author(s): Alex Adjei
- Abstract
- Presentation
Background:
Despite multiple efforts led by the National Cancer Institute (NCI) specific patient populations remained underrepresented in cancer clinical trials (CT). Therefore, we determined the representation of minorities, the elderly, and women in lung cancer CT in the past 16 years.
Method:
Clinicaltrials.gov was queried on December 31[st], 2016 for all completed therapeutic lung cancer trials from 2000 to 2016. Trials with recruitment outside of the U.S. were excluded. Enrollment fraction (EF) was defined as the number of enrollees divided by the 2013 SEER cancer prevalence. Geographic location was classified within the 5 major U.S. regions: Northeast, Southeast, Midwest, Northwest and Southwest.
Result:
Out of 320 CT, only 88 trials (27.5%) reported race/ethnicity comprising 11, 723 enrollees. Industry sponsored 65% of the trials. Non-Hispanic whites (NHW) were more likely to be enrolled in CT (EF 2.8%) than African Americans (AA) (EF 1.5%, p<0.001) and Hispanics (EF 2.1% p<0.03). Asian patients were well represented (EF 9.2 %). Distribution by race and sex is described on Table 1. Only 44 (50%) trials divided participants by age (<65 or ≥65 years). The representation of trial participants was heavily skewed towards the younger age group. Median age was 62 years and 8,440 (72%) participants were <65 years of age (p<0.001). Industry sponsored trials were less likely to enroll Hispanic patients than NCI sponsored trials (1.1% vs. 3.8%). African Americans were less likely to be recruited in first line trials compared to NHW (11% vs. 36%, p<0.0001). Underrepresentation of minorities was not affected by recruitment site geographic location.
Conclusion:
NHW were more likely to be enrolled in clinical trials than African American and Hispanics, independent of the recruitment site geographic location. Collaboration between investigators, NCI, industry, and the community is necessary to ensure broad access of unrepresented populations to clinical trials.Race/Ethnicity 2000-2016 Trial Participants n/% Enrollment Fraction % 2013 Lung Cancer Prevalence % Non-Hispanic White 9,350 (79.8) 2.8 82.7 African American 638 (5.4) 1.5 10.6 Hispanic 314 (2.7) 2.1 3.6 Asian/PI 1083 (9.2) 8.7 3.1 Native American 75 (0.6) N/A N/A Other 263 (2.2) Sex Female 4,571 (39) 2.0 55.2 Male 7,152 (61) 3.8 44.8
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MTE 11 - How to Write a Scientific Paper (Sign Up Required) (ID 560)
- Event: WCLC 2017
- Type: Meet the Expert
- Track: Education/Publication/Career Development
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 07:00 - 08:00, Room 511 + 512
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MTE 11.01 - How to Write a Scientific Paper that will be Accepted (ID 8126)
07:00 - 08:00 | Presenting Author(s): Alex Adjei
- Abstract
- Presentation
Abstract not provided
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P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.04-013 - Phase 1b Multi-Indication Study of the Antibody Drug Conjugate Anetumab Ravtansine in Patients with Mesothelin-Expressing Advanced or Recurrent Malignancies (ID 10897)
09:30 - 09:30 | Presenting Author(s): Alex Adjei
- Abstract
Background:
Mesothelin is expressed in a wide variety of tumors, including mesothelioma, ovarian, pancreatic, gastric/GEJ, NSCLC, triple-negative breast cancer, cholangiocarcinoma, and thymic carcinomas. Anetumab ravtansine (BAY 94-9343), is a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4 and has shown encouraging anti-tumor activity in mesothelioma and ovarian cancer patients in a phase I study. We will therefore conduct a signal generating study with anetumab ravtansine in six additional high unmet medical need malignancies with mesothelin expression (NCT03102320).
Method:
Eligibility criteria include: ≥18 years, unresectable locally advanced or metastatic recurrent or relapsing disease, one or more prior lines of therapy, and availability of tumor tissue for mesothelin expression testing. Mesothelin-positive patients with selected adenocarcinomas (NSCLC, triple negative breast, gastric including gastroesophageal junction) and thymic carcinoma will receive anetumab ravtansine as monotherapy at 6.5 mg/kg IV on a 21-day cycle. Patients with cholangiocarcinoma will receive anetumab ravtansine in combination with cisplatin (25 mg/m2 IV day 1 and 8 on a 21-day cycle for up to 6 cycles) and patients with pancreatic adenocarcinoma will receive anetumab ravtansine in combination with gemcitabine (1000 mg/m2 IV day 1 and 8 on a 21-day cycle). A safety run-in phase (18-24 patients each) will be conducted for the combination regimens prior to enrolling patients in the main study phase. The primary objective of the main phase of the study is objective response rate (ORR) of anetumab ravtansine as monotherapy or combination therapy in patients with either of two mesothelin expression levels: high (≥30% positive tumor cells with moderate and stronger membrane staining intensity) and low-mid (≥5% all intensities and <30% positive tumor cells with moderate and stronger membrane staining intensity). Secondary objectives include safety, disease control rate, duration of response, durable response rate, and progression-free survival. Approximately 348 patients will be enrolled.
Result:
Section not applicable
Conclusion:
Section not applicable
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-039 - Blood Biomarkers Correlate with Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Anti PD-1 Antibodies (ID 9050)
09:30 - 09:30 | Author(s): Alex Adjei
- Abstract
Background:
Anti-PD-1 antibodies have demonstrated improved overall survival (OS) and progression free survival (PFS) in a subset of patients with metastatic or locally advanced non-small cell lung cancer (NSCLC). Currently, no blood biomarkers in NSCLC predict clinical outcome to anti-PD-1 antibodies.
Method:
A retrospective analysis of locally advanced or metastatic NSCLC patients treated with anti-PD-1 antibodies at Mayo Clinic was performed. White blood cell count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute neutrophil to lymphocyte count ratio (ANC/ALC), absolute eosinophil count (AEC), platelet counts and myeloid to lymphoid ratio (M:L) at baseline and throughout treatment were assessed. Kaplan–Meier and Cox regression analysis were performed.
Result:
157 patients were treated with nivolumab or pembrolizumab between 1/2015 and 4/2017. At median follow-up of 20 months, median OS and PFS were 13.4 and 2.6 months respectively. Higher baseline ANC, AMC, ANC/ALC ratio and M:L ratio significantly correlated with worse clinical outcomes. A baseline ANC/ALC ratio ≥ 5.9 had a significantly increased risk of death [hazard ratio (HR) = 1.65; 95% CI 1.06–2.56, p 0.027] and disease progression [HR = 1.65; 95% CI 1.17–2.34, p 0.005] compared with patients with ANC/ALC ratio <5.9. A baseline M:L ratio ≥ 11.3 had significantly increased risk of death [HR = 2.13; 95% CI 1.32–3.44, p 0.002] even after a multivariate analysis [HR = 1.89, p 0.015] compared to those with lower ratio. An increase from baseline values at 8 weeks for ANC [HR 1.10, p 0.006] and WBC [HR 1.11, p 0.004] was significantly associated with worse OS. Figure 1
Conclusion:
Increased baseline ANC/ALC ratio and M:L ratio were associated with poor PFS and OS in NSCLC patients treated with anti-PD-1 antibodies. The potential predictive value of these biomarkers might help with risk stratification, treatment strategies and warrant further investigation in a larger, prospective study.
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-054 - Inclusion of Central Nervous System Metastasis in Lung Cancer Early Phase Clinical Trials (ID 8407)
09:00 - 09:00 | Author(s): Alex Adjei
- Abstract
Background:
Central nervous system (CNS) metastases are commonly seen in lung cancer patients; up to 40% will have CNS involvement during the course of the disease. However, clinical trials often exclude this patient population due to the increased morbidity/mortality associated with CNS metastases, subsequent reduction of overall survival and poor CNS pharmacokinetics or uncertainty about CNS pharmacokinetics in humans. Therefore, we studied the effects of CNS metastases on the enrollment of lung cancer patients in early phase clinical trials.
Method:
Trials were extracted from ClinicalTrials.gov on April 1[st], 2017. Completed and active trials from 2000-2016 were included in the analysis. Exclusion of CNS metastasis was treated as a binary variable and grouped as strict exclusion vs. allowed. Logistic regressions were used for statistical analysis.
Result:
598 trials were reviewed, 308 (52%) were phase 2, 164 (27%) were phase 1, and 126 (21%) were combined phase 1/2 trials. 304 (51%) trials were conducted in the U.S., 82 (14%) in Asia, 74 (12%) in Europe and 138 (23%) internationally. Most trials were funded by industry (59%), followed by investigator initiated/institutional (23%) and NIH funded (18%). Patients with CNS metastasis were strictly excluded in 130 (22%) trials, allowed if controlled/asymptomatic in 156 (26%) and allowed with no prior treatment in 42 (7%) trials. Patient requiring steroids for their CNS metastasis were excluded in 156 (26%) trials. CNS criteria were not referenced in 114 (19%) trials and these were excluded from further analysis. Of the 194 trials that included survival as one of their end points, 121 (62%) excluded patients with CNS disease. On univariate analysis, the odds of CNS metastasis exclusion were significantly higher in immunotherapy trials (OR: 1.26, 95%CI: 1.07-1.50, p<0.006) and significantly lower in NIH funded trials (OR: 0.35 95% CI: 0.17-0.73, p<0.005). In multivariate analysis, U.S. based trials had higher odds of exclusion of CNS disease (OR: 1.18, 95%CI: 1.06-1.31, p<0.001) compared to European, Asian and International trials. 58 phase 1 trials were followed by phase 2 trials, when comparing exclusion criteria, no changes were made regarding CNS metastasis.
Conclusion:
Many patients with lung cancer and brain metastases are excluded from participation in early phase clinical trials. Broader inclusion of patients with CNS metastasis, or separate clinical trials for those with CNS disease would help determine the efficacy of novel agents for those with CNS metastasis and provide clinical trial options for this patient population.
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YI 01 - Young Investigator and First Time Attendee Session (ID 588)
- Event: WCLC 2017
- Type: Young Investigator
- Track: Education/Publication/Career Development
- Presentations: 1
- Moderators:Peter Goldstraw, Giorgio Vittorio Scagliotti
- Coordinates: 10/15/2017, 08:00 - 11:30, F201 + F202 (Annex Hall)
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YI 01.07 - How to Get Your Paper Published (ID 7850)
09:40 - 09:55 | Presenting Author(s): Alex Adjei
- Abstract
- Presentation
Abstract not provided
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