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Eun Kyung Cho
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MA 01 - SCLC: Research Perspectives (ID 650)
- Event: WCLC 2017
- Type: Mini Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 12
- Moderators:John V Heymach, Eun Kyung Cho
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 503
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MA 01.01 - Metastatic Behavior of Pulmonary Neuroendocrine Carcinomas Is Associated with Epithelial to Mesenchymal Transition Gene Profile (ID 9362)
11:00 - 11:05 | Presenting Author(s): Tabatha Gutierrez Prieto | Author(s): Vanessa Karen De Sá, E.H.R. Olivieri, E.C.A. Da Silva, R.M. Reis, D.M. Carraro, Vera Luiza Capelozzi
- Abstract
- Presentation
Background:
The new 2015 WHO classification broadly divided pulmonary neuroendocrine tumor (NET) of the lung in low-grade typical carcinoid (TC) and atypical carcinoid (AC), to the high-grade large-cell neuroendocrine carcinoma (LCNEC) and the small-cell carcinoma (SCLC). The molecular alterations underlying the pathogenesis of these tumors have been studied showing two blocks of entities with independent cellular mechanisms. Many of the differences between the two NETs blocks can be ascribed to tobacco consumption, which induces epithelial to mesenchymal transition activation, responsible for invasive and metastatic behavior. These correlations further highlight the difference in OS for patients with low and high grade metastatic NETs. Therefore, epithelial to mesenchymal transition (EMT) genes profile emerge promise as indicator of invasion and metastasis in NETs.
Method:
Fresh frozen tissue from SCLC (n = 10), LCNEC (n = 4), AC (n = 5), TC (n = 5) and matched normal tissue samples were collected for qRT-PCR analysis carried out on StepOnePlus™ Real-Time PCR System (Applied Biosystems) with RT[2] Profiler PCR Array System for the EMT pathway with 84 target genes (Qiagen, Dusseldorf, Germany). Linear regression was done to evaluate association between gene expressions. Clinical variable such as age, gender, tobacco history, lymph node metastasis and histologic types were associated with gene expression. Differences were regarded as statistically significant at P < 0.05.
Result:
High expression of membrane receptor EGFR (p = 0.003), protein of the matrix metalloproteinase MMP3 (p = 0.044), transcriptional factor TCF3 (p = 0.022) and signaling pathway factor WNT5A (p = 0.013) were observed in patients with tobacco history. Metastatic LCNEC and SCLC presented significant lower expression of JAG1 gene and higher level of EGFR (p<0.01), transmembrane protein DSP (p = 0.03), TCF3 (p = 0.01), TGF-B3 (p = 0.04) and WNT5A (p = 0.01) compared to TC and AC. In addition to these genes, AKT1 and MAP1B were equally high expressed in metastatic NE carcinomas. Importantly, increased expression of these genes added of MMP2 gene was significantly associated with poor OS of the patients.
Conclusion:
A panel of 84 EMT genes was tested and the best biomarkers included EGFR, MMP2, MMP3, TCF3, WNT5A, JAG1, TGFB3, AKT1 and MAP1B with impact on unfavorable prognostic and overall survival of patients, highlight that EMT play a fundamental role in pathogenetic pathway of metastasis in NETs. Supported by CNPq project 301411/2016-6; FAPESP 2013/10113-7.
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MA 01.02 - Multigene Mutation Profiling and Clinical Characteristics of Small-Cell Lung Cancer in Never-Smokers Versus Heavy Smokers (ID 10335)
11:05 - 11:10 | Presenting Author(s): Andrés F. Cardona | Author(s): Oscar Arrieta, L. Rojas, Z.L. Zatarain-Barron, L. Corrales, Claudio Martin, J. Rodriguez, J. Rodriguez, P. Archila, Alejandro Ruiz-Patiño, Rafael Rosell
- Abstract
- Presentation
Background:
Small-cell lung cancer (SCLC) has been occasionally detected in never-smokers as smoking rates decrease worldwide. We investigated the clinical and genetic characteristics of SCLC in never-smokers (Geno1.3-CLICaP)
Method:
A cohort of patients diagnosed with SCLC were grouped into smokers (n=10) and ever/never-smokers (n=10). For both groups, somatic mutation profiling was carried out using a comprehensive NGS assay (TruSight Tumor 170) targeting the full coding regions of 170 cancer-related genes. Epidermal growth factor receptor (EGFR) mutation was confirmed by RT-PCR (Cobas[TM]). The clinical outcomes of the two groups were compared using Kaplan-Meier and Cox proportional models.
Result:
Median age was 58 years (r, 46-81), 55% (n = 11) were men, most patients had extended disease (85%) and the dominant tumor involvement site was pleura and lungs (65%). No significant differences were found in age, disease distribution, baseline performance status and cerebral metastases in relation to tobacco exposure. The ORR to first-line therapy were 50% and 90% between smokers and ever/never-smokers, respectively (p=0.032). The median overall survival (OS) was 29.1 months in ever/never-smokers (95%CI 23.5-34.6) versus 17.3 months in smokers (95%CI 4.8-29.7; p=0.0054). Never-smoking history (HR 0.543, 95%CI 0.41-0.80), limited stage disease (HR 0.56, 95%CI 0.40-0.91) and response to first line platinum based chemotherapy (HR 0.63, 95%CI 0.60-0.92) were independently related with good prognosis. Among ever/never smokers main genetic mutations were TP53 (80%), RB1 (40%), CYLD (30%), EGFR (30%), MET (20%), SMAD4 (20%) and BRIP1 (20%). None of the smokers had mutations in EGFR, MET or SMAD4, but there was a greater involvement in RB1 (80%, p=0.04), CDKN2A (30%, p=0.05), CEBPA (30%, p=0.05), FANCG (20%), GATA2 (20%), and PTEN (20%).
Conclusion:
Never-smokers with SCLC are increasingly prevalent and have a better prognosis than their smoker counterpart. EGFR, MET and SMAD4 are frequent mutations among SCLCs of ever/never smokers, and RB1, CDKN2A and CEBPA among smokers. Figure 1
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MA 01.03 - The Potential of ctDNA Sequencing in Disease Monitoring and Depicting Genomic Evolution of Small-Cell Lung Cancer Under Therapy (ID 9682)
11:10 - 11:15 | Presenting Author(s): Vincent K Lam | Author(s): J. Wang, Y. Gong, J. Nong, Y. Yi, Y. Guan, L. Yang, H. Jia, S. Zhang, X. Yi, Z. Liao, Vassiliki A Papadimitrakopoulou, Ignacio I. Wistuba, John V Heymach, B. Glisson, A. Futreal, X. Xia, Jianjun Zhang
- Abstract
- Presentation
Background:
Although small cell lung cancer (SCLC) is sensitive to initial therapy, almost all patients relapse and survival remains poor. Outgrowth of treatment-resistant subclones could be responsible for recurrence. However, genomic evolution of SCLC after treatment hasn’t been well investigated, partially due to the challenge of obtaining longitudinal samples. CT is the standard modality for response assessment and disease monitoring. But it doesn’t always accurately assess the disease status. SCLC is characterized by early hemagenous spread, which makes circulating tumor DNA (ctDNA) analysis a promising modality for genomic profiling and disease monitoring of SCLC.
Method:
Targeted-capture deep sequencing (mean target coverage 538x-1866x) of 545 cancer genes was performed to 44 ctDNA samples collected before therapy as baseline and at different timepoints during treatment from 23 SCLC patients. Pretreatment tumor biopsies from 8 patients were also sequenced (mean target coverage 348x-1281x) of the same gene panel. DNA from peripheral blood mononuclear cells was served as the germline control.
Result:
Mutations were identified in all 44 ctDNA samples with a median of 16 mutations per sample (average mutation burden of 6.6/Mb). TP53 and RB1 were the most frequently mutated genes, detected in 91% (21/23) and 65% (15/23) patients, respectively. 74 mutations were identified from the 8 tumor biopsies, among which, 69 (93.2%) were detected in matched ctDNA. We inferred subclonal architecture of each ctDNA sample based on cancer cell fraction derived using PyClone. A median of 10 (ranging 2-26) subclones was inferred from each ctDNA sample and only 17% (2% to 60.%) of mutations were clonal mutations suggesting substantial genomic heterogeneity. Single gene mutations were not associated with survival. However, mean variant allele frequency of clonal mutations (clonal-VAF) at baseline was associated with progression-free survival (PFS) and overall survival (OS) independent of stage, age, or platinum sensitivity. The median PFS of patients with higher versus lower than median clonal-VAF was 5.2 months (95% CI, 4.6 to 5.8 months) versus 10.0 months (95% CI, 9.3 to 10.7 months), p=0.002. The median OS was 8.1 months (95% CI, 5.5 to 10.7 months) versus 24.9 months (95% CI, 0.0 to 51.2 months) in patients with higher versus lower than median clonal-VAF, respectively, p=0.004. Analysis of serial ctDNA before and during treatment showed that clonal-VAF closely tracked closely with treatment responses.
Conclusion:
ctDNA sequencing is a promising modality for genomic profiling and disease monitoring for SCLC patients. Clonal VAF may be a better ctDNA metric than single gene mutations.
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MA 01.04 - Discussant - MA 01.01, MA 01.02, MA 01.03 (ID 10847)
11:15 - 11:30 | Presenting Author(s): Charles Andrew Butts
- Abstract
- Presentation
Abstract not provided
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MA 01.05 - Activity and Safety of the Combination of PM01183 and Doxorubicin in Relapsed SCLC. Final Results of a Phase Ib Trial (ID 9249)
11:30 - 11:35 | Presenting Author(s): Emiliano Calvo | Author(s): M. Forster, V. Moreno, M.E. Olmedo, M.P. Lopez Criado, Jose Antonio Lopez-Vilariño, C. Kahatt, A. Soto-Matos
- Abstract
- Presentation
Background:
Lurbinectedin (PM01183) is a new anticancer drug that binds to DNA, inhibits transactivated transcription and modulates tumor microenvironment. Preclinical evidence of synergism was observed for PM01183 in combination with doxorubicin (DOX).
Method:
Multicenter, phase I clinical trial to determine the recommended dose (RD) of the combination of PM01183 and DOX. An expansion cohort was recruited after finding striking activity in second-line small cell lung cancer (SCLC) patients. Due to hematological toxicity, the trial was amended to use a lower DOX dose and thus improve safety of the combination in selected indications. SCLC patients <75 years with ECOG performance status (PS) 0-1 and pretreated with no more than one chemotherapy line were included. Stable brain metastases were allowed. DOX was interrupted after 10 cycles and PM01183 could be continued as single-agent. Primary G-CSF prophylaxis was not mandatory.
Result:
48 patients were treated: 21 in Cohort A (PM01183 3-5 mg flat dose [FD] Day (D)1 + DOX 50 mg/m2 D1 every 21 days [q21d]), and 27 in Cohort B (PM01183 2 mg/m2 D1 + DOX 40 mg/m2 D1 q21d). Males: 74%; median age: 64 (48-77) years, ECOG 0-1: 37%-63%; known central nervous system (CNS) involvement: 10%; bulky disease (>50 mm): 67%. 85% responded to first line, including 4% with complete response (CR). Median chemotherapy free interval (CTFI): 3.4 months. Refractory (CTFI<30 days) 23%; resistant (CTFI 30-90 days) 34%; sensitive (CTFI>90 days) 43%. RD: PM01183 4 mg FD (or 2 mg/m2) + DOX 50 mg/m2 D1 q21d. Confirmed ORR: 50% (95CI: 35-65%) with 6% CR in both cohorts; ORR=69% (95CI: 49-85%) with 10% CR in sensitive patients. Cohort A: ORR=67% (95%CI: 43-85%) with 10% CR; ORR=92% (95%CI: 62-100%) in sensitive patients. Cohort B: ORR=37% (95%CI: 19-58%) with 4% CR; ORR=53% (95%CI: 28-77%) in sensitive patients. Median PFS (mPFS) 4.6 months (95%CI: 3.1-5.8), with mPFS 1.5 months (95%CI: 1.2-3.8) in resistant patients and 5.8 months (95%CI: 3.6-7.9) in sensitive patients. In both cohorts, grade 4 neutropenia/anemia/thrombocytopenia appeared in 73%/4%/15% of patients and febrile neutropenia in 21% (11% at RD). Non-hematological toxicity was mainly fatigue (G3=14%) and nausea (G3=5%).
Conclusion:
PM01183/DOX combination showed remarkable activity as second line in SCLC, especially in patients with CTFI>90 days, regardless of dose. Activity is higher than reported for CAV or topotecan in this setting. Reversible myelosuppression was the most frequent and expected side effect. A phase III trial with this combination in relapsed SCLC is ongoing.
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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 | Presenting Author(s): Hongbin Chen | Author(s): Grace K Dy, A. Groman, E. Farrell, A. Miller, P. Bushunow, 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 01.07 - Lanreotide Maintenance in SCLC Expressing Somatostatine Receptors: Efficacy Results of Multicenter Randomized G04.2011 Trial (ID 8480)
11:40 - 11:45 | Presenting Author(s): Sara Pilotto | Author(s): E. Bria, Domenico Galetta, Francesco Grossi, G. Fasola, G. Romano, L. Bonanno, A. Bearz, M. Papi, A. Caprioli, A. Catino, A. Follador, E. Rijavec, A. Misino, G. Surico, A. Favaretto, L. Giannone, G. Tortora, D. Giannarelli, A. Santo
- Abstract
- Presentation
Background:
SCLC is featured by both a rapid response and progression during/after standard upfront therapy. Thus, maintenance strategies emerged as potential treatment opportunities, although to date all drugs failed to significantly improve prognosis. SCLC cells harbor a neuroendocrine phenotype, frequently expressing somatostatine (SST) receptors. This study aimed to investigate the efficacy of somatostatine (SST) analogue Lanreotide (LAN) as a maintenance strategy for SCLC patients (pts) after response to standard upfront treatment.
Method:
A multicentre, randomized, open-label, no-profit national trial was conducted, randomizing (1:1) SCLC (limited/extended disease, L/ED) pts expressing SST receptors (by SST receptor scintigraphy) with objective response (CR or PR) after upfront platinum-based chemotherapy plus/minus radiotherapy to receive maintenance LAN 120 mg subcutaneously every 28 days, up to progressive disease (PD) for 1 year (Arm A), versus observation (Arm B). Primary end-point was 1-year Progression-Free Survival (PFS). Primary intention-to-treat (ITT) analysis was planned (power: 80%; 2-tailed alpha-error: 5%) after 47 PFS events.
Result:
Seventy-one pts (median age 66 [37-82]; male/female 72/28%; L/ED 39/61%; ECOG-PS 0-1/2 97/3%; previous best response CR/PR 6/94%) were randomized in 9 Italian centers. Median time from diagnosis and end-of-1[st] line to inclusion was 5.7 months (3-160) and 30 days (0-119), respectively. Median number of LAN doses and treatment duration (Arm A) was 4 (1-12) and 83 days (1-392), respectively. With a median follow-up of 9.4 months and 62 events, median PFS was 3.6 (95% CI 3.2-3.9) versus 2.3 months (95% CI 1.7-2.9), for Arm A and B (log-rank p=0.11; HR 1.51, 95% CI 0.90-2.50), with a 1-year PFS of 10.3% versus 7.3%, respectively. At the cox-proportional multivariate modelling, stage (ED versus LD, HR 2.88 [95% CI 1.64-5.04, p<0.0001) and treatment arm (B versus A, HR 1.63 [95% CI 0.97-2.72], p=0.06) were independent predictors for PFS. Median PFS of arm A and B was 7.0 [95% CI <1-13.5] and 3.8 months [95% CI <1-8.6] in LD pts (p=0.21), and 3.0 (95% CI 2.2-3.8) and 2.2 (95% 1.7-2.7) in ED pts (p=0.19). Median OS was 9.5 (95% CI 4.8-14.3) and 4.7 months (95% CI 1.7-16.6), for Arm A and B (log-rank p=0.47), respectively. LAN was well-tolerated: serious treatment-related adverse events were grade 3 abdominal pain and electrolyte disorder in overall 2 pts.
Conclusion:
Although the primary end-point was not met, the overall efficacy of LAN as a maintenance strategy after response to standard upfront treatment for SCLC deserves future investigations, particularly in pts with LD.
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MA 01.08 - Discussant - MA 01.05, MA 01.06, MA 01.07 (ID 10848)
11:45 - 12:00 | Presenting Author(s): Anne Tsao
- Abstract
- Presentation
Abstract not provided
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MA 01.09 - Treatment Patterns in Extensive Disease Small Cell Lung Cancer Across the United States, Europe, and Japan (ID 8479)
12:00 - 12:05 | Presenting Author(s): Yong Yuan | Author(s): K. Higginbottom, M. Dibonaventura, J.R. Penrod
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) comprises ~10-15% of lung cancers. The majority of patients with SCLC present with extensive disease (ED) and have extremely poor outcomes; <5% survive 2 years. Although first-line (1L) treatment is typically platinum-based, many patients are platinum-resistant with few effective options after relapse. The study objective was to compare treatment patterns across regions and by platinum resistance/sensitivity.
Method:
This study used data from the Oncology Monitor (Ipsos Healthcare), a global clinical database of oncology patients collected through retrospective medical chart reviews. Treating physicians were invited to submit information on their patients with SCLC treated from January 2014 through December 2016 in the United States (US), the European Union 5 (EU5; France, Germany, Italy, Spain, and the United Kingdom), or Japan.
Result:
A total of 5849 patients with SCLC were included (2605 in the US, 2203 in the EU5, and 1041 in Japan). Mean age was 65.6 years (standard deviation: 8.8); 66.3% were male and 94.0% diagnosed with ED. In all, 73.4% of patients were receiving 1L, 19.8% second-line (2L), and 6.8% third-or-later-line therapy. Platinum/etoposide was the most frequently prescribed 1L therapy, although it was significantly more common in the US (87.0%) than the EU5 (82.1%) or Japan (73.3%) (P<0.05). Cisplatin/etoposide was prescribed more often in 1L in the EU5 (40.8%) than in the US (26.6%) or Japan (23.7%) (P<0.0001). Platinum/irinotecan was an uncommon 1L treatment in the US (2.0%) and EU5 (0.5%) but common in Japan (22.7%; P<0.0001). Platinum-resistance (relapse within ≤3 months of 1L treatment completion) was observed in >40% of patients (US: 45.4%, EU5: 40.9%, Japan: 56.1%). Regardless of platinum-resistance versus sensitivity, the most common 2L treatment in the US and EU5 was topotecan (42.3% vs 47.6%) and (59.5% vs 56.1%), and amrubicin in Japan (52.1% vs 53.1%). Among platinum-resistant patients in the US, EU5, and Japan, 27.3%, 10.8%, and 36.4% received a platinum-based 2L therapy. Additionally, 52.3%, 66.7%, and 44.9% of platinum-sensitive patients did not receive 2L platinum re-challenge.
Conclusion:
Current NCCN and ESMO guidelines (endorsed by JSMO) recommend platinum-resistant patients receive non–platinum-based 2L therapies. The guidelines also recommend that platinum-sensitive patients (relapse >6 months) receive the original 1L regimen as a 2L re-challenge. However, this real-world study found that a significant proportion of platinum-resistant patients were re-challenged with a 2L platinum-based therapy. Conversely, in patients where platinum re-challenge is recommended, a large proportion did not receive platinum-based therapies in 2L.
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MA 01.10 - Outcome Based on Baseline Total Lymphocyte Count & Neutrophil-To-Lymphocyte Ratio in Extensive Stage Small-Cell Lung Cancer (ID 8570)
12:05 - 12:10 | Presenting Author(s): Ryoko Suzuki | Author(s): S.H. Lin, X. Wei, P.K. Allen, J.W. Welsh, L.A. Byers, Ritsuko Komaki
- Abstract
- Presentation
Background:
The prognosis for patients with extensive stage small-cell lung cancer (ES-SCLC) is dismal. Immune suppression and systemic inflammation have been linked with outcomes for patients with a variety of malignancies, including lung cancer. The purpose of this study was to investigate the impact of baseline immune suppression and systemic inflammation as assessed with hematologic markers such as total lymphocyte count (TLC) and neutrophil-to-lymphocyte ratio (NLR) on overall survival (OS) in patients with ES-SCLC.
Method:
We retrospectively investigated 253 consecutive patients with pathologically and radiographically proven ES-SCLC treated at a single tertiary cancer center from 1998 through 2015. Potential correlations between initial complete blood counts & differential and other clinicopathologic characteristics were sought. Hematologic markers such as pretreatment TLC, NLR, platelet count, and platelet-to-lymphocyte ratio and other clinical characteristics including age, sex, performance status, race, TNM stage (M1a vs. M1b), weight loss, smoking status, number of initial chemotherapy cycles (<4 vs. ≥4 cycles), thoracic radiation therapy (TRT) dose (<45 Gy vs. ≥45 Gy), and receipt of prophylactic cranial irradiation (PCI) were evaluated for correlation with OS. Median values for each hematologic marker were used as cutoffs. Factors identified as important by univariate analysis were selected as covariates to construct a multivariate Cox model for OS.
Result:
Pretreatment TLC was below the lower limit of normal (i.e., <1.0×10[3]/µL) in 58 patients (23%). Median OS was 11.0 months for the entire cohort. Median OS time was significantly worse in patients with lower pretreatment TLC (TLC ≤1.5×10[3]/µL: 9.8 months, 95% confidence interval [CI] 8.9‒10.7 vs. TLC >1.5×10[3]/µL: 11.6 months, 95% CI 9.3‒13.9) and higher pretreatment NLR (NLR >4.0: 9.3 months, 95% CI 8.8‒9.8 vs. NLR ≤4.0: 13.9 months, 95% CI 11.2‒16.6). Multivariate analysis identified lower pretreatment TLC (hazard ratio [HR] 0.735, 95% CI 0.561‒0.962, P=0.025) and elevated pretreatment NLR (HR 1.534, 95% CI 1.182‒1.991, P=0.001) as being independent predictors of inferior survival. Six other clinicopathologic factors (age >63 years, being male, performance status score ≥2, having <4 initial chemotherapy cycles, TRT <45 Gy, and no PCI) were also shown to be independent predictors of worse OS in multivariate analysis (P<0.05).
Conclusion:
Pretreatment TLC and NLR are useful prognostic markers for OS in patients with ES-SCLC. These findings have important implications for stratifying patients with ES-SCLC for various treatment approaches, possibly including immune modulation.
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MA 01.11 - Timing of Thoracic Radiotherapy Is More Important Than Dose Escalation in Patients with Limited-Stage Small Cell Lung Cancer (ID 7354)
12:10 - 12:15 | Presenting Author(s): Xiao Hu | Author(s): B. Xia, Y. Bao, Y.J. Xu, J. Wang, H.L. Ma, Y. Jin, M. Fang, H.R. Tang, M.Y. Chen, B.Q. Dong, X. Fu, M. Chen
- Abstract
- Presentation
Background:
The optimal thoracic radiation dose/fraction for limited-stage small cell lung cancer (SCLC) is still in debate. This study mainly aims to retrospectively compare the impact on local/regional progression-free survival (LRPFS) of different thoracic radiation dose/fraction schedules from two prospective trials.
Method:
Patients in the hyperfractionated arm received thoracic radiotherapy consisted of 1.5 Gy twice a day in 30 fractions to 45 Gy. Patients in the hypofractionated arm received 2.5 Gy daily in 22 fractions to 55 Gy. Kaplan-Meier method was used to estimate survival data. Multivariate prognosis analysis was made by Cox proportional hazard regression analysis.
Result:
Nighty-two and 96 patients were accrued into to the hyperfractionated and hypofractionated arm respectively. The 1-year, 2-year LRPFS rates of the two arms were 82.1%, 60.7% and 84.9%, 68.8% respectively (P=0.27). The median OS time (months) of the two arms were 28.3 and 22.0 respectively, while 1-year, 3-year, 5-year OS rates were 85.2%, 40.8%, 27.1% and 76.9%, 34.3%, 26.8% respectively (P=0.37). On multivariate Cox regression study, the time (days) from the initiation of chemotherapy to thoracic radiotherapy (TCT) ≤ 43 (HR: 0.397, 95%CI: 0.207-0.762, P=0.005) was independently associate with improved LRPFS. The time (days) from the start of chemotherapy to end of thoracic radiotherapy (SER) ≤ 63 (HR: 0.508, 95%CI: 0.322-0.762, P=0.044) and PCI (HR: 0.433, 95%CI: 0.298-0.630, P=0.000) were favorably related to OS. Grade 2 and 3 acute radiation esophagitis were observed in 28.3%, 8.7% and 15.5%, 2.1% of patients in hyper- and hypofractionated arm respectively (P=0.009). Figure 1
Conclusion:
Both hyperfractionated and hypofractionated radiotherapy had achieved good LRPFS and OS in this study, although there was no statistical significance between the two arms. Keep TCT ≤ 43, SER ≤ 63 resulted in better LRPFS and OS. However, the incidence of acute radiation induced esophagitis was significantly more common in the hyperfractionated arm than in hypofractionated arm.
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MA 01.12 - Discussant - MA 01.09, MA 01.10, MA 01.11 (ID 10849)
12:15 - 12:30 | Presenting Author(s): Anand Swaminath
- Abstract
- Presentation
Abstract not provided
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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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P3.05 - Early Stage NSCLC (ID 721)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.05-010 - NOTCH 1 and NOTCH 3 Expressions for Early Stage of Non-Small Cell Lung Cancer (ID 9703)
09:30 - 09:30 | Presenting Author(s): Eun Kyung Cho
- Abstract
Background:
Notch gene Encode 300kDa single-pass transmembrane receptors. It can variously serve as an oncogene or a tumor suppressor and a repressor or inducer of terminal differentiation. It also regulate cell division, differentiation and survival of stem and/or progenital cells in wide range tissues. We examined Notch 1 and 3 to study the correlation of Notch expression and prognosis for non-small cell lung cancer.
Method:
Paraffin-embedded tissue microarrays were constructed. We analyzed Notch 1 and 3 by immunohistochemical stain on surgical tumor specimens.
Result:
One hundred fifty-nine of 185 resected tissues for lung cancer (median age 62 years) were available for immunohistochemical stain. The types of tumor histology were adenocarcinoma;54, squamous cell carcinoma:79, others;26. 121 patients were taken lobectomy and 38 were done pneumonectomy. Notch 1 and 3 receptors were detected in 119 (74.8%) and 130 (81.7%) of total 159 (M:F=114:45) tumor tissues, respectively. Notch 1 receptors showed higher expressions on squamous cell carcinoma than non-squamous cell carcinoma (58.8% vs. 37.8%, p=0.03). However, it was not correlated with sex, smoking status or advanced stages. Five year-relapse free survival (RFS) and overall survival (OS) were 57.4 % and 59.3 % in 159 patients, respectively. Patients with any expression of Notch1 or 3 have correlated with neither RFS nor OS. 5 year OS for patients who showed Notch 3 expression were 62 % and the others were 47.8%, however, it was not statistically significant (p= 0.165). Both of their expressions were detected in 106 of 159 (66.7%) tumor tissues. Sixteen (10 %) had negative expressions in both of them. The patients with both positive expressions had the tendency of longer OS than all negative patients. Their 5 year OS were 60.8 % vs. 38.2% (p=0.068) and 5 year RFS were 56.5% vs. 49.7 % (p=0.35).
Conclusion:
Notch 1 showed higher expression on squamous cell carcinoma. Neither Notch 1 nor 3 have correlated with RFS or OS, but patients with both expressions had the tendency of longer overall survival.
