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John V Heymach
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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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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 01.03 - 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 | Author(s): John V Heymach
- 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 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.02 - STK11/LKB1 Loss of Function Genomic Alterations Predict Primary Resistance to PD-1/PD-L1 Axis Blockade in KRAS-Mutant NSCLC (ID 10367)
15:50 - 15:55 | Author(s): John V Heymach
- Abstract
- Presentation
Background:
The genomic landscape of primary resistance to PD-1 blockade in lung adenocarcinoma (LUAD) is largely unknown. We previously reported that co-mutations in STK11/LKB1 (KL) or TP53 (KP) define subgroups of KRAS-mutant LUAD with distinct therapeutic vulnerabilities and immune profiles. Here, we present updated data on the clinical efficacy of PD-1/PD-L1 inhibitors in co-mutation defined KRAS mutant and wild-type LUAD patients and examine the relationship between genetic alterations in individual genes, tumor cell PD-L1 expression and tumor mutational burden (TMB) using cohorts form the SU2C/ACS Lung Cancer Dream Team and Foundation Medicine (FM).
Method:
The cohorts included 924 LUAD with NGS (FM cohort) and 188 patients with KRAS non-squamous NSCLC (SU2C cohort) who received at least one cycle of PD-1/PD-L1 inhibitor therapy and had available molecular profiling. Tumor cell PD-L1 expression was tested using E1L3N IHC (SU2C) and the VENTANA PD-L1 (SP142) assay (FM). TMB was defined as previously described and was classified as high (TMB-H), intermediate (TMB-I) or low (TMB-L).
Result:
188 immunotherapy-treated (83.5% nivolumab, 11.7% pembrolizumab, 4.8% anti-PD1/PD-L1 plus anti-CTLA-4) pts with KRAS-mutant NSCLC were included in the efficacy analysis. The ORR differed significantly between the KL (8.8%), KP (35.9%) and K-only sub-groups (27.3%) (P=0.0011, Fisher’s exact test). KL LUAC exhibited significantly shorter PFS (mPFS 1.8m vs 2.7m, HR=0.53, 95% CI 0.34-0.84, P<0.001, log-rank test) and OS (mOS 6.8m vs 15.6m, HR 0.53, 95% CI 0.34 to 0.84, P=0.0072, log rank test) compared to KRAS-mutant NSCLC with wild-type STK11. Loss-of function (LOF) genetic alterations in STK11 were the only significantly enriched event in PD-L1 negative, TMB-I/H compared to PD-L1 high positive (TPS≥50%), TMB-I/H tumors in the overall FMI cohort (Bonferroni adjusted P=2.38x10[-4], Fisher’s exact test) and among KRAS-mutant tumors (adjusted P=0.05, Fisher’s exact test) . Notably, PD-1 blockade demonstrated activity among 10 PD-L1-negative KP tumors, with 3 PRs and 4SDs recorded. In syngeneic isogenic murine models PD-1 blockade significantly inhibited the growth of Kras mutant tumors with wild-type LKB1 (K), but not those with LKB1 loss (KL), providing evidence that LKB1 loss can play a causative role in promoting PD-1 inhibitor resistance.
Conclusion:
Loss of function genomic alterations in STK11 represent a dominant driver of de novo resistance to PD-1/PD-L1 blockade in KRAS-mutant NSCLC. In addition to tumor PD-L1 status and tumor mutational burden precision immunotherapy approaches should take into consideration the STK11 status of individual tumors.
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MTE 31 - Perspectives of Anti-Angiogenesis (Sign Up Required) (ID 580)
- Event: WCLC 2017
- Type: Meet the Expert
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 07:00 - 08:00, Room 418
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MTE 31.01 - Perspectives of Anti-Angiogenesis (ID 7821)
07:00 - 08:00 | Presenting Author(s): John V Heymach
- Abstract
- Presentation
Abstract not provided
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OA 07 - Biomarker for Lung Cancer (ID 659)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Philip Christopher Mack, Shinichi Toyooka
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 503
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OA 07.02 - Characteristics of Lung Cancer Cell-Free Tumor DNA (CfDNA) Shedding and Correlation with Tumor Burden as Measured by RECIST (ID 9663)
15:55 - 16:05 | Author(s): John V Heymach
- Abstract
- Presentation
Background:
cfDNA is a promising biomarker for early recurrence detection and disease monitoring in the NSCLC curative setting. However, less is known about cfDNA shedding characteristics and correlation with tumor burden in advanced NSCLC.
Method:
We reviewed cfDNA results of NSCLC patients tested at our institution between November 2015 and December 2016 with Guardant 360, a comprehensive cfDNA assay that detects genomic alterations in 70-73 cancer genes. 141 cases with evaluable imaging were selected for this analysis, enriching for EGFR and KRAS mutated cases to facilitate comparisons of major genomic subtypes (Table 1). Tumor burden was approximated using the sum of longest diameters (SLD), per RECIST v1.1.
Result:
There was a statistically significant correlation of moderate strength between cfDNA maximum variant allele frequency (VAF) detected and SLD (Spearman’s rho = 0.35, p < 0.001). This correlation was strongest in KRAS mutant cases (rho = 0.52, p = 0.001) and weakest in EGFR mutated tumors (rho = 0.21, p < 0.24). Multi-variate regression that included stage, histology, and mutation status confirmed the predictive value of cfDNA VAF for SLD (p = 0.03). TP53 mutants had higher cfDNA VAF (Wilcox p < 0.001), even after accounting for SLD. Increased cfDNA VAF was also seen with EGFR mutants and patients with visceral metastasis, though possibly confounded by concomitant EGFR amplification and increased tumor burden, respectively. CNS metastasis was not associated with differential cfDNA shedding. Figure 1
Conclusion:
In this primarily metastatic cohort, cfDNA VAF correlated with radiographic assessment of tumor burden by RECIST. This correlation was partially mediated by the presence of key driver mutations. TP53 and EGFR mutant tumors and the presence of visceral metastasis are associated with higher cfDNA VAF. These findings have potential implications for the use of cfDNA in advanced-stage NSCLC disease monitoring, where RECIST is more clinically applicable than formal volumetrics.
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OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.05 - Identification of Novel Potentially Targetable Genomic Alterations in Paired Tumors with Acquired EGFR TKI Resistance by NGS (ID 9088)
11:45 - 11:55 | Author(s): John V Heymach
- Abstract
- Presentation
Background:
While previous reports have established MET and HER2 amplification as two mechanisms of non-T790M driven EGFR TKI resistance in EGFR mutant NSCLC, resistance occurs in the absence of these modifications in a significant number of patients. Therefore, there exists an unmet need to define additional mechanisms of resistance to EGFR TKIs. We hypothesized that targeted next-generation sequencing could detect additional targetable activating mutations in paired tumor samples from patients with acquired resistance to first or second generation EGFR TKIs.
Method:
We conducted an analysis of clinical and molecular data prospectively collected from 285 EGFR-mutant NSCLC patients enrolled into the MD Anderson Lung Cancer GEMINI database. Of 157 patients treated with first-line therapy (erlotinib, gefitinib, or afatinib), we identified 75 patients with TKI-acquired resistance with matched pre/post-TKI tumor samples. Matched tumor samples were analyzed with targeted gene sequencing. Recurrent alterations were defined as an alteration occurring more than 2 times. Recurrent acquired mutations were expressed in Ba/F3 and EGFR mutant (T790M+/-) NSCLC cells. Mutation expressing Ba/F3 cell lines were assayed for IL-3 independence, and mutation expressing NSCLC cell were screened against combination targeted TKIs.
Result:
EGFR mutant NSCLC patients treated with first-line therapy had a median PFS of 14 months; and, of the patients with pre/post-TKI tumor molecular data, 47% of patients were T790M negative. There were 30 recurrent acquired alterations identified in 13 different genes. Genes included ARAF, BRAF, EGFR, FGFR, GNAS, JAK2, MCL1, PDGFRα, PIK3CA, RAF1, RB1, SMAD4, and TP53. Of the alterations identified, most occurred in 1 of 4 targetable genes: BRAF (N=3), FGFR (N=5), PDGFRα (N=3), or PIK3CA (N=2). Both previously reported and novel mutations were identified, and preliminary screening of mutant expressing Ba/F3 cell lines found that of the mutations tested (BRAF WT & G469H, FGFR2 A371G, PDGFRα WT & L682F, and PIK3Ca E545K) all grew independent of IL-3. HCC827 and H1975 cell lines expressing acquired mutations in BRAF, FGFR, PDGFRα, or PIK3CA were more sensitive to combination targeted therapy compared to EGFR TKIs or mutation specific TKIs alone unlike control cell lines, supporting the possibility that targeting these mutations would be of therapeutic benefit.
Conclusion:
Analysis of patient data identified 30 recurrent genomic alterations in 13 different genes including novel alterations in BRAF, EGFR, FGFR, PDGFRα, RB1, and SMAD4, many of which were found to be activating mutations. Our analysis identified potentially targetable mutations of BRAF, FGFR, PDGFRα, and PIK3CA which merits further pre-clinical and clinical investigation.
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.01 - The Preclinical and Clinical Activity of Poziotinib, a Potent, Selective Inhibitor of EGFR Exon 20 Mutant NSCLC (ID 10369)
11:00 - 11:10 | Author(s): John V Heymach
- Abstract
- Presentation
Background:
Approximately 10% of EGFR mutant NSCLCs have an insertion/mutation in exon 20 of EGFR resulting in primary resistance to currently available tyrosine kinase inhibitors (TKIs). We previously reported that the structural features of poziotinib could potentially enable it to circumvent the steric hindrance induced by exon 20 mutations. Here we further characterize the preclinical activity of poziotinib and report on initial clinical activity of poziotinib in patients with EGFR exon 20 mutations from an ongoing phase II study.
Method:
We evaluated poziotinib activity in vitro using human NSCLC cell lines and the BAF3 model as well as several patient-derived xenograft (PDX) models and genetically engineered mouse models (GEMMs) of exon 20 insertion. We launched a phase 2 investigator-initiated trial of poziotinib in patients with metastatic NSCLC with EGFR exon 20 insertions (NCT03066206).
Result:
In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had ~65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3[rd] generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/insertions compared with T790M. in vivo poziotinib led to >85% reduction in tumor burden in GEM models of EGFR exon 20 insertion (D770insNPG) NSCLC and the PDX model LU0387 (H773insNPH). To date, 8 platinum-refractory patients with EGFR exon 20 insertion mutation metastatic NSCLC have been enrolled in the clinical trial and treated with poziotinib at a dose of 16 mg PO daily. Two patients have reached the first interval-imaging time point (at 8 weeks of therapy per protocol). Both patients exhibited dramatic partial response, with one patient reporting improvement in dyspnea and cough at one week of therapy. In this early stage of the study, one case of grade 3 paronchycia was observed. One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis. The patient achieved partial response after three weeks of treatment.
Conclusion:
Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting.
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OA 12.05 - Spectrum of 1,014 Somatic BRAF Alterations Detected in Cell-Free DNA of Patients with Advanced Non-Small Cell Lung Cancer (ID 9984)
11:40 - 11:50 | Author(s): John V Heymach
- Abstract
- Presentation
Background:
Somatic BRAF V600E is a National Comprehensive Cancer Network clinical therapeutic target in non-small cell lung cancer (NSCLC), occurring in 6% of tumors from patients with lung adenocarcinoma. However, approximately half of BRAF alterations are non-V600E that do not respond to FDA-approved vemurafenib or dabrafenib. Emerging evidence suggests some non-V600E mutations exhibit clinical response to novel therapeutic agents. We analyzed the landscape of BRAF mutations in a very large cohort of patients with NSCLC who underwent somatic genomic testing utilizing a CLIA-certified/CAP-accredited/NYSDOH-approved 73 gene cell-free circulating tumor DNA (cfDNA) panel which evaluates single nucleotide variants, and selected indels, fusions, and copy number amplifications.
Method:
The Guardant Health laboratory database was queried for cfDNA tests from patients with a diagnosis of NSCLC where a BRAF variant was identified. Literature was queried for a description of the known function of non-V600E BRAF mutations on serine-threonine kinase activity.
Result:
A total of 1,014 BRAF alterations were observed in 914 tests, with 234 unique alterations identified. The majority of variants were observed only once (75.6%; N=177). 43 alterations were synonymous and excluded from analysis. Plasma-detected BRAF amplification was the most common alteration, observed in 484 tests. Of the remaining variants, 33 of 190 had functional consequence reported in the literature (17.4%), 18 with gain of function or predicted gain of function, 13 with loss of function or predicted loss of function and 2 with no effect. BRAF V600E accounted for 51.1% of occurrences of variants with gain of function or predicted gain of function (N=95 occurrences). Recurrent (>10 occurrences) non-V600E gain of function mutations included G469A (13.4%; N=25 occurrences), K601E (8.0%: N = 15 occurrences), and N581S (7.0%; N=13 occurrences). Fourteen additional gain of function variants comprised the remaining 21% of occurrences. Recurrent loss of function BRAF mutations (>10 occurrences) included G466V and D594G.
Conclusion:
This is the largest reported cohort of somatic BRAF alterations in metastatic non-small cell lung cancer. Non-V600E alterations accounted for almost 50% of the gain of function variants. The spectrum of non-V600E alterations was consistent with reports from The Cancer Genome Atlas and prior published results from tissue genomic sequencing. The recurrent non-V600E variants identified in this cohort are emerging therapeutic targets with promising early clinical data. These findings advocate for more comprehensive BRAF genomic profiling and identification of patients eligible for clinical trials targeting these non-V600E classic mutations and demonstrate the ability of plasma-based cfDNA to detect these alterations.
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OA 13 - Immuno-Biology (ID 677)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:Hiroyuki Suzuki, Scott N. Gettinger
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 301 + 302
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OA 13.01 - CD38-Mediated Immunometabolic Suppression as a Mechanism of Resistance to PD-1/PD-L1 Axis Blockade (ID 10157)
11:00 - 11:10 | Author(s): John V Heymach
- Abstract
- Presentation
Background:
Although immune checkpoint inhibitors of the PD-1/PD-L1 axis provide significant clinical benefit for patients with lung cancer, effective use of these agents is encumbered by a high rate of primary or acquired resistance. Strategies for optimal therapeutic application of immunotherapy require a thorough understanding of resistance mechanisms. To date, there have been only a few studies reporting potential mechanisms of resistance to PD-1/PD-L1 blockade.
Method:
In multiple immunocompetent syngeneic and spontaneous animal models of K-ras/p53 mutant lung cancer, we explored the resistance mechanisms to PD-1/PD-L1 blockade using both pharmacologic and genetic approaches (therapeutic antibody treatment and CRISPR/Cas9-mediated editing). The molecular and immune profiles of the tumor microenvironment were evaluated. Additionally, to determine the applicability to patients with lung cancer, we analyzed 259 tumor specimens with IHC staining and mRNA expression, and further confirmed the analyses in publically-available TCGA datasets.
Result:
In multiple models of antibody blockade and genetic knockout of PD-L1, we identified the up-regulation of CD38 on tumor cells as a marker of treatment resistance. Furthermore, by manipulating CD38 on a panel of lung cancer cell lines we demonstrated in vitro and in vivo that CD38 expression inhibits CD8[+] T cell proliferation, anti-tumor cytokine secretion, and tumor cell killing capability. The T cell suppressive effect is dependent upon the ectoenzyme activity of CD38 that regulates the extracellular levels of adenosine. To test whether CD38 blockade might be therapeutically efficacious to prevent anti-PD-L1/PD-1 resistance, we applied combination therapy with anti-CD38 and anti-PD-L1 and demonstrated dramatic therapeutic benefit on primary tumor growth and metastasis. Additionally, in a set of 259 resected lung cancer specimens, ~15% exhibited positive staining for CD38 on tumor cells, and the expression correlated with cytolytic T cell score and an immune/inflammatory signature across multiple large datasets.
Conclusion:
CD38 was found to be a novel mechanism for tumor escape from immune checkpoint PD-1/PD-L1 inhibitor therapy. Targeting this resistance pathway may broaden the benefit of PD-L1/PD-1 axis blockade for lung cancer treatment.
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OA 13.05 - Immune, Molecular and T Cell Repertoire Landscape of 235 Resected Non-Small Cell Lung Cancers and Paired Normal Lung Tissues (ID 8766)
11:45 - 11:55 | Author(s): John V Heymach
- Abstract
- Presentation
Background:
Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types responding to immune checkpoint blockade, likely through harnessing of the anti-tumor T cell response. However, the lung is continuously exposed to the outside environment, which may result in a continuous state of inflammation against outside pathogens unrelated to the tumor microenvironment. Therefore, further investigation into the T cell repertoire and T cell phenotypes across normal lung and tumor is warranted.
Method:
We performed T cell receptor (TCR) sequencing on peripheral blood mononuclear cells (PBMC), normal lung, and tumor from 225 NSCLC patients, among which, 96 patients were also subjected to whole exome sequencing (WES) of PBMC, tumor and normal lung tissues. We further performed Cytometry by Time-of-Flight (CyTOF) on 10 NSCLC tumors and paired normal lung tissues to phenotype immune and T cell subsets.
Result:
Comparison of the T cell repertoire showed 9% (from 4% to 15%) of T cell clones were shared between normal lung and paired tumor. Furthermore, among the top 100 clones identified in the tumor, on average 57 (from 0 to 95) were shared with paired normal lung tissue. Interestingly, T cell clonality was higher in the normal lung in 89% of patients suggesting potential differences in the immune response and immunogenicity. A substantial number of somatic mutations were also identified not only in NSCLC tumors (average 566; from 147 to 2819), but also in morphologically normal lung tissues (average 156; from 50 to 2481). CyTOF demonstrated striking differences in the immune infiltrate between normal lung and tumor, namely a lower frequency of PD-1+CD28+ T cells (both CD4+ and CD8+) in the normal lung (2.7% versus 3.0% in tumor). In addition, a unique GITR+ T cell subset (0.96%) was entirely restricted to the normal lung. Conversely, increases in regulatory T cell frequency (CD4+FoxP3+) were observed in the tumor (10.4% vs 1.7% in normal lung), further highlighting the differences in T cell phenotype and response across normal lung and tumor.
Conclusion:
These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be residential T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes including increases in immunosuppressive T cells within the tumor which may further highlight the differences in the anti-tumor immune response.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-013 - Investigation of Genomic and TCR Repertoire Evolution of AAH, AIS, MIA to Invasive Lung Adenocarcinoma by Multiregion Exome and TCR Sequencing (ID 9192)
09:30 - 09:30 | Author(s): John V Heymach
- Abstract
Background:
Carcinogenesis may result from accumulation of molecular aberrations (molecular evolution) and escaping from host immune surveillance (immunoediting). It has been postulated that atypical adenomatous hyperplasia (AAH) represents preneoplastic lesion that may progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). However, due to lack of appropriate study materials, the molecular and immune landscape of AAH, AIS or MIA have not been well studied and the definition and management of these lesions remain controversial.
Method:
With the intent to delineate the pivotal molecular and immune events during early carcinogenesis of lung adenocarcinoma, we have collected 119 resected pre- and early neoplastic lung lesions including AAH (N=24), AIS (N=27), MIA (N=54) and ADC (N=14) from 53 patients including 41 patients presenting with multifocal lesions and 25 patients carrying more than one type of pathology. Two to five spatially separated regions from each lesion were subjected to whole exome sequencing and T cell receptor sequencing.
Result:
Mutation burden (average SNVs) was found to progressively increase from 1.32/Mb in AAH to 2.55/MB in AIS, 5.42/MB in MIA and 15.38/MB in ADC. Genomic heterogeneity has also become more complex with neoplastic progression with mean Shannon index of 1.53 in AAH, 1.78 in AIS, 1.56 in MIA and 1.79 in ADC. An increase in C>A transversions coincident with a decrease in A>G transitions and progressively increasing APOBEC enrichment scores (4.13 in AAH, 5.63 in AIS, 6.02 in MIA and 6.59 in ADC) were observed with neoplastic disease progression. Furthermore, phylogenetic analysis revealed varying evolutional processes in AAH, AIS, MIA and ADC with canonical cancer gene mutations in KRAS, ATM, TP53 and EGFR etc. as key drivers in a subset of patients. TCR sequencing demonstrated a progressive decrease in T cell density (average percent T cells among all nuclear cells: 12% in AAH, 8% in AIS, 7% in MIA and 4% in ADC) and a progressive decrease in productive TCR clonality (average productive TCR clonality: 0.0434 in AAH, 0.0427 in AIS, 0.0399 in MIA and 0.0395 in ADC) suggesting suppressive T cell repertoire in more advanced diseases.
Conclusion:
Our results provide molecular evidence supporting the model of early lung carcinogenesis from AAH, to AIS, MIA and ADC and demonstrated that with disease progression, genomic landscape of lung neoplastic lesions has become progressively more complex along with progressive immunosuppressive TCR repertoire.
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-014 - Computing the Impact of Immunotherapy on NSCLC Landscape: The Advanced Non-Small Cell Lung Cancer Holistic Registry (ANCHoR) (ID 9505)
09:30 - 09:30 | Author(s): John V Heymach
- Abstract
Background:
Anti-PD-1 and anti-PD-L1 antibodies including pembrolizumab, nivolumab and atezolizumab have entered clinical practice in the management of metastatic NSCLC as monotherapy and immunotherapy-based combinations. We have established a real-world Advanced Non-Small Cell Lung Cancer Holistic Registry (ANCHoR) to understand how the emergence of immunotherapy impacts choice of treatment, clinical outcomes, and patient reported outcomes (PROs) in the different histo-molecular subtypes of metastatic NSCLC. The objectives of ANCHoR are to determine the treatment choice and treatment sequence by PD-L1 status in the various histo-molecular categories of NSCLC and to understand the impact of such treatment choice on response rates, progression-free survival (PFS), and overall survival (OS). Additionally we will measure the impact the treatment choices have on the PROs by utilizing the validated instruments, EuroQol-5D version 5L (EQ-5D-5L) and MD Anderson Symptom Inventory module specific to lung cancer (MDASI-LC).
Method:
The study will enroll patients with metastatic NSCLC diagnoses who are treated at MD Anderson Cancer Center (MDA) between January 1, 2017 and December 31, 2020. The study period will end on June 30, 2021 to allow a minimum of six months of follow-up. Trained abstractors will collect demographic, diagnostic, clinical, molecular (biomarker and PD-L1), treatment (regimens utilized in sequence and reason for discontinuation), response and survival (including PFS and OS), health care resource utilization and PRO (EQ-5D-5L and MDASI-LC) information that will be integrated in a comprehensive database. Information from the MDA electronic medical record will be extracted and populated in the GEnomic Marker-guided therapy INItiative (GEMINI) database and the PRO database which are linked. EQ-5D-5L followed by MDASI-LC will be completed directly by the patients and these will be automatically populated in the web-based PRO database at treatment initiation, at the time of response assessments and when switching lines of therapy.
Result:
Interim analysis will be conducted every six months to measure the impact of immunotherapy over time. Study results will be presented using descriptive statistics for continuous variables (mean, standard deviation, median, and interquartile range), categorical variables (frequency and proportions), and time-to-event variables (Kaplan-Meier). Regression models will be used for estimating the relationship between dependent variable and one or more predictors. Cox proportional hazards model will be used to estimate hazard ratios for time-to-event outcomes.
Conclusion:
The ANCHoR study is the first comprehensive registry of its kind that will enable the quantification of the changing impact of immunotherapy on the real-world NSCLC treatment landscape.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-062a - Single Institutional Experience of the Use of PD-1 Inhibitors to Non-Small Cell Lung Cancer Patients with Preexisting Autoimmune Diseases (ID 10307)
09:30 - 09:30 | Author(s): John V Heymach
- Abstract
Background:
Safety of PD-1/PD-L1 pathway inhibitors in patients with preexisting autoimmune disease is not well defined since these patients are generally excluded from immunotherapy trials. In this study we aimed to provide our institutional experience for the safety of PD-1 inhibitors in NSCLC patients with a history of autoimmune diseases.
Method:
In a retrospective study we collected genomic, demographic, clinical and pathologic data from patients with a history of autoimmune disease who received PD-1 inhibitors for their stage IV NSCLC as standard of care at MD Anderson Cancer Center (MDACC). Qualifying autoimmune diseases included autoimmune thyroiditis, rheumatologic, neurologic and dermatologic autoimmune conditions.
Result:
Between March 2016 and February 2017, 975 NSCLC patients were treated with PD-1 inhibitors, as standard of care at MDACC and 14 of those patients had preexisting autoimmune disease (5 rheumatoid arthritis, 3 seronegative arthritis, 3 psoriasis, 2 hashimoto thyroiditis, and 1 polymyalgia rheumatica). Three patients experienced flare of the autoimmune disease (2 psoriasis, and 1 rheumatoid arthritis) while on therapy and two of those patients were symptomatic from their preexisting autoimmune disease prior to the treatment. Median duration of exposure to therapy prior to flare was 21.4 weeks (range 7-48 weeks). These patients did not require treatment break or steroid use for autoimmune disease flare. 35% (5/14) of patients developed at least one immune related adverse effect (irAEs, one grade 2 and four grade 3) unrelated to the underlying autoimmune disease. There were no grade 4-5 irAEs observed. Updated results from larger patient cohort will be reported at the conference.
Conclusion:
In our single center experience, symptomatic flare of underlying autoimmune diseases was uncommon. However, patients with history of immune disease may be at higher risks for immune related toxicities during therapy with PD-1 pathway inhibitor. Further studies are needed to identify the safety profile of the PD-1 directed therapies in patient subsets with preexisting autoimmune diseases.
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P2.07-062b - DNA Damage Repair Targeting Upregulates PD-L1 Level and Potentiates the Effect of PD-L1 Blockade in Small Cell Lung Cancer (ID 9733)
09:30 - 09:30 | Author(s): John V Heymach
- Abstract
Abstract not provided
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P2.15 - SCLC/Neuroendocrine Tumors (ID 716)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.15-016a - Exploiting G2-M Cell Cycle Checkpoint Dependency in Small Cell Lung Cancer (SCLC) by Targeting Checkpoint Kinase 1 (CHK1) (ID 9680)
09:30 - 09:30 | Author(s): John V Heymach
- Abstract
Abstract not provided
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-076 - Glutaminase Inhibitor CB-839 Radiosensitizes KRAS-Mutant Lung Cancer Cells in a LKB1- and KEAP1/NRF2-Pathway Dependent Manner (ID 10295)
09:30 - 09:30 | Author(s): John V Heymach
- Abstract
Background:
KRAS mutant non-small cell lung cancers (NSCLC) bearing co-mutations in LKB1 (KL tumors) have a distinct biology, molecular vulnerabilities, and therapeutic sensitivities. KL tumors are characterized by upregulation of the NRF2/KEAP1 pathway which may serve as a compensatory mechanism to maintain redox homeostasis in the face of oxidative stress. The NRF2/KEAP1 pathway plays a role in regulating glutathione synthesis from glutamate. We hypothesized that glutaminase inhibition would reduce intracellular glutamate, reduce the ability to tolerate oxidative stress, and enhance radiotherapy sensitivity in KL tumors with KEAP1/NRF2 pathway upregulation.
Method:
Expression of NRF2 and NRF2 related genes were analyzed by Western blotting in isogenic KRAS-mutant LKB1 deficient/proficient NSCLC cell lines. Intracellular reactive oxygen species (ROS) levels were monitored using 2’7’-dichlorofluorescein (DCFDA) and flow cytometry. Cell apoptosis analysis was determined using PE-conjugated annexin-V/7-AAD staining and carried out by flow cytometry. Cell growth was evaluated by Cell Titer Glo Assays. Ionizing radiation sensitivity was assessed by clonogenic cell survival assay (CSA).
Result:
LKB1 loss increased ROS accumulation and resulted in up-regulation of NRF2 and NRF2 target genes in isogenic KRAS-mutant cell lines. KL cells were significantly more resistant to ROS than cells with KRAS mutation alone, as determined by the treatment with the ROS donor H~2~O~2~. NRF knockdown abrogated this resistance to in KL cells. KL cells also were more resistant to radiotherapy. Re-expression of LKB1 or NRF2 pathway suppression (via KEAP1 expression or NRF2 knockdown) enhanced radiotherapy sensitivity as measured by CSA with a dose enhancement ratio (DER) 1.6 and 1.2, respectively, at a surviving fraction of 0.5. The glutaminase inhibitor CB839 enhanced the radio-sensitivity of KL cells with NRF2 pathway activation (via KEAP1 mutation). Re-expression of LKB1 or NRF2 pathway suppression abrogated the CB839-induced radiosensitization.
Conclusion:
Our results suggest that upregulation of the NRF2/KEAP1 pathway in NSCLC bearing co-mutations in KRAS and LKB1 is critical to maintain redox homeostasis and GLS inhibition can sensitize KL tumors to radiotherapy in an LKB1- and KEAP1/NRF2-dependent manner.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-013 - Identification of Proteasomal Catalytic Subunit PSMA6 as a Therapeutic Target for Lung Cancer through a Pooled shRNA Screen (ID 8867)
09:30 - 09:30 | Author(s): John V Heymach
- Abstract
Background:
Recent advances in high-throughput genetic analysis revealed that single lung cancer cells harbour a number of genetic and epigenetic changes. Nevertheless, findings from cancer epidemiology and the experimental models of the multi-step lung carcinogenic process, which were developed by our group and others, suggested that only a handful of changes are ‘drivers’ whereas others are only ‘passengers’. Thus, it is very important to identify those that truly contribute to the oncogenic properties of cancer cells by performing functional screening. To this end, we performed screening with a pooled shRNA library in search for genes that are critical for the survival and/or proliferation of lung cancer cells using a lung cancer cell line.
Method:
NCI-H460 cell line was used for semi-genome-wide dropout viability analysis using a pooled shRNA library that targeted 5,043 genes. Two Cdk4/hTERT-immortalised normal human bronchial epithelial cell lines, HBEC3 and HBEC4 were used as controls. Pathway analysis was done using NIH-DAVID. Microarray gene expression analysis was done using Illumina Human WG-6 v3.0 Expression BeadChip for 163 non-small cell lung cancer (NSCLC) cell lines and 59 normal control cell lines. DNA copy number analysis with array CGH was done for 108 NSCLC cell lines. Proteasome activity was measured using a 20S proteasome activity assay kit. 20 pairs of resected lung cancer and matched normal lung samples were used for immunohistochemistry of PSMA6. Cell growth was evaluated by WST-1 colorimetric proliferation assay. Cell cycle analysis was done using FACS for cells stained with propidium iodide.
Result:
shRNA screening targeting 5,043 genes in NCI-H460 identified 51 genes as candidates for therapeutic targets. Pathway analysis revealed that the 51 genes were enriched for the five pathways, including ribosome, proteasome, RNA polymerase, pyrimidine metabolism and spliceosome pathways. We focused on the proteasome pathway that involved six candidate genes because its activation has been demonstrated in diverse human malignancies, including lung cancer. Microarray expression and array CGH data showed that PSMA6, a proteasomal subunit of a 20S catalytic core complex, was highly expressed in lung cancer cell lines, with recurrent gene amplifications in some cases. Therefore, we further examined the roles of PSMA6 in lung cancer. Silencing of PSMA6 induced apoptosis or G2/M cell cycle arrest in cancer cell lines but not in an immortalised normal lung cell line.
Conclusion:
Our data suggested that PSMA6 serves as an attractive target with a high therapeutic index for lung cancer.
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P3.03-027 - LKB1 Loss Is Associated with Resistance to Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer Mouse Models (ID 10259)
09:30 - 09:30 | Author(s): John V Heymach
- Abstract
Background:
LKB1 is a protein kinase that is mutated and down-regulated in 20-30% of non-small cell lung cancer (NSCLC). LKB1 mutations co-occur with KRAS alterations in 7%-10% of NSCLC, resulting in an aggressive phenotype with short survival. Because LKB1 activates AMPK, the master sensor of cellular energy, many of the best known functions of LKB1 are attributed to its ability to control metabolic alterations in the cells. However LKB1 also plays an important role in regulating angiogenesis, likely as a strategy to overcome energetic depletion of tumor microenvironment. Bevacizumab, the human anti-VEGF antibody, improves the PFS and OS of NSCLC patients combined with chemotherapy, but often the benefit is transient and therapeutic resistance occurs. Our laboratory has previously identified alterations in cell metabolism and in vasculature of LKB1-deficient tumors when compared to LKB1 wild type in NSCLC.
Method:
LKB1 KO murine NSCLC cell lines were generated using CRISPR/Cas9 system in a KRAS[G12D] mutant background (LKR10 & LKR13). Syngeneic NSCLC models were established via s.c. injection of LKB1 intact and KO murine cells in immunocompetent mice. After tumors reached 150 mm[3] mice were randomly assigned to treatment groups consisting of vehicle, mouse anti-VEGF and nintedanib. Tumor volumes were measured and compared using student’s t test and samples were collected for vasculature analysis. Survival curves will be calculated using log rank test. Hypoxia experiments were preformed and apoptosis was measured using annexin V and 7ADD staining.
Result:
Treatment with anti-VEGF or nintedanib significantly inhibited tumor progression in LKB1 wt KRAS[G12D] mutant mouse model (p<0.001) but did not show any therapeutic effect in the LKB1 KO KRAS[G12D] group. Furthermore in the LKB1 wt group, the median survival of anti-VEGF and nintedanib treated mice was 111 days and 84 days respectively and 37 days in the vehicle group. No improvement in survival was detected in the LKB1 KO group after treatment with anti-VEGF. In vitro studies showed that LKB1 loss is associated with a decrease in oxygen consumption and enhanced glycolysis. Furthermore LKB1 KO NSCLC cells showed a decrease in apoptosis under hypoxic and low nutrient conditions compared to LKR13 LKB1 wt cells.
Conclusion:
NSCLC LKB1-deficient tumors showed resistance to anti-angiogenic therapy and this effect is driven by the regulation of metabolic adaptations that allow cells to survive under hypoxic and low nutrient conditions.
