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R. Govindan
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ED01 - Biology of Lung Cancer (ID 263)
- Event: WCLC 2016
- Type: Education Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:R. Rosell, M. Filipits
- Coordinates: 12/05/2016, 11:00 - 12:30, Hall C1
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ED01.03 - Insights from TCGA (ID 6423)
11:50 - 12:15 | Author(s): R. Govindan
- Abstract
- Presentation
Abstract:
Advances in sequencing technologies have made it possible to characterize and catalogue genomic alterations in several cancers in an unbiased manner. Multiple individual groups and large-scale consortia such as The Cancer Genomic Atlas (TCGA), have sequenced close to a thousand lung cancer samples to date. [1-8]Apart from furthering our understanding of the frequently altered pathways in common histological subtypes of lung cancer, data from these studies have also highlighted the molecular heterogeneity underlying this disease. Investigators from TCGA initially reported genomic, transcriptomic, methylation and copy-number alterations in 230 adenocarcinoma (LUAD) and 178 squamous cell carcinoma (SQCC) samples.[1][,][2]An updated analysis, that included a total of 660 LUAD and 484 SQCC samples, was subsequently published in early 2016.[9] While the majority of lung cancer patients have a history of cigarette smoking, nearly 10% of patients are lifelong never-smokers.[3]Lung cancers that arise in smokers exhibit some of the highest mutational burdens across all human cancers (8-10 mutations/Mb). The vast majority of these mutations are C>A transversions. On the contrary, tumors from never smokers demonstrate a much lower mutational burden (0.8-1 mutations/Mb) and are enriched for C>T transitions. [1][,][2] Single nucleotide variations (SNVs) and copy number alterations (CNAs) While both LUAD and SQCC show frequent inactivation of the tumor suppressors TP53 and CDKN2A, these alterations are considerably more common in SQCCs. CDKN2A harbors the loci for two isoforms, p14ARF and p16INK4A, and is inactivated in SQCC through homozygous deletion (29%), methylation (21%), inactivating mutations (18%), or exon 1b skipping (4%). [1][,][2]These findings indicate a strong selective pressure for the loss of these tumor suppressors in NSCLC. The pattern of oncogenic alterations varies considerably between LUAD and SQCC. While LUADs typically showed activating RTK/RAS/RAF pathway mutations, these mutations are highly infrequent in SQCCs - which predominantly showed alterations in oxidative stress response (NFE2L2, KEAP1 and CUL3) and squamous differentiation pathways (SOX2, TP63, NOTCH1, etc.) in 44% of samples. [1,2]KRAS is the most commonly mutated oncogene in LUAD, followed by EGFR, BRAF, PIK3CA, and MET. The majority of EGFR mutations in LUAD are targetable (L858R or exon 19 deletion) with tyrosine kinase inhibitors (TKIs).[1]In contrast, such alterations are absent in SQCC. Two SQCC samples however demonstrated L861Q mutations in EGFR, which are potentially targetable with TKIs. [1][,][2]Although SQCC and LUAD shared several CNAs at the chromosomal arm level, amplification of 3q was frequent in SQCC. This region harbors important oncogenes such as SOX2, PIK3CA, and TP63. LUADs frequently showed amplifications in genes such as NKX2-1, TERT, MDM2, KRAS, and EGFR.[1][,][2]Oncogenic activation of kinases such as ALK, ROS1, and RET through rearrangement has been well described in LUAD, and these fusions are targetable with TKIs. These fusions were seen in 1-2% (ALK : 3/230, ROS1: 4/230, and RET: 2/230 samples) of LUADs. [1][,][2] Transcriptome analysis Deregulated splicing can be a consequence of mutations that alter splice-sites within a gene or splicing factors. Mutations in the proto-oncogene MET that lead to exon 14 skipping, and abnormal splicing of proto-oncogenes such as CTNNB1 as a result of U2AF1 mutation have been described in LUAD. [1] Transcriptome analyses have also enabled a reclassification of LUADs and SQCCs into three and four distinct subtypes, respectively. LUAD samples can be categorized as terminal respiratory unit (enriched for EGFR mutations and fusions; favorable prognosis), proximal-inflammatory (NF1 and TP53 co-mutation), or proximal-proliferative (KRAS and STK11 alterations) subtypes. Similarly, SQCCs can be classified as classical, basal, secretory, or primitive. Alterations in genes that participate in the oxidative stress response pathway, hypermethylation, and chromosomal instability are characteristic of the classical subtype (associated with heavy smoking and poor prognosis). [1][,][2] Key pathogenic alterations TCGA analysis revealed alterations in well known oncogenic drivers involving RAS signaling pathway in 62% of LUAD.. These samples with readily identifiable oncogenic driver alterations were collectively labeled ‘oncogene-positive’. Additional analyses of the ‘oncogene-negative’ sample cohort showed enrichment for RIT1, and NF1 mutations. Given the role of RIT1 and NF1 in RTK/RAS/RAF signaling, samples with these mutations were reclassified as oncogene positive, increasing the overall percentage of oncogene positive samples in LUAD to 76%. Nearly 69% of SQCC samples showed alterations in genes regulating PI3K/AKT, or RTK/RAS signaling. [1][,][2] The inability to readily identify an oncogenic driver in nearly a third of sequenced lung cancer samples highlights the need for greater powering of subsequent studies to identify novel low frequency genomic alterations. For instance, previously uncharacterized alterations in the RTK/RAS/RAF pathway were observed in RASA1, SOS1 in the updated TCGA analysis which analyzed a much larger cohort of samples.[9] Overall, despite showing a few similarities between LUAD and SQCC, investigators of TCGA reported prominent differences between the genomic landscapes of these subtypes. These subtypes have more of their alterations in common with other cancers than with one another. SQCCs more closely resembled head and neck squamous cell and bladder cancer, while LUAD resembled glioblastoma multiforme and colorectal cancer in this regard. [9] Immunotherapies The vast majority of lung cancers do not harbor alterations that are targetable by TKIs. [1][,][2 ]Immune checkpoint inhibitors are approved for use in patients with metastatic NSCLC. There is a clear need to develop optimal predictive biomarkers to identify those who are likely to respond to immune checkpoint inhibitors. Mutational burden has been correlated with better response to checkpoint inhibitors. Furthermore, using exome and transcriptome sequencing and sophisticated bioinformatics, it is now possible to identify mutated and expressed genes that could potentially serve as a trigger for immune response (so called neoantigens) once immune checkpoints like programmed death-1 or programmed death ligand-1 are inhibited.. Swanton and colleagues performed a neoantigen and clonality analysis on TCGA samples to examine characteristics such as neoantigen burden and intratumor heterogeneity (ITH), and their impact on survival. In LUAD, a higher neoantigen burden was significantly associated with longer survival. Although not statistically significant, there was a trend towards longer survival in molecularly homogeneous tumors (<1% ITH) as opposed to heterogeneous tumors. The updated TCGA analysis showed that 47% of LUAD and 53% of SQCC samples exhibited at least five predicted neoantigens. Efforts are ongoing to develop personalized vaccine therapy using predicted neoantigens in lung cancer and other malignancies. Outcomes for patients with advanced lung cancer are likely to improve in the near future with further advances in genome sequencing, molecularly targeted therapies and immunotherapies . [12] References 1. Network CGAR. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543-50. 2. Network CGAR. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-25. 3. Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 2012;150:1121-34. 4. Imielinski M, Berger AH, Hammerman PS, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012;150:1107-20. 5. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47-53. 6. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012;44:1111-6. 7. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:1104-10. 8. Seo JS, Ju YS, Lee WC, et al. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 2012;22:2109-19. 9. Campbell JD, Alexandrov A, Kim J, et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet 2016;48:607-16. 10. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012;4:120ra17. 11. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 2010;363:1734-9. 12. McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463-9.
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ISS09 - Industry Supported Symposium: Targeted Therapy on the Horizon for SCLC - AbbVie (ID 442)
- Event: WCLC 2016
- Type: Industry Supported Symposium
- Track:
- Presentations: 3
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ISS09.03 - Emerging Novel Agents – A New Day for SCLC Treatment (ID 7021)
07:55 - 08:15 | Author(s): R. Govindan
- Abstract
Abstract not provided
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ISS09.04 - Panel Discussion: Looking Over the Horizon – Future Treatment of SCLC (ID 7022)
08:15 - 08:25 | Author(s): R. Govindan
- Abstract
Abstract not provided
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ISS09.05 - Question & Answer (ID 7023)
08:25 - 08:30 | Author(s): R. Govindan
- Abstract
Abstract not provided
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MA06 - Locally Advanced NSCLC: Risk Groups, Biological Factors and Treatment Choices (ID 379)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:P. Van Houtte, M. Zemanová
- Coordinates: 12/05/2016, 16:00 - 17:30, Strauss 2
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MA06.10 - A Pooled Analysis Comparing the Outcomes of Elderly to Younger Patients on NCTN Trials of Concurrent CCRT for Stage 3 NSCLC (ID 4219)
17:06 - 17:12 | Author(s): R. Govindan
- Abstract
- Presentation
Background:
Concurrent chemoradiotherapy (CCRT) is the standard treatment (TRT) for stage 3 NSCLC. Elderly patients (pts) are common, may have increased toxicity,& poorer results from CCRT
Methods:
Individual patient data (IPD) from NCTN phase 2/3 trials of CCRT for stage 3 NSCLC from 1990-2012 was collected. We compared the overall survival (OS), progression-free survival (PFS), & adverse events (AE’s) for pts age ≥70 years (yrs) (elderly) vs. <70 yrs (younger). Unadjusted & adjusted Hazard Ratios (HRs) for survival time & their confidence intervals (CIs) were estimated by single-predictor & multivariable Cox models. Unadjusted & adjusted Odds Ratio (OR) for AE’s & their CIs were obtained from single-predictor & multivariable logistic regression models
Results:
IPD from 16 trials were analyzed; 2,768 pts were younger & 832 were elderly. Median OS & PFS for elderly & younger pts are in the table. In the unadjusted & multivariable models elderly pts had worse OS (HR=1.23; 95%CI =1.13-1.35, and 1.20; 95%CI=1.10-1.32, respectively). In the unadjusted & multivariable models, elderly & younger pts had a similar PFS (HR=1.02; 95% CI=0.94-1.11 and 1.01, 95% CI=0.92-1.10, respectively). Elderly pts had a higher rate of grade ≥3 AE’s in the unadjusted & multivariable models (OR=1.25; 95% CI=1.00-1.57 and 1.30; 95%CI=1.03-1.62, respectively). A lower percentage of elderly pts compared to younger completed TRT (47% and 57%, respectively; P<0.0001) & higher percentage stopped due to AE’s (20% and 13%; P<0.0001). Grade ≥ 3 AE’s (occurring at a rate ≥ 2.5%) with a higher rate in the elderly: neutropenia, dyspnea, fatigue, anorexia, vomiting, dehydration, hypoxia, hypotension, & pneumonitis (P<0.05).
a: Log-rank test for survival times, chi-square test for AE’s, and Fisher’s exact test for deaths. The P-values from these tests are unadjusted. b: Data available on 2,091 patientsAge ≥ 70yrs Age < 70 yrs P-value[a] Median OS (months) 17.0 20.7 < 0.01 Median PFS (months) 8.7 9.1 0.68 All toxicities grade ≥3 86% 84% 0.04 Hematologic AE’s grade ≥3 65% 61% 0.04 Non-hematologic AE’s ≥3 68% 62% <0.01 Grade 5 AE’s 9.0% 4.4% <0.01 TRT related deaths[b] 3.2% 2.0% 0.12
Conclusion:
Elderly pts in CCRT trials had worse OS, similar PFS, & a higher rate of severe AE's.
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA07.01 - Updated Pooled Analysis of CNS Endpoints in Two Phase II Studies of Alectinib in ALK+ NSCLC (ID 5354)
11:00 - 11:06 | Author(s): R. Govindan
- Abstract
- Presentation
Background:
Based on two single-arm, multicentre, phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]), the FDA approved the ALK inhibitor alectinib for use in ALK+ NSCLC patients after prior crizotinib. Alectinib was well tolerated in both phase II studies and showed efficacy against both systemic and central nervous system (CNS) disease, the latter being a common progression site in ALK+ NSCLC. This analysis uses pooled data from the latest cut-offs (22 Jan 2016 for NP28761; 1 Feb 2016 for NP28673) to examine the long-term CNS efficacy of alectinib.
Methods:
Both studies enrolled crizotinib-refractory patients ≥18 years with ECOG PS 0–2 and locally advanced or metastatic ALK+ NSCLC (confirmed by FDA-approved test). CNS metastases were permitted if asymptomatic. Patients received 600mg oral alectinib BID. The primary endpoint in both studies was objective response rate (ORR) by independent review committee; secondary CNS endpoints included CNS ORR, CNS duration of response (DoR), and CNS disease control rate (DCR). CNS response and progression were determined by RECIST v1.1. All patients had baseline imaging to assess CNS metastases, with further imaging every 6 or 8 weeks for NP28761 and NP28673, respectively.
Results:
The overall pooled analysis population comprised 225 patients (n=87 from NP28761; n=138 from NP28673); median follow-up for this updated analysis was 18.8 (0.6–29.7) months (>6 months additional follow-up). At baseline, 50 patients had measurable and 86 had non-measurable CNS disease; together, these groups comprised 136 patients, 60% of the overall pooled population. Seventy percent of patients had prior CNS radiotherapy; 58% of these completed radiotherapy >6 months before study entry. Updated CNS data are shown in the Table and are consistent with systemic results.Measurable CNS disease at baseline (n=50) Measurable and non-measurable CNS disease at baseline (n=136) CNS ORR, n (%) [95% CI] 32 (64.0) [49.2–77.1] 60* (44.1) [35.6–52.9] Complete response (CR), n (%) 11 (22.0) 39* (28.7) CNS DCR, n (%) [95% CI] 45 (90.0) [78.2–96.7] 117 (86.0) [79.1–91.4] Median CNS DoR, months [95% CI] Patients with event, n (%) 11.1 [7.6–NE] 18 (56.3) 13.8 [11.0–21.5] 32 (53.3) * N.B. Non-measurable disease response can only be classified as CR, non-CR/non-progressive disease (PD) or PD
Conclusion:
This updated pooled analysis with mature data confirms that alectinib can provide long-term control of CNS metastases in ALK+ NSCLC, with a high CR rate.
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OA05 - Treatment Advances in SCLC (ID 373)
- Event: WCLC 2016
- Type: Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:A. Ardizzoni, J. Pujol
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 2
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OA05.03 - Single-Agent Rovalpituzumab Tesirine, a Delta-Like Protein 3 (DLL3)-Targeted Antibody-Drug Conjugate (ADC), in Small-Cell Lung Cancer (SCLC) (ID 4648)
14:40 - 14:50 | Author(s): R. Govindan
- Abstract
- Presentation
Background:
SCLC is one of the most deadly malignancies. Rovalpituzumab tesirine (SC16LD6.5, Rova-T) is a first-in-class ADC directed against DLL3, a novel target identified in tumor initiating cells and expressed in over 80% of SCLC cases.
Methods:
Seventy-four patients with progressive SCLC after at least one previous systemic therapy were enrolled in a first-in-human study (NCT01901653), irrespective of DLL3 expression, including 68 at active doses of 0.2-0.4 mg/kg administered intravenously every 3 or 6 weeks. Available archived tumor tissue (n=48) was assessed retrospectively by immunohistochemistry for DLL3.
Results:
Among 60 evaluable subjects, active dose levels resulted in a confirmed objective response rate (ORR) of 18% and a confirmed clinical benefit rate (CBR; stable disease or better) of 68%. Among 26 evaluable subjects with DLL3 expression in at least 50% of tumor cells (DLL3-high), confirmed ORR and CBR were 39% and 89%, respectively. Median duration of response was 5.6 months. One-year survival rates among all and DLL3-high subjects were 18% and 32%, respectively. Among primary sensitive relapse patients, confirmed ORR and CBR among all subjects were 24% (8/33) and 67% (22/33); and among DLL3-high subjects were 53% (8/15) and 100% (15/15), with one-year survival rates of 17% and 33%, respectively. Among primary resistant/refractory relapse patients, confirmed ORR and CBR among all subjects were 12% (3/25) and 72% (18/25); and among DLL3-high subjects were 18% (2/11) and 73% (8/11), with one-year survival rates of 21% and 29%, respectively. The most common grade 3 or higher toxicities included thrombocytopenia (12%), serosal effusions (11%), and skin reactions (8%). ADC pharmacokinetics were linear with a terminal half-life of 10 - 14 days and anti-therapeutic antibodies did not develop
Conclusion:
Rovalpituzumab tesirine demonstrates encouraging single-agent anti-tumor activity with a manageable safety profile, including among patients with disease resistant or refractory to primary chemotherapy. Further development of rovalpituzumab tesirine in SCLC is warranted.
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OA19 - Translational Research in Early Stage NSCLC (ID 402)
- Event: WCLC 2016
- Type: Oral Session
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:G. Heller, G. Goss
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 3
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OA19.01 - A Standardized and Validation of Prognostic Gene Expression Signatures for Squamous Cell Lung Carcinoma by the SPECS Lung Consortium (ID 4329)
11:00 - 11:10 | Author(s): R. Govindan
- Abstract
- Presentation
Background:
High-throughput gene expression profiling led to proposal of multiple expression-based prognostic signatures for squamous cell lung carcinoma (SCC), but none has been validated. A multi-institutional squamous lung cancer consortium of investigators is developing prognostic signatures through the US NCI Lung SPECS (Strategic Partnership for Evaluation of Cancer Signatures) program. Six institutions contributed tumor specimens and published/unpublished expression-based prognostic signatures for validation using standardized sample cohorts (a primary validation cohort comprising institutional cases, and additional validation cohorts from two prospective cooperative group studies) and quality controlled assessment in independent laboratory and statistical cores. Here, we report the results of the primary validation.
Methods:
Cases of primary SCC (by central pathology review) meeting clinical (Stage I-II; surgical treatment only; 3-year followup) and specimen quality criteria (Tumor cellularity >= 50%; necrosis <= 20%) were submitted. Clinical, pathological and outcome data were uploaded to a central database. Frozen tumor samples underwent centralized mRNA extraction (Qiagen Symphony), quality control (RIN >= 6.0) and microarray profiling (Affymetrix U133) in core labs. An independent statistical core assessed validation of 7 pre-existing mRNA signatures and generated new models using MCP clustering.
Results:
Among 250 cases meeting entry criteria, median age was 70 (43-92), 161 (65%) were male, and most were former (70%) or current (28%) smokers. Surgery was pneumonectomy: 5%; bilobectomy: 2%; lobectomy: 74%; sublobar: 18%. Pathologic staging was T1: 49%; T2: 50%; T3: 1%; N0: 88%; N1: 12%, and grade was G1: 4%; G2: 50%; G3: 44%. At followup, 148 (59%) were deceased. Three mRNA signatures demonstrated significant univariable association with OS and added independent prognostic value (see Figure) to a multivariable model accounting for age, sex and stage (c-index = 0.641).
Conclusion:
The validated signatures, along with two novel signatures generated from the current dataset, are currently undergoing further validation studies using two prospective co-operative group cohorts. Figure 1
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P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.05-001 - Creation and Early Validation of Prognostic miRNA Signatures for Squamous Cell Lung Carcinoma by the SPECS Lung Consortium (ID 6088)
14:30 - 14:30 | Author(s): R. Govindan
- Abstract
Background:
Despite overall favorable prognosis for operable early stage non-small cell lung cancer, predicting outcome for individual patients has remained challenging. Small retrospective studies have reported potential non-coding micro(mi)RNAs that might have prognostic significance; however, these studies lacked statistical power and validation. To refine these initial findings to clinical application, the investigators have undertaken a collaborative, structured evaluation of multiple signatures putatively prognostic for lung squamous cell carcinoma (SCC) under a NCI/SPECS (Strategic Partnerships fo Evaluating Cancer Signatures) award. The study design specifies a primary validation cohort comprising institutional cases, and additional validation cohorts of Cooperative Group cases, all profiled via a common pipeline.
Methods:
Completely resected SCC (confirmed by central pathology review) meeting clinical (Stage I-II; complete 3-year follow-up) and specimen quality criteria (Tumor cellularity ≥ 50%;necrosis ≤ 20%) were submitted by 6 institutions. Clinical, pathological and outcome data were uploaded to a central database. Lysates from 5 um sections of FFPE SSC tumor samples were run on the HTG EdgeSeq Processor (HTG Molecular Diagnostics, Tucson, AZ) using the miRNA whole transcriptome assay in which an excess of nuclease protection probes (NPPs) complimentary to each miRNA hybridize to their target. S1 nuclease then removes un-hybridized probes and RNA leaving behind only NPPs hybridized to their targets in a 1-to-1 ratio. Samples were individually barcoded (using a 16-cycle PCR reaction to add adapters and molecular barcodes), individually purified using AMPure XP beads (Beckman Coulter, Brea, CA) and quantitated using a KAPA Library Quantification kit (KAPA Biosystems, Wilmington, MA). Libraries were sequenced on the Illumina HiSeq platform (Illumina, San Diego, CA) for quantification. Standardization and normalization was provided to the project statistical core for validation of two pre-existing signatures and generation of new models (MCP clustering).
Results:
Among 224 cases with miRNA data, median age was 70 (43-92), 143 (64%) male, with 67% former (67%) and current (26%) smokers. All patients were completely resected stage I or II. . At follow-up, 59 (26%) had documented recurrence and 129 (58%) were deceased. To date, we have been unable to validate the previous models, but have created a novel signature of three miRNAs (see Figure) that is being validated in the second phase of the project using an independent, blinded multi-institutional cohort.
Conclusion:
The Squamous Lung Cancer SPECS Consortium has established well-annotated and quality-controlled resources for validation of prognostic miRNA signatures. A new candidate 3-miRNA signature has been identified for further development as a clinically useful biomarker.
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P1.05-027 - Novel Prognostic Gene Expression Signatures for Squamous Cell Lung Carcinoma: A Study by the SPECS Lung Consortium (ID 4490)
14:30 - 14:30 | Author(s): R. Govindan
- Abstract
Background:
A multi-institutional squamous lung cancer consortium of investigators is developing prognostic signatures through the US NCI Lung SPECS (Strategic Partnership for Evaluation of Cancer Signatures) program. Six institutions contributed tumor specimens and published/unpublished expression-based prognostic signatures for validation using standardized sample cohorts (a primary validation cohort comprising institutional cases, and additional validation cohorts from two prospective cooperative group studies) and quality controlled assessment in independent laboratory and statistical cores. Here, we report on de novo prognostic signatures derived using the pooled institutional dataset.
Methods:
Highly quality-controlled cases of primary SCC from the pooled cohort (N=249) were analyzed to generate de novo prognostic signatures from among the 147 genes comprising pre-existing signatures, and from among all profiled genes. Minimax Concave Penalty (MCP) selection and Ward’s minimum variance clustering yielded survival analyses with 2 clusters that were evaluated using Cox regression and bootstrap cross validation (bCV; 500 iterations).
Results:
Two significantly prognostic models were generated (see Figure): Pooled Model A (PMA) was the optimal 2-cluster model using probesets representing 6 genes selected from components of pre-existing signatures: CASP8, MDM2, SEL1L3, RILPL1, LRR1, COPZ2. Pooled Model B (PMB) was the optimal 2-cluster model using probesets representing 6 genes selected from among all those profiled: SSX1, DIAPH3, LOC619427, CASP8, EIF2S1, HSPA13. PMA and PMB each remained independently prognostic in multivariable analyses incorporating an a priori baseline model (age, sex, stage; c-index = 0.641).
Conclusion:
Two de novo prognostic signatures were derived using a pooled multi-institutional cohort of SCC assembled for validation of pre-existing signatures. PMA and PMB were each found to be independently prognostic, accounting for established clinical predictors. Both now move forward, along with validated pre-existing signatures, to additional assessment of discrimination, calibration and clinical usefulness using additional independent prospective US co-operative group cohorts of cases. Figure 1
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P1.05-047 - Early Mortality in Patients with Non-Small Cell Lung Cancer Undergoing Adjuvant Chemotherapy (ID 5523)
14:30 - 14:30 | Author(s): R. Govindan
- Abstract
Background:
Although adjuvant chemotherapy improves survival in patients with completely resected non-small-cell lung cancer (NSCLC) compared to surgery alone, it is also associated with potentially disabling or lethal adverse events. Since there is limited information on the early mortality among patients undergoing adjuvant chemotherapy, we used the National Cancer Data Base (NCDB) to calculate the percentage of deaths within the first 6 months from starting chemotherapy.
Methods:
The NCDB was queried for patients aged 18 or older, diagnosed with stage IB to IIIA NSCLC (AJCC 7[th] edition) from 2004 to 2012, who underwent surgery with negative margins followed by multi-agent chemotherapy, starting within 120 days from the surgical resection. Patients who received radiation therapy were excluded. Age groups were divided into <50, 51-60, 61-70, 71-80 and >80 years. Early mortality from months 1 to 6 were calculated and multivariate logistic regression was performed to identify clinical variables independently associated with mortality at six months from the date of initiation of adjuvant chemotherapy.
Results:
A total of 19,791 patients met the eligibility criteria. The median age was 65 (range 19-89). The percentage of deaths at 1, 2, 3, 4, 5 and 6 months were 0.6%, 1.3%, 1.9%, 2.6%, 3.3% and 4.2% respectively. The percentages of death at 6 months for each age group from < 50 years to > 80 years were 2.7%, 3.2%, 4.1%, 5.3% and 7.8% respectively. Factors independently associated with increased 6-month mortality included increased age, male gender, higher Charlson-Deyo co-morbidity score (CDCS), type of surgery, length of stay (LoS) > 6 days and 30-day readmission (Table).
Conclusion:
There is a high risk for early mortality among patients undergoing adjuvant chemotherapy for NSCLC, particularly in patients older than 70, with high co-morbidity score and a more complicated post-operative period.Table. Multivariable analysis
Variable OR (95% CI) P-value Age ≤ 50 Reference Reference 51-60 1.08 (0.74-1.60) 0.68 61-70 1.33 (0.91-1.95) 0.15 71-80 1.59 (1.06-2.38) 0.03 > 80 2.27 (1.29-3.98) 0.004 Gender Male Reference Reference Female 0.70 (0.59-0.82) < 0.001 CDCS 0 Reference Reference 1 1.13 (0.95-1.34) 0.15 2 1.58 (1.26-1.98) < 0.001 Surgery Sub-lobar Reference Reference Lobectomy 0.72 (0.53-0.97) 0.03 Pneumonectomy 0.97 (0.68-1.39) 0.87 Stage IB Reference Reference II 1.29 (1.04-1.59) 0.02 IIIA 2.28 (1.81-2.87) < 0.001 LoS ≤ 6 days Reference Reference > 6 days 1.24 (1.06-1.46) 0.008 30-day readmission No Reference Reference Yes 1.54 (1.20-1.99) 0.001
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-035 - Circulating Cell-Free Tumor DNA (cfDNA) Testing in Small Cell Lung Cancer (ID 6193)
14:30 - 14:30 | Author(s): R. Govindan
- Abstract
Background:
The diagnosis of small cell lung cancer (SCLC) is often made using fine needle aspiration or small biopsy of tumor specimens that are typically insufficient for next generation sequencing (NGS) analysis. Guardant360 (G360), a blood-based liquid biopsy that analyzes circulating free tumor DNA, may allow the detection of potentially targetable gene abnormalities without the need for repeated tissue biopsies.
Methods:
Peripheral blood samples from patients with SCLC were collected in two 10 mL tubes. Cell-free DNA was extracted and analyzed by digital sequencing for the detection of single nucleotide variants (SNVs), small Insertions and Deletions (INDELs), Copy Number Alterations (CNAs), and gene fusions. The Tumor Alterations Relevant for Genomics-Driven Therapy (TARGET) curated database (http://www.broadinstitute.org/cancer/cga/target) was queried for potentially actionable alterations.
Results:
240 samples from 227 de-identified patients were collected between June 2014 and June 2016. 7 patients had more than one sample analyzed. During this time period, the number of genes in the panel increased from 54 (10 samples) to 68 (87 samples) and finally to 70 (143 samples). The median time from sample collection to reporting was 13 days (range 8-28 days). Alterations in at least one gene were found in 222 (92.5%) of samples and 210 (92.5%) patients. SNVs in TP53 and RB1 were seen in 72.4% (152/210) and 25.7% (35/136) of patients with detectable alterations respectively. The most common potentially actionable alterations were amplifications of FGFR1 (11.8%) and ERBB2 (7.1%). MYC amplification, which was not considered an actionable alteration by TARGET but has been associated with sensitivity to Aurora kinase inhibitors in pre-clinical studies, was observed in 15.8% of patients. Eight patients had EGFR activating mutations (exon 21 L858R mutation or exon 19 deletion), of which 2 patients also had EGFR T790M mutation, likely representing transformation from NSCLC following targeted therapy with EGFR Tyrosine kinase inhibitors. KIF5B-ALK and AFAP1-RET fusions were seen in 1 patient each.
Conclusion:
G360 is a rapid non-invasive NGS platform which may be particularly useful in patients with advanced stage SCLC where tissue samples may be suboptimal for NGS. Due to the limited treatment options in this patient population, the detection of potentially actionable genes through G360 may provide valuable information to guide treatment decisions.
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-002 - Patterns of Chemotherapy Use and Overall Survival (OS) of Patients with Stage IV Squamous Lung Cancer (SCC) (ID 5216)
14:30 - 14:30 | Author(s): R. Govindan
- Abstract
Background:
Chemotherapy is standard of care for patients with metastatic SCC. There is limited information on the use and outcome of patients with metastatic SCC who receive chemotherapy. We used the National Cancer Data Base (NCDB) to investigate the use and survival of patients receiving chemotherapy for stage IV SCC.
Methods:
The NCDB was queried for patients≥ 18 years, diagnosed with stage IV SCC between 2004-2013 for whom chemotherapy data was available. The percentage of patients receiving chemotherapy within 2 months of diagnosis was calculated. Patients were stratified by age (<50, 50-70 and >70 years), Charlson-Deyo comorbidity score (0, 1 and 2), gender, and period of diagnosis (2004-2006, 2007-2009, 2010-2012) to evaluate patterns of chemotherapy use. Median, 1-year and 2-year OS were calculated for patients that received chemotherapy using Kaplan Meier method.
Results:
Among the 86,200 patients that met the eligibility criteria, 40,147 (46.6%) patients received chemotherapy, which included single agent (n=3,912; 9.7%) multiagent (n=32,737;81.5%) and number of agents unknown (n=3,498;8.7%). A total of 46,053 (53.43%) patients did not receive chemotherapy due to chemotherapy not recommended (n=5,397; 11.7%), patient refusal (n=6,119; 13.3%) and other/unknown reasons (n=34,537; 75%). Patients receiving multi-agent chemotherapy were younger than those receiving single agent chemotherapy (65.6 vs 71.5 years). Chemotherapy use declined with increase in comorbidity score (50.4% for score of 0, 44% for score of 1 and 36.2% for score of 2). The median, 1-year and 2-year OS for patients receiving chemotherapy were 7.5 months, 30.6% and 11.8% respectively (Table).OS for patients receiving chemotherapy by risk factor
Risk factor Median survival (months) 1 year OS 2 year OS Age <50 7.6 29.7% 11.5% 50-70 7.8 32.0% 12.4% >70 7.0 28.5% 10.8% Gender Male 7.3 29.0% 10.7% Female 7.9 33.7% 13.8% Year of diagnosis 2004-2006 7.3 28.8% 10.7% 2007-2009 7.5 31.0% 11.8% 2010-2013 7.7 31.6% 12.7% Charlson-Deyo comorbidity score 0 8.0 32.6% 12.7% 1 7.1 28.4% 10.6% 2 6.3 24.9% 9.2% All patients 7.5 30.6% 11.8%
Conclusion:
Most patients with metastatic SCC do not receive chemotherapy. The OS for patients with metastatic SCC remains poor, especially in patients over the age of 70, in men and those with multiple comorbidities.
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P2.03a-003 - Belinostat in Combination with Carboplatin and Paclitaxel in Patients with Chemotherapy-Naive Metastatic Lung Cancer (NSCLC) (ID 5996)
14:30 - 14:30 | Author(s): R. Govindan
- Abstract
Background:
Belinostat is a potent inhibitor of the enzyme histone deacetylase (HDAC), which influences chromatin accessibility through altering acetylation levels of histone and non-histone proteins. Belinostat may enhance the antitumor activity of carboplatin and paclitaxel. We conducted a phase 1 clinical trial of belinostat in combination with carboplatin and paclitaxel in chemotherapy-naive patients with stage IV NSCLC.
Methods:
This was a multicenter phase 1 open label study of belinostat in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with histologically or cytologically confirmed Stage IV NSCLC, PS 0-1. A standard 3+3 dose escalation design was used to determine the primary endpoint of maximum tolerated dose (MTD) of belinostat administered intravenously on days 1-5 of a 21 day cycle in combination with carboplatin (AUC 6) and paclitaxel 200mg/m2 intravenously on day 3 of each cycle for up to 6 cycles. MTD was defined as the dose at which fewer than 2 of 6 patients experienced protocol defined dose-limiting toxicities (DLT) during cycle 1. Maintenance belinostat was allowed after sponsor approval. The starting dose of belinostat was 1000mg/m2. Secondary endpoints were safety and tolerability, progression free survival (PFS) and objective response rate (ORR) of the combination regimen.
Results:
Twenty three patients were enrolled and treated at the following belinostat levels: 1000 mg/m2 (n=5), 1200 mg/m2 (n=6), 1400 mg/m2 (n=6), 1600 mg/m2 (n=6). At the dose of 1600 mg/m2, 2 of 6 patients experienced DLTS (grade 3 syncope and grade 3 hypotension) and 1400 mg/m2 was determined as the belinostat MTD. Median cycles of belinostat: 10, 7, 5.5 and 4, median cycles of chemotherapy 6, 6, 5.5 and 4 in each of the four cohorts respectively. The most frequent adverse events (all grades) were fatigue (91%), nausea (78%), constipation (74%) anemia and diarrhea (65%) alopecia, arthralgia, decreased appetite, insomnia and neutropenia (61%) dizziness and vomiting (57%) and headache (52%). Median PFS was 5.7 months (95% CI: 2.8, 8.8). 13/23 patients had available response data at the end of cycle 6 with ORR of 35%. The responses observed were partial response in 8 patients (35%), stable disease in 4 patients (17%) and progressive disease in 1 patient (4%). Two patients with partial response at cycle 6 continued on belinostat maintenance and later achieved a complete response.
Conclusion:
The combination of belinostat and carboplatin and paclitaxel is feasible with observed toxicities consistent with expected side effect profile. Preliminary antitumor activity of this combination was also demonstrated.
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-016 - Pooled Efficacy and Safety Data from Two Phase II Studies (NP28673 and NP28761) of Alectinib in ALK+ Non-Small-Cell Lung Cancer (NSCLC) (ID 5044)
14:30 - 14:30 | Author(s): R. Govindan
- Abstract
Background:
Alectinib is an FDA-approved ALK TKI, for treatment of patients with ALK+ metastatic NSCLC who have progressed on, or are intolerant to, crizotinib. Systemic and CNS efficacy was demonstrated in two single-arm, phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]). We report the pooled systemic efficacy and safety analysis of alectinib from 2016 cut-offs 22 January, NP28761 and 1 February, NP28673.
Methods:
Patients were ≥18 years, had locally advanced or metastatic ALK+ NSCLC [FDA-approved FISH test] and had progressed on, or were intolerant to, crizotinib. Patients received oral alectinib 600mg twice daily until disease progression, death or withdrawal. The pooled analysis assessed objective response rate (ORR) by an independent review committee (IRC) using RECIST v1.1 (primary endpoint in both studies); disease control rate (DCR); duration of response (DOR); progression-free survival (PFS); overall survival (OS); and safety.
Results:
The pooled dataset included 225 patients, (n=138 NP28673; n=87 NP28761). Median age was 53 years, 60% of patients had baseline CNS metastases and 77% had received prior chemotherapy. The response-evaluable (RE) population by IRC included 189 patients (84%). Median follow-up was 18.8 months (0.6–29.7). In the RE population (n=189) ORR by IRC was 51.3% (95% CI 44.0–58.6; all partial responses), a DCR of 78.8% (95% CI 72.3–84.4), with a median DOR of 14.9 months (95% CI 11.1–20.4) after 58% of events. In patients with prior chemotherapy (n=148), IRC ORR was 49.3% (95% CI 41.0–57.7); DCR: 79.1% (95% CI 71.6–85.3); median DOR: 14.9 months (95% CI 11.0–21.9) after 59% of events. In patients who were chemotherapy-naïve (n=41), IRC ORR was 58.5% (95% CI 42.1–73.7); DCR: 78.0% (95% CI 62.4–89.4); median DOR: 11.2 months (95% CI 8.0–NE) after 54% of events. In the total pooled population (n=225) median PFS by IRC was 8.3 months (95% CI 7.0–11.3) after 69% of events and median OS was 26.0 months (95% CI 21.4–NE) after 43% of events. Grade ≥3 adverse events (AEs) occurred in 40% of patients and the most common were dyspnoea (4%), elevated levels of blood creatine phosphokinase (4%) and alanine aminotransferase (3%). The mean dose intensity was 94.6%. Fourteen patients withdrew due to AEs; 20.9% had AEs leading to dose interruptions/modification.
Conclusion:
This pooled analysis confirmed alectinib has robust systemic efficacy with a durable response in this population and in patients with or without prior chemotherapy. Alectinib had an acceptable safety profile.
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SH01 - WCLC 2016 Scientific Highlights - Prevention, Biology, Pathology (ID 483)
- Event: WCLC 2016
- Type: Scientific Highlights
- Track: Epidemiology/Tobacco Control and Cessation/Prevention
- Presentations: 1
- Moderators:M. Filipits, T. Mitsudomi
- Coordinates: 12/05/2016, 07:30 - 08:30, Hall C1
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SH01.02 - Biology (ID 7118)
07:50 - 08:10 | Author(s): R. Govindan
- Abstract
- Presentation
Abstract not provided
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