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P. Lara
Moderator of
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 12
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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- Abstract
- Presentation
Background:
Conventionally, the classification of lung cancer and many other malignancies is determined by the histology of a tumor. Large cell neuroendocrine carcinoma (LCNEC) is traditionally classified as a histological variant of large cell carcinoma (LCC), which is a subtype of non-small cell lung cancer (NSCLC). However, LCNEC exhibits differential cytological, morphological, clinical and biological features than those of classic LCC, thus rendering controversies regarding its classification. In 2015, with the integration of immunohistochemical analyses, the World Health Organization (WHO) has re-classified LCNEC under neuroendocrine tumors. Due to the rareness of LCNEC, few studies have been conducted on the molecular genetic profiling of LCNEC. In this study, we characterized molecular signature associated with a cohort of LCNEC, SCLC and LCC using capture-based targeted sequencing.
Methods:
We performed capture-based targeted sequencing on 30 surgically resected samples from patients with lung cancer using BurningRock Biotech’s OncoScreen Panel. This panel, consisting of all exons and critical introns of 295 genes, covering multiple classes of somatic mutations, including single nucleotide variation (SNVs), rearrangements, copy number variations (CNVs) and insertions and deletions (INDELs), can be used to detect genetic alterations both qualitatively and quantitatively. Among the 30 patients, 15 of them were diagnosed with LCNEC, 5 with LCC and 10 with small cell lung cancer (SCLC).
Results:
While no statistically significant difference was observed in total number of mutations among the three subtypes, LCC carries the most number of somatic mutations followed by LCNEC then SCLC. Overall, we identified 331 mutations with TP53 being the most frequently mutated gene in all three subtypes. Genes with recurrent somatic mutations detected in LCNEC, but not in LCC or SCLC include RUNX1, ERBB4, BRCA1, and EPHA3. Copy number analysis revealed a higher prevalence of CNV in LCNEC, with 60% of cases harboring such alteration. There is no common CNVs shared among all three subtypes. NFкBIA amplification is the only common CNV found in both LCNEC and LCC; and AKT2 amplification is shared by LCNEC and SCLC. Most CNVs are subtype-specific. Interestingly, one RET-fusion was discovered in one LCC sample and one EGFR exon 19 deletion accompanied by EGFR copy number amplification was discovered in one LCNEC sample.
Conclusion:
Targeted deep sequencing reveals distinct genetic profile for LCNEC compared to LCC and SCLC. LCNEC harbors more CNV and contains a panel of genes, including RUNX1, ERBB4, BRCA1 and EPHA3 that are more frequently mutated comparing to LCC and SCLC.
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MA11.02 - Mutational Burden in Pulmonary Neuroendocrine Tumors (puNETs) (ID 6099)
14:20 - 15:50 | Author(s): I. Sullivan, M. Kossai, G. Le Teuff, M. Deloger, N. Dorvault, L. Gianoncelli, V. De Montpreville, B. Job, M.V. Bluthgen, B. Besse, J. Soria, J. Adam, J. Scoazec, E. Baudin, D. Planchard
- Abstract
- Presentation
Background:
Tumor mutational load (TML) by whole-exome sequencing (WES) is a potential determinant of response to immune checkpoint blockers. The use of PD-L1 as a predictive biomarker for use of PD-1/PD-L1 inhibitors is limited. To date, there are few data concerning TML in puNETs.
Methods:
WES was performed in fresh-frozen tumor-normal pairs from 35 typical carcinoid (TC), 4 atypical carcinoid (AC) and 9 large-cell neuroendocrine carcinoma (LCNEC) consecutively collected. Exome enriched libraries were sequenced on an Illumina HiSeq 2000 with a paired-end 2 x 100 bp protocol. Reads were aligned to the reference hg19 using an implementation of the Burrows-Wheeler Aligner, and a BAM file was produced for each tumor and normal sample using the Picard pipeline. The MuTect algorithm was used to identify SSNVs in WES data. We used a minimal allelic fraction cutoff of 0.1. Patients' characteristics and TML were described (median and interquartile for quantitative variables and frequencies for qualitative variables). To evaluate the effect of some factors on the TML, an analysis of variance was used. A log transformation was performed according to the distribution of the TML. The median follow-up was estimated using the Schemper's method. The number of relapses and deaths was reported.
Results:
Cohort included 24 male and 24 female. Median age at diagnosis was 57 [Q1= 46; Q3= 70] years, 38% of carcinoids (TC+AC) and 89% of LCNEC were smokers, 26 (54%) stage I, 16 (34%) stage II, 3 (6%) stage III and 3 (6%) stage IV. All patients underwent surgery and 5 (10%) received neoadjuvant treatment. Median follow-up was 32.6 (min= 4.4; max= 179.9) months; there were 8 (17%) relapses (6/9 LCNEC, 2/39 carcinoids) and 10 deaths. On average, 11.6 Gb of sequence were produced per sample, aiming a mean coverage of 72X. Overall median TML was 0.31/Mb [Q1= 0.22; Q3= 0.67], significantly lower in carcinoids tumors than LCNEC (0.28 [Q1= 0.20; Q3= 0.38]/Mb vs. 2.98 [Q1= 1.20; Q3= 4.84]/Mb, respectively, p<0.0001). Similar findings were observed among smoker vs. non-smoker patients (0.28 [Q1= 0.18; Q3= 0.38]/Mb vs. 0.60 [Q1= 0.28; Q3= 2.98]/Mb, respectively, p=0.04). Both variables were found to be independently correlated with TML within the ANOVA test (p=0.0016).
Conclusion:
Our findings provide a unique portrait of puNETs, revealing different histotype mutational burden. Continued work in harnessing immunological data in puNETs are needed for better understanding immunotherapy-treatment option in this orphan disease.
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MA11.03 - INSM1 is a Novel Biomarker and a Crucial Regulator of the Neuroendocrine Differentiation Pathway in Neuroendocrine Tumours of the Lung (ID 5205)
14:20 - 15:50 | Author(s): F. Kosuke, K. Yasufuku, M. Suzuki, T. Ito
- Abstract
- Presentation
Background:
Insulinoma-associated protein 1 (INSM1) is expressed predominantly in embryonic developing neuroendocrine (NE) tissues, and the expression is significantly reduced/restricted in adult tissues. We previously revealed that INSM1 is expressed exclusively in small cell lung cancer (SCLC) compared to non-small cell lung cancer (NSCLC). The significance of the expression of INSM1 in lung cancer has been largely unknown. We investigated the utility of INSM1 as a novel immunohistochemical marker and researched the biological significance in lung cancer cell lines.
Methods:
We compared INSM1 as an immunohistochemical marker for NE tumours of the lung to conventional markers (chromogranin A (CGA), synaptophysin (SYP), and CD56). To elucidate the biological function of INSM1 in the NE differentiation pathway, we conducted INSM1 gene knockdown/overexpression experiments using human lung cancer cell lines.
Results:
INSM1 was expressed in 100% of SCLCs (44/44), Large cell neuroendocrine cell carcinomas (7/7), and Carcinoids (11/11), but was not expressed in NSCLCs (90 adenocarcinomas and 47 squamous cell carcinomas). This novel immnohistochemical marker showed high sensitivity and specificity when compared to conventional NE markers. We demonstrated that knockdown of INSM1 expression resulted in significant reduction of NE molecules in SCLC cell lines, and overexpression of INSM1 induced NE differentiation in NSCLC cell lines.
Conclusion:
INSM1 was a superior NE immunohistochemical marker when compared to conventional markers. Furthermore, our biological molecular experiments revealed that INSM1 is a critical upstream regulator of the NE differentiation pathway in SCLC cell lines. The elucidation of the significance of INSM1 expression in lung cancer strongly supports the diagnosis of NE tumours of the lung and promotes the understanding of the molecular biology of these tumours.
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MA11.04 - Discussant for MA11.01, MA11.02, MA11.03 (ID 7083)
14:20 - 15:50 | Author(s): J. Pujol
- Abstract
- Presentation
Abstract not provided
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MA11.05 - A Case-Control Study to Test the Use of ctDNA in the Early Detection of SCLC Reveals TP53 Mutations in Non-Cancer Controls (ID 4915)
14:20 - 15:50 | Author(s): L. Fernandez-Cuesta, S. Perdomo, P.H. Avogbe, N. Leblay, T.M. Delhomme, V. Gaborieau, B. Abedi-Ardekani, E. Chanudet, M. Olivier, D. Zaridze, A. Mukeria, M. Vilensky, I. Holcatova, J. Polesel, L. Simonato, C. Canova, P. Lagiou, C. Brambilla, E. Brambilla, G. Byrnes, G. Scelo, F. Le Calvez-Kelm, M. Foll, J.D. McKay, P. Brennan
- Abstract
- Presentation
Background:
Circulating-tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays universal inactivation of TP53 (Peifer and Fernandez-Cuesta et al., Nat Genet 2012; George et al., Nature 2015).
Methods:
We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. The results were further validated in an independent series of 102 non-cancer controls. We identified mutations using Needlestack (Delhomme et al., in preparation; https://github.com/IARCbioinfo/needlestack), a pipeline specifically designed to accurately detect variants at very low allelic fractions (AF).
Results:
We detected TP53 mutations in the cfDNA of 49% of the SCLC patients (35.7% of the stage I-II). While statistically significant in cases versus controls (p-value=6x10[-9]), TP53 mutations were also detected in the cfDNA of 11.4% of the non-cancer controls, and these results were confirmed in the replication series (10.8%). The presence of TP53 mutations in controls was not correlated with age, smoking, or alcohol-intake status. There was a statistically significant difference between the mutational patterns found in cases versus controls (p-value=0.008): within controls the fraction of nonsense, indel, or splicing mutations was lower than in cases. The median AF of the TP53 mutations detected in the five stage I-II SCLC (0.9%) was not significantly different from that found in controls (1.2%; p-value=0.64), while it differed from the median AF of stage III-IV SCLC tumors (8.2%; p-value=2x10[-6]). Finally, we sequenced the DNA extracted from the white-blood cells (WBC) of 39 cfDNA TP53-positive patients, from which material was available (19 cases and 20 controls). Four cfDNA TP53 mutations (1 case and 3 controls) were detected in the WBC DNA, with similar AFs to those found in the cfDNA. These AFs, below 11%, are consistent with a somatic origin in both cfDNA and WBC DNA.
Conclusion:
The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests for the early diagnosis of cancer (Fernandez-Cuesta, Perdomo, and Avogbe et al., EBioMedicine 2016). We will discuss these results as well as follow-up analyses in retrospective and prospective series.
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- Abstract
- Presentation
Background:
Patients with extensive stage small cell lung cancer (ES-SCLC) who progress after frontline platinum-based chemotherapy are often considered “platinum-sensitive” (progression ≥ 90 days from last platinum dose) or “platinum-refractory” (progression < 90 days), as each group reportedly has differential overall survival (OS) outcomes. In a pooled analysis of recent SWOG trials of second and/or third-line targeted therapy, we showed that platinum-sensitivity status may no longer be as strongly associated with OS (Lara et al, JTO 2015). We assessed post-progression survival (PPS) following frontline platinum-based therapy in the context of platinum sensitivity status in ES-SCLC patients treated on SWOG 0124, a phase III trial of Irinotecan/Cisplatin vs Etoposide/Cisplatin.
Methods:
Data from 657 patients enrolled in S0124 were pooled. PPS was calculated as OS from the reported progression date. Crude PPS was evaluated according to platinum-sensitivity status. Hazard ratios (HRs) for PPS accounting for platinum-sensitivity and baseline clinical covariates (i.e., measured at the time of first line therapy) were calculated using single and multivariable Cox Proportional Hazard models. Baseline covariates were included in a logistic regression model to identify predictors of platinum-sensitivity. Recursive partitioning analysis (RPA) was performed to define prognostic risk groups.
Results:
Of 657 patients, 534 had a progression date and thus included in the analysis: 162 (25%) were platinum-sensitive and 372 (75%) refractory. Fewer patients with PS 0 (32% vs. 41%) and more patients with weight loss > 5% (40% vs. 31%) were seen in the refractory group. Crude unadjusted PPS was higher in platinum-sensitive vs refractory patients (median PPS 7.5 vs. 4.3 months; HR=1.64, p <0.001, 95%CI 1.356, 1.981). A multivariable Cox model showed that baseline elevated serum lactate dehydrogenase (LDH; HR=0.66, p<0.001) and platinum-sensitivity status (HR=1.54, p<0.001) were independently associated with PPS. None of the baseline covariates predicted for platinum-sensitivity. Prognostic groups with differential PPS based on platinum-sensitivity status, gender, and LDH were identified by RPA.
Conclusion:
PPS was significantly higher for S0124 patients categorized as platinum-sensitive vs. refractory. Limitations of this work include lack of relevant clinical data at the time of progression and number and type of post-progression therapies. These data have implications for the development of ES-SCLC trials in the salvage setting. [Supported by NIH/NCI/NCTN grants to SWOG: CA180888, CA180819, and in part by Pharmacia & Upjohn, a subsidiary of Pfizer. ClinicalTrials.gov Identifier: NCT00045162]
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MA11.07 - Improved Small Cell Lung Cancer (SCLC) Response Rates with Veliparib and Temozolomide: Results from a Phase II Trial (ID 5517)
14:20 - 15:50 | Author(s): L.A. Byers, L.M. Krug, S.N. Waqar, A. Dowlati, C.L. Hann, A. Chiappori, T.K. Owonikoko, K.M. Woo, Y. Bensman, B. Hurtado, R. Cardnell, L. Diao, Y. Fan, J. Fujimoto, J. Rodriguez-Canales, L. Long, E.P. Sulman, I. Wistuba, J. Wang, W.D. Travis, A.P. Chen, C. Rudin, M.G. Kris, M. Fleisher, J. Heymach, M.C. Pietanza
- Abstract
- Presentation
Background:
PARP1 is overexpressed in small cell lung cancer (SCLC) and represents a novel therapeutic target for this disease. Preclinical data indicates that combining veliparib (an oral PARP-1/2 inhibitor) and temozolomide (TMZ) results in synergistic tumor growth delay or regression. In this study, we investigated whether adding veliparib to TMZ would improve outcomes in patients with relapsed sensitive and refractory SCLCs. Candidate predictive biomarkers, including SLFN11, were then explored.
Methods:
SCLC patients previously treated with 1 or 2 prior regimens were enrolled in the trial and randomized 1:1 to receive oral TMZ 150-200mg/m[2]/day (D1-5) with either veliparib or placebo 40mg twice daily, orally (D1-7) (NCT01638546). Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in patients with platinum sensitive (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Archived tissue was available for 53 patients for biomarker analysis.
Results:
104 patients were enrolled and 100 patients were treated. Baseline characteristics were balanced between treatment arms: 52% female; median age 62.5 (range, 31-84); 59% refractory disease; 33% needing 3rd-line therapy. Progression free survival at 4-months was similar between the two arms, 36% vs. 27% (p=0.39). However, in 93 evaluable pts, response rate was significantly higher in pts treated with veliparib/TMZ compared to TMZ alone (39% vs 14%, p =0.016). Median overall survival: 8.2 mos (95% CI: 6.4-12.2) in veliparib arm and 7 mos (95% CI: 5.3-9.5) in placebo arm, p = 0.50. Grade 3/4 thrombocytopenia and neutropenia more commonly occurred in the veliparib/TMZ arm: 50% vs 9% and 31% vs 7%, respectively. Levels of SLFN11, a marker of SCLC response to PARP inhibition in preclinical models, were assessed by immunohistochemistry. High SLFN11 in patient tumors (obtained at original diagnosis) was associated with a trend towards better overall survival in the veliparib/TMZ arm, but no difference in outcome in the TMZ alone arm. Additional correlative studies are ongoing, including assessment of MGMT promoter methylation, and will be available at the time of presentation.
Conclusion:
The combination of veliparib/TMZ increased response rates significantly, compared to TMZ alone. Hematologic toxicities of the combination may have impacted PFS (which was not significantly different between the arms) by limiting dosing. Biomarkers such as SLFN11, ATM, or MGMT promoter methylation could potentially help guide patient selection in the SCLC population.
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MA11.08 - Discussant for MA11.05, MA11.06, MA11.07 (ID 7017)
14:20 - 15:50 | Author(s): A. Ardizzoni
- Abstract
- Presentation
Abstract not provided
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MA11.09 - Progastrin-Releasing Peptide (ProGRP) to Rule out Progressive Disease in Patients with Small Cell Lung Carcinoma (SCLC) (ID 4002)
14:20 - 15:50 | Author(s): T. Muley, X. Zhang, S. Holdenrieder, C.M. Korse, X. Zhi, R. Molina, Z. Liu, G. Hartmann, M. Van Den Heuvel, K. Qian, R. Marrades, C. Engel, Y. He, B. Wehnl, F. Dayyani, F.J. Herth
- Abstract
- Presentation
Background:
For patients with SCLC, response to chemotherapy is monitored by computed tomography (CT) scans, which can be costly and inconvenient. A previous study showed that baseline levels (>100 pg/ml) of the tumor marker, ProGRP, were positively correlated with advanced SCLC, and a decline in ProGRP levels during treatment was associated with response.[1] However, the best approach to fully exploit ProGRP for monitoring treatment response is still unknown. The objective of this study was to determine if progression could be ruled out solely by combining the changes in ProGRP levels over two chemotherapy cycles.
Methods:
Patients with SCLC receiving first-line platinum-based doublet chemotherapy or a single-agent cytotoxic in any subsequent treatment line were included from six centers in Europe and China. Samples were collected prospectively and ProGRP levels were measured in serum or plasma samples using a fully automated ProGRP assay at baseline and after chemotherapy cycles 1 and 2. Only patients with blood samples taken at these time points and with elevated baseline ProGRP >100 pg/ml were eligible for this analysis. A logistic regression model was calculated to incorporate changes after the first cycle (i.e. from baseline to the end of cycle 1) and in between cycles (i.e. end of cycle 1 to the end of cycle 2). Progression was ascertained with CT scans. A non-progressor was defined as a patient with complete response, partial response, or stable disease, according to the RECIST v1.1 or WHO criteria. Progressors were patients with progressive disease only.
Results:
Overall, 123 patients (n=108 non-progressors, n=15 progressors) satisfied the eligibility criteria. Median age was 62.0 years (range 36.0–83.0), 56% were male, and 78% reported to be current or past smokers. In this population, a decline in ProGRP from both baseline to cycle 1 and from cycle 1 to cycle 2 was associated with non-progression (AUC 91.5%; 95% CI: 85.3−97.8; sensitivity 100%; specificity 71%). All patients who experienced a >25% relative decline in ProGRP levels after the first chemotherapy cycle, followed by any further decrease (>0%) after the second cycle, were found to be non-progressors.
Conclusion:
By measuring the change in ProGRP levels at baseline and after each of the two subsequent chemotherapy cycles, we were able to identify patients with non-progressive disease. This might reduce the need for interim CT scans. References 1. Muley, et al. Journal of Thoracic Oncology 2015; 10(9) Supplement 2:MINI27.13
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MA11.10 - Prospective Study of Genome-Wide Strexome and Transcriptome Profiling in Patients with Small Cell Lung Cancer Progressing after 1st Line Therapy (ID 4197)
14:20 - 15:50 | Author(s): G.J. Weiss, A. Sangal, H. Barilla, S. Byron, J.A. Kiefer, J.L. Aldrich, T.G. Whitsett, J.D. Carpten, D.W. Craig
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) that has progressed after 1[st] line therapy has few effective treatments and no new class of approved therapies in over 20 years. Paired tumor-normal exome and transcriptome sequencing efficiency, coverage, cost, and analytics has improved over the last decade and has begun to be applied in the clinic. In this prospective study, we used genome-wide strexome (exome+structural variation) plus whole transcriptome sequencing (NGS) to identify genomic events and associated expression changes in advanced SCLC and attempt to prescribe systemic therapy based on the results (NCT02297087, study was funded by SU2C).
Methods:
After informed consent a prospective fresh frozen tumor biopsy was obtained. Germline DNA was extracted from PBMC and reference normal tissue RNA was obtained commercially. Strexome and RNA-seq libraries were prepped and NGS, data analysis, and reporting were performed in a CLIA-certified CAP accredited environment.
Results:
The study completed its accrual goal of 12 evaluable patients. There was one screen failure due to anticipated inadequate sample yield because of tumor location. The cohort included 10 women, median age was 56.5 years and had 3 never smokers. All patients received prior platinum-based chemotherapy and were receiving >1[st] line systemic treatment while awaiting NGS results. The minimum tumor content for successful NGS was 20%. The median turnaround time from sample collection to report was 27 days (range 21-38). Average strexome coverage was 420X (tumor), 200X (germline), with an average of 277 million RNA reads generated for tumors. All patients had ³2 clinically actionable targets identified (associated with a commercially available, FDA-approved drug by predefined rules), median 4 targets (range 2-8). Three patients received treatment identified by NGS. One has continuing partial response by RECIST 1.1 >8 months on a clinical trial involving PD-1 inhibitor+irinotecan (MLH1 mutation); treatment linked to NGS was already initiated prior to the report becoming available. One is too early to evaluate on olaparib (PARP1 mutation), and one had disease progression on dasatinib (KIT overexpression) as best overall response. One patient has not yet received NGS recommended therapy, and the remaining 8 evaluable patients had clinical deterioration or died before NGS recommended therapy was initiated.
Conclusion:
SCLC after 1[st] line therapy tends to have more rapid progression and deterioration making NGS application for systemic therapy challenging. Either applying NGS earlier in the earlier stages of disease course or further improvements in turnaround time may better address these challenges.
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MA11.11 - Is Hippocampal Avoidance during Whole Brain Radiotherapy Risky for Small Cell Lung Cancer Patients? (ID 3735)
14:20 - 15:50 | Author(s): E.K. Kirakli, O. Oztekin
- Abstract
- Presentation
Background:
Hippocampal avoidance (HA) during whole brain radiotherapy (WBRT) is performed to prevent neural stem-cell injury causing decreased neurocognitive function. Nevertheless, the estimated risk for metastases in HA area in small cell lung cancer (SCLC) patients is unknown. The current study aimed to characterize the metastatic distribution within the brain relative to the hippocampus and estimate the incidence of hippocampal metastasis in SCLC patients and also identify clinical and radiographic variables that may be associated with the presence of metastases within the HA area.
Methods:
SCLC patients treated with WBRT between January 2010 and December 2015 were reviewed. T1-wighted, post-contrast axial MRI (1.5 or 3 Tesla) images obtained just before therapeutic cranial irradiation were retrieved and reviewed for each patient. The HA area was generated by expanding the hippocampal contour by 5 mm volumetrically to account for necessary dose fall-off between the hippocampus (HP) and the whole brain planning target volume. Metastatic lesions within HP or HA area were defined as HP metastasis. HP metastasis rate was evaluated and characteristics of patients with HP metastasis were analyzed and compared to patients without HP metastasis.
Results:
54 patients evaluated with cranial MRI were enrolled. HP metastasis rate was 32% (17 patients). 4.4% of all metastases involved the HP and HA area (2.2% of metastases each) Figure 1. The most common location of metastasis was frontal lobe followed by cerebellum and temporal lobe. Having diabetes mellitus (OR: 12.1, 95% CI: 1.1-137.4, p=0.045) and being younger than 65 years of age (OR: 4.8, 95% CI: 1-23.2, p=0.049) were found to be independent risk factors for HP metastasis.
Conclusion:
HP metastasis might be more common in SCLC patients. Reducing the dose to the HP by HA-WBRT plan in SCLC may be risky for the development of HP metastasis compared with other malignant solid tumors.
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MA11.12 - Discussant for MA11.09, MA11.10, MA11.11 (ID 7084)
14:20 - 15:50 | Author(s): H. Kunitoh
- Abstract
- Presentation
Abstract not provided
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Author of
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ED14 - Small Cell Lung Cancer (ID 283)
- Event: WCLC 2016
- Type: Education Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:J.B. Sørensen, S. Zöchbauer-Müller
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall C2
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ED14.01 - Chemotherapy of Small Cell Lung Cancer (ID 6501)
14:30 - 15:45 | Author(s): P. Lara
- Abstract
- Presentation
Abstract:
Small cell lung cancer, which accounts for 10-15% of all lung cancers, is a biologically and clinically virulent malignancy that has a propensity to disseminate systemically and therefore is often initially diagnosed at an advanced incurable stage. Although typically associated with heavy tobacco use, there have been recent clinical observations of histologic evolution from adenocarcinoma to a SCLC phenotype, particularly in tumors harboring activating mutations in the epidermal growth factor receptor (EGFR) gene that had been treated with EGFR inhibitors. Due to its high proliferative rate, SCLC is known to be highly responsive – at least initially - to cytotoxic chemotherapy. Tumor response rates of 50-70% following platinum-based chemotherapy are usually expected. Intracranial metastases, a common feature of ES-SCLC, have been also shown to respond at a similar rate to cytotoxic therapy as that of metastases to other visceral organs. The standard frontline chemotherapy for ES-SCLC, unchanged for the past three decades, has been platinum (either cisplatin or carboplatin) plus etoposide. No other regimen has convincingly been demonstrated to be superior to platinum-etoposide in the frontline setting. Neither dose intensification approaches nor the incorporation of other cytotoxic agents into the platinum backbone have yielded any palpable or tangible survival benefits. In recent years, only prophylactic cranial irradiation and (in highly selected patients) consolidative thoracic irradiation have been shown to marginally improve survival outcomes. Furthermore, despite the high initial response rates to chemotherapy, drug resistance and subsequent tumor progression are universal events. Following failure of frontline platinum-based therapy, therapeutic options are limited and generally are of very modest clinical benefit. Current investigations into optimizing cytotoxic therapy include the development of novel cytotoxics (e.g., alisertib), sequential/combination strategies that involve novel “targeted” therapies and immunotherapeutics such as checkpoint inhibitors, or conjugating a cytotoxic payload onto a monoclonal antibody directed against an antigen expressed on SCLC, among others. A critical appraisal of the current status and future directions of cytotoxic therapy in ES-SCLC will be presented.
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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MA11.06 - SWOG 0124: Platinum-Sensitivity Status and Post-Progression Survival in Patients with Extensive-Stage Small Cell Lung Cancer (ID 3974)
14:20 - 15:50 | Author(s): P. Lara
- Abstract
- Presentation
Background:
Patients with extensive stage small cell lung cancer (ES-SCLC) who progress after frontline platinum-based chemotherapy are often considered “platinum-sensitive” (progression ≥ 90 days from last platinum dose) or “platinum-refractory” (progression < 90 days), as each group reportedly has differential overall survival (OS) outcomes. In a pooled analysis of recent SWOG trials of second and/or third-line targeted therapy, we showed that platinum-sensitivity status may no longer be as strongly associated with OS (Lara et al, JTO 2015). We assessed post-progression survival (PPS) following frontline platinum-based therapy in the context of platinum sensitivity status in ES-SCLC patients treated on SWOG 0124, a phase III trial of Irinotecan/Cisplatin vs Etoposide/Cisplatin.
Methods:
Data from 657 patients enrolled in S0124 were pooled. PPS was calculated as OS from the reported progression date. Crude PPS was evaluated according to platinum-sensitivity status. Hazard ratios (HRs) for PPS accounting for platinum-sensitivity and baseline clinical covariates (i.e., measured at the time of first line therapy) were calculated using single and multivariable Cox Proportional Hazard models. Baseline covariates were included in a logistic regression model to identify predictors of platinum-sensitivity. Recursive partitioning analysis (RPA) was performed to define prognostic risk groups.
Results:
Of 657 patients, 534 had a progression date and thus included in the analysis: 162 (25%) were platinum-sensitive and 372 (75%) refractory. Fewer patients with PS 0 (32% vs. 41%) and more patients with weight loss > 5% (40% vs. 31%) were seen in the refractory group. Crude unadjusted PPS was higher in platinum-sensitive vs refractory patients (median PPS 7.5 vs. 4.3 months; HR=1.64, p <0.001, 95%CI 1.356, 1.981). A multivariable Cox model showed that baseline elevated serum lactate dehydrogenase (LDH; HR=0.66, p<0.001) and platinum-sensitivity status (HR=1.54, p<0.001) were independently associated with PPS. None of the baseline covariates predicted for platinum-sensitivity. Prognostic groups with differential PPS based on platinum-sensitivity status, gender, and LDH were identified by RPA.
Conclusion:
PPS was significantly higher for S0124 patients categorized as platinum-sensitive vs. refractory. Limitations of this work include lack of relevant clinical data at the time of progression and number and type of post-progression therapies. These data have implications for the development of ES-SCLC trials in the salvage setting. [Supported by NIH/NCI/NCTN grants to SWOG: CA180888, CA180819, and in part by Pharmacia & Upjohn, a subsidiary of Pfizer. ClinicalTrials.gov Identifier: NCT00045162]
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.10 - Lung-MAP (S1400) Lung Master Protocol: Accrual and Genomic Screening Updates (ID 3995)
14:20 - 15:50 | Author(s): P. Lara
- Abstract
- Presentation
Background:
Lung-MAP (S1400), is a master protocol that incorporates genomic testing of tumors through a next generation sequencing (NGS) platform (Foundation Medicine) and biomarker-driven (matched) therapies for patients with squamous cell lung cancer (SCCA) after progression on first-line chemotherapy.
Methods:
The Lung-MAP trial, activated June 16, 2014, includes 3 matched- and 1 non-match study. Matched studies include: S1400B evaluating taselisib, a PI3K inhibitor, S1400C evaluating palbociclib, a CDK 4/6 inhibitor and, S1400D evaluating AZD4547, an FGFR inhibitor. The non-match study S1400I tests nivolumab + ipilimumab vs. nivolumab. Two studies have closed: S1400E evaluating rilotumumab an HGF monoclonal antibody + erlotinib closed 11/26/2014 and S1400A evaluating MEDI4736 in non-match pts, closed 12/18/2015.
Results:
From June 16, 2014 to June 15, 2016, 812 pts were screened and 292 pts registered to a study: 116 to S1400A, 27 to S1400B, 53 to S1400C, 32 to S1400D, 9 to S1400E and 55 to S1400I. Demographics: Screening was successful for 705 (87%) of screened eligible pts. Median age 67 (range 35-92); male 68%; ECOG PS 0-1 88%, PS 2 10%; Caucasian 85%, Black 9%, other 5%; never/former/current smokers 4%/58%/36%. Table 1 displays biomarker prevalence; 39% of pts matched; 33.9%, 4.8%, and 0.3% with 1, 2, and all 3 biomarkers, respectively. Tumor mutation burden (TMB) was available for 636 (90.4%) of eligible pts. The distribution of TMB is: 126 (19.8%) low (≤5 mutations Mb), 415 (65.1%) intermediate (6-19 mutations/Mb), and 96 (15.1%) high (≥20 mutations/Mb). The median TMB was 10.1.
Conclusion:
Genomic screening is feasible as part of this master protocol designed to expedite drug registration, confirm anticipated prevalence of targeted alterations in SCCA and reveal intermediate or high TMB in most (80.2%) pts. Treatment results are not yet available as patients continue to accrue. Clinical trial information: NCT02154490Total FGFR CDK PIK3CA FGFR (15.9%) 12.9% 2.4% 0.6% CDK (18.8%) 14.6% 1.8% PIK3CA (8.8%) 6.4% Biomarker prevalence and overlap.
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OA10 - EGFR Mutations (ID 382)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
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OA10.01 - Comprehensive Genomic Profiling and PDX Modeling of EGFR Exon 20 Insertions: Evidence for Osimertinib Based Dual EGFR Blockade (ID 4375)
11:00 - 12:30 | Author(s): P. Lara
- Abstract
Background:
EGFR exon 20 insertion mutations (EGFRex20ins) comprise a subset of EGFR activating alterations relatively insensitive to 1[st] and 2[nd] generation EGFR-TKIs. Comprehensive genomic profiling (CGP) integrated with PDX modeling may identify new EGFR-inhibition strategies for EGFRex20ins.
Methods:
EGFRex20ins and co-occurring genomic alterations were identified by hybrid-capture based CGP performed on 14,483 consecutive FFPE lung cancer specimens to a mean coverage depth of >650X for 236 or 315 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. An EGFRex20ins(N771_P772>SVDNP)/EGFR-amplified tumor (24 copies) from this cohort was implanted subcutaneously into the flank of NOD.Cg-Prkdc[scid]Il2rg[tm1Wjl]/SzJ (NSG) mice for tumor growth inhibition studies (TGI) with vehicle, erlotinib (50 mg/kg PO daily), osimertinib (25 mg/kg PO daily), and osimertinib (25 mg/kg PO daily) plus cetuximab (10 mg/kg IV, 2x/week) administered for 21 days.
Results:
CGP identified 263/14,483 cases (1.8%) with EGFRex20ins, which represent 12% (263/2,251) of EGFR activating mutations in this series. 90% (237/263) were NSCLC-adenocarcinoma, 9% (23/263) were NSCLC-NOS, and 1% (2/263) were sarcomatoid carcinoma. Over 60 unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%); 6% (15/263) harbored EGFR A763_Y764insFQEA, an EGFRex20ins typically sensitive to erlotinib. Among EGFRex20ins cases, EGFR-amplification occurred in 22% (57/263). Putative co-occurring driver alterations including EGFR (ex19del and L858R), Her2, MET and KRAS tended to be mutually exclusive, occurring only in 5% (12/263) of cases. The most common co-occurring alterations affected TP53 (56%), CDKN2A (22%), CDKN2B (16%), NKX2-1 (14%) and RB1 (11%). Average tumor mutation burden was low (mean 4.3 mutations/Mb, range 0-40.3 mutations/Mb). Clinical outcomes to 1st and 2nd generation EGFR-TKIs were obtained for a subset of cases with various EGFRex20ins, and 0/6 patients had responses. However, robust TGI was observed with combination osimertinib and cetuximab in a highly EGFR-amplified PDX model with a conserved EGFRex20ins (N771_P772>SVDNP) not associated with response to earlier generation EGFR-TKI, and was superior to vehicle, erlotinib or osimertinib alone (D21 mean tumor size 70 mm[3] vs. 1000, 800, 225 mm[3] respectively; p-values all <0.001).
Conclusion:
Diverse EGFRex20ins were detected in 12% of EGFR-mut NSCLC. Available clinical outcomes data demonstrated lack of response to 1[st] and 2[nd] generation EGFR-TKIs. Identification of co-occurring EGFR-amplification in 22% of cases led to testing of a dual EGFR blockade strategy with an EGFR monoclonal antibody and osimertinib, which demonstrated exceptional tumor growth inhibition in an EGFRex20ins PDX minimally responsive to erlotinib. These findings can rapidly be translated into an ongoing clinical trial of osimertinib and necitumumab.
