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C. Genova
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MA10 - Facing the Real World: New Staging System and Response Evaluation in Immunotherapy (ID 393)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Radiology/Staging/Screening
- Presentations: 2
- Moderators:P. Kosmidis
- Coordinates: 12/06/2016, 14:20 - 15:50, Stolz 2
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MA10.09 - Comparison between CT Scan Evaluation Criteria and PERCIST for Evaluation of Immune Check-Point Inhibitors Response (ID 6227)
15:20 - 15:26 | Author(s): C. Genova
- Abstract
- Presentation
Background:
Immune check-point inhibitors (ICPIs) exert their activity by blocking inhibitory signaling and therefore enhancing T-cell activity against tumor cells; however, this peculiar mechanism of action might lead to many difficulties in evaluating clinical response with the usual CT imaging due to inflammatory patterns that could confuse the evaluation. The aim of this study was to assess the role of FDG-PET to support clinical decision based on CT scan.
Methods:
From May 2015 to April 2016, 74 patients with advanced pretreated NSCLC received at least one dose of nivolumab (3 mg/Kg every 14 days) within a single-institutional translational research trial. Among these, 58 patients were evaluable for response assessment. The patients underwent CT scan and FDG-PET every four cycles and, in case of progressive disease, an additional evaluation was performed after two further cycles in order to confirm it. We evaluated the response to treatment by CT scan with RECIST criteria, Immuno-related Response Criteria (irRC), WHO criteria and immunoRECIST criteria, while the metabolic response has been determined with PERCIST criteria. Finally, we determined the concordance in terms of response between CT evaluation criteria and metabolic response obtained with PERCIST; concordance was calculated with kappa value.
Results:
Our findings showed a low concordance of all CT scan evaluation criteria to PERCIST, the best concordance being between PERCIST and RECIST (K=0.500) and the worst agreement being between PERCIST and irRC (K=0.295) . In particular, PERCIST seems to underestimate the progressive disease (PD). In fact, between 46% and 55% of patients, defined in progression with CT evaluation criteria were considered in stable metabolic disease (SMD) by PERCIST; among these, 50% of patients in the RECIST PD group and 80% of RECIST SD patients were alive at 6 months. Furthermore, in our sample, between 9% and 18% of patients were considered in progression with CT evaluation criteria when they were in partial response with PERCIST; these patients were still alive with a survival similar to those who defined in partial response with RECIST (>9 months).
Conclusion:
FDG-PET evaluation by PERCIST could not be helpful when SMD is reported, in fact, patients that have a RECIST PD maintain a poor prognosis compared to RECIST SD between the patients define as SMD. Conversely, PERCIST evaluation could be informative when it define a partial response, specially when RECIST criteria show a PD.
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MA10.11 - Comparison among Different Radiological Criteria for Assessing Response to Nivolumab in Advanced Non-Small Cell Lung Cancer (ID 6181)
15:32 - 15:38 | Author(s): C. Genova
- Abstract
- Presentation
Background:
Immune check-point inhibitors have dramatically changed the management of advanced non-small cell lung cancer (NSCLC); however, their mechanism of action creates concerns on the most appropriate method to determine radiological responses to this drug class. The aim of this study is to compare a set of different evaluation criteria for patients receiving nivolumab for advanced NSCLC.
Methods:
Patients with pre-treated advanced NSCLC were enrolled in a single-institutional translational research study in the San Martino Hospital – National Institute for Cancer Research, Genova, Italy and received nivolumab (3 mg/kg every 14 days). Computed tomography (CT) was performed at baseline and after every 4 administrations. The assessments were performed according to Immune-related response criteria (irRC), response evaluation criteria in solid tumors (RECIST 1.1), World Health Organization (WHO), and immune-related RECIST (irRECIST), which are recently proposed based on the original RECIST with the following differences derived by irRC: 1) new lesions do not automatically define progressive disease (PD), but are added to the target lesions count; 2) PD has to be confirmed with a subsequent CT-scan after 2 additional cycles. The concordance among the different criteria was determined with Cohen’s kappa coefficient (K).
Results:
Fifty-two patients were eligible: median age= 70 years (44-85); male/female: 70%/30%; current or former smokers= 87%; non-squamous/squamous histology= 79%/21%; median number of cycles= 6 (4-29). The following responses were observed:
Generally, the concordance between first evaluation and best response was good for all the criteria (K ranging from 0.783 to 0.839); the concordance between irRECIST and irRC was high (K= 0.828) and RECIST 1.1 had a good concordance with IRC (K= 0.734), irRECIST (K= 0.767), and WHO (0.766).Partial Response Stable Disease Progressive Disease First evaluation (4 cycles) RECIST 1.1 4 (7.7%) 19 (36.5%) 29 (55.8%) irRC 3 (5.8%) 23 (44.2%) 26 (50%) WHO 3 (5.8%) 20 (38.5%) 29 (55.8%) irRECIST 4 (7.6%) 24 (46.2%) 24 (46.2%) Best Response Partial Response Stable Disease Progressive Disease RECIST 1.1 9 (17.3%) 14 (26.9%) 29 (55.8%) irRC 8 (15.4%) 19 (36.5%) 25 (48.1%) WHO 7 (13.5%) 17 (32.7%) 28 (53.8%) irRECIST 11 (21.2%) 18 (34.6%) 23 (44.2%)
Conclusion:
The different response assessment methods were generally concordant. Since response is more easily assessed with irRECIST than with irRC, the former might be proposed as an appropriate method of response evaluation.
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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): C. Genova
- 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: 2
- 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): C. Genova
- 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): C. Genova
- 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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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-035 - EGFR FISH as Potential Predictor of Necitumumab Benefit with Chemotherapy in Squamous NSCLC: Subgroup Analyses from SQUIRE (ID 5708)
14:30 - 14:30 | Author(s): C. Genova
- Abstract
Background:
Necitumumab (Neci) is a monoclonal antibody directed against the human epidermal growth factor receptor (EGFR). In the SQUIRE trial (NCT00981058), the addition of Neci to gemcitabine plus cisplatin (Gem-Cis) in squamous cell lung cancer resulted in a significant advantage in terms of overall survival (OS), but the expression of EGFR assessed by immunohistochemistry was not able to robustly predict the benefit from Neci. In a post-hoc analysis of SQUIRE, EGFR gene copy number gain determined by fluorescence in situ hybridization (FISH) showed a trend towards improved OS (HR=0.70) and progression-free survival (PFS) (HR=0.71) with the addition of Neci. We present the analysis of granular EGFR-FISH data from SQUIRE to examine the potential predictive role of high polysomy (HP) vs gene amplification (GA) as both were included in the “FISH-positive” category.
Methods:
Suitable specimens from SQUIRE patients underwent FISH analysis. Probe hybridization was performed in a central laboratory and each sample was analyzed using the Colorado EGFR scoring criteria. FISH was considered positive in cases of HP (≥40% cells with ≥4 EGFR copies) or GA (EGFR/CEP7 ≥2 or ≥10% cells with ≥15 EGFR copies). The correlation of granular FISH parameters with clinical outcomes was assessed.
Results:
FISH analysis was available for 557 patients (out of 1093); 208 patients (37.3%) were FISH+, including 167 (30.0%) with HP and 41 (7.4%) with GA. The outcome data for HP and GA are reported below:HIGH POLYSOMY GENE AMPLIFICATION Neci+Gem-Cis (N=89) Gem-Cis (N=78) Neci+Gem-Cis (N=22) Gem-Cis (N=19) Median OS in months (95% CI) 12.58 (11.04-16.00) 9.53 (7.16-12.48) 14.78 (10.02-31.51) 7.62 (4.99-16.10) Hazard ratio within subgroup (interaction model) 0.77 (0.55-1.08) p = 0.133 0.45 (0.21-0.93) p = 0.033 Interaction p value 0.189 Median PFS in months(95% CI) 6.08 (5.59-7.59) 5.13 (4.24-5.72) 7.36 (4.27-11.40) 5.55 (2.79-8.34) Hazard ratio within subgroup (interaction model) 0.70 (0.50-0.99) p = 0.044 0.69 (0.33-1.45) p = 0.334 Interaction p value 0.980
Conclusion:
The OS benefit from the addition of Neci to Gem-Cis appeared to be more pronounced in the small subset of patients with GA when compared to HP, but the same trend was not observed for PFS. The potential predictive value of different EGFR FISH parameters should be evaluated in future studies.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 6
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-036 - Management of Early Disease Progression during Treatment of Advanced Non-Small Cell Lung Cancer with Nivolumab (ID 6249)
14:30 - 14:30 | Author(s): C. Genova
- Abstract
Background:
Immune check-point inhibitors have recently become a cornerstone of the management of advanced non-small cell lung cancer (NSCLC). The peculiar mechanism of action of this drug class implies the possibility to treat patients beyond progressive disease (PD) on the basis of parameters such as the observation of clinical benefit or mild progression at computed tomography scan (CT-scan); however, a guideline for managing early PD during cancer immunotherapy has not been clearly defined yet. The aim of this study is to evaluate the approaches to patients experiencing early PD during treatment with nivolumab for advanced NSCLC.
Methods:
Patients treated with nivolumab (3 mg/Kg every 14 days) for advanced NSCLC between April 2015 and May 2016 within a single-institutional translational research study conducted in the San Martino Hospital – National Institute for Cancer Research, Genoa, Italy (approved by the local ethical committee) were considered eligible if their first response assessment (after 4 cycles) was PD. The response evaluation criteria in solid tumors (RECIST) and the immune-related response criteria (irRC) were employed. Since IRC imply the confirmation of PD after 2 further cycles, a cut-off of 6 cycles was set to define the patients who continued nivolumab beyond progression.
Results:
Globally, 31 patients were eligible: median age= 69 years (50-81); males/females= 74%/26%; current or former smokers= 90%; non-squamous/squamous histology= 67%/33%; 25 patients had PD as first evaluation with both criteria, while 4 had PD only with RECIST and 2 had PD only with IRC. With RECIST, 35% of the patients received nivolumab beyond progression (median= 10 cycles) and 80% of such patients were alive at the time of the analysis; on the contrary, only 53% of the patients who discontinued nivolumab at PD were still alive at the time of the analysis. With irRC, 30% of the patients received nivolumab beyond progression (median= 10 cycles) and 75% of such patients were alive at the time of the analysis, compared to only 47% of the patients who discontinued nivolumab at PD. The decision of continuing nivolumab beyond PD was based on the reported clinical benefit (67%), on the observation of a very limited progression at the CT-scan (22%) or on discordance between response criteria (11%).
Conclusion:
Administering nivolumab beyond progression might influence the outcomes of selected patients. Additional parameters for discriminating which patients are going to benefit from nivolumab continuation need to be investigated.
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P3.02c-039 - Endocrinological Side-Effects of Nivolumab in Advanced Non-Small Cell Lung Cancer (ID 6246)
14:30 - 14:30 | Author(s): C. Genova
- Abstract
Background:
Immune check-point inhibitors (ICPIs) are considered well-tolerated drugs. Previous experience with ipilimumab in advanced melanoma have shown possible endocrine toxicities, while less data have been collected about Nivolumab. ICPIs act by blocking inhibitory signaling and, therefore, enhancing T-cell activity against tumor cells. This mechanism might result in impaired self-tolerance with subsequent development of immune-related adverse events (irAEs), and endocrine toxicities are especially relevant.
Methods:
From May 2015 to April 2016, 74 patients with advanced pretreated NSCLC (52 Male, 22 Female, mean age: 64 years) received at least one dose of nivolumab (3 mg/Kg every 14 days) within a single-istitutional translational research trial . Blood samples were collected at baseline and at each cycle in order to monitor hormone (TSH, ACTH, cortisol, Prolactin[PRL] and testosterone) serum levels and autoantibodies (ATG, ATPO and anti-TSH) formation. Thyroid morphology was evaluated by ultrasonography at baseline, eventually repeated if TSH anomaly was observed.
Results:
Thyroid function was assessed in all 74 patients. At baseline, 6 patients had impaired thyroid function: 5 with reduced TSH, including two undergone previous thyroidectomy that required reduction in levothyroxine replacement therapy, and 1 with increased TSH. During treatment, 4 patients developed transient thyrotoxicosis evolving to hypothyroidism in 75% of cases. All patients with transient thyrotoxicosis reported increased thyroid autoantibodies; 8 patients developed hypothyroidism, with negative thyroid autoimmunity. Adrenocortical axis was evaluable in 55 subjects, of which 14 under steroid (equivalent of 10 mg of prednisone) therapy (one had partial hypopituitarism). Among the remaining 31 patients, 7 showed significant cortisol alterations (2 elevated, 5 reduced). Gonadal axis was evaluated in 38 male patients; among these, one was taking testosterone replacement therapy for partial hypopituitarism and one was receiving GnRH antagonists. No significant change on gonadal status was observed. PRL was assessed in 56 patients; among these, 10 were treated with drugs known to increase PRL levels; 20 patients had at least one elevated prolactin value, 7 from baseline and 13 developed during treatment. However, only 8 showed significantly increased values (>50 mcg/L in n=6, developed during therapy in 50% of cases; >100 mcg/L in n=2 from baseline).
Conclusion:
Thyroid function abnormalities, in particular non-autoimmune hypothyroidism and transient thyrotoxicosis on autoimmune basis, seem the major endocrine adverse event related to nivolumab. With respect to other hormonal axes, further conclusions might be drawn after a longer follow-up, due to the heterogeneity of available results and the presence of interfering factors.
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P3.02c-054 - Prognostic Role of cfDNA in Patients with NSCLC under Treatment with Nivolumab (ID 6275)
14:30 - 14:30 | Author(s): C. Genova
- Abstract
Background:
Nivolumab is a programmed death-1 (PD-1) immune checkpoint inhibitor approved for previously treated advanced non-small cell lung cancer (NSCLC). Liquid biopsy is a non-invasive blood test that detects cell-free DNA (cfDNA) shed from the tumour into the bloodstream. Monitoring cfDNA in patients with NSCLC under treatment with Nivolumab may be helpful to assess efficacy of the therapy and may be related with patients’ survival.
Methods:
Peripheral blood samples were obtained from 74 patients with pretreated advanced NSCLC within a single-institutional translational research trial from May 2015 to April 2016. Patients received intravenous Nivolumab at 3 mg/kg every 2 weeks until progression or unacceptable toxicity. All the patients underwent CT-scan every 4 cycles and responses were classified according to immune related Response Criteria. CfDNA was extracted from plasma using the Circulating Nucleic Acid Kit (Qiagen). The quantification of cfDNA (ng/ml plasma) was performed by qPCR using hTERT single copy gene. Kaplan-Meier survival function was used to compare the survival curves from cfDNA at baseline and at the time of first evaluation (after 4 cycles of Nivolumab).
Results:
Among the 74 enrolled patients 72 were evaluable for cfDNA survival analyses; 14 experienced early death, 25 progressive disease (PD), nine partial response (PR),19 stable disease (SD) and five were not evaluable for response. 27 out of the 28 responsive patients (PR+SD) are still alive at the time of analysis. In 25 evaluable patients with PD after the first radiological evaluation, median cfDNA < 786 ng/ml was significantly associated with an improved median survival as compared to cfDNA ≥786 ng/ml (295 vs 96 days respectively, HR=0.09290, 95% CI 0.019987-0.4322, p-value: 0.0052); similar results have been obtained in the subset of 25 patients progressing at best response (p-value: 0.0042). Analyzing the OS of the 72 evaluable patients, median survival of those with cfDNA<786 ng/ml is still undetermined, while it is equal to 181 days for those with cfDNA>786 ng/ml (HR 0.3559, 95%CI 0.1674-0.7568, p-value 0.0035).
Conclusion:
Our preliminary data show a significantly improved survival for NSCLC patients treated with Nivolumab having cfDNA<786 ng/ml than those with higher cfDNA; the correlation with OS is observed in patients at the first radiological evaluation and in those with PD at best response.
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P3.02c-072 - Predictive Immunologic Markers of Response to Nivolumab in Non-Small Cell Lung Cancer (ID 6228)
14:30 - 14:30 | Author(s): C. Genova
- Abstract
Background:
Nivolumab has become a consolidated therapeutic approach for previously treated non-small cell lung cancer (NSCLC); however, consistent prognostic and predictive factors are still lacking. Since these agents act by enhancing the immune response against tumor cells, it is possible that distinctive patterns in the circulating T cell sub-populations might be associated with different responsiveness. The aim of this study is to determine whether variations in these sub-populations might predict objective response to nivolumab in NSCLC.
Methods:
Blood samples were collected and stored from patients receiving nivolumab (3 mg/Kg every 14 days) for advanced NSCLC within a single-institutional translational research study conducted in the San Martino Hospital – National Institute for Cancer Research, Genova, Italy (approved by the local ethical committee). Sample collection was performed before each administration for 4 consecutive cycles, followed by computed tomography (CT)-scan. Response assessment was performed with the response evaluation criteria in solid tumors (RECIST) v. 1.1 and the immune-related response criteria (irRC); responses were defined as partial response (PR), stable disease (SD), and progressive disease (PD). Additional CT-scans were performed at 4 cycles intervals. Peripheral blood mononuclear cells (PBMC) were analyzed for the frequency of the major adaptive cell subsets, including B cells, natural killer (NK) cells, and T-cells; the latter were divided into CD8+ T cells, exhausted CD8+ T cells, CD4+ cells, and regulatory T cells (Tregs); the relative frequencies and the ratios between the sub-populations at each sample collection were compared with radiological response.
Results:
Fifty-four patients were considered eligible: median age= 70 (44-85); male/female: 70%/30%; current or former smokers= 87%; non-squamous/squamous histology= 80%/20%. Patients achieving PR at the first RECIST assessment had a significant upregulation of Tregs (CD4+ Foxp3+ CD39+ cells; p= 0.021), as well as a decreased CD8+/Treg ratio (p= 0.033) at the baseline sample. Conversely, patients experiencing PD at the first RECIST assessment had a significantly upregulated CD8+/Treg ratio at cycle 2 (p= 0.029). Finally, patients experiencing PD at irRC had a higher proportion of activated T cells (PD1+ CD56+ CD3+) compared to the other patients (P= 0.018) at cycle 2.
Conclusion:
The proportions of Tregs and activated T cells appear to be correlated with different responses to nivolumab according to RECIST and irRC. While the immunologic mechanism at the basis of these findings has to be defined, further studies involving PBMC as predictors of response to immunotherapy for NSCLC are highly advised.
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P3.02c-074 - Evaluation of a Pretreatment Serum Tests for Nivolumab Benefit in Patients with Non-Small Cell Lung Cancer (ID 5505)
14:30 - 14:30 | Author(s): C. Genova
- Abstract
Background:
Anti-PD1 inhibitors are becoming the treatment of choice for 2[nd] line non-small cell lung cancer (NSCLC). While existing testing for PDL-1 expression may correlate with anti-PD1 benefit, current data do not support these tests to be sufficient to guide therapy. We evaluated the utility of a serum-based pre-treatment test first developed to identify patients benefitting from anti-PD1 therapy in metastatic melanoma[1] in patients with NSCLC. These results were compared to the data obtained from application of the established VeriStrat[2] test to the same samples.
Methods:
60 advanced NSCLC patients treated with nivolumab in an observational study were included. Pretreatment serum samples were classified using the fully locked mass spectrometry-based multivariate tests BDX008 and VeriStrat. BDX008 generates a classification of positive (BDX008+, good outcomes) or negative (BDX008-, poor outcomes); VeriStrat classifies samples as Good and Poor. The association of test classifications with overall survival (OS), progression-free survival (PFS), and time-to-failure (TTF) were assessed using Kaplan-Meier method and Cox proportional hazards model.
Results:
37% of patients were classified as BDX008+ and 63% as BDX008-; 62% were classified as VeriStrat Good and 38% as Poor. Both tests significantly stratified OS (Table), but not PFS or TTF, and remained significant for OS in multivariate analyses (p=0.0167 and 0.0184, for BDX008 and VeriStrat, respectively). Out of 11 patients who died before the first radiological evaluation, 10 were classified as BDX008-, 9 as VeriStrat Poor.Test Log-rank p value CPH HR [95% CI] Median Survival (months) [95% CI] BDX0008 (+ vs -) 0.0026 0.189 [0.056-0.637] BDX0008+: Not reached BDX0008-: 5.5 [2.6-11.9] VeriStrat (Good vs Poor) 0.0186 0.390 [0.173-0.880] VS Good: Not reached VS Poor: 4.1 [1.0-Undef.]
Conclusion:
BDX008 developed for immunotherapy of patients with melanoma can be applied to NSCLC patients, and shows a significant separation for OS. Clinical utility of BDX008 will need to be further evaluated. VeriStrat is also prognostic for the same patients. 1. J. Weber et al, “Pre-treatment patient selection for nivolumab benefit based on serum mass spectra”, SITC 2015. 2. V. Gregorc et al, The Lancet Oncology, p713, 15(7), 2014.
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P3.02c-077 - Cardiac Troponin-I Elevation in Patients with Non-Small Cell Lung Cancer during PD1/PDL1 Inhibition with Nivolumab (ID 6258)
14:30 - 14:30 | Author(s): C. Genova
- Abstract
Background:
Immune check-point inhibitors are effective for the treatment of advanced non-small cell lung cancer (NSCLC); however, their mechanism of action is associated with peculiar immune-related adverse events (irAEs). While cardiac irAEs are seldom reported, animal data suggest that the myocardium might be sensitive to PD1/PD-L1 impairment. Minimal alterations of Cardiac Troponin-I (CTnI) can identify subclinical cardio-toxicity induced by antineoplastic agents like anthracyclines. The aim of this study is to determine whether CTnI might be used as a biomarker of cardiologic irAEs during treatment with nivolumab in advanced NSCLC.
Methods:
Serum samples were collected and stored from 61 patients receiving nivolumab (3 mg/Kg every 14 days) for advanced NSCLC within a single-institutional translational research study conducted in the San Martino Hospital – National Institute for Cancer Research, Genova, Italy (approved by the local ethical committee); samples were collected at baseline and at each cycle up to 5 cycles, and then every 2 cycles. Cardiac Troponin-I was retrospectively quantified with the luminescent oxygen channeling immunoassay (LOCI™) optimized on the Dimension Vista[®] analytical platform (Siemens Healthcare, Milan, Italy); and defined as undetectable (<0.015 μg/L) or detectable (>0.015 μg/L); a value of 0.045 μg/L was considered significant. Cardiologic anamnesis of the patients with detectable CTnI was collected from clinical documentation; additionally, patients alive at the time of the analysis underwent cardiologic evaluation.
Results:
Fifty-nine patients were evaluable: median age= 69 years (44-81); male/female: 69%/31%; current or former smokers= 86.4%; non-squamous/squamous histology= 80%/20%; median number of cycles= 6 (1-29). Twenty-six out of 351 collected samples had detectable CTnI levels. Thirteen patients (22%) had detectable CTnI levels in at least one sample; among these, 6 (10%) patients had significant alterations in at least one sample, and in 3 cases (5%) this alteration was reported in multiple samples. No specific time-related pattern was identifiable for CTnI alterations. Five patients with detectable CTnI, of which 2 with significant alterations (0.292 μg/L and 0.285 μg/L), had neither evident cardiovascular disease, nor cancer-related para-cardiac infiltration. Two patients had pericardial effusion, while two other had concurrent irAEs (hyperthyroidism and hepatitis).
Conclusion:
Troponin-I was altered in a considerable number of patients receiving nivolumab, in some cases with no evident concurrent cardiovascular disease or manifest indirect noxae. Although a rationale for immunotherapy-related myocardial inflammation is acknowledged, further investigations on the cardiovascular effects of PD1/PDL1 inhibitors are required to draw meaningful conclusions, such as studies involving prospective cardiovascular assessments of patients receiving these agents.
