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F. Biello
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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): F. Biello
- 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): F. Biello
- 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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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-067 - The Relevance of CEA and CYFRA21-1 as Predictive Factors in Nivolumab Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Patients (ID 6121)
14:30 - 14:30 | Author(s): F. Biello
- Abstract
Background:
CEA, CYFRA21-1 and NSE are tumor markers acknowledged as useful predictors of response to chemotherapy for advanced adenocarcinoma, squamous and small-cell lung cancer, respectively. However, their role in cancer immunotherapy needs to be investigated.
Methods:
We analyzed 56 patients with advanced NSCLC treated with nivolumab (3 mg/kg) every 14 days within a single-institutional translational research study. Blood samples were collected at baseline and at each cycle up to 5 cycles, and then every two cycles. All patients underwent a CT-scan every 4 cycles and responses were classified according to RECIST and Immune-Related Response Criteria (irRC). The serum level of CEA was measured with a Chemiluminescent Microparticle Immunoassay while CYFRA21-1 and NSE with an Immuno Radiometric Assay. The markers levels at baseline and after 4 cycles were used to analyze the relationship between their median variation and the objective response rate (ORR). The performance of tumor markers in predicting ORR was analyzed by ROC analysis and a reduction of 20% was used as cut-off level.
Results:
Forty-eight patients were evaluated: median age: 71 years (44-85); male/female: 73%/27%; current or former smokers: 87.5%; non-squamous/squamous histology: 79%/21%. Baseline median levels were 4.8 ng/ml for CEA, 3.47 ng/ml for CYFRA21-1 and 7.51 ng/ml for NSE. At baseline, values over the upper normal limit of CEA, CYFRA21-1 and NSE were detected in 23 (48%), 26 (54%), and 7 (14%) patients respectively. Significant differences were observed between responders and non-responders and CEA variation (-9% vs.+41%, p=0.003 for RECIST; -10% vs.+31%, p=0.015 for irRC), CYFRA21-1variation (-39% vs.+92%, p<0.001 for RECIST; -35% vs.+72%, p=0.003 for irRC) and NSE variation (-30% vs.+23%, p=0.005 for RECIST; -23% vs.+36%, p=0.004 for irRC). Significant correlations were observed between CEA and CYFRA21-1 decrease with RECIST or irRC: with RECIST, a decrease of 20% of CEA was achieved in 43% of responders and in 8% of non-responders (p=0.013), while a decrease of 20% of CYFRA21-1 occurred in 67% of responders and in 8% of non-responders (p<0.007). With irRC, a decrease of 20% of CEA was achieved in 42% of responders and in 9% of non-responders (p=0.018), while a decrease of 20% of CYFRA21-1 occurred in 58% of responders and in 14% of non-responders (p=0.002). Multivariate analysis confirmed the positive association between CYFRA 21-1 (≤20%) and ORR (RECIST: p=0.004; irRC: p=0.016).
Conclusion:
The reduction in serum level of CEA and CYFRA21-1 might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 5
- 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): F. Biello
- 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): F. Biello
- 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): F. Biello
- 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): F. Biello
- 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-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): F. Biello
- 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.
