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E. Rijavec



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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: 1
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      MA10.09 - Comparison between CT Scan Evaluation Criteria and PERCIST for Evaluation of Immune Check-Point Inhibitors Response (ID 6227)

      14:20 - 15:50  |  Author(s): E. Rijavec

      • Abstract
      • Presentation
      • Slides

      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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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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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 - 15:45  |  Author(s): E. Rijavec

      • 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: 1
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      P3.02c-039 - Endocrinological Side-Effects of Nivolumab in Advanced Non-Small Cell Lung Cancer (ID 6246)

      14:30 - 15:45  |  Author(s): E. Rijavec

      • 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.