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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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      MA10.11 - Comparison among Different Radiological Criteria for Assessing Response to Nivolumab in Advanced Non-Small Cell Lung Cancer (ID 6181)

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

      • Abstract
      • Presentation
      • Slides

      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:

      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%)
      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).

      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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    P1.06 - Poster Session with Presenters Present (ID 458)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P1.06-017 - Observational Study on Prolonged Disease Stabilization in Advanced NSCLC EGFR WT/Unknown Patients Treated with Erlotinib in Second Line (ID 4998)

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

      • Abstract
      • Slides

      Background:
      In advanced NSCLC, erlotinib treatment was shown to improve survival independently of EGFR status and induce high rates of prolonged stable disease (SD). It has previously been reported that, after second-/third-line erlotinib, PFS and OS are long-lasting and similar between patients with SD ≥8 months and those attaining partial/complete response (PR/CR). The present study investigated the clinical value of SD in a real-world setting of advanced NSCLC.

      Methods:
      This Italian multicenter observational study enrolled patients with stage IIIB-IV NSCLC on second-line erlotinib and wild-type/unknown EGFR mutational status, with SD, CR or PR per RECIST v1.1 lasting for ≥4 weeks. Patients were observed from the beginning of erlotinib for approximately 8 months or until death. Primary end-points were the rate and duration of SD (i.e. time interval from erlotinib start to the last evidence of SD by RECIST) or CR+PR. Secondary end-points were OS and PFS (i.e. time interval from the erlotininb start to the first evidence of progression), estimated by the Kaplan-Meier method and calculated by response duration or disease stabilization. Adverse events occurring during the observation period were also recorded.

      Results:
      At the cut-off date of 30/04/16, 144/172 (83.7%) enrolled patients were evaluable for response (mean age 69.1 years, 61.8% males). At the start of erlotinib treatment, 85.4% were non-smokers, 89.6% had an ECOG-PS of 0-1, and 84.7% had stage IV NSCLC (83.3% adenocarcinoma and 11.8% squamous cell carcinoma). Following second-line erlotinib, 82.6% (119/144) of patients achieved SD and 17.4% (25/144) PR. Notably, SD was maintained for ≥8 months in 27% (39/144) of cases. At the end of the observation period, 12 (8.3%) patients had deceased, none with SD ≥8 months. Median OS had not been reached by the entire population. According to SD duration, median OS was 4.3 months if <2 months, 6.8 if between 2 and 5 months, and not reached if ≥5 months or if PR. Median PFS was 9.0 months in the entire population, 8.7 among patients with SD and 10.8 with PR. According to SD duration, PFS was 1.4 if <2 months, 4.4 months if between 2 and 5 months, 7.5 if between 5 and 8 months and 10.5 if ≥8 months. No unexpected toxicities were observed.

      Conclusion:
      In advanced NSCLC, second-line erlotinib yielded a high rate of SD, lasting ≥8 months in 27% of cases, with PFS similar to PR patients and low mortality rate.

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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
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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 - 15:45  |  Author(s): E. Rijavec

      • 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-054 - Prognostic Role of cfDNA in Patients with NSCLC under Treatment with Nivolumab (ID 6275)

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

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

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

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

      • 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.