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F.D. Merlo
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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.D. Merlo
- 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.D. Merlo
- 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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 3
- 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.D. Merlo
- 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 - 14:30 | Author(s): F.D. Merlo
- 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.D. Merlo
- 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.
