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Bartomeu Massuti
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FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP12.09 - Molecular Insight into NADIM Clinical Trial: Potential Immune Biomarkers of Pathological Response for NSCLC Patients. (ID 3552)
00:00 - 00:00 | Author(s): Bartomeu Massuti
- Abstract
- Presentation
Introduction
Many studies have demonstrated that chemo-immunotherapy is a promising approach for NSCLC patients but still exists a lack of prediction biomarkers of survival. We have recently showed that pathological response is a surrogate of progression free survival (PFS) including infiltrating immune cells as potential biomarker of pathological response in NADIM clinical trial (Provencio et al., 2020. Lancet Oncology, in press).
New biomarkers in peripheral blood are being described, focused on the immune system response. Preliminary data was presented at WCLC 2019 however additional results are included in this report. Here we describe the effect of chemo-immune neoadjuvant treatment on resectable NSCLC stage III patients’ immune system and describe blood biomarkers that could help to identify responders to this combination therapy.
Methods
Peripheral mononuclear cells (PBMCs) and plasma from NADIM clinical trial patients before and after chemo-immune neoadjuvant treatment were used. Phenotyping and activation levels of immune cell populations were analyzed by flow cytometry, focused on CD4 T cells, CD8 T cells, T cells NK like and NK cells. Moreover, characterization of the immune response was evaluated by a cytokine array.
Clinical evaluation of pathological response, classified patients in 3 groups, complete (CPR, 0% tumor cells), major (MPR, <10% viable tumor) and incomplete (IPR, >10% viable tumor). Wilcoxon and Kruskall-Wallis statistic tests were used.
Results
Even though we have previously described a decrease of T lymphocytes on tissue after treatment, we do not see these changes on blood. Thus, percentages of PBMCs (T cells, B cells, NK cells and macrophages) did not vary after neoadjuvant treatment. However, lower levels of activated CD4 T cells and NK cells were observed. Interestingly, this decrease was exclusively statistically significant for patients who achieved a CPR, but no differences were observed for MPR or IPR. As expected, detection of PD1+ cells after neoadjuvant Nivolumab (anti-PD1) treatment was almost completely abrogated, however, a trend for higher PD1+ cell proportions was observed in patients achieving CPR at diagnosis.
Furthermore, many cytokines involved in immune response and described as putative biomarkers for immunotherapy in NSCLC as IL-2, IL-15, IL-6, IL-13 or IFN-gamma, among others, were decreased after neoadjuvant treatment. Notably, stratifying by pathological responses, this decrease was statistically significant only for non-complete responses.
Conclusion
The analysis of immune cell markers on blood samples could be a source for potential surrogate markers of pathological response to neoadjuvant treatment on NSCLC patients.
Similarly, to what occurs in tissue, CPRs showed differences compared to MPR or IPR in some blood markers, both at the cellular and cytokine level. Thus, after treatment, patients achieving CPRs do not seem to reduce their levels of cytokines such as IL-2, IL-15, IL-6, IL-13 or IFN-g associated with anti-tumor response, but they do reduce their levels of activated CD4 and NK cells
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P52 - Staging - Prognosis and Staging (ID 186)
- Event: WCLC 2020
- Type: Posters
- Track: Staging
- Presentations: 3
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P52.05 - Lung Cancer Symptoms at Diagnosis: Data from the Thoracic Tumors Registry (TTR Study). (ID 3023)
00:00 - 00:00 | Author(s): Bartomeu Massuti
- Abstract
Introduction
Lung cancer is the most common cancer worldwide and is the leading cause of cancer death in Western countries. Despite its high incidence and mortality there are few studies that describe its symptoms at diagnosis and their relationship with tumor stage and tobacco use. The objective of this study is to describe the frequency of the most common symptoms of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) at diagnosis and their connection with stage of disease and smoking habit.
Methods
This was a case series study that analysed cases collected from the Thoracic Tumour Registry (TTR) sponsored by the Spanish Lung Cancer Group (SLCG) from August 2016 to June 2019.
Results
9,876 patients were included. 74% male, the median age was 65 years (57-72), 12% were never smokers. The most frequent histologic type was adenocarcinoma (52%) followed by squamous cell carcinoma (24%) and small cell lung cancer (12.5%). 46.6% of the patients was stage IV at diagnosis. The most common symptoms were cough (33.9%) and dyspnoea (26.7%). No symptom was present in 59% of patients diagnosed stage I NSCLC and in 27.7% of patients stage IV NSCLC. The number of symptoms was similar across the respective smoking categories in NSCLC and differences between the symptoms analysed did not exceed 7% in any case
TABLE:
Table. 1 Symptom description by tobacco consumption: NSCLC
Symptoms at diagnosis+
Never smokers**
Ex-smokers**
Current smokers**
p-trend
Cough
387 (34.1)
1,310 (31.7)
1,099 (34.5)
0.163
Pain
318 (28.0)
990 (24.0)
1,008 (31.6)
<0.001
Dyspnoea
330 (29.1)
1,014 (24.5)
823 (25.8)
0.365
Haemoptysis
70 (6.2)
511 (12.4)
389 (12.2)
<0.001
Weight loss
223 (19.7)
678 (16.4)
842 (26.4)
<0.001
Anorexia
66 (5.8)
185 (4.5)
226 (7.1)
0.001
Asthenia
114 (10.1)
315 (7.6)
331 (10.4)
0.024
Superior vena cava syndrome
3 (0.3)
6 (0.1)
15 (0.5)
0.039
Aphonia or voice alterations
331 (2.7)
100 (2.4)
104 (3.3)
0.085
Number of symptoms++
0
1
2
3
4 or more
341 (30.1)
252 (31.0)
236 (20.8)
127 (11.2)
78 (6.9)
1,531 (37.0)
1,121 (27.1)
812 (19.6)
427 (10.3)
242 (5.8)
879 (27.6)
887 (27.8)
694 (21.8)
454 (14.2)
272 (8.4)
<0.001
0.263
0.113
<0.001
<0.001
**Never smoker: participant smoked less than 100 cigarettes in lifetime. Ex-smoker: stopped smoking more than 1 year before diagnosis. Current smoker: declared smoking during the year before diagnosis. 89 participants had unknown tobacco consumption.
+Percentages calculated as a total of the sample.
++Totals calculated for each smoking category.
Conclusion
In conclusion, this study provides valuable information on the frequency and type of lung cancer symptoms at diagnosis and their relationship with stage and tobacco use. The most relevant findings are that 28% of stage IV lung cancers do not present any symptoms at diagnosis, and that there are no relevant differences in symptom presentation by reference to smoking status. This information confirms the lack of specificity of lung cancer symptoms and the fact that the absence of the most frequent symptoms (i.e., cough, pain, dyspnoea) should in no case lead to a decision to rule out the presence of this disease.
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P52.08 - Thoracic Tumors Registry (RTT): Analysis of Clinical Features and Survival in Patients with mNSCLC in Spain. (ID 3022)
00:00 - 00:00 | Author(s): Bartomeu Massuti
- Abstract
Introduction
The lung cancer is the leading cause of death due to cancer in Western countries, the prognosis it depends on the tumor stage and the clinical, histological and molecular characteristics. The Thoracic Tumors Registry (RTT) of the Spanish Lung Cancer Group is a database who include the data of patients with lung malignant neoplasms.
Methods
The objective of this retrospective study is to descriptive the clinical and epidemiological aspects of non-small cell lung cancer (NSCLC) in the Spanish population.
Results
The total of patients included in the RTT is 12.897 (Aug 2016 - Jan 2020) and this report is based in the analysis of 5.049 of them. The clinical and demographic data are described in the table 1. Adenocarcinoma (72,2%), squamous cell carcinoma (SCC) (18,6%), others types. The sites of metastasis: contralateral lung (34.3%), bone (31%), liver (12.8%) and CNS (6.02%). The first-line of treatment was chemotherapy (CT) in 66,54%, oral target therapy 13,45%, immunotherapy (IO) 8,62% and CT+IO 2,46%. The median of PFS of 7.4 months (7.13-7.6 months) in all population with an estimated at 6, 12, 24, and 60 months of 58.3% (95%CI 56.81% - 59.74%), 29.97% (95%CI 28.56% - 31.4%), 13.4% (95%CI 12.2% - 14.6%) and 2.6% (95%CI 1.98%-3.5%) respectively. The median of OS was 15.5 months (14.8-16.4). According to the histological type (SCC vs non-SCC), the median (in months) of PFS was 6.67 (6.1- 7.1) vs 7.53 (7.3-7.9) (HR 0.78, 95% CI 0.72 - 0.85) and OS 13.8 (12.6-15.6) vs 16.9 (15.7 - 18) in non-SSC, p <0.001. The analysis of survival in patients with or without liver metastasis showed a median OS of 15 months (14.3-16m) vs 18.1 months (16.1- 19.9m), HR 0.88, 95%CI 0.79-0.98 (p<0.05).
N=5049
Age, Median
68,29-y (25-96)
Sex
M: 71,16% - F: 28,83%
Smoking habit
Smoker
Former smoker
Never smoker
42,42%
41,06%
15,56%
Asbestos exposure
2,14%
Patient history of cancer
13,5%
Family history of cancer
40,82%
Conclusion
The results of our study show a similarity in the clinical characteristics of patients with NSCLC in the Spanish population with the data in the western population previously describe. Both the histological subtype and the presence of liver metastases are predictive factors for survival.
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P52.10 - Profile of Comorbidities and Cancer History in Patients with mNSCLC in the Spanish Population (Thoracic Tumors Registry). (ID 3024)
00:00 - 00:00 | Author(s): Bartomeu Massuti
- Abstract
Introduction
Lung cancer is the most commonly diagnosed cancer worldwide and places a considerable burden on public health. The prognosis depends on the tumor stage and the clinical, histological and molecular characteristics. However, the comorbidities are also an important factor, not only in the diagnostic procedures but on the oncologic treatment strategies. The Thoracic Tumors Registry (RTT) of the Spanish Lung Cancer Group is a database that includes the data of patients with lung malignant neoplasms
Methods
The objective of this retrospective study is to describe the profile of comorbidities and cancer history in patients with NSCLC in the Spanish population.
Results
The total of patients included in the RTT is 12.897 (Aug 2016 - Jan 2020) and this report is based in the analysis of 5.049 of them. The median of age was 68,9-y (25-96). The most prevalent histology was the adenocarcinoma (72,2%) followed by the squamous cell carcinoma (SCC) (18,6%), others types include sarcomatoids, large cell, neuroendocrine and NOS carcinoma. Seventy-one percent of patients were male and 28,83% female and, according to the smoking habit, 42,42% were smoker, 41,06% former smoker and 15,56% never smoker. The asbestos exposure was informing in 108 cases (2,14%). A total of 4153 patients (82.25%) had comorbidities and these including: hypertension (50,13%), dyslipemia (34,36%), diabetes mellitus (22,9%), COPD (21,04%), heart disease (16,23%), depressive syndrome / anxiety (7,89%), vasculopathy (6,79%), obesity (4,94%), among others. 681 patients had a previous history of cancer (13,49%), the mains include the bladder and urinary tracts (14,39%), head and neck (10,43%), colorectal (10%), breast (8.08%), non-melanoma skin (6,31%), lung (2,5%), lymphoma (2,5%), among others.
Conclusion
Our study shows the real comorbidity profiles of patients with NSCLC in Spain. The cardiovascular and pulmonary diseases and the metabolic disorders are the most common pathologies in our patients. Theses comorbidities may have determined the selection of the treatment and influence the prognosis in lung cancer as well as and pose a major clinical challenge in the care of cancer patients.
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P60 - Tumor Biology and Systems Biology - Basic and Translational Science - Immune Bio (ID 198)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P60.07 - TMB and Selected Mutations in Resectable Stage IIIA NSCLC Patients Receiving Neo-Adjuvant Chemo-Immunotherapy from NADIM Trial (ID 2142)
00:00 - 00:00 | Author(s): Bartomeu Massuti
- Abstract
Introduction
Tumor Mutational Burden (TMB) assessment and identification of specific mutations associated to anti-PD1 blockade therapy resistance have become a novel approach to predict the clinical benefit to anti-PD1/PDL1 therapy. However, the clinical relevance of these parameters in terms of pathological response and PFS in neo-adjuvant chemo-immunotherapy has not been established. To answer this question we analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab.
Methods
Pretreatment TMB, defined as the number of nonsynonymous variants (missense and nonsense single nucleotide variants (SNVs)), plus insertion and deletion variants (INDELs) detected per megabase (Mb) of exonic sequence, was estimated from 27 patients that had enough diagnostic material for next generation sequencing using the Oncomine Tumor mutation Load assay (ThermoFisher) following manufacturer’s instructions. The panel covers 1.7 Mb of 409 genes with known cancer associations. Regarding pathological responses, patients were classified into 3 groups: pathologic complete response (pCR) (0% viable tumour at any localization tested), major pathologic response (MPR, <10% viable tumour) and pathologic incomplete response (pIR) (>10% of viable tumour). At data analysis, median follow-up time was 22.7 months.
Results
Median TMB was 5.89 (range 1.68 – 73.95). No differences in TMB value between histologies (adenocarcinoma vs squamous cell), smoking status (former vs current), age or sex were observed. Somatic mutations were identified in lung cancer driver genes such as TP53, KRAS, EGFR, CDKN2A, NOTCH1, BRAF and in specific genes associated with resistance to immunotherapy such as STK11, KEAP1, and RB1. No genomic alterations in ALK, ROS1, PTEN or ERBB2 were found.
Based on literature, a poor prognosis mutation signature (presence of EGFR, STK11, KEAP1 or RB1 mutations) was generated. A third of the sequenced patients (9/27) harboured at least one mutation in one of these genes.
Pathological response data was available from 23 out of 27 patients sequenced. Both the TMB value and the presence of these resistance mutations were not associated with the degree of pathological response.
Regarding PFS, TMB alone was not predictive of disease progression using different thresholds. However, the presence of these resistance mutations was associated with shorter PFS (log-rank p-value=0.032). The median PFS for mutated patients was 21.4 months (95% CI 16-26 months) while median PFS was not reached in non-mutated patients.
Additionally, the combination of this mutational signature with TMB (absence of resistance mutations and TMB-Higher than median) was able to distinguish patients that strongly benefit from this therapy. Although the median PFS was not reached in both groups yet, statistically significant differences were observed (log-rank p-value=0.046). PFS at 18 and 24 months was 100% (95% CI not estimable) for Non-mutated patients with TMB-High vs 70% (95% CI 50-89%) and 58% (95% CI 35-81%) for the rest of patients (mutated patients plus Non-mutated patients with TMB-Low).
Conclusion
TMB did not predict benefit from chemo-immunotherapy induction in our cohort. However, the presence of EGFR/STK11/KEAP1/RB1 mutations alone, or in combination with TMB, may help identify patients that unlikely benefit from neo-adjuvant chemo-immunotherapy
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P60.11 - TCR Repertoire Predicts Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemoimmunotherapy from NADIM Trial (ID 3417)
00:00 - 00:00 | Author(s): Bartomeu Massuti
- Abstract
Introduction
Characterization of the T-cell receptor (TCR) repertoire has become a novel approach to monitor immunotherapy responses, however there is lack of knowledge about its clinical relevance as predictive biomarker of pathological response in neoadjuvant chemoimmunotherapy. For this purpose, we analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant Paclitaxel + Carboplatin + Nivolumab for 3 cycles, achieving a 63% of complete pathologic responses (CPR). PD-L1 TPS and TMB as CPR biomarkers showed AUC ROC of 0.77 and 0.55, respectively, reinforcing the need for new biomarkers (Provencio, M. et al. 2020).
Methods
TCR repertoires from primary tumours or lymph nodes of 19 NSCLC patients were obtained, at both time points: diagnosis and after neoadjuvant treatment. TCR repertoire was analysed in terms of convergence, diversity, evenness and clonal space, defined as the summed frequency of clones belonging to a frecuency group (top 1%, top 1% to 2%, 2% to 5%, and >5%) relative to the total T-cell repertoire. The results were correlated with pathological response groups and ROC curve analysis was performed to test if TCR repertoire-derived parameters could identify patients with CPR.
Results
There were no statistically significant differences observed in TCR repertoire in biopsy samples in terms of diversity (p = 0,797) or convergence (p = 0,202) between the three pathological response groups or between biopsy and surgery samples. However, we observed differences in terms of evenness in biopsy samples between the pathologic response groups (p=0.037), which were lower in those patients who achieved CPR. The AUC for evenness was 0.844 (IC: 0.667-1.000), p=0,011. An evenness value of <0.8639 showed a sensitivity of 50% and specificity of 100% identifying patients with CPR.
Moreover, the clonal space of the TOP 1% clones in diagnostic samples was higher in patients that achieved CPR (p=0.002). The AUC of this novel biomarker was 0.9667 (IC: 0.897-1.036) (p=0.0006). A TOP 1% clonal space higher than 0.1607 showed a sensitivity of 90% and specificity of 88.9% identifying patients with CPR.
Conclusion
Our results support the association between the uneven distribution of T-lymphocytes clones proportions present in the tissue at diagnosis and response to chemoimmunotherapy. Specifically, higher clonal space occupied by the TOP 1% clones seems to outperform PD-L1 and TMB as predictive biomarker of CPR in NSCLC patients receiving neoadjuvant chemoimmunotherapy.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.03 - Efficacy and Safety of Capmatinib Plus Nivolumab in Pretreated Patients with EGFR Wild-Type Non–Small Cell Lung Cancer (ID 817)
00:00 - 00:00 | Author(s): Bartomeu Massuti
- Abstract
Introduction
Dysregulation of the MET gene can be an oncogenic driver event in non-small cell lung cancer (NSCLC). Capmatinib is a highly potent and selective MET inhibitor. The results of the GEOMETRY mono-1 trial demonstrated efficacy of capmatinib in patients with locally advanced/metastatic METex14-mutated NSCLC (Wolf J. et al, ASCO 2019). In addition, MET was found to directly modulate immune cell function, leading to suppression of anti-cancer immune responses. Further, capmatinib was shown to enhance efficacy of cancer immunotherapy in mice models irrespective of the tumor MET status. Nivolumab is a programmed death receptor-1 inhibitor approved for metastatic NSCLC in patients who progressed after platinum-based chemotherapy. Combining a MET inhibitor with a PD-1 inhibitor may yield sustained clinical benefits in advanced NSCLC.
Methods
This phase 2 trial (NCT02323126) evaluated the efficacy and safety of capmatinib plus nivolumab in patients with advanced/metastatic EGFR wild-type NSCLC who had progressed on platinum-doublet therapy and were anti-PD-1/PD-L1 therapy-naïve. Patients received capmatinib 400 mg orally twice daily plus nivolumab 3 mg/kg intravenous every 2 weeks. Patients were grouped into high MET (immunohistochemistry [IHC]=3+ in ≥50% tumor cells [TCs] or IHC=2+ in ≥50% TCs and gene copy number (GCN)≥5 or METex14+) and low MET (all others) cohorts. The primary endpoint was progression-free survival (PFS) rate at 6 months using RECISTv1.1. Secondary endpoints included overall response rate, disease control rate, other PFS endpoints, 1-year overall survival (OS)-rate and safety.
Results
As of Sep 10, 2019, 46 patients (high MET [n=16] and low MET [n=30]) were enrolled from February 2015–April 2019; median age: 65 years; male: 50%; Stage IV: 93.5%; ECOG PS 0 or 1: 97.8%. At this preliminary data analysis (June 11, 2019), the 6 month-PFS rate (95% CI) was 60.7% (29.1%–81.7%) in the high MET and 41.7% (22.7%–59.6%) in the low MET cohorts, whereas 1-year-OS data was immature. The ORR (95% CI) was 25.0% (7.3%–52.4%) in the high MET cohort compared to 16.7% (5.6%–34.7%) in the low MET cohort. The DCR (95% CI) was 81.3% (54.4%–96.0%) and 43.3% (25.5%–62.6%) in the high MET and low MET cohorts, respectively. Twenty-nine PFS events were reported; high MET: 9 (56.3%) and low MET: 20 (66.7%). The median PFS (95% CI) was 13.8 (3.5–19.2) months in the high MET cohort versus 4.2 (1.8–7.6) months in the low MET cohort. Most frequent AEs (≥30%; any grade) were nausea (54.3%), vomiting (39.1%), increased amylase, asthenia, increased blood creatinine, and peripheral edema (32.6% each). Most frequent Grade 3/4 AEs (≥10%) were dyspnea and increased amylase (15.2% each) and increased lipase (10.9%). Dyspnea (10.9%), pyrexia (8.7%) and vomiting (6.5%) were most commonly reported serious AEs. Serious treatment-related AEs were reported in 23.9% patients, of which the most common were pyrexia and vomiting (6.5% each).
Conclusion
Capmatinib plus nivolumab showed clinical activity in pretreated patients with advanced/metastatic EGFR wild-type NSCLC with a manageable safety profile. While anti-tumor activity was evident in both high MET and low MET cohorts, 6 month-PFS-rate, ORR and DCR were numerically higher in patients with high MET tumors.
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P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P84.14 - Identification of Mechanisms of Resistance to ALK Inhibitors. Next-Generation Sequencing-Based Liquid Biopsy Profiling. (ID 3612)
00:00 - 00:00 | Author(s): Bartomeu Massuti
- Abstract
Introduction
Despite impressive and durable responses, patients treated with ALK inhibitors (ALK-Is) ultimately progress. We investigated potential resistance mechanisms in a series of ALK-positive non-small cell lung cancer (NSCLC) patients progressing on different types of ALK-Is.
Methods
26 plasma and 2 cerebrospinal fluid samples collected upon disease progression to an ALK-I, from 24 advanced ALK-positive NSCLC patients, were analyzed by next-generation sequencing (NGS). A tool to retrieve variants at the ALK locus was developed.
Results
61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1) FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3 and CCND1. Overall, We identified at least one mutation in ALK locus in 10 (38.5%) plasma samples, being the G1269A and G1202R mutations the most prevalent among patients progressing to first- and second-generation ALK-I treatment, respectively. An exon 19 deletion in EGFR was identified in a patient showing primary resistance to ALK-I. Likewise, the G466V mutation in BRAF and the F129L mutation in MAP2K1 (MEK1) were identified as the underlying mechanism of resistance in three patients who gained no or little benefit from second-line treatment with an ALK-I. Putative ALK-I resistance mutations were also found in PIK3CA and IDH2. Finally, a c-MYC gain, along with a loss of CCND1 and a FGFR3, were detected in a patient progressing on a first-line treatment with crizotinib.
Conclusion
NGS analysis of liquid biopsies upon disease progression identified putative ALK-I resistance mutations in most cases, being a valuable approach to devise therapeutic strategies upon ALK-I failure.
