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Angelo Delmonte
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EP1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 206)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.16-04 - Real World Clinical Outcomes for Metastatic Non-Small Cell Lung Cancer (mNSCLC) at IRST Italy (Now Available) (ID 2307)
08:00 - 18:00 | Presenting Author(s): Angelo Delmonte
- Abstract
Background
This study sought to evaluate the real word clinical outcomes concerning overall survival (OS) for patients in first-line treatment for metastatic non-small cell lung cancer (mNSCLC) prior to the availability of immunotherapies in any line.
Method
Patients who received systemic anti-cancer treatment for mNSCLC at IRST between Jan2014-Jun2017 with a minimum follow-up of six months were included. The clinical dataset was obtained from data registered in electronic health records maintained during clinical practice. OS was defined as the interval from start of first-line therapy until death or follow-up end, whichever occurred first. Death information was detected from mortality register. OS was estimated using the Kaplan-Meier method stratified by type of first-line treatment.
Result
Among the 428 first-line patients analyzed, 64.5% were over 65 years old and 62.6% were men (Table 1). A total of 79.0% patients had non-squamous histology whereas 15.0% had squamous histology, with the remaining 6% other histologies. EGFR mutation was detected in 15.7% and ALK translocation in 8.4% of patients. In the first-line the majority (57.0%) of patients received platinum-doublet (mainly platinum+pemetrexed) while single agent chemotherapy was administered in 23.8%, whereas 10.0% received targeted therapy. Conversely overall 9.0% were enrolled in clinical trials, while 0.2% received Immunotherapies. Median OS was 19.9 months (95%CI:9.2-21.7) with targeted therapy, 8.5 months (95%CI:4.8-13.6) for patients enrolled in clinical trials, 6.4 months (95%CI:5.8-7.6) with platinum-doublet and 4.4 months (95%CI:3.7-5.7) with single agent chemotherapy. A total of 34.5% of first-line patients continued to receive second-line treatment.
Conclusion
In this analysis prior to the introduction of immunotherapies for NSCLC, OS was similar to real world OS in the published literature. The survival was worse in the single agent chemotherapy group while it is superior in platinum doublets group. Overall survival was longest in patients treated with targeted therapy.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-59 - Expanding Access to Large-Scale Genomic Mutational Analyses for Patients with Advanced NSCLC in Italy (ID 2410)
09:45 - 18:00 | Author(s): Angelo Delmonte
- Abstract
Background
In NSCLC, large-scale mutational analysis facilitates access to targeted treatments but is still not routinely employed due to significant technological barriers. The Alleanza Contro il Cancro (ACC) network of Italian Cancer Centers developed an affordable targeted sequencing panel for the identification of multiple genetic alterations with potential clinical utility, and designed a prospective multicentric trial to recruit 1000 newly diagnosed advanced NSCLC patients, aiming to i) compare panel performance against a set of externally validated biomarkers, including alterations in standard-of-care (EGFR, ROS1 and ALK) and non-standard-of-care (KRAS, BRAF, MET) biomarkers; ii) identify alterations in a large dataset of driver and potentially actionable genes; iii) correlate genotypes to survival outcomes and toxicity; iv) carry out ancillary studies on additional biomarkers and/or on specific patient groups (e.g. mutational burden, cfDNA, extensive characterization of immunotherapy-treated patients); v) build a centralized data repository for mutation interpretation and clinical recommendation.
Method
Through systematic literature mining and ad-hoc developed bioinformatic pipelines we identified: i) a set of 164 potentially actionable genes in solid tumors; ii) additional 18 genes with predicted driver function in NSCLC; iii) 70 actionable fusion transcripts; iii) 141 SNPs associated with pharmacogenomics markers. We designed a custom enrichment panel (~800 kb target) and compared PCR- and hybridization-based enrichment on semiconductor or by-synthesis sequencing to be subsequently deployed in a large observational trial. Sequencing is decentralized, to allow rapid turnaround time, but raw and processed data are collected in a single informatic infrastructure for centralized quality control and continuous bioinformatic pipeline improvement.
Result
PCR/semiconductor sequencing was selected for deployment based on cost and feasibility (2-day, highly automated workflow). 182 patients have been enrolled to date (90% stage IV, 10% IIIB). Of 65 patients with treatment information available, 28 (43%) subsequently received immunotherapy and 13 (20%) targeted therapy. For 56 patients with complete sequencing data, EGFR and KRAS status was concordant in 9/10 and 38/41 cases; discordant cases are being validated with orthogonal methods. Clinically significant MET amplifications were called in 2/2 cases. Remaining target regions did not show pathogenic alterations. Multiple alterations in potentially actionable genes were identified.
Conclusion
Large-scale sequencing is reliable, feasible and sustainable across multiple hospitals and provides clinically relevant results. The increased availability of genomic information may result in enhanced access to tailored therapies. Data and sample integration in centralized, shared repositories will allow multiple ancillary studies.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-03 - Molecular Determinants for Lorlatinib Activity in ROS1 Positive NSCLC: Results of the Prospective PFROST Trial (ID 1566)
09:45 - 18:00 | Author(s): Angelo Delmonte
- Abstract
Background
Lorlatinib, an ALK/ROS1 inhibitor, demonstrated activity in ROS1+ NSCLC pretreated with crizotinib. However, molecular events predictive for tumor response during lorlatinib treatment are largely unknown.
Method
PFROST was a prospective phase II trial designed to include ROS1+ NSCLC refractory to crizotinib. Eligible patients were treated with lorlatinib at the daily dose of 100 mg until disease progression. Primary end point was response rate (RR). For all included patients pre-lorlatinib tumor tissue or blood sample collection was mandatory. At the time of lorlatinib failure liquid biopsy was recommended. The samples were then run with the NEOliquid assay, specifically designed for liquid biopsies, or NEOselect, a panel optimized for formalin-fixed paraffin-embedded (FFPE) tumor tissue, covering 39 cancer related genes.
Result
From June 2017 to April 2019, 22 ROS1+ crizotinib refractory lung adenocarcinoma patients were included in 10 Institutions. Median age was 56 years (range 39-82); male/female: 8/14; ECOG PS 0 (N=8; 36.4%), PS1 (N=14; 63,6%); The majority had brain metastases at baseline (N=15; 68.1%), were never smokers (N=13; 59.1%) and received lorlatinib as third line therapy (N=16; 72.7%). In all cases crizotinib was the last therapy line before lorlatinib. At the time of the present analysis, trial completed its accrual and 13 patients are still receiving therapy. A total of 18 patients were evaluable for response and 7 had confirmed complete (N=1) or partial (N=6) responses for an overall RR of 38.8%. In 4 patients, response to therapy was not yet evaluated. A total of 10 tissue biopsies and 20 blood samples obtained after crizotinib and before lorlatinib therapy were collected. For 7 samples analyses are ongoing. Among responders, no patient harbored a secondary ROS1 mutation. Conversely, no response was observed among patients with secondary ROS1 mutations (N= 1 ROS1S1861I, N=1 ROS1 V2054A, N=3 ROS1G2032R). All patients harboring the ROS1G2032R mutation rapidly progressed and maintained this aberration in liquid biopsy at the time of radiological evidence of lorlatinib failure.
Conclusion
In our study lorlatinib confirmed its efficacy in crizotinib resistant ROS1+ NSCLC. Molecular profile of refractory patients suggests reduced efficacy in individuals developing secondary ROS1 mutations after crizotinib failure.
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P1.14-05 - TP53 Exon 8 Mutation and Prognosis in EGFR-Mutated NSCLC Patients Treated with First-And-Second-Generation TKIs (ID 457)
09:45 - 18:00 | Author(s): Angelo Delmonte
- Abstract
Background
TP53 mutation seems to be associated with a worse prognosis in epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) treated with first generation tyrosine kinase inhibitors (TKIs). We previously showed that this was mainly significant for exon 8 TP53 mutations (Canale M et al, Clin Cancer Res 2017). However, its role on survival, as well as in relation to response to second generation TKIs is not clearly established.
Method
A retrospective cohort of 270 EGFR-mutated NSCLC treated with first- (gefitinib and erlotinib) and second- (afatinib) generation TKIs, in the first line setting, were considered. TP53 status was evaluated by Sanger Sequencing or Next generation Sequencing. The different mutations were evaluated in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Result
One hundred and forty-four patients (53.3%) received a treatment with gefitinib, 84 (31.1%) with erlotinib and 42 (15.7%) with afatinib. In the overall cohort, ORR and DCR were 61.5% and 86.4%, respectively, with about 50% of patients responsive for more than 10 months. Median PFS and OS were of 11.08 (95% CI 9.3-12.6) and 22.9 (95% CI 20.4-27.5) months, respectively. Overall, 79 (30.7%) patients showed a TP53 mutation. The presence of TP53 exon 8 mutation was associated with a worse outcome with respect to patients wt or with other TP53 mutations. In particular, a lower ORR and DCR were observed for patients with TP53 exon 8 mutation (ORR 94.16% vs 5.84%, p=0.05, and DCR 94.04% vs 5.96%, p<0.001, respectively), together with a worse PFS (HR 1.88 [95% CI 1.20-2.96], p=0.006). These results was even more significant in the subgroup of patients with EGFR exon 19 deletion, where TP53 exon 8 mutation was associated with both worse PFS (HR 4,72 [95% CI 2.31-9.65], p<0,001) and OS (HR 2.60 [95% CI 1.11-6.04], p=0.027).
At the multivariable analysis, EGFR exon 19 deletion and TP53 exon 8 mutation remained independently associated with PFS (HR 0.56 [95% CI 0.35-0.89], p=0.014 and HR 1.81 [95% CI 1.13-2.88], p=0.013, respectively). Moreover, EGFR exon 19 deletion and age resulted independently associated with OS (HR 0.52 [95% CI 0.26-1.03], p=0.059, and HR 1.02 [95% CI 1.01-1.04], p=0.009, respectively). No other patient and clinical covariate showed an association with PFS and OS in the multivariable models.
Conclusion
Our results confirm that TP53 exon 8 mutation confers a worse outcome in patients treated with first and second generation TKIs and that this is particularly evident in patients with EGFR exon 19 deletion.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-15 - Phase II Single Arm Study of CABozantinib in Non-Small Cell Lung Cancer Patients with MET Deregulation (CABinMET) (ID 2637)
10:15 - 18:15 | Author(s): Angelo Delmonte
- Abstract
Background
Mesenchymal-Epithelial Transition gene (MET) amplification and exon 14 skipping mutations are established oncogenic drivers in non-small cell lung cancer (NSCLC), both occurring in about 4% of cases. In patients with MET amplified or mutated lung cancer, oral MET tyrosine kinase inhibitors (TKI) showed promising activity. The American Food and Drug Administration has recently granted crizotinib a breakthrough therapy designation for MET exon 14 mutation positive NSCLC. Cabozantinib is a novel oral inhibitor of MET and other receptor tyrosine kinases that has shown preliminary activity in MET deregulated NSCLC patients pretreated with crizotinib, although definitive data on its therapeutic role are still missing.
Method
CABinMET (NCT03911193) is a phase II, single arm, multicenter study assessing the efficacy of cabozantinib in subject with MET amplification or MET exon 14 skipping mutation pretreated or not with MET inhibitors. The primary endpoint of the trial is overall response rate. Secondary efficacy endpoints are progression free survival, overall survival and disease control rate. Main inclusion criteria include histologically/cytologically confirmed diagnosis of advanced stage NSCLC, presence of MET exon 14 skipping mutation or MET amplification (MET/CEP7 ratio ≥2.2 on FISH analysis) on archival formalin-fixed paraffin-embedded (FFPE) tumor tissue or circulating tumor DNA, measurable disease, ECOG PS 0-1, at least 1 prior line of standard therapy, adequate organ function. Patients with co-existent driver events or with symptomatic brain metastases are excluded from the trial. Cabozantinib is administered orally at 60 mg once daily until disease progression, patient refusal or unacceptable toxicity. Disease is assessed every 8 weeks. Exploratory biomarker analyses are conducted on archival FFPE tumor tissue and on blood samples collected at baseline, at the time of the first disease assessment and at progression.
Result
The study is currently running in 9 Italian centers. Recruitment started in September 2018 and 6 of the planned 25 patients have been enrolled.
Conclusion
Enrollment will be completed in 24 months.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-49 - Nivolumab Plus Ipilimumab (NI) Versus Chemotherapy Plus Nivolumab (CN) in Squamous Cell Lung Cancer (SqCLC): The SQUINT Trial (ID 1557)
10:15 - 18:15 | Author(s): Angelo Delmonte
- Abstract
Background
Treatment landscape for patients with advanced NSCLC is rapidly evolving, with recent randomized phase III trials demonstrating superiority of chemo-immuno combinations versus chemotherapy alone. Role of chemo-free combinations, including NI, is under investigation with limited available data. Aim of the present trial is to investigate outcome of SqCLC patients when treated with NI or CN.
Method
SQUINT (NCT03823625) is an open-label, randomized, parallel, non-comparative phase II study designed to assess the efficacy of NI (Arm A) or CN (Arm B) in patients with advanced, metastatic SqCLC. Eligibility requires age ≥ 18 years, histologically confirmed stage IV or recurrent stage IIIB SqCLC, p63+/p40+ and TTF- tumour tissue, availability of PD-L1 status, no prior systemic therapy, ECOG performance status 0-1, adequate organ functions. Key exclusion criteria include concomitant radiotherapy or chemotherapy, prior treatment with immune checkpoint inhibitors, untreated brain metastases, other serious illness or medical condition potentially interfering with the study or with NI administration. Patients are randomly assigned 1:1 to receive N 360 mg Q3W plus I 1 mg/kg Q6W (Arm A) or plus platinum-based chemotherapy up to 6 cycles plus nivolumab 360 mg Q3W (Arm B), and stratified by PD-L1 expression (<1% versus ≥1%), presence of bone metastases (yes/no) and liver metastases (yes/no). In both arms, immunotherapy is given until disease progression, unacceptable toxicity, patient refusal and in any case for up to 24 months. Primary endpoint is 1-year overall survival (OS) rate in Arm A and B. Secondary endpoints include: response rate (RR), duration of response (DoR), median progression free survival (PFS) and median OS in Arm A and B, and according to predefined stratification factors. Sample size has been calculated assuming for each arm a minimum acceptable 1-year OS rate of 40% and an auspicated 1-year OS rate of 60%, a power of 90% and a one side significant level of 0.05. Based on such premises, the total number of patients required for the study is 112.
Result
At the time of this analysis a total of 11 Italian Centers are recruiting and 25 subjects have been enrolled.
Conclusion
We expect to conclude enrolment by January 2020.
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P2.04-84 - NSCLC Survival Expectancy for Patients Treated with Docetaxel/Nintedanib in the SENECA Trial and Previous Immunotherapy (ID 807)
10:15 - 18:15 | Author(s): Angelo Delmonte
- Abstract
Background
The phase IIb SENECA trial was an Italian real-world experience recently ended, which demonstrated similar progression free survival (PFS) and overall survival (OS) in non-squamous non-small cell lung cancer (nsNSCLC) patients treated with second-line docetaxel/nintedanib, regardless the relapsing-time from end of first-line chemotherapy and the docetaxel schedule employed (weekly or q3wks), with a slightly higher toxicity-trend in the q3wks arm. During accrual period (January 2016-April 2018), no therapeutic alternative to the use of docetaxel was available for patients with recurrent nsNSCLC until April 2017, when the first immune-checkpoint inhibitor was approved and reimbursed in Italy in this setting. At that point, the study was amended allowing enrolment of patients previously treated with immunotherapy (IT). Because of the lack of data about the optimal therapeutic algorithm in this context, aim of the present evaluation is to investigate if survival expectancy of patients treated with docetaxel/nintedanib could positively influenced when previously treated with IT.
Method
In the SENECA trial, 212 nsNSCLC patients, progressing after first-line chemotherapy, were treated with docetaxel plus continuous oral nintedanib, with the possibility of maintenance in case of stabilization or response. This evaluation focus on 16 patients previously treated with IT and compares them to the rest of patient population. Survival analysis is performed using Kaplan Meier curves; Hazard Ratios (HR) with 95% Confidence Interval (95%CI) are reported to compare the two groups.
Result
Patients treated with IT (2 combined with first-line chemotherapy, 14 alone) correspond to 7.5% of the entire study population; they were 9 males and 7 females, with a median age of 62.5 years, mainly current or former-smokers, with an ECOG-performance status 0 in 93.7% of cases. At the cut-off date (December 25th, 2018), after a median follow-up of 35.5 months, no significant differences appear between patients previously treated with IT and the other ones in terms of PFS (5.84 vs 4.31 months, respectively; HR 0.564 [95% CI 0.283-1.122], p-value=0.1029), and OS (9.37 vs 9.02 months, respectively; HR 1.108 [95% CI 0.393-3.123], p-value=0.8456). No significant differences have been observed also in disease-control rates (80.0% vs 66.7%, p-value=0.5436).
Conclusion
Despite this report does not show a greater survival expectancy for patients treated with docetaxel/nintedanib and previous IT, it's likely that the small sample size may affect this result. The longer PFS and greater disease-control rate are attractive hints for future evaluations with larger sample sizes, supposing a new therapeutic algorithm for recurrent nsNSCLC patients.
