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Angelo Delmonte
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MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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MA26.02 - Upfront or Sequential Strategy for New Generation Anaplastic Lymphoma Kinase (ALK) Inhibitors: An Italian Retrospective Study. (ID 12790)
13:35 - 13:40 | Author(s): Angelo Delmonte
- Abstract
- Presentation
Background
Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome benefit, the most effective sequential strategy is still unknown.
a9ded1e5ce5d75814730bb4caaf49419 Method
We retrospectively collected 242 ALK-positive advanced NSCLC diagnosed between 2010 and 2018 in 23 Italian institutions (expanded data collection from Gobbini et al. Lung Cancer 2017). 138 patients received exclusively crizotinib as ALKi (not considered for this analysis). 78 patients received crizotinib and a new (second or third) generation ALKis as further treatments (group A). 26 patients performed a new generation ALKi as upfront agent (group B). These groups are larger than those considered in a previous analysis (15 and 8 patients, respectively).
4c3880bb027f159e801041b1021e88e8 Result
Study population clinical features and treatments received are summarized in Table 1.
Group A
Crizotinib followed by new generation ALKis
N= 78
Group B
Upfront new generation ALKis
N=26
Treatments per line n(%)
1°
2°
3°
4°
1°
2°
3°
4°
Crizotinib
28(36)
50(64)
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2(8)
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Alectinib
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11(14)
18(23)
5(17)
7(27)
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Ceritinib
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9(12)
23(30)
3(4)
8(31)
8(31)
1(4)
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Brigatinib
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6(8)
6(8)
2(3)
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2(8)
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2(8)
Lorlatinib
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4(5)
5(6)
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1(4)
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Chemotherapy
50(64)
2(3)
10(13)
na
11(42)
6(23)
1(4)
Na
Clinical features n(%)
Age (range)
58 (27-83)
55 (24-82)
Male
37(47)
10(38)
p= 0.42
Female
41(53)
16(62)
Current smoker
8(10)
5(19)
p= 0.23
Never/former smoker
70(90)
21(81)
ALKi beyond PD
27(34)
4(15)
p= 0.06
With a median follow-up of 22.6 months (CI 95% 20.09-25.10), 33 patients had died (32%). In group B, the median progression free survival (PFS) for new generation ALKis administered as first (14.0 months, CI 95% 9.52-18.471), second (12.7 months, CI95% 7.22-18.17) or third-line (12.8 months, CI95% 6.24-19.35) was not statistically different (p= 0.522). The median time from the start of crizotinib to the disease progression after the new generation ALKi sequentially performed (group A) was longer than that one detected in group B for the upfront new generation ALKis (29 vs 14 months, HR 2.47 [CI95% 1.35-4.50], p=0.003). This result was confirmed even considering the time lost between the two treatments in group A. The median overall survival (OS) was not reached. The 12-months OS rate was 97% in group A and 84% in group B.
8eea62084ca7e541d918e823422bd82e Conclusion
New generation ALKis maintain their efficacy regardless of the treatment setting considered. The sequential strategy seems to provide a substantial benefit, but a longer follow-up and larger samples are needed to clarify the survival impact.
6f8b794f3246b0c1e1780bb4d4d5dc53Only 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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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-15 - ROS1-Rearranged Non-Small Cell Lung Cancer Is Associated with High Rate of Venous Thromboembolism: Analysis of The METROS Trial (ID 12287)
16:45 - 18:00 | Author(s): Angelo Delmonte
- Abstract
Background
Patients with lung cancer are at increased risk for venous thromboembolism (VTE) and 8% to 15% of patients with advanced non-small-cell lung cancer (NSCLC) experience a VTE event during the course of their disease. The incidence of VTE in molecularly defined NSCLC is still unknown. However, emerging data suggests that patients harbouring ALKrearrangements are at increased risk of VTE. In light of the high amino-acid sequence and structural homology with ALK protein, we undertook this study to determine the incidence of VTE in patients with ROS1-rearranged NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
The METROS trial is a multicentre prospective phase II study designed to assess efficacy, safety and tolerability of Crizotinib in pre-treated metastatic NSCLC with METamplification or METexon 14 mutation or ROS1rearrangement. ROS1-rearranged patients enrolled within cohort A and expansion cohort of the trial were evaluated in this analysis.
4c3880bb027f159e801041b1021e88e8 Result
Among 48 patients with ROS1-rearranged lung adenocarcinomas (median [range] age 50 [28-82]); 17 males [35.4%] and 31 females [64.5%]; PS 0-1 [95.8%], 2 [4.2%]; 21 current/former smokers [43.75], 27 never smokers [56.25]) , 20 (41.6%) had at least one VTE event. VTE events consisted in pulmonary embolism (PE) in 11 patients (55%), deep vein thrombosis (DVT) in 11 patients (55%), renal vein thrombosis in 2 patients (10%). Seven patients (35%) had ≥ 1 VTE event. Patients with VTE were more likely to be older than 65 years (P = 0.029). No other associations between clinical characteristics and development of VTE were observed. The occurrence of VTE was not associated with overall survival.
8eea62084ca7e541d918e823422bd82e Conclusion
The incidence of VET is 3- to 5-fold higher in patients harbouring ROS1-rearrangment than previously observed for the general NSCLC population. Whether molecular profile of NSCLC should be incorporated into a risk-stratification tool and decision-making algorithm for VTE diagnosis, prophylaxis and treatment remains to be determined prospectively.
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P1.01-53 - Bone Metastases and Efficacy of Immunotherapy in Patients with Pretreated Advanced Non-Small-Cell Lung Cancer (NSCLC) (ID 11980)
16:45 - 18:00 | Author(s): Angelo Delmonte
- Abstract
Background
Approximately 40% of NSCLC patients develop bone metastases (BoM). Bone has active functions in regulating immune system. To date, no trial evaluated the role of BoM in modulating response to immunotherapy. Aim of the present study was to investigate whether presence of BoM impact on immunotherapy efficacy.
a9ded1e5ce5d75814730bb4caaf49419 Method
Two different cohorts of pretreated NSCLC patients (cohort A: Non-squamous; cohort B: Squamous) were evaluated for nivolumab efficacy in terms of objective response rate (ORR), progression free survival (PFS), and overall survival (OS) according to presence or absence of BoM. All patients received nivolumab at standard dose of 3 mg/kg every 2 weeks within the Italian Expanded Access Program.
4c3880bb027f159e801041b1021e88e8 Result
Cohort A accounted for 1588 patients with non-squamous NSCLC: 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 370 patients with squamous histology: 102 BoM+ (32%) and 251 BoM- (68%). In Cohort A, BoM+ had a significantly lower ORR (12% versus 34%; p < 0.0001), shorter PFS (2.0 versus 4.0 months, p < 0.0001) and shorter OS (7.4 versus 15.3 months, p <0.0001). In cohort B, BoM+ had significantly lower ORR (15% versus 22%; p < 0.04), shorter PFS (2.7 versus 5.4 months, p <0.0001) and shorter OS (5.0 versus 10.9 months, p <0.0001). Presence of BoM negatively affected outcome irrespective of PS (OS cohort A: PS-0 BoM+ 12.0 versus 20.9 months in PS-0 BoM-, p<0.0001; OS cohort B: PS-0 BoM+ 5.8 versus 16.4 months in PS-0 BoM-, p<0.0001). Multivariate analysis confirmed that presence of BoM independently associated with higher risk of death with HR 1.64 and HR 1.78, for Cohort A and B, respectively.
8eea62084ca7e541d918e823422bd82e Conclusion
Our results, the first assessing BoM in patients treated with immunotherapy, suggested that BoM predict lower efficacy of immunotherapy. BoM should be included as stratification factor in clinical trials.
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P1.01-73 - Preliminary Results of the SENECA (SEcond Line NintEdanib in Non-Small Cell Lung CAncer) Trial: An Italian Experience. (ID 13281)
16:45 - 18:00 | Author(s): Angelo Delmonte
- Abstract
Background
Nintedanib is a multi-target small-molecule with anti-angiogenetic activity which confers longer progression free survival (PFS) and overall survival (OS) as second-line combination treatment with docetaxel versus standard-of-care, in non-squamous non-small cell lung cancer (nsNSCLC) patients, giving to rapidly progressing patients the greatest survival benefit. Considering the higher tolerability of weekly docetaxel than docetaxel q3wks in the real-life, the SENECA trial, a phase IIb, open label, Italian multicentre study, aims to evaluate whether treatment with nintedanib and docetaxel could be effective and safe as second-line option in nsNSCLC patients with the two different schedules.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients from eighteen Italian oncologic centres, with stage IIIB/IV non-oncogene addicted nsNSCLC patients, progressing after first-line chemotherapy, have been treated with docetaxel (T1: 33 mg/mq on days 1 and 8 in a 21-days cycle; T2: 75 mg/mq q3wks) plus continuous oral nintedanib, with the possibility of maintenance in case of stabilization or response. Primary endpoint was PFS (by investigator’s assessment), while secondary endpoints included OS, safety and quality-of-life. Study stratifies patients into two cohorts according to relapse-timing (within or over 3 months) from end of first-line chemotherapy.
4c3880bb027f159e801041b1021e88e8 Result
From January 2016 to data cut-off, on 30th March 2018, 197 patients have been evaluated: 30 were registered as screening failures, mainly for contraindications to nintedanib use. The 167 patients considered in this preliminary analysis had a median age of 63.4 years (range 35-86), were predominantly male (68.9%), smokers or former-smokers (84.4%) and with ECOG-performance status 0 (72.5%). According to investigator’s choice, 82 patients have been treated with T1 docetaxel (49.1%), 85 (50.9%) with T2 docetaxel (median docetaxel treatment 3.5 and 3.7 21-days cycles, respectively). No significant differences in median PFS have been observed between T1 and T2 (3.83 vs 4.32 months, respectively; HR 0.889 [95% IC 0.598-1.321], p-value=0.559). After a median follow-up of 7.28 months (standard deviation=5.55), a trend of similar OS has emerged in both T1 and T2 (6.63 vs 7.91 months, respectively; HR 0.770 [95% IC 0.484-1.225], p-value=0.270). Survival data of relapse-timing cohorts are not yet mature. Commonest toxicities in T1 and T2 were: fatigue (53.6% vs 65.9%, respectively), diarrhea (50.0% vs 47.0%), afebrile neutropenia (13.4% vs 52.9%) and ALT elevation (29.3% vs 20.0%).
8eea62084ca7e541d918e823422bd82e Conclusion
The SENECA trial is a real-life Italian experience, whose preliminary results confirm the efficacy and safety of second-line treatment with nintedanib and docetaxel for nsNSCLC patients, regardless from docetaxel schedule, suggesting higher toxicities for docetaxel q3wks.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-23 - TP53 Mutations as Mechanisms of Primary and Acquired Resistance to Tyrosine Kinase Inhibitors in Patients With EGFR-Mutated NSCLC (ID 13954)
16:45 - 18:00 | Author(s): Angelo Delmonte
- Abstract
Background
Around 80% of patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations usually respond to tyrosine kinase inhibitors (TKIs). We previously demonstrated that TP53 mutations are associated with primary resistance to TKIs in patients with EGFR-mutated lung adenocarcinoma (ADC) treated with a first-line TKI. In the present study we investigated whether TP53 mutations are modulated by TKIs, evaluating its status before and after TKI treatment.
a9ded1e5ce5d75814730bb4caaf49419 Method
Thirty-five patients with EGFR-mutated lung ADC treated with a first-line TKI and who subsequently underwent re-biopsy after disease progression were considered. Tumor tissue was available for evaluation before and after TKI treatment for all patients. EGFR and TP53 mutation analyses were performed by Sanger Sequencing or Next Generation Sequencing methods. The different mutations were evaluated in relation to disease control rate (DCR) [complete response (CR), partial response (PR) or stable disease (SD)] and objective response rate (ORR) (CR, PR).
4c3880bb027f159e801041b1021e88e8 Result
Of the 35 patients, 14 (40%) showed a TP53 mutation, 12 in exons 5-8 (5 in exon 5, 2 in exon 6, 2 in exon 7 and 3 in exon 8) and 2 in other exons (1 in exon 2 and 1 in exon 4) of the gene. The group was treated with a first-line TKI and data on response and follow-up were available for 30 patients. Of these, 11 were treated with gefitinib, 11 with erlotinib, 6 with afatinib and 2 with dacomitinib. Overall DCR and ORR were 90% and 77%, respectively. With regard to TP53 mutations, DCR and ORR were 94% and 83%, respectively, in TP53 wt patients, and 83% and 66% in TP53 mutated cases. All 30 patients underwent re-biopsy at progression and 20 (67%) showed T790M mutation in tumor tissue. Of the 10 T790M-negative patients, 5 (50%) had a TP53 mutation which was not present at baseline in 2 cases. Among the patients who were TP53 wild type at baseline, 4 (22%) showed a mutation at disease progression. Data on progression free survival and overall survival are currently being evaluated.
8eea62084ca7e541d918e823422bd82e Conclusion
TP53 mutations were associated with a lower response to TKIs in EGFR-mutated patients and may have been acquired during TKI treatment, independently of the T790M mutation.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-06 - TP53 Status in Relation to Response to Anti-ALK Agents in Patients with EML4-ALK-Translocated NSCLC (ID 12580)
16:45 - 18:00 | Author(s): Angelo Delmonte
- Abstract
Background
Patients with non-small-cell lung cancer (NSCLC) carrying the EML4-ALK translocation are responsive to anti-ALK agents, such as crizotinib. However, about 30%-40% of patients show primary resistance to treatment. We previously demonstrated that TP53 mutations are associated with poorer prognosis in EGFR-mutated patients treated with tyrosine-kinase inhibitors. In the present study we analyzed the impact of TP53 mutations on response to anti-ALK treatment in EML4-ALK-translocated NSCLC
a9ded1e5ce5d75814730bb4caaf49419 Method
Eighty-three patients with EML4-ALK-translocated NSCLC identified in the Wide Catchment Area of Romagna between 2012 and 2016 were considered. TP53 status was evaluated in 61 patients on the basis of DNA availability. Of these, 28 patients received an anti-ALK agent as second-or-more-line treatment and follow-up data were available. TP53 status was analyzed in relation to disease control rate (DCR): complete response (CR), partial response (PR) or stable disease (SD).
4c3880bb027f159e801041b1021e88e8 Result
Overall, TP53 mutations were observed in 14 (23%) patients, 6 (43%) showing a mutation in exon 5, 1 (7%) in exon 6, 3 (21%) in exon 7 and 4 (28%) in exon 8. We found one insertion (7%), one deletion (7%) and 12 point mutations (86%). Of the 28 patients treated with an anti-ALK agent, 5 (20%) showed TP53 mutations, 2 (40%) in exon 5, 1 (20%) in exon 5 and 2 (40%) in exon 8. Clinical response was not evaluable in 3 patients due to rapid disease progression (2 had a stop mutation in exon 5 of TP53). DCR for the remaining 25 patients was 60% in those with TP53-mutated tumors and 92% in those with TP53 wild-type disease.
8eea62084ca7e541d918e823422bd82e Conclusion
TP53 mutations were associated with a poorer DCR in EML4-ALK-translocated NSCLC patients treated with an anti-ALK agent. These results highlight the potential role of TP53 in determining primary resistance to anti-ALK agents, and should be confirmed in a wider case series.
6f8b794f3246b0c1e1780bb4d4d5dc53
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PL02 - Presidential Symposium - Top 5 Abstracts (ID 850)
- Event: WCLC 2018
- Type: Plenary Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 08:15 - 09:45, Plenary Hall
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PL02.03 - Brigatinib vs Crizotinib in Patients With ALK Inhibitor-Naive Advanced ALK+ NSCLC: First Report of a Phase 3 Trial (ALTA-1L) (ID 11155)
08:30 - 08:40 | Author(s): Angelo Delmonte
- Abstract
- Presentation
Background
Brigatinib has robust efficacy in crizotinib-resistant ALK+ NSCLC, exhibiting median progression-free survival (mPFS) of 16.7 months. We report results of the first interim analysis from the ALTA-1L study of brigatinib vs crizotinib in ALK TKI-naive, ALK+ NSCLC (NCT02737501).
This open-label, multicenter study enrolled patients with stage IIIB/IV ALK+ NSCLC based on local ALK testing (FDA approved/other). Eligible patients had ECOG PS 0–2, ≤1 prior systemic therapy for locally advanced/metastatic NSCLC, and no prior ALK inhibitor. Asymptomatic CNS metastases were allowed. All patients had systematic CNS imaging. Patients were randomized 1:1 to brigatinib 180 mg QD with 7-day lead-in at 90 mg or crizotinib 250 mg BID. Primary endpoint: blinded independent review committee (BIRC)-assessed PFS (RECIST v1.1). Secondary efficacy endpoints included BIRC-assessed objective response rate (ORR), intracranial ORR (iORR), and intracranial PFS (iPFS). Interim analyses were planned at 50% and 75% of planned PFS events (n=198).
275 patients were randomized (brigatinib/crizotinib, n=137/138); median age (years) 58/60. 26%/27% received prior chemotherapy for advanced disease, and 29%/30% had baseline brain metastases. At data cut-off (19 February 2018), median follow-up brigatinib/crizotinib: 11.0/9.25 months; with 99 PFS events, brigatinib met the prespecified threshold for statistical superiority vs crizotinib in the primary endpoint, BIRC-assessed PFS (HR 0.49, 95% CI 0.33–0.74, log-rank P=0.0007); brigatinib mPFS was not reached (95% CI NR–NR) vs crizotinib 9.8 months (95% CI 9.0–12.9). Investigator-assessed PFS HR 0.45 (95% CI 0.30–0.68), log-rank P=0.0001. Table shows additional efficacy data. Most common treatment-emergent AEs grade ≥3: brigatinib: increased CPK (16.2%), increased lipase (13.2%), hypertension (9.6%); crizotinib: increased ALT (9.5%), AST (5.8%), and lipase (5.1%). Any grade ILD/pneumonitis: brigatinib, 3.7%; crizotinib, 2.2%. Discontinuations due to AE (brigatinib/crizotinib): 11.8%/8.8%.
Brigatinib showed a statistically and clinically significant improvement in PFS compared with crizotinib in ALK inhibitor–naive ALK+ NSCLC.
BIRC-Assessed Endpoint, % Brigatinib
(n=137)
Crizotinib
(n=138)
P-Value All patients ORRa 76 (68–83b) 73 (65–80b) Confirmed ORR 71 (62–78b) 60 (51–68b) 0.0678 With any intracranial CNS metastases (n=43) (n=47) iORRa 79 (64–90b) 23 (12–38b) Confirmed iORR 67 (51–81b) 17 (8–31b) <0.0001 Median iPFS, months NR (11–NRb) 6 (4–9b) 1-year iPFS 67 (47–80b) 21 (6–42b) HR 0.27 (0.13–0.54) <0.0001c With measurable intracranial CNS metastases (n=18) (n=21) iORRa 83 (59–96b) 33 (15–57b) Confirmed iORR 78 (52–94b) 29 (11–52b) 0.0028 aResponse, ≥1 assessment; b95% CI; cLog-rank.
a9ded1e5ce5d75814730bb4caaf49419Only 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.
