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E. Dansin
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MINI 25 - Trials, Radiation and Other (ID 142)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:J.M. Clavero, R. Hassan
- Coordinates: 9/08/2015, 16:45 - 18:15, 702+704+706
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MINI25.08 - Systemic Treatment in Advanced Thymic Epithelial Tumors. Insights From a Prospective Cohort of 888 Patients Enrolled in RYTHMIC (ID 1166)
17:25 - 17:30 | Author(s): E. Dansin
- Abstract
Background:
RYTHMIC (Réseau tumeurs THYMiques et Cancer) is the French nationwide network for thymic malignancies. Starting 2012, all patients diagnosed with thymic tumor had to be enrolled, as recommended by the French National Cancer Institute, part of good clinical practice.
Methods:
RYTHMIC prospective database is hosted by the French Thoracic Cancer Intergroup (IFCT), and collects clinical, imaging, treatment, and follow-up data of patients discussed at the reference national multidisciplinary tumor board (MTB). Data cutoff was April 1[st], 2015 for this analysis.
Results:
1089 questions were raised at the MTB about the management of 888 patients with thymic epithelial tumor. Among assessable cases, Masaoka-Koga stage III-IV tumors accounted for 42% of cases; histology was thymoma in 82% of cases, and thymic carcinoma in 18% of cases. First-line treatment of locally advanced disease, and management (diagnosis and treatment) of recurrent disease led to raise 227 (21%), and 234 (21%) questions at the MTB, respectively, 312 (68%) of which were about the modalities of systemic treatment. Figure 2 shows the proposed regimens for primary (A) and exclusive (B) chemotherapy in treatment-naïve patients, and chemotherapy (C) and targeted agents (D) for recurrent tumors. Combination of cisplatin, adriamycin, and cyclophosphamide and carboplatine, paclitaxel were the most frequently proposed regimens as first- and second-line treatment, respectively. Figure 1 Figure 2
Conclusion:
RYTHMIC is an exhaustive registry of thymic malignancies, which provides unique insights in the management of advanced and recurrent tumors with systemic agents. Meanwhile, limited data have been made available in the literature so far, as clinical trials were conducted in small numbers of patients, and existing databases enrolled a majority of surgically resected, early-stage tumors. Through the use of targeted agents, RYTHMIC allows the rapid implementation of new results in clinical practice, while ensuring patients an equal access to therapeutic innovation. Supported by Institut National du Cancer
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ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:S. Gadgeel
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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ORAL33.01 - Crizotinib Outcome and Post-Progression Management in ALK+ NSCLC: IFCT-1302 CLINALK (ID 1355)
16:45 - 16:56 | Author(s): E. Dansin
- Abstract
- Presentation
Background:
Phase III trials have demonstrated the superiority of the ALK tyrosine kinase inhibitor (ALK-TKI) crizotinib compared to standard chemotherapy in advanced ALK positive non-small cell lung cancers (ALK+ NSCLC) in first line and second line setting. Objective response rate (ORR) with crizotinib ranged from 65 to 75% and median progression free survival (PFS) from 7.7 to 10.9 months. However a resistance to crizotinib always occurs. The French Cooperative Thoracic Intergroup (IFCT)-1302 CLINALK study aimed to describe clinical outcome and post-progression management in a large cohort of French patients with ALK+ NSCLC treated with crizotinib.
Methods:
IFCT-1302 CLINALK is a multicentric observational retrospective study. Patients with ALK+ NSCLC from centers of the IFCT network were included according to the main following criteria: advanced stage III or stage IV NSCLC, ALK immunochemistry (IHC) and/or ALK FISH positivity, crizotinib treatment in the setting of the French expanded access cohort program or as approved drug. Epidemiological and clinical data, crizotinib efficacy (objective response based on RECIST, PFS, overall survival (OS)), duration of treatment with crizotinib after disease progression and post progression outcome were collected on a case report form. The study inclusion period was from November 18 2011 to December 31 2013. The data cut-off was December 31 2014.
Results:
318 patients were included (median age 58.3, female 49.4%, caucasian 98.6%, non-smoker 55.1%, performance status 0/1 78.7%, adenocarcinoma 91.7%, stage III 14.5%, stage IV 85.5%, brain metastasis 35.9%). IHC was positive in 151/173 patients and FISH in 279/283 patients. Before crizotinib treatment, patients received platinum-based chemotherapy in 89% of cases and pemetrexed-based chemotherapy in 76.1%. Crizotinib was prescribed as first-line treatment in 17 patients (5.3%), second-line in 168 patients (52.8%), third-line in 58 patients (18.2%) and more than third-line in 75 patients (23.7%). Objective response was complete response in 1 patient (0.3%), partial response in 126 patients (40.0%), stable disease in 62 patients (19.7%) and progression in 58 patients (18.4%). ORR was 40.3 % (95%CI, 34.9-45.7). 262/318 patients presented progressive disease (82.4%) at time of analysis. Median PFS was 6.9 months (95%CI, 5.7-8.6). Median OS with crizotinib was 18.7 months (95%CI, 15.2-22.5). Median duration of treatment with crizotinib after disease progression was 56 days (29-203). Among 143 patients with subsequent treatments, crizotinib was rechallenged in 32 patients (22.4%). 58/143 patients (40.6%) were treated after crizotinib failure with another ALK-TKI, either alectinib (19/58, 32.8%) or ceritinib (40/58, 69.0%). The ALK-TKI sequence was crizotinib-alectinib in 18 patients, crizotinib-ceritinib in 39 patients and crizotinib-alectinib-ceritinib in 1 patient.
Conclusion:
This retrospective study of 318 patients with ALK+ NSCLC showed a remarkable efficacy of crizotinib, with a 18.7 months median OS, a 40.3% ORR and a 6.9 months median PFS. However, ORR and mPFS were lower than those reported in phase III trials, which may be due to less stringent selection criteria. Analysis of predictive factors of response and survival including post-progression strategies will be presented.
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ORAL33.05 - Pooled Analysis of CNS Response to Alectinib in Two Studies of Pre-Treated ALK+ NSCLC (ID 1219)
17:28 - 17:39 | Author(s): E. Dansin
- Abstract
- Presentation
Background:
The central nervous system (CNS) is a frequent site of progression in ALK+ NSCLC patients treated with crizotinib, thus good CNS efficacy is of crucial importance for new ALK inhibitors. Two recent phase II studies examined the efficacy and safety of alectinib in patients with ALK+ NSCLC who progressed after crizotinib; data from both studies were pooled to further examine the efficacy of alectinib in the CNS.
Methods:
Both phase II, single-arm, multicenter studies enrolled ALK+ NSCLC patients previously treated with crizotinib. One study was conducted in North America only (NP28761; NCT01871805), the other was global (NP28673; NCT01801111). All patients received 600mg oral alectinib twice daily. A primary endpoint of both studies was objective response rate (ORR) by independent review committee (IRC) and key secondary endpoints included CNS ORR by IRC and CNS duration of response (DOR). Response was determined according to RECIST v1.1. All patients underwent imaging at baseline to assess CNS metastases.
Results:
The pooled analysis population comprised 225 patients (n=87 from NP28761 and n=138 from NP28673); baseline characteristics were similar to each study population, with most patients being non-smokers, <65 years old with ECOG performance status 0/1. Median follow-up was 27.7 weeks. Fifty patients had measurable CNS disease at baseline (MD) while a further 85 had non-measurable disease (NMD) at baseline; both groups together (M+NMD) comprised 135 patients, 60% of the overall study population. In the MD group, 34 patients (68%) had received prior radiotherapy, but 24 of them had completed that radiotherapy >6 months prior to starting alectinib. For the M+NMD group, 94 patients (70%) had received prior radiotherapy, with 55 completing this >6 months prior to starting alectinib. In the MD group, 30/50 patients had a CNS response (60.0%; 95% CI 45.2–73.6%), with 7 complete responses (CR; 14.0%) and a CNS DCR of 90.0% (78.2–96.7%). In the M+NMD group, 22 additional patients had a CR (29/135; 21.5%), giving a CNS ORR of 38.5% (30.3–47.3%), with a CNS DCR of 85.2% (78.1–90.7%). Complete responses were seen in patients with and without prior radiotherapy. Median CNS DOR after only 17% of events in both groups was 7.6 months (5.8–7.6) in the MD group (n=30) and 7.6 months (5.8–10.3) in the M+NMD group (n=52), which is similar to the systemic DOR reported in both studies (Ou et al, ASCO 2015; Gandhi et al, ASCO 2015). Tolerability was also similar to the overall study population.
Conclusion:
Alectinib showed promising efficacy in the CNS in ALK+ NSCLC patients previously treated with crizotinib, achieving a complete response rate of 22% and a DCR of 85%, irrespective of prior radiotherapy. The CNS response was sustained for an equivalent duration to the systemic response, suggesting that alectinib could provide an effective treatment for patients with ALK+ NSCLC while actively targeting CNS metastases. The ongoing phase III clinical studies will assess the systemic and CNS efficacy of alectinib versus crizotinib as front-line therapy for ALK+ NSCLC patients.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-111 - Gene Polymorphisms in Thoracic Tumors Receiving Cisplatin-Pemetrexed (ID 810)
09:30 - 09:30 | Author(s): E. Dansin
- Abstract
Background:
Chemotherary combining cisplatin and the multitarget antifolate pemetrexed (ALIMTA[®]) is widely used in mesothelioma and metastatic non-squamous non-small cell lung cancer (n-sq NSCLC). Thymidylate synthase (TYMS) expression is recognized as a predictive marker of pemetrexed efficacy. Polymorphisms in TYMS and Excision repair cross-complementing (ERCC) genes have been associated with decreased tumour response to pemetrexed, and 5-10 Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been linked to increased toxicity to pemetrexed. The objective of this pilot study was to examine the feasibility and usefulness of testing gene polymorphisms for predicting pharmacodynamics of cisplatin-pemetrexed.
Methods:
This ancillary study (ALIMESO trial) was conducted on 21 patients (mean age 61, 15 men, 6 women) with malignant pleural mesothelioma (8 epithelioid, 2 sarcomatoid, 2 biphasic, 1 desmoplastic) or n-sq NSCLC (3 adenocarcinoma, 5 large-cell carcinoma) treated by cisplatin (75 mg/m[2]) plus pemetrexed (500 mg/m[2]) for 6 cycles (day 1 = day 22). Response to treatment was evaluated after 3 cycles (RECIST criteria). Toxicity was recorded according to CTC-AE classification. Gene polymorphisms were analyzed in all patients (blood DNA). TYMS polymorphisms in 5’UTR (28 bp repeats rs34743033 along with G>C mutation on 3R allele, rs11540151) were analyzed by PCR-RFLP and 6 bp deletion in 3’UTR (rs11280056) by PCR-electrophoresis. MTHFR C677T (rs1801133) and A1298C (rs1801131) were analyzed by sequencing. ERCC1 AAT118AAC (rs11615), ERCC2 Lys751Gln (rs13181), GSTP1 Ile105Val (rs1695) and Ala114Val (rs1138272) were analyzed by PCR-RFLP.
Results:
13 patients (62%) were evaluable for response (8 patients not assessable due to either no chemo or <3 cycles). ORR was 46% (6PR, no CR) and DCR was 100%. 20 patients (95%) were evaluable for toxicity. 78 chemotherapy-related adverse events were reported with 17 (22%) grade 3/4 (2 anemia, 7 neutropenia, 5 thrombocytopenia, 1 renal failure, 1 asthenia, 1 nausea). There was no toxic death. Chemotherapy was stopped after 3 cycles for 2 patients. Homozygous and heterozygous deletion in 3’UTR of TYMS was observed in 1 and 9 patients, respectively. For TYMS 5’UTR, 13 patients belong to class 2 (2R/2R, 2R/3RC or 3RC/3RC), 6 belong to class 3 (2R/3RG or 3RG/3RC) and one belong to class 4 (3RG/3RG). Other genotypes were as follows. GSTP1 codon 105: 10 Ile/Val and 4 Val/Val; GSTP1 codon 114: 1 Ala/Val; ERCC1 codon 118: 10 C/T and 4 C/C; ERCC2 codon 751: 12 Lys/Gln and one Gln/Gln; MTHFR C677T: 10 C/T and 3 T/T; MTHFR A1298C: 8 A/C and 3 C/C. There was no correlation between any gene polymorphisms and response or G3-4 toxicity. Of note, among the 6 patients homozygous for rare MTHFR alleles (i.e. 677TT or 1298CC), 4 exhibited a high-grade (grade 3/4) haematological toxicity.
Conclusion:
Present results suggest that gene polymorpshism analysis is feasible in the context of pharmacodynamics predictivity. From this limited number of patients, a trend was observed between MTHFR genotype and haematological toxicity. These preliminary data need to be confirmed on a larger set of patients with thoracic tumors treated by cisplatin/pemetrexed.
