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F. Barlesi
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MINI 30 - New Kinase Targets (ID 157)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:K. Park, M. Villalona
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F3+F4
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MINI30.03 - Smoking Predicts Sensitivity to PARP Inhibitor, Veliparib, in Advanced NSCLC Patients (ID 1279)
18:40 - 18:45 | Author(s): F. Barlesi
- Abstract
- Presentation
Background:
Tobacco-related non-small cell lung cancer (NSCLC) is associated with reduced survival and greater genomic instability. Veliparib (V) is a PARP inhibitor that augments platinum-induced DNA damage in preclinical studies, and a recent Phase 2 trial of advanced NSCLC trended to improved survival (HR 0.80; CI 0.54–1.18) when V was added to carboplatin (C) and paclitaxel (P). Here we report outcomes based on smoking status from this randomized Phase 2 study of CP with either V or placebo in advanced NSCLC.
Methods:
Patients with previously untreated advanced/metastatic NSCLC were randomized 2:1 to CP with either V at 120mg BID or placebo (randomization stratified by histology and smoking history). Cotinine was measured in patients’ plasma samples as an index of recent tobacco use.
Results:
Of 158 patients, 68% were male, and 49% had squamous NSCLC. At study entry, 60% pts were self-reported current smokers, 27% former smokers, and 13% never smoked. There were no significant differences in veliparib pharmacokinetic parameters between cotinine-high and low. Grade 3/4 AEs were elevated in current-smokers treated with VCP vs CP (66% vs. 40%, p=0.026); all-grade AEs and SAEs were similar between the two groups. The most common AEs in current-smokers were neutropenia (41% VCP; 27% CP), alopecia (36%; 33%), and anemia (31%; 40%). Figure 1 A sensitivity analysis of heavy vs light-smokers (≥ vs <39 pack-years, current or former smokers) showed advantage of veliparib in heavy-smokers: median PFS [HR(95% CI)] for VCP/CP was 7.0 vs 3.5 [0.43(0.20–0.94)] for heavy-smokers and 4.4 vs 4.2 [0.97(0.49–1.92)] for light-smokers; median OS was 12.6 vs 8.8 [0.52 (0.27–1.02)] for heavy-smokers and 9.9 vs 8.8 [0.92(0.53–1.61)] for light-smokers. A cotinine sensitivity analysis found that outcomes in cotinine-high were similar to current-smokers: PFS, cotinine-high HR was 0.38 (0.19–0.73) and cotinine-low was 0.97 (0.51–1.87); OS, cotinine-high HR was 0.52 (0.29–0.92) and cotinine-low was 1.07 (0.63–1.81). In univariate analyses assessing the influence of baseline characteristics and treatment on outcomes, smoking status and treatment had a significant interaction (p=0.0301 PFS, p=0.0118 OS). Additionally, multivariate analysis including all factors also identified current smoking as predictive of improved outcomes with VCP.
Conclusion:
Smoking status was a strong predictor of efficacy for veliparib-chemotherapy combination in advanced NSCLC. No differences in pharmacokinetics of V were seen based on plasma cotinine; toxicity of VCP was acceptable regardless of smoking history. A Phase 3 study has been initiated in patients with smoking history (M14-359).
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MINI30.07 - Crizotinib in Patients with ROS1 NSCLC. Preliminary Results of the AcSé Trial (ID 2426)
19:05 - 19:10 | Author(s): F. Barlesi
- Abstract
- Presentation
Background:
To avoid uncontrolled off-label use and allow for a nationwide safe access to crizotinib (crz) for patients (pts) with an ALK, MET or ROS1 positive (+) tumor, the French National Cancer Institute (INCa) launched the AcSé program, funding both access to tumor molecular diagnosis and an exploratory multi-tumor 2-stage design phase II trial. We report the preliminary results of the ROS1+ NSCLC cohort.
Methods:
ROS1 status was assessed in 28 regional INCa molecular genetic centers by break-apart FISH assays in tumor samples showing an IHC score of ≥1+. Pts with ROS1 rearrangements, progressing after at least one standard treatment (including a platinum-based doublet, unless pts were considered as unfit for chemotherapy) were proposed to receive crz 250 mg BID. Responses were centrally assessed using RECIST v1.1. The objective response rate (ORR) and disease control rate (DCR) were assessed every 8 weeks.
Results:
From Aug. 5, 2013 to Mar. 1, 2015, 39 pts with ROS1+ NSCLC were enrolled. 37 pts had received crz, leading to 37 pts with clinical information. Median age: 62 years (range 33–81), 70% females, 95% non-squamous histology, and 94% metastatic disease at study entry. Median number of prior treatments: 2 (range 1 –7). Twenty four pts were still on treatment at the cut-off date, 13 have stopped crz (8 PD, 3 adverse events (AEs), 2 deaths). Among the 27 pts evaluable for response at 8 weeks, we observed 16 PR, 7 SD and 4 PD, leading to ORR=59% [95% CI:39-78], and DCR=85% [66-96]. DCR at 6 months was 57% (disease control was achieved in 12/21 evaluable pts). Crz was well tolerated with only 4 grade ≥3 (1 AE + 3 SAEs) and 9 grade 1-2 SAEs. Most common AEs, mainly grade 1, were visual disorders (54% of pts), peripheral edema (51%), diarrhea (48%), nausea (46%), and elevated transaminases (43%).
Conclusion:
Crz was well tolerated and achieved a robust treatment response rate in ROS1+ NSCLC. These results underline the interest of integrating ROS1 in biomarkers routine screening. Survival data and duration of response will be presented.
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ORAL 34 - Quality/Survival/Prognosis in Localized Lung Cancer (ID 153)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:B.C. Cho, R.L. Keith
- Coordinates: 9/09/2015, 16:45 - 18:15, 201+203
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ORAL34.01 - Compliance with Follow-Up Programs After Surgery for Non-Small Cell Lung Cancer in the Phase III IFCT-0302 Trial (ID 2148)
16:45 - 16:56 | Author(s): F. Barlesi
- Abstract
- Presentation
Background:
In patients operated on for non-small cell lung cancer, several guidelines recommend a follow-up based on regular clinic visits and chest CT-scans. However, evidence to support these recommendations is poor, in the absence of randomized data. The IFCT-0302 trial is a randomized multicenter trial which compared 2 follow-up programs after complete resection for a clinical stage I, II, IIIA and T4 (pulmonary nodules in the same lobe) N0-2 NSCLC (TNM 6[th] edition). We present the results of compliance with the follow-up programs for the first 2 years after randomization.
Methods:
In the CXR arm, follow-up consisted of clinic visit and chest X-rays. In the CCT arm, patients underwent clinic visit, chest X-rays, thoraco-abdominal CT scan plus fiberoptic bronchoscopy (only mandatory for squamous cell and large cell carcinomas). In both arms, procedures were repeated every 6 months after randomization during the first 2 years, and yearly until 5 years, in the absence of recurrence or second primary cancer. Supplementary procedures were allowed in case of symptoms. Primary endpoint was overall survival.
Results:
Between January 2005 and November 2012, 1775 patients were randomized (CXR: 888; CCT: 887). Patient characteristics were well balanced between the two arms : males 76.3%, median age 62 years (range: 33-87), adenocarcinomas 56.7%, stage I-II 82.1%, lobectomy or bilobectomy 86,8%, pre- and/or post-operative radiotherapy 8.7%, and pre- and/or post-operative chemotherapy 45%. Surveillance was performed in 97% of patients at 6 months, in 94% at 12 months, in 90% at 18 months and in 84% at 24 months, and did not differ between the 2 arms. Intervals between randomization and visits were respected with no difference between arms (mean +/-SD in months from randomization: 5.93 +/- 0.84; 11.95 +/- 0.98; 18.05 +/- 0.99; 24.18 +/-1.30, respectively). In the 757 patients of the CXR arm, who had a follow-up visit at 6 months and no recurrence, 754 (99.6%) had a clinic visit and 730 (96.4%) a chest X-ray. In the 706 patients of the CCT arm who had a follow-up visit at 6 months and no recurrence, 702 (99.4%) had a clinic visit, 478 (67.7%) a chest X-ray, 678 (96%) a chest CT-scan, and 342 (48.4%) a bronchoscopy. Comparable compliance results were observed at 12, 18 and 24 months. In the CXR arm, supplementary thoracic CT-scans were done in 119 patients (15.7 %) at 6 months, in 96 (14.4 %) at 12 months, in 78 (13.2%) at 18 months and in 58 (11.4%) at 24 months. Other supplementary procedures were more frequent in the CCT arm than in the CXR arm, consisting mostly of brain imaging (at 6 months, in 93 (13.2%) and 39 (5.2%) patients, respectively, p<.001).
Conclusion:
Compliance with the follow-up programs was excellent in terms of timing. Chest X-ray was often omitted in the CCT arm. In the CXR arm, supplementary CT-scans that did not lead to a diagnosis of recurrence or second primary cancer were performed in 10 to 15% of patients. In the CCT arm, the most frequently performed supplementary procedure was brain imaging.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-086 - Ceritinib in ALK+ NSCLC Metastatic to Brain and/or Leptomeninges: The ASCEND-7 Study (ID 290)
09:30 - 09:30 | Author(s): F. Barlesi
- Abstract
Background:
Although the anaplastic lymphoma kinase inhibitor (ALKi), crizotinib achieves high responses in patients with ALK-rearranged (ALK+) non–small cell lung cancer (NSCLC), disease progression within 1 year can occur, with the brain/central nervous system (CNS) as a common site of progression and relapse. Ceritinib is a novel oral ALKi with 20-fold greater potency than crizotinib in enzymatic assays and crosses the blood-brain barrier with good CNS penetration in preclinical studies. In the pivotal phase 1 study (NCT01283516), ceritinib was highly active in ALK+ NSCLC patients (regardless of prior crizotinib exposure) and achieved intracranial responses in 7 of 14 patients with measurable baseline brain lesions. The adverse events profile in these patients was similar to that of the full study population.
Methods:
This international, prospective, phase 2, open-label study is designed to evaluate the antitumor activity of ceritinib in patients with ALK+ NSCLC metastatic to the brain or leptomeninges (ASCEND-7; CLDK378A2205). Eligible patients must have ALK+ (centrally assessed) NSCLC metastatic to the brain and ≥ 1 extracranial measurable lesion using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients must be neurologically stable ≥ 1 week prior to study drug administration and will be allocated to 1 of 5 arms depending on prior treatment:
*Lesion free of local treatment (stereotactic or WBRT) or lesions in unequivocal progression after radiotherapy. Oral ceritinib 750 mg/d will be dosed on a continuous schedule and study assessments are consistent across arms. The primary and key secondary objectives are to evaluate overall response rate and disease control rate, respectively. Other secondary objectives include assessment of intracranial and extracranial responses for all patients and for each of arms 1–4; overall survival and safety for all patients and for each of arms 1–5; and ceritinib pharmacokinetics in all patients. Enrollment is ongoing.Arms 1-4 (patients with active* brain metastases, without leptomeningeal carcinomatosis [LC]) Prior ALKi treatment No prior ALKi treatment Prior whole brain radiotherapy (WBRT) Arm 1 Arm 3 No prior WBRT Arm 2 Arm 4 Arm 5: patients with LC with or without evidence of active lesion at baseline
Results:
This study is in the activation phase.
Conclusion:
This study will demonstrate the efficacy of ceritinib in ALK+ NSCLC brain metastases and leptomeningeal metastases, in both WBRT-naive patients and prior irradiated patients.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-078 - Avelumab (MSB0010718C), an Anti-PD-L1 Antibody, Evaluated in a Phase III Trial versus Docetaxel in Patients with Relapsing NSCLC (ID 1588)
09:30 - 09:30 | Author(s): F. Barlesi
- Abstract
Background:
The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. The phase III study (NCT02395172) is an open-label, multicenter trial of avelumab compared with docetaxel in patients with non-small-cell lung cancer (NSCLC) that has progressed after treatment with a platinum-containing doublet.
Methods:
The primary objective of this head-to-head phase III study is to demonstrate superiority defined by overall survival (OS) of avelumab versus docetaxel in patients with locally advanced unresectable, metastatic, or recurrent NSCLC whose tumors express PD-L1 and whose disease has progressed following treatment with a platinum-containing doublet. Approximately 650 eligible patients (ECOG performance status 0-1 at trial entry, tumor archival material or fresh biopsy suitable for PD-L1 expression assessment, histologically confirmed NSCLC, and known-negative ALK mutation status, among other inclusion and exclusion criteria), including 522 patients with PD-L1—positive tumors, will be randomized 1:1 to receive either avelumab at a dose of 10 mg/kg as a 1h intravenous (IV) infusion Q2W or docetaxel at a starting dose of 75 mg/m2 (per label) by IV infusion Q3W. Patients will be stratified according to PD-L1 status. NSCLC histology and EGFR mutation status will be used to define 3 stratified levels for randomization: squamous cell, non-squamous cell/EGFR wildtype, and non-squamous cell/EGFR-activating mutations. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Responses will be evaluated according to RECIST 1.1 and adjudicated by a blinded independent review committee. In addition to the primary endpoint of OS, secondary endpoints include progression-free survival, best overall response, quality of life assessments, and safety profile. Exploratory endpoints include duration of response, tumor shrinkage in target lesions per timepoint, immunogenicity, PK profile, and evaluation of molecular, cellular, and soluble markers in peripheral blood or tumor tissue that may be relevant to the mechanism of action of, or response/resistance to, avelumab. Safety profiling of trial drugs includes incidence of adverse events (AEs), serious AEs, and other assessments according to NCI-CTCAE v4.03. Patients receiving avelumab who have achieved a complete response (CR) will be treated for a minimum of 6 months and a maximum of 12 months after confirmation. In the case of relapse following a CR, treatment with avelumab may be re-initiated once at the discretion of the investigator and in the absence of treatment-related toxicity. For patients whose disease progresses with avelumab, treatment may continue past the initial determination of disease progression per RECIST 1.1 if the patient’s performance status has remained stable, other criteria are fulfilled, and the investigator’s opinion supports a possible benefit of continued treatment with avelumab. Patients treated with docetaxel may not crossover to the avelumab arm as long as the primary endpoint has not been met in the planned interim or final analyses. Enrollment in this trial began in April 2015. *Proposed INN.
Results:
not applicable
Conclusion:
not applicable
