Virtual Library
Start Your Search
G.J. Weiss
Author of
-
+
ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Gadgeel
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
-
+
ORAL33.06 - Brigatinib (AP26113) Efficacy and Safety in ALK+ NSCLC: Phase 1/2 Trial Results (ID 2125)
17:39 - 17:50 | Author(s): G.J. Weiss
- Abstract
- Presentation
Background:
Brigatinib (AP26113), an investigational oral tyrosine kinase inhibitor with FDA breakthrough therapy designation for the treatment of patients with crizotinib-resistant advanced ALK+ NSCLC, has preclinical activity against both rearranged ALK and clinically identified crizotinib-resistant mutant ALK.
Methods:
This is an ongoing phase 1/2, single-arm, open-label, multicenter study in patients with advanced malignancies (N=137; NCT01449461). Patients received escalating total daily doses of brigatinib from 30–300 mg during phase 1. Daily regimens of 90 mg, 180 mg, or 90 mg for 7 days followed by 180 mg were evaluated in phase 2. Safety is reported for all treated patients; antitumor efficacy (ORR and PFS per RECIST v1.1) is reported for ALK+ NSCLC patients.
Results:
Seventy-nine (58%) patients had ALK+ NSCLC. Median age was 54 (29–83) years, 49% were female, 90% had prior crizotinib, and 47% had ≥2 prior chemotherapy regimens. As of February 17, 2015, 45/79 (57%) ALK+ NSCLC patients remained on study, with median time on treatment of 12.6 months (1 day to 35.5 months; n=79); ORR/PFS for evaluable ALK+ NSCLC patients was 74%/13.4 months (additional data shown in Table). In a post hoc independent radiological review of patients with brain metastases at baseline (as of January 19, 2015), 8/15 (53%) patients with measurable brain lesions ≥10 mm had an intracranial response (≥30% decrease in sum of longest diameters of target lesions) and 9/30 (30%) patients with only nonmeasurable lesions had disappearance of all lesions. Treatment-emergent AEs in ≥30% of total patients, generally grade 1/2, included nausea (52%), fatigue (42%), diarrhea (40%), headache (33%), and cough (32%). Early-onset pulmonary events, which occurred ≤7 days after treatment initiation and included dyspnea, hypoxia, and new pulmonary opacities on chest CT consistent with pneumonia or pneumonitis, were reported in 13/137 (9%) patients overall (6/44 [14%] at 180 mg qd; 2/50 [4%] at 90 mg qd [maintained or escalated to 180 mg qd after 7 days]).Response and PFS With Brigatinib All Evaluable ALK+ NSCLC Patients n=78 Prior Crizotinib n=70 No Prior Crizotinib n=8 Response, n(%) OR (CR+PR) 58(74) 50(71) 8(100) [95% CI] [63–84] [59–82] [63–100] CR 7(9) 4(6) 3(38) PR 51(65) 46(66) 5(63) SD 11(14)[a] 11(16)[a] 0 PD 6(8) 6(9) 0 Termination before scan 3(4) 3(4) 0 Median duration of response,[b] mo 11.2[c] 9.9[d] Not reached[e] Median PFS,[b] mo 13.4 13.4 Not reached [a]Includes non-CR/non-PD for 4 patients with no measurable disease at baseline [b]Kaplan-Meier estimate [c]n=55 evaluable [d]n=48 evaluable [e]n=7 evaluable
Conclusion:
Brigatinib has promising antitumor activity in ALK+ NSCLC patients with (71% ORR; PFS 13.4 months) or without (100% ORR) prior crizotinib, including patients with brain metastases (53% ORR in patients with measurable brain lesions). Early-onset pulmonary events were less frequent when starting at 90 vs 180 mg qd. A pivotal global phase 2 trial (ALTA) of brigatinib 90 mg qd vs 90 mg qd for 7 days followed by 180 mg qd in crizotinib-resistant ALK+ NSCLC is ongoing.
Only 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.
-
+
ORAL 37 - Novel Targets (ID 146)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.S. Ramalingam, E. Thunnissen
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
-
+
ORAL37.08 - Discussant for ORAL37.04, ORAL37.05, ORAL37.06, ORAL37.07 (ID 3465)
18:01 - 18:11 | Author(s): G.J. Weiss
- Abstract
- Presentation
Abstract not provided
Only 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.
-
+
P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P2.04-060 - Analysis of Lung Microbiome From Patients Undergoing Bronchoscopy (ID 1072)
09:30 - 09:30 | Author(s): G.J. Weiss
- Abstract
Background:
Recent studies have demonstrated diversity in the lung microbiomes of chronic obstructive pulmonary disease and healthy individuals. Lung microbial communities may not just serve as a predictor of cancer development, but also as a target of pharmacological cancer prevention strategies. We sought to characterize the lung microbiome diversity within patients with lung cancer for comparison to those without lung cancer.
Methods:
Signed informed consent was obtained from patients ages 18 years and older that underwent a bronchoscopy during the course of clinical evaluation at one of two cancer centers. A bronchial lavage was collected for research purposes after routine bronchoscopic procedures were completed. The lavage sample was collected in a sterile collection container and immediately placed on dry ice. Subsequently, samples were diluted 1:1, incubated with dithiothreitol to aid in mucus dissolution, and then mechanically homogenized. DNA was extracted and 515F/806R 16S rRNA primers used to amplify Variable Region 4. Amplicons were sequenced using the Illumina MiSeq. Sequences were clustered into operational taxonomic units (OTUs) using QIIME’s open reference OTU picking workflow, and taxonomy was assigned to OTUs by classification against the Greengenes database using the RDP Classifier. Microbial communities were compared using phylogenetic beta diversity metrics based on 16S rRNA reads. Statistical significance of diversity between samples was determined by comparing the UniFrac distances between pairs of samples using parametric and non-parametric Monte Carlo-based t-tests. Differences in alpha diversity were tested using a t-test comparing the distributions of diversity values across the sample types.
Results:
None of the patients undergoing a research-related bronchial lavage experienced a significant adverse event from the procedure. There were seven lung cancer patients with a median age of 56.0 years (range 45-75). Of these, six were current/former smokers with an average of 32.5 pack-years. All seven lung cancer patients were Caucasian with five using prescription inhalers and none on recent antibiotics. Five patients had adenocarcinoma and one each of squamous cell carcinoma and small cell lung cancer. There were six non-lung cancer patients with a median age of 57.5 years (range 39-68). Of these, three were current/former smokers with an average of 40 pack-years. All six non-lung cancer patients were Caucasian with three using prescription inhalers and one recently taking antibiotics. Analyses of the microbiota present in lung samples show the presence of multiple bacterial taxonomic groups in each sample, however, the phylogenetic diversity of the bacterial community is low compared to other body sites. Fusobacteria represented a significant portion of the bacterial community of lavage samples. Not surprisingly, the community composition of these samples is most similar to human oral communities, however, a portion of these communities is unlike communities from other characterized human body sites and we are still actively investigating these differences.
Conclusion:
Microbiota associated with lung cancer have not been well-characterized or associated with treatment and outcome. Our analyses suggest that bacterial communities may play an important role in cancer development and present an opportunity to better characterize these communities and their components. Updated results will be presented at WCLC.
-
+
P2.07 - Poster Session/ Small Cell Lung Cancer (ID 222)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P2.07-003 - Attempt to Validate Drug Repositioning for Metastatic Small Cell Lung Cancer (SCLC) Therapy Identifies Statins Associated with Survival Benefit (ID 2277)
09:30 - 09:30 | Author(s): G.J. Weiss
- Abstract
Background:
SCLC is an aggressive malignancy with limited treatment options. Based on in vitro data and results of a recent drug repositioning study, some medications approved by the FDA for the treatment of various non-malignant disorders were demonstrated to have anti-SCLC activity in preclinical models. Drug dose levels that demonstrated anti-cancer activity were similar to those used in the clinics. The aim of our study is to confirm whether use of these medications is associated with survival benefit in a large cohort of SCLC patients from a single institution.
Methods:
Consecutive patients with cytologically or histologically confirmed, metastatic SCLC evaluated between 2000-2013 at the National Koranyi Institute of Pulmonology were analyzed in this retrospective analysis. Patients that were prescribed statins, aspirin, clomipramine (a tricyclic antidepressant [TCA]), selective serotonin re-uptake inhibitors (SSRIs), doxazosin, and prazosin were identified. Next, we evaluated the associations amongst these various medications, clinicopathological characteristics (including gender, age, and Eastern Cooperative Oncology Group performance status [ECOG PS]), and overall survival (OS) in univariate and multivariate analyses with Bonferroni correction applied.
Results:
There were a total of 876 patients (508 men and 368 women) with a median age of 61 years (range, 33-86). 75% of the chemotherapy administered in the first line setting was platinum-based. Aspirin, statin, SSRIs, doxazosin, prazosin, and TCA were administered in 138, 72, 20, 14, 14, and 5 cases; respectively. Univariate analysis identified age, ECOG PS, and statin treatment as significant prognostic factors (p<0.001; p<0.001; and p=0.002; respectively). A statistically significant increase in OS was observed only in statin-treated patients when compared to those not receiving any of the aforementioned medications (median OS, 8.4 vs. 6.1 months; respectively). The administration of SSRIs, TCA, aspirin, prazosin, or doxazosin did not result in a statistically significant OS benefit (median OS, 8.5, 7.2, 6.8, 6.8, and 4.6 months; respectively). The multivariate Cox model showed that besides age and ECOG PS, statin treatment was an independent survival predictor (Hazard Ratio, 1.41; 95% confidence interval, 1.1–1.8; p=0.007).
Conclusion:
Statins appear to provide a statistically significant survival benefit in metastatic SCLC. Other classes of medications analyzed in this study did not validate the preclinical drug repositioning studies previously reported. Drug repositioning studies using only preclinical data or small numbers of patients should be treated with caution before application in the clinic.
-
+
P2.07-008 - CTC 11-001: PhI Study of Carfilzomib (C) + Irinotecan (I) in Relapsed, Irinotecan Sensitive Solid Tumors (ID 241)
09:30 - 09:30 | Author(s): G.J. Weiss
- Abstract
Background:
Inactivation of proteasome function allows for increased apoptosis and the potential for enhanced antitumor effect by chemotherapy. Carfilzomib (C) and Irinotecan (I) potentially synergize by increasing camptothecin-induced apoptosis and interfering with topoisomerase-I degradation, preventing DNA damage repair. This report describes the initial phase I study of C + I in adults with relapsed, irinotecan-sensitive cancers including small cell lung cancer (SCLC).
Methods:
The primary endpoint was determination of the MTD of 28-day cycle 1 of I (D1,8,15) and C (D1,2,8,9,15,16) using a standard 3+3 Ph1 design. Toxicity and response were evaluated using NCI CTCAE (v4) and RECIST (v1.1). Pharmacodynamics endpoints (proteasome activity, topo-1 expression, and gamma-H2AX protein expression in PBMC) were assessed on C1D1 and C1D2.
Results:
16 patients were enrolled at 3 dose levels of C (mg/m2/d) using stepped-up dosing: 20 mg given C1D1 & C1D2 then increased to the dose indicated: 20/27 (N=4), 20/36 (N=9), 20/45 (N=3) and I dosed at 125 mg/m2d. Median age: 64 (range 56-78), 8 M/8F. Tumor types included: SCLC (N=13), non-small cell lung cancer (NSCLC) (N=2) and ovarian (N=1). 6 subjects completed 2 or more cycles of therapy, 4 subjects were not evaluable for dose-limiting toxicity (DLT) secondary to rapid progressive disease (PD) or withdrawal and were replaced. 2 DLTs were observed in cohort 3, Grade (Gr)4 thrombocytopenia lasting ≥ 7 days and Gr3 diarrhea lasting ≥ 7 days) and 1 DLT in cohort 2 (Gr3 diarrhea lasting > 7 days). Serious adverse events (SAEs) by dose level: 20/27: Gr3 Dysphagia and recurrent laryngeal nerve palsy, (unrelated); Gr3 peripheral motor neuropathy and Gr3 urinary incontinence, (unrelated); 20/36: Gr3 fatigue, multiple occurrences; Gr3 diarrhea with dehydration; Gr3 cholelithiasis with dehydration (unrelated); 20/45: Gr3 dehydration, Gr3 anemia, Gr2 anemia and Gr3 acute on chronic kidney disease. Common Gr3/4 AEs were: fatigue (19%), thrombocytopenia (19%), diarrhea (13%), anemia (6%), neutropenia (6%), and leukopenia (6%). One patient (25%), five patients (55%), and two patients (67%) experienced Gr3/4 AEs in cohorts 1, 2, and 3, respectively. The maximum tolerated dose was exceeded at 20/45. Antitumor activity (stable disease or better) was observed in 3 SCLC subjects to date, with updated follow-up to be reported.
Conclusion:
C and I is a well-tolerated combination with anti-tumor activity in heavily pretreated patients. The recommended phase 2 dose of Carfilzomib is 20/36 mg/m2/d in combination with Irinotecan 125 mg/m2/d. A phase 2 study in SCLC is ongoing through the Lung Cancer Research Team (LCRT). This study was supported by Onyx Pharmaceuticals, a subsidiary of Amgen Corporation. Clinical trial information: NCT01941316.
-
+
P3.07 - Poster Session/ Small Cell Lung Cancer (ID 223)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P3.07-008 - Phase Ib/II Study of Pembrolizumab plus Chemotherapy in Advanced Cancer: Results of Lung Cancer Patients Receiving ≥ 1 Prior Line of Therapy (ID 377)
09:30 - 09:30 | Author(s): G.J. Weiss
- Abstract
Background:
Pembrolizumab (pembro) is a selective anti-PD-1 antibody that blocks the interaction between programmed death-1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumor cells. We report safety and clinical activity of pembro combined with chemotherapy in patients with advanced small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) progressing after ≥ 1 line of chemotherapy (NCT02331251).
Methods:
Patients were treated with pembro 2 mg/kg on day 1 every 21 days with either irinotecan on day 1 every 21 days or gemcitabine with or without vinorelbine on days 1 and 8 every 21 days until progression or toxicity. Eligibility included at least 1 measurable tumor lesion, Karnofsky Performance Status (KPS) of 70-100%, and adequate organ function. Tumors were assessed every 3 cycles using RECIST 1.1 and immune-related response criteria (irRC) and unconfirmed best overall response (BOR) was evaluated.
Results:
Eight lung cancer patients have been enrolled at the time of submission. Median age was 52.5 (range 33-74) and median KPS was 80%. Histology was adenocarcinoma (62.5%), including one with an EGFR T790M mutation and three SCLC (37.5%). One SCLC patient is on pembro plus gemcitabine 1,000 mg/m2, one NSCLC patient is on gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2, and the remaining six patients were treated with irinotecan 250-300 mg/m2. Two NSCLC had prior exposure to nivolumab for ≥ 2 months. The maximum tolerated dose (MTD) was exceeded for irinotecan 300 mg/m2, and subsequently all patients receiving irinotecan are currently dosed at 250 mg/m2. Any grade drug-related treatment adverse events (AEs) occurred in 88% of patients; the most common (n>1) were skin rash, fatigue, diarrhea, anorexia, and extremity edema. No infusion-related reactions were observed. Dose limiting toxicities (DLTs) with pembro plus irinotecan were fatigue and nausea/vomiting. DLT with gemcitabine and vinorelbine was hypoxia. No grade 3 AEs were observed thus far with pembro plus gemcitabine. Five patients are currently evaluable for BOR. Two of two SCLC on pembro plus irinotecan have partial response as BOR and continue on study. One NSCLC patient on pembro plus gemcitabine and vinorelbine had stable disease, and two NSCLC patients had PD as BOR.
Conclusion:
In patients with previously treated SCLC and NSCLC, pembro plus chemotherapy appears to be safe to administer with a toxicity profile similar to the individual components of the regimen utilized. Establishment of the recommended phase 2 dose is ongoing for these treatment arms. Since the median follow-up is ~2 months, updated results including any new lung cancer patients enrolled, median progression-free survival (PFS), and overall survival will be presented at the WCLC.
