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J.W. Riess
Moderator of
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MO07 - NSCLC - Targeted Therapies II (ID 114)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 14
- Moderators:T. John, J.W. Riess
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside Auditorium B, Level 1
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MO07.01 - Clinical benefit of continuing crizotinib beyond initial disease progression in patients with advanced <em>ALK</em>-positive non-small-cell lung cancer (ID 2843)
16:15 - 17:45 | Author(s): S.I. Ou, G.J. Riely, Y. Tang, D. Kim, G.A. Otterson, L. Crinò, C.H. Bartlett, D.P. Cohen, J.W. Clark, P.A. Jänne
- Abstract
- Presentation
Background
Crizotinib is approved multinationally to treat advanced ALK-positive non-small-cell lung cancer (NSCLC). Most patients with crizotinib-treated ALK-positive NSCLC ultimately develop progressive disease (PD). We investigated whether continuing ALK inhibition beyond PD is clinically beneficial and the clinicopathologic characteristics associated with patients who experience clinical benefit.Methods
Patients with advanced ALK-positive NSCLC enrolled in two ongoing multicenter, single-arm trials (the molecularly enriched expansion cohort of the phase I trial PROFILE 1001 and the phase II trial PROFILE 1005) who developed RECIST-defined PD were allowed to continue crizotinib if, in the investigator's opinion, they were deriving ongoing clinical benefit. In the present retrospective analyses, continuation of crizotinib beyond PD (CBPD) was defined as >3 weeks of crizotinib treatment after PD documentation. Baseline and post-progression characteristics, sites of PD, progression-free survival (PFS), and overall survival (OS) were compared in patients who continued CBPD versus those who did not. The impact of continuing CBPD on OS after adjusting for potential confounding factors was assessed.Results
Among 194 crizotinib-treated patients with RECIST-defined PD, 120 (62%) continued CBPD. A higher proportion of patients who continued CBPD responded to initial crizotinib treatment (74% vs. 55%), had an ECOG performance status of 0/1 at PD (96% vs. 82%), and had brain (56% vs. 28%) and/or bone (20% vs. 9%) as sites of PD compared with patients who did not continue CBPD. CBPD patients also had numerically longer median PFS from initial crizotinib treatment (7.3 months vs. 5.7 months) and significantly longer OS from the time of PD (median 16.4 months vs. 3.9 months; HR, 0.27; 95% CI: 0.17−0.42; P<0.0001; Figure 1). Multiple-covariate Cox regression analysis revealed that CBPD remained significantly associated with improved OS post-PD after adjusting for relevant factors. Figure 1. OS of patients who continued CBPD versus those who did not, from the time of PD. Shaded areas are 95% Hall-Wellner confidence bands. Figure 1Conclusion
Continuing ALK inhibition after PD may provide survival benefit to a majority of patients with advanced ALK-positive NSCLC. Prolonged PFS on initial crizotinib, good performance status at PD, and progression in brain and/or bone are characteristics that were commonly found in patients who benefited from continued ALK inhibition.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.
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MO07.02 - Clinical experience with crizotinib in patients with advanced <em>ALK</em>-rearranged non-small cell lung cancer and brain metastases in PROFILE 1005 and PROFILE 1007 (ID 2932)
16:15 - 17:45 | Author(s): D.B. Costa, A.T. Shaw, S.I. Ou, B.J. Solomon, G.J. Riely, M. Ahn, C. Zhou, S..M. Shreeve, R. Wiltshire, P. Selaru, A. Polli, P. Schnell, D..R. Camidge, L. Crinò
- Abstract
- Presentation
Background
Crizotinib is an oral tyrosine kinase inhibitor targeting ALK and is approved multinationally for the treatment of advanced ALK-rearranged non-small cell lung cancer (NSCLC) due to its efficacy in controlling systemic tumor burden. The clinical effects of crizotinib in patients with brain metastases have not been previously studied in detail. To evaluate the clinical outcomes of patients with brain metastases on crizotinib, we conducted a retrospective analysis of pooled data from PROFILE 1005 (NCT00932451; a large ongoing global open-label, single-arm phase II study of crizotinib in patients with ALK-rearranged NSCLC who have received one or more treatment regimen for advanced/metastatic disease) and PROFILE 1007 (NCT00932893; an ongoing global randomized phase III study that compared crizotinib with standard second-line chemotherapy [docetaxel or pemetrexed] for advanced ALK-rearranged NSCLC; Shaw et al, N Engl J Med 2013). Subgroup analysis in PROFILE1007 showed that progression-free survival was longer with crizotinib than with chemotherapy for both patients with brain metastases (HR 0.67) and patients without brain metastases (HR 0.43) at baseline.Methods
Patients with previously treated (but ALK-inhibitor-naïve) advanced ALK-rearranged NSCLC enrolled in either PROFILE 1005 or PROFILE 1007 (and randomized to crizotinib) were included in this analysis. Patients with asymptomatic brain metastases were eligible for both studies. The starting dose of crizotinib was 250 mg twice daily. Tumor assessments were evaluated by investigators based on RECIST. Baseline brain imaging (with either computed tomography or magnetic resonance imaging) was required in both studies, and if brain metastases were detected, subsequent brain imaging was required at 6-week intervals. Otherwise, imaging to assess brain metastases on treatment was performed as clinically indicated. Brain metastases were monitored as non-target or target lesions.Results
A total of 275 patients, 31% of 888 patients included in this retrospective analysis, had asymptomatic brain metastases at baseline. Of the 888 patients included, 109 patients (12%) had no prior radiotherapy and 166 patients (19%) had prior radiotherapy for their brain metastases. Among the 109 patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR; % complete responses + partial responses + stable disease) at 12 weeks was 63%, with a systemic objective response rate (ORR) of 53%, and the intracranial DCR at 12 weeks was 56%, with an intracranial ORR of 7%. Among the 166 patients with previously treated brain metastases, the systemic DCR at 12 weeks was 65%, with a systemic ORR of 46%, and the intracranial DCR at 12 weeks was 62% weeks, with an intracranial ORR of 7%. Additional data, including outcomes for patients without brain metastases at baseline, will be presented.Conclusion
In this large retrospective analysis, crizotinib was associated with an initial intracranial DCR of approximately 60% at 12 weeks in patients who were ALK-inhibitor-naïve and had untreated or previously treated brain metastases identified prior to initiation of therapy. Prospective studies may help to determine if crizotinib can delay the natural occurrence or progression of brain metastases in advanced ALK-positive NSCLC.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.
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MO07.03 - Crizotinib therapy for patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC) (ID 2777)
16:15 - 17:45 | Author(s): S.I. Ou, D. Kim, D..R. Camidge, G. Riely, R. Salgia, G. Shapiro, B. Solomon, J.A. Engelman, E.L. Kwak, J.W. Clark, L. Tye, K. Wilner, T. Usari, M. Varella-Garcia, K. Bergethon, A.J. Iafrate, A.T. Shaw
- Abstract
- Presentation
Background
Rearrangements of the ROS1 receptor tyrosine kinase gene identify a subset of NSCLC sensitive to the small-molecule ALK and MET inhibitor crizotinib, approved multinationally for the treatment of advanced ALK-positive NSCLC. Here we present updated efficacy and safety data for crizotinib in an expanded cohort of patients with advanced ROS1-rearranged NSCLC.Methods
ROS1 status was determined by break-apart FISH assays, and patients were enrolled into an expansion cohort of an ongoing phase I crizotinib study (PROFILE 1001; NCT00585195, Pfizer). Where available, samples were also tested for concurrent ALK rearrangement and MET amplification. Patients received crizotinib 250 mg BID, and responses were assessed using RECIST v1.0.Results
At the data cut-off, 35 of 40 patients with ROS1-positive NSCLC were evaluable for response. Median age was 51 years (range 31–77), 80% of patients were never-smokers, and 98% had adenocarcinoma histology; 40% had received one prior regimen, and 45% had received 2–6 regimens for advanced/metastatic disease. 25 samples tested for concurrent ALK rearrangement (24 by FISH and 1 by PCR) and 12 samples tested for concurrent MET amplification (11 by FISH and 1 method not recorded) were all negative. The objective response rate (ORR) was 60% (95% CI: 42–76), with 2 complete responses, 19 partial responses, and 10 cases of stable disease. Median progression-free survival (PFS) had not been reached, with 25 patients (63%) still in follow-up for PFS; six patients (15%) experienced disease progression, and two (5%) died before progression occurred; 6-month PFS probability was 76% (95% CI: 55–88). The disease-control rate was 80% at 8 weeks and 66% at 16 weeks. The most common treatment-related adverse events (AEs) were visual impairment (80%), diarrhea (35%), and nausea (30%), with most patients (68%) reporting only AEs of grade 1 or 2 severity. Peripheral edema (28%) and elevated transaminases (18% AST, 15% ALT) were also reported, similar to previous experience with crizotinib. There were no treatment-related serious AEs and one patient discontinued treatment due to treatment-related nausea. Accrual of patients with ROS1-positive NSCLC is ongoing.Conclusion
Similar to results obtained in ALK-positive NSCLC, crizotinib had marked antitumor activity with a high ORR (60%) in patients with ROS1-positive NSCLC, with a generally tolerable and manageable AE profile. These data suggest that crizotinib is an effective therapy for patients with advanced ROS1-positive NSCLC.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.
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MO07.04 - Clinical Implication of a Population Pharmacokinetic Analysis of XALKORI (crizotinib) in 1,182 Patients with Non-Small Cell Lung Cancer (NSCLC) and 32 Patients with Other Solid Tumors (ID 3082)
16:15 - 17:45 | Author(s): D. Nickens, E. Wang, A. Bello, R. Khosravan, M. Amantea, W. Tan
- Abstract
- Presentation
Background
XALKORI[Ò] (crizotinib) is a selective small-molecule inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK) and its oncogenic variants (ie, ALK fusion events and selected ALK mutations). Crizotinib is also an inhibitor of the hepatocyte growth factor receptor (HGFR, c-Met), c-ros oncogene 1 (ROS1), and Recepteur d’Origine Nantais (RON) RTKs. Clinical studies were conducted globally to determine the maximum tolerated dose, pharmacokinetics, antitumor efficacy and safety of crizotinib in patients with ALK-positive NSCLC and other tumors sensitive to crizotinib. The major objectives of this analysis were (1) to develop a population PK model that describes crizotinib plasma PK using pooled PK data across studies in cancer patients;.and (2) to identify potential covariates which may account for the inter-individual variability in crizotinib PK.Methods
Population pharmacokinetic models were developed from a dataset comprised of 8,973 pharmacokinetic samples from 1,214 cancer patients receiving crizotinib at a starting dose of 250 mg BID in Phase I, II, and III trials. The effects of pre-defined covariates pertaining to demographic characteristics, baseline renal (creatinine clearance) and hepatic function (AST, albumin, and total bilirubin) on the pharmacokinetics of crizotinib were tested in the models.Results
The study population consisted of 533 males (44%) and 681 females (56%). The patients were characterized by a wide range of body weights (33 to 160 kg) and ages (19 to 83 years). There were 189 (15.6%) elderly patients (over 65 years). The majority of patients in the analysis were White (52.8%) and Asian (43.1%), followed by Black (1.8%), Hispanic (1.2%), and Other (1%). Crizotinib PK was characterized by a two-compartment model with first-order absorption and a time-dependent decrease in apparent (oral) clearance (CL/F) from baseline following multiple 250 mg BID dosing. The interindividual variability was moderate, with 40% for CL/F and 52% for the apparent central volume of distribution (V2/F), respectively. The typical PK parameters for a 65 kg non-Asian male cancer patient with baseline creatinine clearance 91.6 mL/min and total bilirubin 0.41 mg/dL were 136 L/hr, 76 L/hr, 3,520 L, and 0.73 hr-1 for the CL/F after the first dose, CL/F at steady state, V2/F, and absorption rate constant (Ka), respectively. Age, AST, albumin, smoking, or ECOG performance status were not significant covariates for crizotinib CL/F (P>0.001). Asian race, gender, body weight, creatinine clearance, and total bilirubin described a portion of the variability in CL/F, and Asian race and gender also explained some of variability in V2/F. Asian race had the greatest effect on crizotinib exposure, with a 97% probability that a typical area under the plasma drug concentration-time curve at steady state (AUCss) in an Asian patient would be >25% higher than a typical AUCss value in a Non-Asian patient. None of the other covariates investigated were found to markedly affect the systemic exposure of crizotinib.Conclusion
There was moderate inter-patient variability in crizotinib disposition. No starting dose adjustments of crizotinib 250 mg BID are recommended based on age, gender, body weight, or race.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.
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MO07.05 - DISCUSSANT (ID 3952)
16:15 - 17:45 | Author(s): J. Soria
- Abstract
- Presentation
Abstract not provided
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MO07.06 - Updated results of a first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies (ID 2400)
16:15 - 17:45 | Author(s): D..R. Camidge, L. Bazhenova, R. Salgia, G.J. Weiss, C.J. Langer, A.T. Shaw, N.I. Narasimhan, D.J. Dorer, V.M. Rivera, J. Zhang, T. Clackson, F.G. Haluska, S.N. Gettinger
- Abstract
- Presentation
Background
AP26113 is a novel tyrosine kinase inhibitor (TKI) that exhibits pan-ALK inhibitory activity against all 9 clinically-identified crizotinib-resistant mutants, including the L1196M gatekeeper, in preclinical experiments. AP26113 also inhibits ROS1 and selectively inhibits mutant EGFR (EGFRm) in preclinical experiments, including the T790M resistance mutation, without affecting the native receptor.Methods
We report data from the dose finding component (3+3 design) of a phase 1/2 open-label, multicenter study in patients with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Dosing was once daily (QD) or twice daily.Results
As of 17 April 2013, 55 patients were enrolled: 30mg (daily dose) n=3, 60mg n=3, 90mg n=8, 120 mg n=15, 180mg n=15, 240mg n=9, 300mg n=2; 62% female, median age 58 yrs; diagnoses: non-small cell lung cancer (NSCLC, n=47), other (n=8). 33 patients discontinued: 22 disease progression, 6 adverse event (AE), 4 deaths (2 possibly related: sudden death, hypoxia), 1 withdrawal by subject. The most common AEs included fatigue (40%), nausea (36%), and diarrhea (33%), which were generally grade 1/2 in severity. The most common grade 3/4 AE was pneumonia (5%). Two patients experienced dose limiting toxicities: grade 3 ALT increase in 1 patient (240mg QD); grade 4 dyspnea and grade 3 hypoxia in 1 patient (300mg QD). Twenty-eight patients had ALK+ history (24 NSCLC, 4 other). Among 24 evaluable ALK+ patients, 15 responded. Responses were observed in 2/4 (50%) ALK+ TKI-naïve patients and 13/17 (76%) ALK+ patients with prior crizotinib therapy and no other ALK inhibitor exposure. Among ALK+ NSCLC patients with prior crizotinib only, 12/16 (75%) responded. The longest response is 40+ weeks (ongoing). 4 of 5 ALK+ patients with untreated or progressing CNS lesions at baseline and with follow-up scans had evidence of radiographic improvement in CNS, including 1 patient resistant to crizotinib and LDK378 (overall response = stable disease). CNS lesion improvements in all 4 patients are ongoing, with durations ranging from 15+ to 28+ weeks. Twenty patients had EGFRm history (19 NSCLC, 1 SCLC); 18 had ≥1 prior EGFR TKI. Of 18 evaluable EGFRm patients, 1 patient (prior erlotinib) responded at 120mg QD (duration 26+ weeks, ongoing), 7 patients had stable disease, including 4 with T790M by history (1 ongoing at 240mg QD, duration 16+ weeks). The maximum tolerated dose has not been defined; however, based on safety, efficacy, and pharmacokinetics, the recommended phase 2 dose (RP2D) is 180mg QD. Updated data will be presented.Conclusion
AP26113 has promising anti-tumor activity in patients with ALK+ NSCLC and other ALK+ tumors, with initial evidence of activity in EGFRm patients, and is generally well tolerated. Five phase 2 cohorts are enrolling at the RP2D (180mg QD): 1) ALK inhibitor-naïve ALK+ NSCLC, 2) crizotinib-resistant ALK+ NSCLC, 3) single EGFR TKI-resistant NSCLC with documented T790M, 4) other tumors with AP26113 targets, 5) crizotinib-naïve or –resistant ALK+ NSCLC with active CNS metastases. Further phase 1 testing at 240mg QD will occur in EGFRm patients with documented T790M. NCT01449461Only 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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MO07.07 - Combined pan-ERBB and ALK/ROS1/MET inhibition with dacomitinib and crizotinib in advanced non-small cell lung cancer (NSCLC): update of a phase I trial (ID 2740)
16:15 - 17:45 | Author(s): G. Giaccone, D.R. Camidge, P.A. Jänne, B. Solomon, L.P. James, Y. Tang, J. Martini, Z. Goldberg, S..M. Shreeve, A.T. Shaw
- Abstract
- Presentation
Background
EGFR T790M mutation and MET amplification have been implicated as mechanisms of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in advanced NSCLC. We evaluated the feasibility of combining dacomitinib and crizotinib to overcome acquired resistance in patients with NSCLC whose last prior treatment was either single-agent erlotinib or gefitinib. Dacomitinib is an orally bioavailable, irreversible, small-molecule inhibitor of all kinase-active HER-family tyrosine kinases (EGFR/HER1, HER2, and HER4) with in vitro activity against T790M-mutated EGFR. Crizotinib is an ALK, ROS1, and MET TKI with demonstrated efficacy in the treatment of advanced ALK-positive and ROS1-positive NSCLC and several MET-amplified tumor types. Here we update previous data reported for PROFILE 1006 (Jänne et al, ESMO 2012; Pfizer, NCT01121575).Methods
The study comprised a 3+3 design dose-escalation phase followed by an expansion phase of two concurrent cohorts: A) combined dacomitinib plus crizotinib and B) single-agent dacomitinib until progression, followed by combined dacomitinib plus crizotinib. The study enrolled patients with advanced NSCLC who had progressed after ≥1 line of chemotherapy/targeted therapy. The expansion phase was restricted to patients with acquired resistance to single-agent erlotinib or gefitinib, which was defined as PD following either a response or SD for 6 months. Patients in the expansion phase had a mandatory tumor biopsy for biomarker analysis at study entry. Endpoints included safety, best overall objective response rate (ORR), progression-free survival, and biomarkers in tumor and blood that are potentially predictive of antitumor activity.Results
33 patients were enrolled in the dose-escalation phase of the study. Dose-limiting toxicities (DLTs) were the following grade 3 events: diarrhea (n=1), elevated ALT (n=1), and mucositis (n=1). The dacomitinib 30 mg qd plus crizotinib 200 mg bid combination showed no DLTs in 10 evaluable patients and was taken forward into the expansion phase. At the time of data cut-off on 31 December 2012, 27 patients had enrolled in the expansion phase (23 in cohort A and 4 in cohort B). Patient characteristics were as follows: M/F, 11/16; median age, 60 years (range 42–82); ECOG PS 0/1/2, 4/19/4; Caucasian/Asian, 22/5; never-smokers/ex-smokers/smokers, 18/7/2; number of prior systemic therapies 1/2/3/>3, 9/8/3/6. Nine patients (33%) in the expansion phase had started ≥4 cycles (approximately 12 weeks) of the combination. There were 20 evaluable patients in expansion cohort A, with an ORR of 5%. A further 8 patients (40%) experienced SD, and 1 of these patients had an unconfirmed PR. Tumor samples were available for biomarker analyses from 18 patients in expansion cohort A. Analyses to date revealed 1/17 patient samples had MET amplification (MET:CEP7 ratio >2); 1/5 had EGFR amplification; 7/12 harbored the EGFR T790M mutation; 1/11 displayed a KRAS mutation; 18/18 were negative for ALK rearrangement by FISH.Conclusion
The dacomitinib 30 mg qd plus crizotinib 200 mg bid combination was administered with a manageable tolerability profile and was associated with clinical activity in patients with EGFR TKI-resistant advanced NSCLC. Analysis of predictive tumor biomarkers is underway in all patients in the expansion phase.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.
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- Abstract
- Presentation
Background
To determine the frequency and predictive impact of ROS1-rearrangements on treatment outcomes in never-smoker patients with lung adenocarcinoma.Methods
We concurrently analyzed ROS1- and ALK- rearrangements and mutations in the epidermal growth factor receptor (EGFR), and KRAS in 208 never-smokers with lung adenocarcinoma. ROS1- and ALK- rearrangements were identified by fluorescent in situ hybridization.Results
Of 208 tumors screened, seven (3.4%) were ROS1-rearranged, and 15 (7.2%) were ALK-rearranged. CD74-ROS1 fusions were identified in two patients using reverse transcriptase polymerase chain reaction. The frequency of ROS1-rearrangement was 5.7% (6/105) among EGFR/KRAS/ALK-negative patients. Patients with ROS1-rearrangement had a higher objective response rate (ORR; 60.0 vs. 8.5%; P=0.01) and a longer median progression-free survival (PFS; not reached vs. 3.3 months; P=0.008) to pemetrexed than those without ROS1/ALK-rearrangement. The PFS to EGFR-TKIs in patients harboring ROS1-rearrangement was shorter than those without ROS1/ALK rearrangement (2.5 vs. 7.8 months; P=0.01).Conclusion
The frequency of ROS1-rearrangements in clinically selected patients is higher than that reported for unselected patients, suggesting that ROS1-rearrangement is a druggable target in East-Asian never-smokers with lung adenocarcinoma. Given the different treatment outcomes to conventional therapies and availability of ROS1 inhibitors, identification of ROS1-rearrangement can lead to successful treatment in ROS1-rearranged lung adenocarcinomas.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.
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MO07.09 - Feasibility and clinical impact of re-biopsy in advanced non-small cell lung cancer: a prospective multicentric study in real world setting (GFPC study 12-01) (ID 1045)
16:15 - 17:45 | Author(s): C. Dujon, C. Chouaid, P. Do, I. Monnet, A. Madroszyk, H. Le Caer, J. Auliac, H. Berard, P. Thomas, H. Lena, G. Robinet, S. Hominal, N. Baize, A. Bizieux-Thaminy, G. Fraboulet, C. Locher, J. Le Treut, A. Vergnenegre
- Abstract
- Presentation
Background
In case of progression under initial treatment, repeat biopsy is a new option procedure in advanced non-small cell lung cancer (NSCLC). Its justification is based on the assessment of biological markers (comparison to the initial status, emergence of resistance to chemotherapy or new biomarkers). The aim of this pragmatic prospective multicenter study was to assess feasibility and clinical utility of re-biopsy in real world setting in advanced NSCLC.Methods
Patient’s main inclusion criteria was advanced NSCLC with an indication of repeat biopsy by the referent clinician. The primary outcome was the percentage of successful procedures; secondary outcomes were localization of the new biopsy, type of procedure, new biological status (comparison to initial status, new biomarkers, resistance biomarkers) and tolerance of the procedure.Results
From May 2012 to May 2013, 18 centers included 102 patients. The characteristics of the 67 first patients were: male: 40%; age: 64.8 ± 10.9 years; PS 0/1: 87%; adenocarcinoma: 85%; EGFR mutated: 46.2%; no biological available assessment: 16.4%; controlled disease as best response to first line: 70%. Repeat biopsy was possible in 80.6%. The main failure reasons were: inaccessible lesion: 4.5%, medical contraindications: 14.9%. Main procedures were: bronchial endoscopy: 48.1%, trans thoracic needle biopsy: 24.1%. The procedure permits to find, in EGFR wild type population, 3 patients with a driver oncogene (1 HER2, 1 Ros1, 1 EML4 ALK); in EGFR mutated patients, 2 T790M mutations and to obtain in 3 patients with no biological data’s at the diagnosis, a biological profile. Complications were very low: 2 cases of moderate bleeding and 1 case of pneumothorax.Conclusion
Repeat biopsy is a feasible procedure with acceptable adverse events. Recommendations should be realized on the indications of re-biopsy, the timing and the recommended site (primary versus metastasis, progressive target versus no progressive). Analysis of the complete population (n=102) will be presented at the meeting. Supported by an academic grant from Boehringer Ingelheim Company and Hoffmann-La Roche Company.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.
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MO07.10 - DISCUSSANT (ID 3953)
16:15 - 17:45 | Author(s): N. Pavlakis
- Abstract
- Presentation
Abstract not provided
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MO07.11 - A randomised placebo-controlled multicentre phase II trial of erlotinib plus whole brain radiotherapy for patients with advanced non-small cell lung cancer with multiple brain metastases (TACTIC) (ID 2305)
16:15 - 17:45 | Author(s): S.M. Lee, C. Lewanski, N. Counsell, C. Ottensmeier, A.T. Bates, N. Patel, C. Wadsworth, Y. Ngai, A. Hackshaw, C. Faivre-Finn
- Abstract
- Presentation
Background
Median survival of non-small cell lung cancer (NSCLC) patients with brain metastases is poor. We examined concurrent erlotinib and whole brain radiotherapy (WBRT) followed by maintenance erlotinib in patients with untreated brain metastases, given the potential radiosensitising properties of erlotinib and its direct effect on brain metastases and systemic activity.Methods
Eighty NSCLC patients with KPS≥70 and multiple brain metastasis were randomised to placebo (n=40) or erlotinib (100mg, n=40) given concurrently with WBRT (20 Gy in 5 fractions). Following WBRT, patients continued with placebo or erlotinib (150mg) until disease progression. The primary end-point was neurological progression-free survival (nPFS).Results
Fifteen patients (37.5%) from each arm were alive and without neurological progression 2 months after WBRT. Median nPFS was 1.6 months in both arms; nPFS HR 0.95 (95% CI, 0.59-1.54; p=0.84). Median overall survival (OS) was 2.9 and 3.4 months in the placebo and erlotinib arms; HR 0.95 (95% CI, 0.58-1.55; p =0.83). The frequency of EGFR mutations was low with only 1 out of 35 (3%) patients with available samples had activating EGFR-mutations. Grade 3/4 adverse event rates were similar between the two groups (70% in each arm), except for rash 20% (erlotinib) vs. 5% (placebo), and fatigue 17% vs. 35%. No significant QoL differences were found.Conclusion
Our study showed no advantage in nPFS or OS for concurrent erlotinib and WBRT followed by maintenance erlotinib in patients with predominantly EGFR wild-type NSCLC and multiple brain metastases. Future studies should focus on the role of erlotinib with or without WBRT in patients with EGFR mutations.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.
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- Abstract
- Presentation
Background
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have shown efficacy in advanced NSCLC with brain metastases (BM). Icotinib is a new EGFR-TKI. A randomized, double blind phase III trial proved that icotinib was non-inferior to gefitinib in terms of median progression free survival (PFS) in advanced NSCLC. We have conducted a phase II study to evaluate the efficacy and safety of icotinib in combination with WBRT in Chinese NSCLC patients with BM, and investigated the cerebrospinal fluid (CSF) concentrations of icotinib. .Methods
From January 2012 to January 2013, 20 patients aged 18-75 years with Eastern Cooperative Oncology Group performance status 0-2 and BM from NSCLC,were recruited regardless of EGFR status. The treatment comprised icotinib 125mg, TID concurrently with WBRT (30Gy/10f/2w). CSF and plasma samples were collected at the same time from 10 patients at least 5 days after icotinib treatment. The concentrations of icotinib in the CSF and plasma were measured by high performance liquid chromatography coupled with tandem mass spectrometry. The primary end point was progression-free survival (PFS) determined by RECIST. Additional end points were response rate, safety and CSF concentrations of icotinib. EGFR mutation status was tested by Amplification Refractory Mutation System( ARMS)Results
The median PFS was 7.3 months [95% confidence interval (CI) 4. 2-9.8]. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease [NR versus 4.2 months (95% CI 2.9-5.1); P = 0.000]. The most prevalent site of first failure was extracranial in seven patients (70.0%）. The CNS response rates were 25% complete response (n=5), 55% partial response (n= 11), 15% stable disease (n=3), and 5% progressive disease (n =1). The overall response rate was 80% (n = 16). The most common adverse events were rash (40.0%), diarrhea (15.0%),nausea(45.0%), vomiting(20.0%), headache(35.0%), fatigue (45.0%). And no patient experienced grade ≥ 3 toxicity. The mean plasma and CSF concentrations of icotinib were 936.47 ± 503.80 and 8.93 ± 8.01ng/ml, respectively, and the mean ratio of CSF-plasma concentration was 1.04% ± 0.95.Conclusion
Icotinib was well tolerated and showed promising activity in combination with WBRT in patients with BM from NSCLC. The concentrations of icotinib in CSF were much lower than that of plasma. Further randomized trials are warranted.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.
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MO07.13 - Efficacy of afatinib vs. chemotherapy in treatment-naïve patients with non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations with or without metastatic brain disease (ID 1923)
16:15 - 17:45 | Author(s): M. Schuler, J.C. Yang, L.V. Sequist, V. Hirsh, K. O'Byrne, N. Yamamoto, D. Massey, M. Shahidi, V. Zazulina, T. Mok
- Abstract
- Presentation
Background
Afatinib, an irreversible ErbB Family Blocker, was superior to pemetrexed/cisplatin in previously untreated patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) in a global Phase III trial, LUX-Lung 3. In patients with the two most common EGFR mutations (Del19, L858R) median progression-free survival (PFS) was 13.6 vs. 6.9 months (HR=0.47, 95% CI: 0.34–0.65; p<0.0001). Here we present the results for subgroups of patients with or without brain metastases (BM) with NSCLC harbouring common EGFR mutations.Methods
In LUX-Lung 3 EGFR mutation-positive patients were randomized 2:1 to afatinib 40 mg daily or up to 6 cycles of pemetrexed/cisplatin at standard doses. Patients with stable BM (asymptomatic, stable >4 weeks with no treatment required) were allowed. Presence of BM was documented by the investigator during screening. Tumour assessments were performed every 6 weeks until 48 weeks and every 12 weeks thereafter until progression, and reviewed independently and by the investigator.Results
308 patients with common EGFR mutations were randomized (afatinib: 204, pemetrexed/cisplatin: 104), including 35 with baseline BM (afatinib: 20, pemetrexed/cisplatin: 15). Of these, Del19 mutation was detected in 11 (afatinib) and 8 (pemetrexed/cisplatin) patients and L858R in 9 (afatinib) and 7 (pemetrexed/cisplatin) patients. The baseline characteristics of patients with or without BM were comparable (females: 74% vs. 66%, median age: 61 vs. 62 years, ECOG 0: 31% vs. 41%, median time since diagnosis: 1.2 vs. 1.1 months, respectively). Within the BM group, baseline characteristics were balanced between treatment arms with the exception of ECOG 1; 80% of afatinib-treated patients had ECOG 1 compared with 53% of those treated with pemetrexed/cisplatin. Median PFS by independent review was 13.7 (afatinib) vs. 8.1 (pemetrexed/cisplatin) months in patients without BM (HR=0.47, 95% CI: 0.33–0.68; p<0.0001), and 11.1 (afatinib) vs. 5.4 (pemetrexed/cisplatin) months in patients with BM (HR=0.52, 95% CI: 0.22–1.23; p=0.13). Objective response in patients without BM was 59% (afatinib) vs. 23% (pemetrexed/cisplatin), odds ratio=4.8, p<0.0001, and 70% (afatinib) vs. 20% (pemetrexed/cisplatin), odds ratio=11.0, p=0.007, in patients with BM. Investigator review showed a median PFS of 13.6 (afatinib) vs. 6.9 (pemetrexed/cisplatin) months in patients without BM (HR=0.38, 95% CI: 0.27–0.53; p<0.0001), and 6.7 (afatinib) vs. 5.4 (pemetrexed/cisplatin) months in those with BM (HR=0.67, 95% CI: 0.29–1.57; p=0.36). By investigator review, progressive disease in the brain was observed for 4.2% (7/167) and 3.7% (3/82) of patients without BM at baseline for afatinib and pemetrexed/cisplatin, respectively. All but one of these patients (on afatinib) had intracranial progression only. The median (range) time to progression in the brain in this small group was 11.6 (1.3, 20.2) months (afatinib) and 5.5 (2.6, 8.2) months (pemetrexed/cisplatin).Conclusion
In patients with previously untreated NSCLC harbouring common EGFR mutations afatinib remains efficacious regardless of the presence or absence of BM. Control of synchronous asymptomatic BM with afatinib compares favourably with existing data for cranial radiation therapy.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.
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MO07.14 - DISCUSSANT (ID 3954)
16:15 - 17:45 | Author(s): M. Ahn
- Abstract
- Presentation
Abstract not provided
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Author of
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MO03 - Thymic Malignancies (ID 123)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:F. Detterbeck, M. Okumura
- Coordinates: 10/28/2013, 10:30 - 12:00, Bayside Gallery B, Level 1
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MO03.08 - Increased Galectin-1 Expression in a Thymic Epithelial Tumor Tissue Microarray (TMA) and Galectin-1 Knockdown Studies in a Thymoma Cell Line (ID 1238)
10:30 - 12:00 | Author(s): J.W. Riess
- Abstract
- Presentation
Background
Thymoma is a rare malignancy with a paucity of data on biology. Thymic epithelial tumors are often admixed with developing T-lymphocytes in the microenvironment. Galectin-1 (gal-1) is a beta-galactosidase binding protein involved in T-cell development via thymic stromal and thymocyte interaction as well as thymocyte development through negative selection. Gal-1 also induces apoptosis of effector T-lymphocytes, promotes angiogenesis, and is a poor prognostic indicator when overexpressed in several tumor types. To our knowledge expression of gal-1 has not been examined in thymic epithelial tumors.Methods
A TMA was constructed from 68 patients with thymic malignancies and 8 benign thymic controls at Stanford University School of Medicine (Stanford, CA). Immunohistochemical stains for galectin-1 (1:200 dilution; citrate pre-treatment; mouse monoclonal; Novocastra) were performed on 4 µM-thick TMA sections. Galectin-1 cytoplasmic staining of the epithelial cell component was scored as negative (0), focal positive (1+), or strong positive (2+) by a Stanford pathologist, who was blinded to the clinical data. Gal-1 expression was averaged for each patient sample. Statistical analysis was performed using SAS Enterprise Guide v5.0 (Cary, NC). Non-parametric statistical analyses were used to compare average patient gal-1 expression between thymic tumors and benign thymic controls. Stable gal-1 knockdown was achieved in IU-TAB1, a human thymoma WHO type AB cell line, using the pLKo.1 vector with gal-1 shRNA (Open Biosystems). Lentivirus was produced using the Trans-Lentiviral Packaging System (Thermo Scientific). In vitro proliferation cell counts were performed by hemocytometer. After hypoxia exposure (0.5% O~2~), apoptotic cells were labeled using the APO-Direct kit and quantified by flow cytometry (BD Biosciences).Results
Demographics for 68 patients: M:F (53%/47%), Mean age at diagnosis: 55 years, WHO Histology: A (10%), B (57%), AB (24%), C (4%), unclassified (4%), Pathologic Maseoka Stage: I (46%), IIa (18%), IIb (4%), III (18%), IVa (9%) IVb (6%). Gal-1 expression was increased among thymic tumor tissue compared to unpaired controls (mean avg gal-1 expression 1.5 vs. 0.125, p=0.0012, Kruskal-Wallis test). Logistic regression of tumor vs. control thymus by gal-1 generated a C-statistic of 0.845. A significant increase in gal-1 expression was noted across all WHO thymoma subtypes except thymic carcinoma (type C) (p < 0.05, non-parametric ANOVA with post-hoc ranked Dunnett’s t-test). Among 11 thymic tumors analyzed with paired adjacent resected benign thymus tissue from the same patient, a significant increase was noted in gal-1 expression among tumor compared with adjacent resected normal benign thymus (mean avg gal-1 1.82 vs. 0.35, p=0.004, sign-rank test). In vitro, gal-1 knockdown did not affect IU-TAB1 proliferation. Preliminary results showed gal-1 knockdown increased apoptosis under hypoxia compared to scramble control.Conclusion
Gal1 expression was increased among thymoma compared with benign thymus controls and paired adjacent resected benign thymus. A robust C-statistic of 0.845 indicates that gal-1 expression may discriminate tumor from benign thymus. Increased gal-1 expression was conserved across WHO histologic subtype except for thymic carcinoma—whose analysis was limited due to small sample size. Gal-1 knockdown might increase apoptosis under hypoxia. We are continuing to investigate the biologic and clinical significance of increased gal-1 expression in thymoma.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.
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P1.24 - Poster Session 1 - Clinical Care (ID 146)
- Event: WCLC 2013
- Type: Poster Session
- Track: Supportive Care
- Presentations: 1
- Moderators:
- Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P1.24-048 - Stage 1 results of a 2-stage phase II trial of single agent amrubicin in patients with previously treated thymic malignancies (ID 3175)
09:30 - 16:30 | Author(s): J.W. Riess
- Abstract
Background
There are limited treatment options for patient with advanced thymic malignancies and the utility of many of the available chemotherapies is restricted by cumulative toxicity such as neuropathy (taxanes) and cardiomyopathy (anthracyclines). We designed this study to look at single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor with minimal cardiac toxicity, in patients with advanced thymic malignancies.Methods
Eligible patients have confirmed thymic malignancy (thymoma (T) or thymic carcinoma (TC)) with progression or relapse after at least 1 prior chemotherapeutic regimen, and adequate organ function including left ventricular ejection fraction (LVEF) of >50%. The initial treatment plan consisted of amrubicin at 40 mg/m[2] IV days 1-3 repeated in 3-week cycles. The study is a Simon 2-stage design based on a null hypothesis of a true response rate <5%, with 90% power to detect a 20% true response rate and a plan to accrue 12 evaluable patients in stage 1, then if at least 1 response is seen, to add 25 additional evaluable patients in stage 2 for a total of 39 patients.Results
Enrollment was initiated in July 2011. Here, we report on the first 12 patients, all enrolled at Stanford University over a 19-month period. Of the first 12 patients enrolled, 11 were dosed. All were pre-treated (5 with prior anthracycline). There were 5 women and 7 men; age range of 30-67 years old; 6 were of Asian ethnicity, 5 were non-Hispanic White and 1 was Hispanic. After enrollment of the first 8 patients, of whom 3 were hospitalized with febrile neutropenia (FN) (38%), the study was amended to a starting dose of 35 mg/m[2] days 1-3 repeated in 3-week cycles. Other than FN in the 3 patients mentioned above, G4 thrombocytopenia in 1 patient, and treatment-related G3 fatigue in 2 patients, other toxicities were generally mild and well tolerated. No significant changes in LVEF have been noted on serial echocardiograms. Of the 11 treated patients, there were 3 partial responses (2 T and 1 TC), 7 with stable disease for at least 4 cycles, and 1 with progressive disease (PD) after 2 cycles (TC). Of the 11 treated patients, only 1 patient, with PD after C2, has stopped before completing 6 cycles, and 5 to date have tolerated >10 cycles (with others still on treatment who may receive >10 cycles), with 15 cycles as the highest number to date.Conclusion
Amrubicin, at 35 mg/m[2] IV days 1-3 on a 3-week cycle, shows promise as a single agent in pre-treated patients with thymoma and thymic carcinoma with a 27% RR in the first 11 treated patients. This exceeded the threshold for proceeding to step 2 and the study will now continue to a total of 39 patients and has expanded to other sites including Indiana University.
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P2.15 - Poster Session 2 - Thymoma (ID 191)
- Event: WCLC 2013
- Type: Poster Session
- Track: Thymoma & Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P2.15-003 - Gli1, Notch1 and CTNNB1 Expression by Automated Quantitative Immunofluorescence (AQUA) in a Thymic Malignancy Tissue Microarray (TMA) (ID 778)
09:30 - 16:30 | Author(s): J.W. Riess
- Abstract
Background
Thymoma is a rare malignancy, with a paucity of data on its biology and on the role of targeted therapeutics. Wnt, notch and sonic hedgehog pathway interactions between thymocytes and thymic stroma are important to both thymus and T-cell development. AQUAnalysis[®] is a digital image analysis software that continuously measures multiplexed protein expression and has the potential to overcome limitations of small sample sizes and tissue heterogeneity in the tumor microenvironment. We analyzed a thymoma TMA for gli1, notch1 and CTNNB1 (β-Catenin) expression by AQUA[®] as surrogate markers of activity of the sonic hedgehog, notch and wnt pathways, respectively. We hypothesized this preclinical screen may provide rationale for attacking these pathways with targeted therapeutics in thymoma.Methods
A TMA was constructed from 68 patients with thymic malignancies and 8 benign thymic controls at Stanford University School of Medicine (Stanford, CA). Gli1, notch1 and CTNNB1 expression were assayed using quantitative fluorescent immunohistochemistry at the Tom Baker Cancer Center (Alberta, Canada). The TMA was stained with anti-gli1 rabbit mAb (monoclonal antibody), clone EPR4523 (Epitomics, Burlingame, CA, USA); anti-Notch1 rabbit mAb, clone EP1238Y (Epitomics, Burlingame, CA, USA); and anti-beta-catenin mouse mAb, clone β-Catenin-1 (Dako Mississauga, ON, Canada) using a Dako autostainer. To isolate expression of these stem-cell pathway proteins separately in the tumor and the lymphocytes, the TMA was also stained with anti-pan-cytokeratin guinea pig mAb (Acris, San Diego, CA, USA); anti-vimentin rat mAb, clone 280618 (R&D Systems, Minneapolis, MN, USA); and anti-CD45 rabbit mAb, clone EP322Y (Epitomics, Burlingame, CA, USA). Automated image acquisition was performed using an Aperio Scanscope FL (Aperio Inc., Vista, CA, USA). Images were then analyzed using the AQUAnalysis® program, version 2.3.4.1. A tumor-specific mask and a tumor cytoplasmic mask were generated to distinguish thymoma cells from surrounding stromal tissue by thresholding the pan-cytokeratin images to identify pan-cytokeratin positive cells as tumor cells and define the tumor cytoplasm. Statistical analysis was performed using SAS Enterprise Guide v5.0 (Cary, NC). Two-tailed t-tests were used to compare the differences between thymic tumor and benign control tissue. ANOVA and Dunnett’s t-test was used to compare differences in gli1, notch1, and CTNNB1 expression by WHO histology.Results
Demographics for 68 patients: M:F (53%/47%), Mean age at diagnosis: 55 years, WHO Histology: A (10%), B (57%), AB (24%), C (4%), unclassified (4%), Pathologic Masaoka Stage: I (46%), IIa (18%), IIb (4%), III (18%), IVa (9%) IVb (6%). No difference in gli1 (mean 201 vs. 211, p=0.31), CTNNB1 (mean 396 vs. 418, p=0.66) or notch1 expression (mean 317 vs. 325, p=0.82) was noted between thymic tumors and controls. In a subset analysis, we found no significant differences by WHO histology compared to controls.Conclusion
AQUA® was used to help overcome limitations of analyzing protein expression in histologically heterogeneous thymic tumors with small sample sizes. We found no clinically or statistically significant increased expression of gli1, notch1, and CTNNB1 in thymoma compared to benign thymic tissue. Thus, this study provides no evidence for upregulation of the sonic hedgehog, notch or wnt pathways in thymic tumors.
