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S..M. Shreeve
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MO07 - NSCLC - Targeted Therapies II (ID 114)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 2
- Moderators:T. John, J.W. Riess
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside Auditorium B, Level 1
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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): S..M. Shreeve
- 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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MO07.07 - 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): S..M. Shreeve
- 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.
