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G.J. Riely
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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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MO07.01 - 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): G.J. Riely
- 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): G.J. Riely
- 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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MO13 - SCLC I (ID 118)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:C.K. Liam, E.S. Santos
- Coordinates: 10/29/2013, 10:30 - 12:00, Bayside 201 - 203, Level 2
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MO13.10 - Prospective Molecular Evaluation of Small Cell Lung Cancer (SCLC) Utilizing the Comprehensive Mutation Analysis Program at Memorial Sloan-Kettering Cancer Center (MSKCC) (ID 3137)
10:30 - 12:00 | Author(s): G.J. Riely
- Abstract
- Presentation
Background
Oncogenic events in adenocarcinoma and squamous cell cancers of the lung are well described. In contrast, the repertoire of possible molecular targets in SCLC still is unclear. Recent studies using next generation sequencing on rare resected SCLC specimens have provided insights into the molecular heterogeneity of this disease. Comprehensive, prospective molecular profiling of patients with SCLC using the biopsy specimens available in clinical practice has not been performed.Methods
Utilizing an IRB-approved protocol to prospectively test SCLC tumors (Small Cell Lung Cancer Mutation Analysis Program, “SCLC-MAP”), these biopsies are evaluated by: FISH for FGFR1 and MET amplification; immunohistochemistry (IHC) for MGMT and PTEN loss; point mutation genotyping with Sequenom for PIK3CA (and others); and next-generation sequencing with our MSK-IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets). MSK-IMPACT uses exon capture followed by massively parallel sequencing to profile all protein-coding exons and select introns of 279 cancer-associated genes, enabling the identification of mutations, indels, and copy number alterations of these genes. First, we tested the feasibility of this approach in a series of SCLC patients that were identified retrospectively as they had banked matched tumor and normal pairs. We performed next generation sequencing with MSK-IMPACT, with findings confirmed by FISH on these samples. We are prospectively collecting and evaluating SCLC tumors of our patients in active treatment, as detailed above.Results
For our feasibility cohort, we identified 21 patients with SCLC with FFPE samples available from both matched normal tissue and small tumor biopsies. After histologic review and DNA extraction, 10 patients had adequate tissue for MSK-IMPACT (3 core biopsies, 7 fine needle aspirates). The following were noted: recurrent mutations in Rb1 (N=7) and p53 (N=8), FGFR1 amplification (N=2), and MET amplification (N=1), using as little as 15 nanograms of DNA. FGFR1 and MET amplification were confirmed by FISH testing. We have initiated this prospective SCLC-MAP program for our SCLC patients undergoing active treatment. Since 2/2013, 25 patients have provided consent and tumor tissue for analysis (8 surgical resections, 12 core biopsies, 3 lymph node dissections, 2 fine needle aspirates). Preliminary data are available for 16 patients: AKT1 E17 mutation by Sequenom (N=1), MGMT loss by IHC (N=1); and PTEN loss by IHC (N=2).Conclusion
As adequate biopsy specimens are necessary to match lung cancer patients and treatments, increased number of patients with SCLC are presenting with more tissue. Comprehensive molecular evaluation of SCLC is feasible on clinically available specimens, as seen in our feasibility cohort. Prospective collection of SCLC tumor samples and mutational analyses are ongoing. Such analyses will allow us to characterize the molecular diversity of this disease and identify patients who will be candidates for targeted therapies. Funded, in part, by the Lung Cancer Research Foundation.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.
