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S. Malik
Moderator of
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MINI 31 - ALK (ID 158)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 15
- Moderators:S. Malik, I. Ou
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 1a-1f
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MINI31.01 - Diverse Characteristics of ALK+ NSCLC Patients in the United States (ID 1383)
18:30 - 18:35 | Author(s): E. Bendaly, M. Sasane, J. Zhang, E. Swallow, A.R. Macalalad, D. Patel, A. Kageleiry, P. Galebach, J. Kercheval, K. Stein, A. Guerin
- Abstract
- Presentation
Background:
ALK rearrangements in non-small cell lung cancer (NSCLC) have been associated with younger age of onset, East Asian ethnicity, non- or light-smoking history, and adenocarcinoma histology. The objective of this study was to evaluate data from two retrospective multicenter chart review studies conducted in 2013 and 2014 to assess characteristics of ALK+ NSCLC patients and further understand the epidemiology of ALK rearrangements in NSCLC patients.
Methods:
This analysis included data from two chart review studies of patients diagnosed with locally-advanced or metastatic ALK+ NSCLC conducted among two separate panels of US oncologists. In the first study conducted in September and October 2013, 27 oncologists contributed data on 273 patients; in the second study conducted between July and November 2014, 49 oncologists contributed data on 153 patients. In both studies, collected information included the age at diagnosis of NSCLC, sex, ethnicity, smoking history at primary NSCLC diagnosis, and tumor histology. Data from these studies were analyzed to assess ALK+ NSCLC patient characteristics.
Results:
Patients from the 2014 cohort tended to be younger than patients from the 2013 cohort at diagnosis of locally-advanced or metastatic NSCLC (Table). In both cohorts, a little over half of the patients were male. Racial composition was diverse in both patient groups. Patients had varied smoking histories in both studies, with approximately one third of patients reported as never-smokers, one third as light smokers, and one third as moderate/heavy smokers. Tumor histology was heterogeneous in both cohorts. However, a particularly large proportion of patients in the 2014 cohort had squamous cell histology (14%).Table. Characteristics of ALK+ NSCLC Patients from the 2013 and 2014 Studies
Notes: IQR = inter-quartile range [1] Wakelee HA, Sasane M, Zhang J, et al. Description of ALK+ NSCLC patient characteristics and ALK testing patterns. J Clin Oncol 32:5s, 2014 (suppl; abstr 8062). [2] Reported at primary NSCLC diagnosis. [3] Includes patients with unreported smoking history as well as 16 former smokers in the 2014 study with unknown smoking histories.2013 Study[1] N=273 2014 Study N=153 Age (years), median (IQR) 67 (58-72) 59 (52-67) Male (%) 52% 57% Race/Ethnicity (%) Caucasian 59% 63% Black/African American 18% 14% Asian 13% 14% Hispanic/Latino 8% 2% American Indian/Alaska Native 1% 6% Unknown 0% 1% Smoking History[2] (%) Never 33% 27% Light 33% 24% Moderate/heavy 33% 37% Unknown[3] 1% 13% Cancer Histology[2] (%) Adenocarcinoma 81% 65% Squamous cell carcinoma 3% 14% Large cell carcinoma 5% 8% Mixed 11% 9% Unknown 0% 4%
Conclusion:
Assessment of patient characteristics in the two chart reviews suggests that ALK+ NSCLC patients may have diverse characteristics with varied racial composition, smoking histories, and tumor histology to an extent not previously detected. These results suggest that physicians may be testing NSCLC patients more frequently, yielding more diverse histology than expected among ALK+ tumors. Molecular testing could be informative for all newly diagnosed NSCLC patients, including patients with squamous cell histology.
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- Abstract
- Presentation
Background:
Clinical trials have shown superior efficacy of ALK inhibitors compared with chemotherapies for patients diagnosed with ALK+ non-small cell lung cancer (NSCLC). In Korea, crizotinib was approved for ALK+ NSCLC in 2011 but is not yet reimbursed. The objective of this study was to describe real-world patient characteristics, ALK testing and treatment patterns, and survival among Korean patients diagnosed with locally-advanced or metastatic ALK+ NSCLC.
Methods:
A retrospective patient chart review was conducted in two major cancer centers in Korea. Participating physicians (N=4) reviewed patient charts and reported patient characteristics, ALK testing and treatment patterns, and survival of patients diagnosed with ALK+ locally-advanced or metastatic NSCLC. ALK inhibitor treatment duration and overall survival (OS) were estimated using Kaplan-Meier analyses.
Results:
In late 2014, 55 ALK+ NSCLC patients were identified for this study. The median follow-up time among these patients was 24.8 months. The median age at locally advanced or metastatic NSCLC diagnosis was 60 years (interquartile range: 52 - 67); 53% of patients were female, 51% were never-smokers, 2% were former smokers, 33% were current smokers, 15% had unknown smoking status, and 98% were diagnosed with adenocarcinoma. At primary diagnosis, 67% of patients had metastatic disease. ALK rearrangement was confirmed by fluorescent in situ hybridization (78%) or immunohistochemistry (22%). 27% of patients had their ALK rearrangement detected more than three months after their locally-advanced or metastatic diagnosis. The majority of patients received initial systemic chemotherapy; only 13% received an ALK inhibitor in the first-line, and 62% received an ALK inhibitor by the end of follow-up. Out of 30 patients who received crizotinib, 83% discontinued (median duration of 6.3 months) and 13% died while still on crizotinib. Of those who discontinued, 32% switched to chemotherapy, 16% switched to a different ALK inhibitor, and 52% received no further antineoplastic therapy. After discontinuing crizotinib, the median OS was 4.3 months.
Conclusion:
In this study of locally-advanced or metastatic ALK+ NSCLC patients in Korea, OS was poor following discontinuation of crizotinib with a median survival of 4.3 months. Additionally, many patients had delays in receiving ALK testing. Among patients who failed crizotinib treatment, over half received no further antineoplastic therapy. These findings suggest the need to provide timely access to ALK testing and effective treatments following crizotinib discontinuation for ALK+ NSCLC patients in Korea.
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MINI31.03 - Crizotinib Outcomes in ALK-Positive Advanced NSCLC Patients with Brain Metastases (ID 1363)
18:40 - 18:45 | Author(s): K.L. Davis, J.A. Kaye, S. Iyer
- Abstract
- Presentation
Background:
Crizotinib is an oral small-molecule tyrosine kinase inhibitor, which was approved in the United States (US) in August of 2011 for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). There are currently limited data on crizotinib treatment and related outcomes in ALK-positive advanced NSCLC patients with brain metastases at diagnosis in real world settings. The main objective of the current analyses was to assess and report the response rates in the ALK-positive advanced lung cancer patients with brain metastases treated with crizotinib in regular clinical practice.
Methods:
Physicians in the US (N=107) and Canada (N=40) were recruited from cancer centers or teaching hospitals (48%) or free standing oncology clinics (47%) to abstract data retrospectively from medical records of adult (≥18 years) patients diagnosed with ALK-positive advanced NSCLC and treated with crizotinib as first- or later-line therapy from 8/1/2011-3/31/2013 (for the US) or 4/12012-3/31/2013 (for Canada) in non-clinical trial settings. IRB approval was obtained. A secure web-based form was used by physicians to abstract data and all patient data were de-identified and anonymous. Descriptive analyses were conducted to summarize objective response rate (ORR) in the subgroup with brain metastases. One-year survival rates from initiation of crizotinib were descriptively analyzed for the subgroup with brain metastases using the Kaplan-Meier method.
Results:
Data were extracted from 212 patient records in US (N=147) and Canada (N=65), which included 33 ALK-positive advanced NSCLC patients with brain metastases present prior to crizotinib initiation. The mean (SD) patient age at diagnosis for these 33 patients was 57.4 (12.0) years and a majority were male (58%), Caucasian (76%), current or former smokers (67%), ECOG status 0 or 1 (55%), adenocarcinoma histology (85%) and initially diagnosed at the locally advanced or metastatic stage (70%). The majority (71%) of these patients had been treated with either whole brain radiotherapy (16 patients) or stereotactic radiosurgery (8 patients) prior to initiation of crizotinib treatment. Of these 33 patients, 21 received crizotinib as 1[st] line therapy for advanced ALK-positive NSCLC. Approximately 61% were alive at time of medical record data abstraction. The ORR was estimated to be 61% and 60% for these patients with brain metastases who received crizotinib as 1[st] and later line treatment, respectively. The Kaplan-Meier estimates of 1-year survival from crizotinib initiation were 81% and 77% in patients with brain metastases, who received crizotinib as 1[st] line and later line treatment, respectively.
Conclusion:
In ALK-positive advanced NSCLC patients with brain metastases, complete or partial response was reported in majority of patients during treatment with crizotinib in real world settings.
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MINI31.04 - Intracranial Efficacy of First-Line Crizotinib vs. Chemotherapy in ALK-Positive NSCLC (ID 1238)
18:45 - 18:50 | Author(s): B.J. Solomon, F. Cappuzzo, E. Felip, F. Blackhall, D.B. Costa, D. Kim, K. Nakagawa, Y. Wu, T. Mekhail, J. Paolini, J. Tursi, T. Usari, K.D. Wilner, P. Selaru, T. Mok
- Abstract
- Presentation
Background:
The ongoing multicenter, randomized, open-label phase III study PROFILE 1014 recently demonstrated superior efficacy of crizotinib compared with chemotherapy in patients with previously untreated advanced ALK-positive NSCLC (Solomon et al, N Engl J Med 2014). Intracranial efficacy of crizotinib vs. chemotherapy was compared prospectively in this trial.
Methods:
Patients with previously untreated advanced non-squamous ALK-positive NSCLC (N=343) were randomized 1:1 to receive crizotinib 250 mg orally BID (n=172) or intravenous chemotherapy (pemetrexed 500 mg/m[2 ]+ cisplatin 75 mg/m[2] or carboplatin at AUC 5–6; all q3w for ≤6 cycles; n=171). Patients with treated brain metastases that were stable for ≥2 weeks with no ongoing requirement for corticosteroids were eligible. Treatment was continued until PD. Continuation of, or crossover to, crizotinib after PD (per independent radiology review [IRR]) was allowed for patients randomized to crizotinib or chemotherapy, respectively. Brain scanning was performed every 6 weeks in patients with baseline brain metastases and every 12 weeks in those without baseline brain metastases. Protocol-specified efficacy endpoints included PFS (primary endpoint), ORR, OS, and 12- and 18-month OS, as well as intracranial TTP. Intracranial DCR at 12 and 24 weeks was also evaluated. Efficacy was evaluated in the ITT population and in two subgroups of patients: those with and without baseline brain metastases.
Results:
Of 343 patients in the ITT population, 79 had brain metastases at baseline identified by IRR (23%) and 263 did not (77%; data not reported for one patient). Baseline characteristics of patients randomized to receive crizotinib or chemotherapy were generally well balanced within these two patient subgroups. Among the patients with baseline brain metastases, a significantly higher proportion achieved intracranial disease control with crizotinib than with chemotherapy at 12 weeks (33/39 [85%] vs. 18/40 [45%], respectively; P=0.0003) and at 24 weeks (22/39 [56%] vs. 10/40 [25%]; P=0.006). There was a numerical improvement in prospectively measured intracranial TTP with crizotinib in the ITT population (HR 0.60, P=0.069), as well as in patients either with baseline brain metastases (HR 0.45, P=0.063) or without baseline brain metastases (HR 0.69, P=0.323). The frequency of progression in the brain was low in the ITT population (15%) and in patients with and without baseline brain metastases (27% and 11%, respectively). Overall PFS was significantly longer with crizotinib than with chemotherapy in both subgroups (brain metastases present: HR 0.40, P=0.0007, median 9.0 vs. 4.0 months; brain metastases absent: HR 0.51, P≤0.0001, median 11.1 vs. 7.2 months), as it was in the ITT population (HR 0.45, P<0.0001, median 10.9 vs. 7.0 months). Twenty-five patients in the crizotinib arm of the study experienced intracranial PD; 22 of these patients received crizotinib for ≥3 weeks beyond PD and 19 also received intracranial radiotherapy.
Conclusion:
In this prospective assessment of intracranial efficacy, crizotinib demonstrated significantly greater intracranial disease control and overall efficacy compared with chemotherapy in patients with baseline brain metastases. These findings provide further confirmation of crizotinib as the standard of care for patients with previously untreated advanced ALK-positive NSCLC, including those patients with brain metastases at baseline.
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MINI31.05 - Discussant for MINI31.01, MINI31.02, MINI31.03, MINI31.04 (ID 3389)
18:50 - 19:00 | Author(s): A. Shaw
- Abstract
- Presentation
Abstract not provided
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MINI31.06 - Crizotinib and Interstitial Lung Disease: Systematic Review of Four Clinical Trials (ID 1580)
19:00 - 19:05 | Author(s): K.Y. Yoneda, J.R. Scranton, K.D. Wilner, N. Stollenwerk
- Abstract
- Presentation
Background:
Tyrosine kinase inhibitors (TKIs) have been associated with the development of a rare but serious and potentially fatal lung injury syndrome referred to as drug-induced interstitial lung disease (ILD). This has been best characterized for the epidermal growth factor receptor (EGFR) TKIs, with a typical presentation of delayed but rapidly progressive dyspnea leading to respiratory failure and death in up to one third of cases. While case reports of crizotinib-associated ILD have been published, little is known regarding the incidence, clinical characteristics, and mortality of crizotinib-associated ILD. In an effort to better understand this adverse event (AE), we performed a systematic review of respiratory-related events in the four largest clinical trials with crizotinib.
Methods:
An independent three-person panel composed of a pulmonologist, radiologist, and oncologist, none of whom were associated with any of the clinical studies, was convened to analyze respiratory AEs of grade ≥3 and any-grade AEs reported by the investigator as pneumonitis, ILD, or radiation pneumonitis in four crizotinib studies (PROFILE 1001, 1005, 1007, and 1014). After review by each panel member individually followed by consensus review, the events were classified either as disease progression or true respiratory AEs. Respiratory AEs were then further sub-classified as due to: 1) de novo ILD, 2) exacerbation or recurrence of pre-existing ILD, 3) concurrent illness (recurrence or progression of pre-existing condition), or 4) other toxicity not thought to be related to ILD (e.g. bacterial pneumonia).
Results:
There were a total of 1,669 patients in the four studies, among whom 446 events in 368 patients met the criteria for further analysis. Of these 446 events, 77 were attributed to progressive disease, 310 to other toxicity not thought related to ILD, 20 to de-novo ILD, 9 to concurrent illness, and 3 to exacerbation of underlying ILD. 27 cases (25 patients) were felt to have insufficient data to draw firm conclusions. Overall, the incidence of crizotinib-associated ILD was 1.2% (20/1,644) across the four studies, with no difference in incidence seen between Asian and Caucasian populations. The mean onset of ILD was 82 days. The mortality rate for patients identified with crizotinib-associated ILD was 50% (10/20). There was a trend towards improved survival if crizotinib was stopped rather than continued on presentation (64% [9/14] vs. 17% [1/6], P=0.065). Early administration of systemic corticosteroids did not seem to affect survival.
Conclusion:
This report represents the largest systematic review of TKI-associated ILD that has been performed by an independent multidisciplinary review panel. Crizotinib-associated ILD occurred in approximately 1.2% of patients who were administered crizotinib and displayed a characteristic pattern of delayed but rapidly progressive dyspnea and hypoxemia with a mortality of 50% (10/20). This pattern is similar to that seen with the EGFR TKIs, but appears to have a more delayed onset and a higher mortality rate. In contrast to EGFR TKI-associated ILD, which has a markedly higher incidence in the Asian population, there appears to be no such predilection for crizotinib-induced ILD. Immediate cessation of crizotinib may improve survival.
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- Abstract
- Presentation
Background:
Crizotinib (XALKORI [TM], Pfizer) , a tyrosine kinase inhibitor targeting ALK, ROS1 and MET, is used for the therapy of advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Cardiac toxicity is one of its adverse events which may interrupt the administration of crizotinib. Elevation of CK-MB has been reported but it remains to be determined whether the level of CK-MB can reflect cardiac toxicity of crizotinib therapy. We investigated the clinical manifestations and relevant frequency of heart-related side effects in 94 advanced ALK-rearranged NSCLC patients with treatment of crizotinib to share experiences of management of cardiac toxicity of crizotinib.
Methods:
A retrospective analysis was conducted to demonstrate the clinical manifestations as well as the corresponding frequency of cardiac toxicity in advanced ALK-rearranged NSCLC patients with treatment of crizotinib enrolled in our hospital in the past 4 years.
Results:
In the past 4 years, 95 advanced ALK-rearranged NSCLC patients were treated with crizotinib in our hospital, among which one patient dropped the treatment in 3 days due to grade 4 vomiting. In 94 eligible patients who continue the therapy more than one month, the heart-related side effects include QT interval prolongation (2/94), bradycardia (12/94), hypotension (3/94), aggravation of atrial fibrillation (1/94) and elevation of creatine kinase-MB(CK-MB) (59/94). Consequently, one of 2 patients with QT interval prolongation reduced dosage from 250 mg to 200mg twice daily for QT interval >500 ms on two electrocardiograms and then well tolerated. 12 patients with bradycardia presented asymptomatic and one patient with profound sinus bradycardia (heart rate [HR]≦45) continued crizotinib without dose reduction as she was asymptomatic and benefiting from continuous crizotinib treatment against the deadly disease. Patients with hypotension and aggravation of atrial fibrillation are tolerated and under close follow-up without dose reduction. Remarkably, we observed that majority of our patients (62.77%) experienced elevation of CK-MB and no correlation between age and CK-MB elevation (Pearson Correlation =-0.153，p=0.137).
Conclusion:
Cardiac toxicity is common during crizotinib treatment so that heart-related examinations, such as ECG as well as CK-MB, should be performed regularly especially for those with prior heart disease.
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MINI31.08 - Real-World Persistence and Adherence to Crizotinib in over 3800 US Patients (ID 835)
19:10 - 19:15 | Author(s): I. Rudychev, M. Chioda, G. Veneziano, B. Murray, R. Horblyuk
- Abstract
- Presentation
Background:
Crizotinib is an oral tyrosine kinase inhibitor that has been studied in patients with advanced ALK-positive non-small cell lung cancer and has demonstrated median therapy durations ranging from 23 weeks to 10.9 months. In the real-world setting, persistence and adherence to oral therapies may be suboptimal compared with physician-administered treatments. Little is known about crizotinib treatment experiences outside of clinical trials. The objective of this analysis was to evaluate persistence on and adherence to crizotinib using US pharmacy records.
Methods:
De-identified records from five closed-distribution US specialty pharmacies supplying crizotinib in the 50 states and US territories were analyzed. Patients with at least one record of a shipped crizotinib prescription between 8/30/2011 and 8/1/2014 were eligible. Persistence − the duration of time from initiation to discontinuation of therapy − was defined as the total number of days between the first and last prescription shipment dates plus the days' supply of the last prescription. Adherence − the extent to which a patient acts in accordance with the prescribed regimen − was evaluated using a medication possession ratio (MPR): the ratio of the total days' supply over the entire duration of therapy for patients with at least two crizotinib prescriptions. A grace period of 60 days between prescriptions was allowed. Sensitivity analyses of persistence and adherence were performed assuming grace periods between prescriptions of 30 and 90 days.
Results:
A total of 3845 crizotinib patients were identified and included in the analysis. Most were commercially insured (69%), <65 years of age (61%), and female (56%). The cohort was well balanced geographically. Most prescriptions (89%) were for doses of 250 mg BID. Average duration of therapy was 11.4 months (95% CI: 11.2−11.6), with a median of 7.5 months. 51% and 34% of patients remained on therapy at 6 and 12 months, respectively. 16% of patients remained on crizotinib >24 months (Figure 1). Figure 1 An average MPR of 95% was observed in the sub-cohort of 3072 patients with two or more prescriptions of crizotinib. Sensitivity analyses revealed that persistence (11.2−11.6 months) and adherence (93−96%) estimates were not impacted by the alternative grace-period definitions applied.
Conclusion:
In the real-world setting, the duration of crizotinib therapy was similar to that reported in clinical trials. Adherence to crizotinib was high and may be indicative of its acceptable tolerability. Further research is warranted to evaluate experiences associated with crizotinib using other real-world data sources.
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MINI31.09 - Association of Crizotinib Toxicity with Pharmacokinetics and Pharmacogenomics in Non-Small Cell Lung Cancer Harboring ALK Fusion Gene (ID 464)
19:15 - 19:20 | Author(s): Y. Tambo, K. Yamada, S. Umemura, S. Saeki, Y. Nakamura, T. Shukuya, Y. Urata, Y. Okuma, T. Fukui, Y. Kogure, H. Daga, Y. Hasegawa, Y. Tsubata, T. Yoshida, S. Oizumi, Y. Tamura, H. Mizugaki, Y. Fujiwara, A. Hamada, Y. Ohe
- Abstract
- Presentation
Background:
Crizotinib, a standard care for advanced ALK-positive NSCLC, is a substrate for ABCB1-encoded P-glycoprotein, and is primarily metabolized by CYP3A4/5. The most common adverse events (AEs) are visual disorder, gastrointestinal disorders, and elevated transaminase levels. Serious AEs such as grade (Gr) ≥ 3 elevated transaminase levels and interstitial lung disease (ILD) occasionally develop.
Methods:
ALK-positive NSCLC patients were enrolled in cohort A (enrollment before starting crizotinib therapy) or cohort B (enrollment during crizotinib therapy). Trough concentrations of crizotinib at steady state were measured using LC/MS/MS and ABCB1 polymorphisms were analyzed. We evaluated clinically significant AEs, defined as Gr 4 hematological toxicity, Gr ≥ 3 non-hematological toxicity, or any ILD. AEs during 8 weeks were also evaluated prospectively on the patients enrolled in cohort A.
Results:
A total of 78 patients at 17 institutions were enrolled. In cohort A (n = 47), AEs which occurred in more than 40% of patients during 8 weeks were ALT increased (75.0%), visual disorder (47.2%), anorexia (45.5%), nausea (45.5%), and AST increased (43.2%). In both cohorts (n = 75), 26 clinically significant AEs (n = 25) were observed: Gr ≥ 3 elevated transaminase level (14.7%), ILD (4.0%), Gr 4 neutropenia (4.0%), Gr 3 thromboembolic event (4.0%), Gr 3 esophagitis (2.6%), and Gr 3 QTc prolongation (2.6%). There was one treatment-related death (1.3%) due to ILD. Clinically significant AEs tended to occur more frequently in females than males, albeit without significance (38.4% vs. 19.2%, respectively; p = 0.09). Blood samples for trough concentrations of crizotinib at steady state were collected from 63 patients. The geometric mean of trough concentrations were 396 (95% CI, 325-483) ng/ml in male and 395 (95% CI, 329-474) ng/ml in female, respectively (p=0.569, Mann-Whitney U test). No clinical factors including gender, weight, body surface area, and age which influenced trough concentrations or AEs of crizotinib were identified. Moreover, the trough concentration of crizotinib was not significantly different between patient with clinically significant and without (429 [95% CI, 361-509] ng/ml vs. 378 [95% CI, 313-456] ng/ml, respectively [p=0.365]).
Conclusion:
In this multicenter study, we observed crizotinib AEs as previously reported. Clinically significant AEs tended to occur more frequently in females than males, albeit without significance. Furthermore, we will present the association of clinically significant AEs and trough concentration with ABCB1 polymorphism.
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MINI31.10 - Discussant for MINI31.06, MINI31.07, MINI31.08, MINI31.09 (ID 3390)
19:20 - 19:30 | Author(s): S.I. Ou
- Abstract
- Presentation
Abstract not provided
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MINI31.11 - Comparison of Different ALK Tests in Non-Small Cell Lung Cancer (NSCLC) Patients before and after Crizotinib and Their Clinical Outcome (ID 2687)
19:30 - 19:35 | Author(s): A. Van Der Wekken, N. 't Hart, T. Hiltermann, W. Timens, H. Groen, E. Schuuring
- Abstract
- Presentation
Background:
The screening algorithm for detection of ALK-rearranged NSCLC is still under investigation. The Break-Apart ALK FISH is the standard diagnostic test for the treatment with crizotinib. However, immunohistochemistry (IHC) with different antibodies shows excellent results when compared to ALK FISH. The efficacy of crizotinib is studied in relation to ALK FISH. We compared IHC outcome and the number of ALK breaks estimated by FISH with clinical outcome and retested at disease progression on crizotinib treatment
Methods:
Patients treated with crizotinib who had biopsies with sufficient tumor tissue were selected. Tumor response was assessed by CT using RECIST v1.1. Fluorescence in situ hybridization (FISH) was performed with Vysis LSI ALK Break Apart FISH Probe KIT (Abbott Molecular Inc., Des Plaines, IL) and immunohistochemistry with Ventana (Ventana Medical Systems Inc, Tucson, AZ) ALK IHC Kit using D5F3 antibody. The same tests were performed on re-biopsy material after progression on crizotinib.
Results:
Twenty-nine patients with ALK positive advanced NSCLC were treated with crizotinib. Median (range) age was 54 yrs (21-75); 26 had an adenocarcinoma, 3 had large-cell carcinoma. We confirmed the presence of EML4-ALK fusions in all samples either by FISH or IHC. Median percentage of ALK breaks was 47% (2-76). Tumor responses occurred in 9 pts having a median of 51 (6-76) breaks per tumor sample. The 20 non-responders had a median of 27 (15-64) breaks per tumor sample with 64 being an outlyer. In IHC positive pts 9/11 had a response to crizotinib treatment. In those who were IHC negative no pts (0/14) had a response (12 PD; 2 SD). Median PFS for positive IHC is 7.9 mo (95% CI., 5.5 – 10.3) and for negative IHC 1.6 mo (1.3 – 1.8), n=17, p<0.0001. Overall survival is 6.5 mo (95% CI., 0 – 17.8) and 18.3 mo (95% CI., 11.1 – 25.6) respectively, n=29, p=0.05. In 8 pts with progressive disease re-biopsies were performed. Only in one pt FISH ALK became negative. In the other pts IHC and FISH remained both positive. In pts who progressed on crizotinib, 4 pts had extra red in the FISH, which may be treatment related.
Conclusion:
All IHC positive advanced NSCLC patients responded to crizotinib. Extra red in the FISH test may cause progression to treatment with crizotinib.
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MINI31.12 - Quality of Life for Crizotinib vs. Chemotherapy in Asian ALK-Positive NSCLC Patients (ID 845)
19:35 - 19:40 | Author(s): F. Blackhall, T. Mok, M. Nishio, D. Kim, K.D. Wilner, A. Reisman, S. Iyer, B.J. Solomon
- Abstract
- Presentation
Background:
PROFILE 1014 compared the efficacy and safety of the ALK inhibitor crizotinib with platinum based chemotherapy in previously untreated advanced ALK-positive advanced NSCLC (Pfizer; NCT01154140). The primary endpoint was progression-free survival. The main objective of this post-hoc analysis was to compare patient-reported symptom and global quality of life (QOL) between crizotinib and chemotherapy in the subgroup of patients of Asian ethnicity in the ongoing study PROFILE 1014.
Methods:
Patients in the ongoing PROFILE 1014 study were randomized to crizotinib (250 mg PO bid; n= 172) or chemotherapy (pemetrexed 500 mg/m[2] + either cisplatin 75 mg/m[2] or carboplatin AUC 5–6; all IV q3w for ≤6 cycles; n= 171). Patient-reported outcomes were assessed at baseline, day 7 and day 15 of cycle 1, day 1 of subsequent 3-week cycles and end of treatment using the validated cancer specific questionnaire EORTC QLQ-C30 and its lung cancer module QLQ-LC13. Validated translations of the questionnaires in Asian languages (Japanese, Chinese, Korean etc) were made available. Higher scores (range 0−100) indicated higher symptom severity or better functioning/QOL. A positive change from baseline score indicates improvement for global QOL/functioning and deterioration in symptoms. Repeated measures mixed-effects analyses were performed to compare change from baseline scores between the treatment arms, with no adjustments made for multiple comparisons.
Results:
Of 343 patients randomized, 46% were of Asian ethnicity (crizotinib, n=77; chemotherapy, n=80). Completion rates at baseline were ≥95% in each group and scores were balanced. A statistically significantly greater overall improvement from baseline was observed with crizotinib compared with chemotherapy for global QOL (5.6 vs -7.7; p<0.001), emotional functioning (9.5 vs 2.7;p<0.05), physical functioning (5.0 vs - 2.7 p<0.001) and role functioning (3.7 vs. -7.2;p<0.001). A statistically significantly greater overall improvement was observed with crizotinib compared with chemotherapy for cough (-17.3 vs. -11.2; p<0.05), dyspnea (-9.5 vs.-1.1; p<0.001), pain in arm or shoulder (-11.4 vs.-2.2; p<0.001), pain in chest (-7.3 vs.3.3; p<0.001), pain in other parts (-11.2 vs. -0.4;p<0.001), fatigue (-9.9 vs. 3.9; p<0.001), insomnia (-10.3vs. -2.0; p<0.05), pain (-12.2 vs.-1.2; p<0.001) and appetite loss (-5.3 vs. 5.7; p<0.001). A statistically significantly greater overall deterioration was observed in the crizotinib arm for diarrhea (12.6 vs. 2.4; p<0.001) compared with chemotherapy. No statistically significant differences were observed for social functioning, sore mouth, dysphagia, nausea & vomiting, constipation and alopecia between crizotinib and chemotherapy.
Conclusion:
Consistent with previously reported results in the overall study population, treatment with crizotinib showed statistically significantly greater overall improvement in patient-reported lung cancer symptoms and global QOL compared with chemotherapy in the subgroup of patients of Asian ethnicity with previously untreated advanced ALK-positive NSCLC.
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MINI31.13 - Symptoms and QOL with Ceritinib in ALK+ NSCLC Patients with/without Brain Metastases (ID 1655)
19:40 - 19:45 | Author(s): L. Crinò, M. Ahn, F. De Marinis, H.J.M. Groen, H.A. Wakelee, T. Hida, T. Mok, A. Shaw, E. Felip, M. Nishio, G.V.V. Scagliotti, F. Branle, C. Emeremni, S. Sutradhar, M. Quadrigli, J. Zhang, D.R. Spigel
- Abstract
Background:
In the pivotal ASCEND-1 study, ceritinib, an anaplastic lymphoma kinase inhibitor (ALKi), showed clinical activity in patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC), including in patients with brain metastases (BrM). Here, patient-reported outcomes (PROs) from the recently reported ASCEND-2 study (NCT01685060) are described for chemotherapy- and ALKi-pretreated patients with ALK+ NSCLC with and without baseline BrM
Methods:
In ASCEND-2, adult patients with ALK+ NSCLC previously treated with chemotherapy and an ALKi (crizotinib) received oral ceritinib 750 mg daily. PROs were assessed at baseline and Day 1 of treatment cycles 2, 3, and every two cycles thereafter (1 cycle=28 days), using the Lung Cancer Symptom Scale (LCSS) and EORTC quality of life and lung cancer surveys (QLQ-C30 and QLQ-LC13, respectively). Data were analyzed by presence/absence of baseline BrM. Data beyond cycle 9 are not reported due to small sample sizes.
Results:
All 140 patients enrolled (median age [range] 51 [29–80] years; 50.0% male), had received ≥2 antineoplastic regimens and 100 (71.4%) had BrM at baseline. At data cutoff (13 August 2014), median follow-up was 11.3 months. PRO questionnaire compliance was at least 91.2% up to cycle 9. In the overall patient population, investigator-assessed disease control rate (DCR) was 77.1% and median duration of response (DOR) 9.7 months. Investigator-assessed whole-body DCR [95% confidence interval (CI)] in patients with and without baseline BrM was 74.0% [64.3, 82.3] and 85.0% [70.2, 94.3], respectively, while DOR [95% CI] was 9.2 [5.5, 11.1] and 10.3 [7.4, 16.6] months, respectively. Analysis of PROs data demonstrated that treatment with ceritinib improved lung cancer symptoms in patients with and without baseline BrM (Figure). QLQ-LC13 outcomes were broadly consistent with those of LCSS. In general, mean global quality of life (QLQ-C30) was maintained on treatment for both patient subgroups, with mean change from baseline in QLQ-C30 global health status ranging from -3.06 to +7.25 in patients without baseline BrM and -2.83 to +3.55 in those with baseline BrM. Figure 1
Conclusion:
In patients with ALKi-pretreated ALK+ NSCLC who received prior chemotherapy and ceritinib, clinical efficacy was demonstrated and cancer symptoms were mostly improved, with health-related quality of life generally maintained regardless of presence or absence of baseline BrM.
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MINI31.14 - PROs with Ceritinib in ALKi-Naive ALK+ NSCLC Patients with and without Brain Metastases (ID 1528)
19:45 - 19:50 | Author(s): K. Park, E. Felip, S. Orlov, C. Yu, C. Tsai, M. Nishio, M. Cobo Dols, M. McKeage, W. Su, T. Mok, G.V.V. Scagliotti, D.R. Spigel, J. Zhang, F. Branle, C. Emeremni, S. Sutradhar, M. Quadrigli, A. Shaw
- Abstract
Background:
In the pivotal ASCEND-1 study, ceritinib, an anaplastic lymphoma kinase inhibitor (ALKi), demonstrated sustained clinical activity in ALKi-naive patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC), including in patients with brain metastases (BrM). ASCEND-3 (NCT01685138) evaluated patient-reported outcomes (PROs) as well as clinical outcomes with ceritinib, in ALKi-naive ALK+ NSCLC patients with and without baseline BrM.
Methods:
Adult patients with ALK+ NSCLC previously treated with up to 3 lines of cytotoxic therapy received oral ceritinib 750 mg daily. PROs were assessed using Lung Cancer Symptom Scale (LCSS) and EORTC (QLQ-C30, QLQ-LC13) quality of life and lung cancer surveys at baseline and Day 1 of treatment cycles 2, 3, and every two cycles thereafter (1 cycle=28 days). Data were analyzed by presence/absence of baseline BrM. Data beyond cycle 9 are not reported due to small sample sizes.
Results:
Of 124 enrolled patients (median age [range] 56 [27–82] years; 40.3% male), 50 (40.3%) had BrM at baseline. At data cutoff (27 June 2014), median follow-up was 8.3 months. Up to cycle 9, PRO questionnaire compliance was at least 97.0%. In the overall patient population, investigator-assessed disease control rate (DCR) was 89.5% and median duration of response (DOR) 9.3 months. Investigator-assessed whole-body DCR [95% confidence interval (CI)] in patients with and without baseline BrM was 86.0% [73.3, 94.2] and 91.9% [83.2, 97.0], respectively, while DOR [95% CI] was 9.1 [7.5, Not Estimable] and 10.8 [9.3, 10.8] months, respectively. Mean change from baseline in patients’ total LCSS score ranged from -3.4 to -11.4 while receiving ceritinib, with 82.1% of patients experiencing symptom improvement; symptoms improved in patients with and without baseline BrM (Figure). QLQ-LC13 outcomes were broadly consistent with those of LCSS in the full patient population and in the subgroups of patients with and without baseline BrM. In general, mean global quality of life (QLQ-C30) was maintained on treatment for all patients. Patients reported diarrhea and nausea and vomiting symptoms were worse than baseline, however, nausea and vomiting symptoms did reduce over time. Figure 1
Conclusion:
In ALKi-naive patients with ALK+ NSCLC, treatment with ceritinib demonstrated clinical efficacy and improved cancer symptoms, with health-related quality of life generally maintained regardless of baseline BrM status. Improvements were greatest for the lung-related symptoms, cough and pain.
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MINI31.15 - Discussant for MINI31.11, MINI31.12, MINI31.13, MINI31.14 (ID 3391)
19:50 - 20:00 | Author(s): L. Horn
- Abstract
- Presentation
Abstract not provided
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ED 07 - How to Treat Advanced Squamous Carcinoma of the Lung (ID 7)
- Event: WCLC 2015
- Type: Education Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:B.C. Cho, P. Lara Jr.
- Coordinates: 9/08/2015, 14:15 - 15:45, Four Seasons Ballroom F1+F2
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ED07.03 - Lung Master Protocol in Squamous Cell Lung Cancer (Lung-MAP, S1400) (ID 1800)
15:00 - 15:20 | Author(s): S. Malik
- Abstract
- Presentation
Abstract:
In recent years, our understanding of non-small cell lung cancer (NSCLC) has evolved from thinking of this malignancy as a single disease, or a small number of histologic subtypes, to now a multitude of genomically-defined subsets, both in adenocarcinoma and squamous lung cancer. In development of new targeted therapies against these abnormalities, so-called Master Protocols offer a number of advantages over traditional single study designs for drug-biomarker approval, including a common infrastructure, homogeneous patient populations with consistent eligibility across multiple independent sub-studies, and the ability to screen large numbers of patients in rapid fashion. Thus, the Lung-MAP project was designed to facilitate approval of targeted therapy-predictive biomarker combinations in squamous lung cancer, a recognized area of unmet need. Lung-MAP is constructed as a unique public-private partnership engaging the National Cancer Institute (NCI) and its Thoracic Malignancies Steering Committee (TMSC), the Foundation of the NIH (FNIH), the pharmaceutical industry and advocacy groups such as Friends of Cancer Research (FOCR), along with an advisory role by the Federal Drug Administration (FDA). The design is multiple simultaneously running Phase II/III trials, each capable of independently opening and/or closing without affecting the other sub-studies, in which patients eligible for 2[nd] line therapy for lung SCC have their cancers genomically screened through a next generation sequencing (NGS) platform (Foundation Medicine). Patients are then randomized into one of several sub-studies, each comparing an experimental targeted therapy with standard of care therapy, based on identification of candidate predictive biomarkers associated with each sub-study. At launch, drug targets under study consisted of “match sub-studies” for PI3K, FGFR, CDK 4/6 and HGF, and a non-match sub-study testing PD-L1-directed therapy, as described below. Rapid turn-around time of NGS screening results, within 2 weeks, allows real time assignment into the appropriate sub-study. For those patients with cancers that do not “match” into a biomarker-driven sub-study, there is a ‘non-match” sub-study, in which a predictive biomarker is not yet of sufficient validation to utilize it in a drug-biomarker registration strategy. Due to changes in the therapeutic landscape since the launch of Lung-MAP, a number of amendments and modifications have been implemented, which will be discussed during this presentation.
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MS 28 - Future Clinical Trials (ID 46)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Other
- Presentations: 1
- Moderators:S. Mandrekar, M. Redman
- Coordinates: 9/09/2015, 14:15 - 15:45, 205+207
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MS28.02 - Master Protocols (ID 1974)
14:40 - 15:00 | Author(s): S. Malik
- Abstract
- Presentation
Abstract:
Major advances in the understanding of molecular pathways that regulate tumor growth have led to development and FDA approval of new anticancer agents leading to improved survival in patients with certain cancer types. A common cancer like Non Small Cell Lung Cancer (NSCLC) is now subdivided in a number of molecularly defined subsets. Large randomized trials are not feasible anymore. This challenge to accrue to small subsets with availability of multiple drugs for each has led to novel trial design strategies like “Master Protocols” with multiple arms that are biomarker driven. Master Protocols are ideal if multiple molecular targets are known to drive tumor growth, if there is pre-clinical/clinical evidence that these targets can be pharmacologically inhibited and if the drugs to be tested are available. These protocols provide consistency of drug development approach regardless of intended target, utilize resources (including patient resources) in an efficient manner and have potential of bringing safe and effective drugs to patients faster. On the other hand these trials are time and resource intense, and some trials with public/private partnership have added need of a high level coordination. Part of NCI precision medicine initiative has led to “Master Protocols” like Lung-MAP, ALCHEMIST and NCI-MATCH. The Lung-MAP trial is evaluating patients with squamous cell lung cancer who have progressed beyond at least one line of therapy. The study divides patients into multiple treatment arms based on the molecular profiles of their cancers testing efficacy of targeted drugs. Promising results in any arm can lead to testing the drugs in that treatment arm in more patients, with the goal of more rapid drug approvals in these small subsets of squamous cell lung cancer patients. ALCHEMIST is testing the benefits of molecularly targeted adjuvant (post-surgical) treatment of patients with early-stage lung adenocarcinomas whose tumors have either an EGFR gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement. Depending on the genetic abnormality in a tumor, the patient will be randomized to receive the EGFR protein kinase inhibitor erlotinib or the ALK protein kinase inhibitor, crizotinib against a placebo. The Food and Drug Administration (FDA) has approved these molecularly targeted therapies for advanced lung adenocarcinoma in patients with the relevant genetic changes. It is expected that most patients with early lung adenocarcinoma who are screened will not be eligible for the therapeutic portion of this trial because their tumors will not have the necessary mutations. However, the tumor samples from these patients will be saved, and, if they relapse while on standard treatment, their tumors will be biopsied again and analyzed for insight into the progression of their disease and for potential therapeutic approaches suggested by this analysis. The NCI-MATCH trial will test a large number of agents in virtually any tumor type in which appropriate abnormalities are identified. This umbrella protocol will examine between 20 and 25 drugs, including those that have been FDA-approved for the treatment of cancer at another tumor site or experimental agents that have shown activity against a known target at one or more tumor sites. If the response rate to a particular agent is high, the number of patients evaluated with that treatment would be expanded to further explore whether the targeted treatment represents a substantial advance over standard chemotherapy. If a tumor becomes resistant to the first test drug, it will be re-biopsied to see if another targeted therapy might be effective and to understand the basis for resistance to the initial treatment. By studying multiple agents at the same time, a higher proportion of patients will be eligible for the trial, and efficient progress can be made in the assessment of clinical benefit.
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