Virtual Library

Start Your Search

I. Ou

Moderator of

  • +

    MINI 31 - ALK (ID 158)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 15
    • +

      MINI31.01 - Diverse Characteristics of ALK+ NSCLC Patients in the United States (ID 1383)

      18:30 - 20:00  |  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
      • Slides

      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
      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%
      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.

      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.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      MINI31.02 - Real-World Characteristics and Outcomes for ALK+ NSCLC in Korea (ID 535)

      18:30 - 20:00  |  Author(s): S.H. Lim, K.A. Yoh, J. Lee, M. Ahn, Y.J. Kim, S.H. Kim, J. Zhang, D. Patel, E. Swallow, A. Kageleiry, H. Yi, K. Stein, R. Degun, K. Park

      • Abstract
      • Presentation
      • Slides

      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.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      MINI31.03 - Crizotinib Outcomes in ALK-Positive Advanced NSCLC Patients with Brain Metastases (ID 1363)

      18:30 - 20:00  |  Author(s): K.L. Davis, J.A. Kaye, S. Iyer

      • Abstract
      • Presentation
      • Slides

      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.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      MINI31.04 - Intracranial Efficacy of First-Line Crizotinib vs. Chemotherapy in ALK-Positive NSCLC (ID 1238)

      18:30 - 20:00  |  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
      • Slides

      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.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      MINI31.05 - Discussant for MINI31.01, MINI31.02, MINI31.03, MINI31.04 (ID 3389)

      18:30 - 20:00  |  Author(s): A. Shaw

      • Abstract
      • Presentation

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

    • +

      MINI31.06 - Crizotinib and Interstitial Lung Disease: Systematic Review of Four Clinical Trials (ID 1580)

      18:30 - 20:00  |  Author(s): K.Y. Yoneda, J.R. Scranton, K.D. Wilner, N. Stollenwerk

      • Abstract
      • Presentation
      • Slides

      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.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      MINI31.07 - Cardiac Toxicity of Crizotinib Therapy in Advanced ALK-Rearranged Non-Small Cell Lung  Cancer (ID 2626)

      18:30 - 20:00  |  Author(s): Y. Zhang, Y. Wang, J. Li, X. Hao, D. Ma

      • Abstract
      • Presentation
      • Slides

      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.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      MINI31.08 - Real-World Persistence and Adherence to Crizotinib in over 3800 US Patients (ID 835)

      18:30 - 20:00  |  Author(s): I. Rudychev, M. Chioda, G. Veneziano, B. Murray, R. Horblyuk

      • Abstract
      • Presentation
      • Slides

      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.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      MINI31.09 - Association of Crizotinib Toxicity with Pharmacokinetics and Pharmacogenomics in Non-Small Cell Lung Cancer Harboring ALK Fusion Gene (ID 464)

      18:30 - 20:00  |  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
      • Slides

      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.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      MINI31.10 - Discussant for MINI31.06, MINI31.07, MINI31.08, MINI31.09 (ID 3390)

      18:30 - 20:00  |  Author(s): S.I. Ou

      • Abstract
      • Presentation

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

    • +

      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)

      18:30 - 20:00  |  Author(s): A. Van Der Wekken, N. 't Hart, T. Hiltermann, W. Timens, H. Groen, E. Schuuring

      • Abstract
      • Presentation
      • Slides

      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.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      MINI31.12 - Quality of Life for Crizotinib vs. Chemotherapy in Asian ALK-Positive NSCLC Patients (ID 845)

      18:30 - 20:00  |  Author(s): F. Blackhall, T. Mok, M. Nishio, D. Kim, K.D. Wilner, A. Reisman, S. Iyer, B.J. Solomon

      • Abstract
      • Presentation
      • Slides

      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.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      MINI31.13 - Symptoms and QOL with Ceritinib in ALK+ NSCLC Patients with/without Brain Metastases (ID 1655)

      18:30 - 20:00  |  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
      • Slides

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      MINI31.14 - PROs with Ceritinib in ALKi-Naive ALK+ NSCLC Patients with and without Brain Metastases (ID 1528)

      18:30 - 20:00  |  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
      • Slides

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      MINI31.15 - Discussant for MINI31.11, MINI31.12, MINI31.13, MINI31.14 (ID 3391)

      18:30 - 20:00  |  Author(s): L. Horn

      • Abstract
      • Presentation

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.



Author of

  • +

    ORAL 33 - ALK (ID 145)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
    • +

      ORAL33.03 - Updated Efficacy/Safety Data From the Phase 2 NP28761 Study of Alectinib in ALK+ NSCLC (ID 1261)

      16:45 - 18:15  |  Author(s): I. Ou

      • Abstract
      • Presentation
      • Slides

      Background:
      ALK gene rearrangements occur in approximately 3–6% of patients with non-small-cell lung cancer (NSCLC). Crizotinib has demonstrated efficacy in ALK+ NSCLC, however many patients experience systemic and/or central nervous system (CNS) disease progression within one year of treatment. Alectinib, a CNS-penetrant and highly selective ALK inhibitor, has shown preclinical activity in the CNS (Ou, et al. JTO 2013) and clinical efficacy in crizotinib-naïve (Ohe, et al. ASCO 2015) and pre-treated (Ou, et al. ASCO 2015; Gandhi, et al. ASCO 2015) ALK+ NSCLC patients. We will present updated efficacy and safety outcomes from the phase II NP28761 study (NCT01871805).

      Methods:
      North American patients ≥18 years of age with ALK+ NSCLC (by FDA-approved FISH test), disease progression following first-line crizotinib, and ECOG PS ≤2 were enrolled. Patients received oral alectinib (600mg) twice daily until progression, death or withdrawal. The primary endpoint was overall response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included investigator-assessed ORR; progression-free survival (PFS); quality of life (QoL); CNS response rate; disease control rate (DCR); and safety.

      Results:
      At data cut-off (24 October 2014), 87 patients were enrolled in the intent-to-treat population. Median age was 54 years; 74% had received prior chemotherapy; 60% of patients had baseline CNS metastases, of whom 65% (34/52) had prior brain radiation therapy. Median follow-up was 20.7 weeks. ORR by IRC was 48% (95% CI 36–60); median PFS was 6.3 months (Table 1). In patients with measurable CNS lesions at baseline (n=16), IRC CNS ORR was 69% (95% CI 41–89) and CNS DCR was 100% (complete response, 13%; partial response, 56%; stable disease, 31%). In patients with measurable or non-measurable CNS disease (n=52), IRC CNS ORR was 39% (95% CI 25–53) and 11 patients (21%) had complete CNS responses. The most common grade ≥3 AEs were elevated levels of blood creatine phosphokinase (8%), alanine aminotransferase (6%) and aspartate aminotransferase (5%); no GI toxicities leading to treatment withdrawal were reported. Clinically meaningful improvements were seen in EORTC QLQ-C30 items, including Global Health Status. Figure 1



      Conclusion:
      Alectinib (600mg twice daily) was well tolerated and demonstrated clinical efficacy in patients with ALK+ NSCLC disease who had progressed on prior crizotinib. A clinical benefit with alectinib was also observed in patients with CNS lesions at baseline. These data are preliminary; updated efficacy and safety data from a cut-off date of 27 April 2015 will be presented.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

    • +

      ORAL33.05 - Pooled Analysis of CNS Response to Alectinib in Two Studies of Pre-Treated ALK+ NSCLC (ID 1219)

      16:45 - 18:15  |  Author(s): I. Ou

      • Abstract
      • Presentation
      • Slides

      Background:
      The central nervous system (CNS) is a frequent site of progression in ALK+ NSCLC patients treated with crizotinib, thus good CNS efficacy is of crucial importance for new ALK inhibitors. Two recent phase II studies examined the efficacy and safety of alectinib in patients with ALK+ NSCLC who progressed after crizotinib; data from both studies were pooled to further examine the efficacy of alectinib in the CNS.

      Methods:
      Both phase II, single-arm, multicenter studies enrolled ALK+ NSCLC patients previously treated with crizotinib. One study was conducted in North America only (NP28761; NCT01871805), the other was global (NP28673; NCT01801111). All patients received 600mg oral alectinib twice daily. A primary endpoint of both studies was objective response rate (ORR) by independent review committee (IRC) and key secondary endpoints included CNS ORR by IRC and CNS duration of response (DOR). Response was determined according to RECIST v1.1. All patients underwent imaging at baseline to assess CNS metastases.

      Results:
      The pooled analysis population comprised 225 patients (n=87 from NP28761 and n=138 from NP28673); baseline characteristics were similar to each study population, with most patients being non-smokers, <65 years old with ECOG performance status 0/1. Median follow-up was 27.7 weeks. Fifty patients had measurable CNS disease at baseline (MD) while a further 85 had non-measurable disease (NMD) at baseline; both groups together (M+NMD) comprised 135 patients, 60% of the overall study population. In the MD group, 34 patients (68%) had received prior radiotherapy, but 24 of them had completed that radiotherapy >6 months prior to starting alectinib. For the M+NMD group, 94 patients (70%) had received prior radiotherapy, with 55 completing this >6 months prior to starting alectinib. In the MD group, 30/50 patients had a CNS response (60.0%; 95% CI 45.2–73.6%), with 7 complete responses (CR; 14.0%) and a CNS DCR of 90.0% (78.2–96.7%). In the M+NMD group, 22 additional patients had a CR (29/135; 21.5%), giving a CNS ORR of 38.5% (30.3–47.3%), with a CNS DCR of 85.2% (78.1–90.7%). Complete responses were seen in patients with and without prior radiotherapy. Median CNS DOR after only 17% of events in both groups was 7.6 months (5.8–7.6) in the MD group (n=30) and 7.6 months (5.8–10.3) in the M+NMD group (n=52), which is similar to the systemic DOR reported in both studies (Ou et al, ASCO 2015; Gandhi et al, ASCO 2015). Tolerability was also similar to the overall study population.

      Conclusion:
      Alectinib showed promising efficacy in the CNS in ALK+ NSCLC patients previously treated with crizotinib, achieving a complete response rate of 22% and a DCR of 85%, irrespective of prior radiotherapy. The CNS response was sustained for an equivalent duration to the systemic response, suggesting that alectinib could provide an effective treatment for patients with ALK+ NSCLC while actively targeting CNS metastases. The ongoing phase III clinical studies will assess the systemic and CNS efficacy of alectinib versus crizotinib as front-line therapy for ALK+ NSCLC patients.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.

  • +

    ORAL 37 - Novel Targets (ID 146)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
    • +

      ORAL37.04 - Comprehensive Genomic Profiling (CGP) of Advanced Cancers Identifies MET Exon 14 Alterations That Are Sensitive to MET Inhibitors (ID 3156)

      16:45 - 18:15  |  Author(s): I. Ou

      • Abstract
      • Presentation
      • Slides

      Background:
      Amplifications and activating mutations in the c-MET proto-oncogene are known oncogenic drivers that have proven responsive to targeted therapy. Mutations causing skipping of MET exon 14 are also oncogenic, but less well characterized. We undertook comprehensive genomic profiling (CGP) of a large series of advanced cancers to further characterize MET exon 14 alterations.

      Methods:
      DNA was extracted from 40 microns of FFPE sections from 38,028 advanced cancer cases. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of >500x using three versions of the FoundationOne test. Hybridization capture baits for the MET gene were identical for all three versions of the test. Base substitution, indel, copy number alteration, and rearrangement variant calls were examined to identify those nearby to the splice junctions of MET exon 14. These genomic alterations were then manually inspected to identify those likely to affect splicing of exon 14, or delete the exon entirely.

      Results:
      221 cases harboring MET ex14 alterations were identified. These patients had a median age of 70.5 years (range 15-88), with 97 males and 124 females. The cases were lung carcinoma (193), carcinomas of unknown primary (15), brain glioma (6), and one each of adrenal cortical carcinoma, hepatocellular carcinoma, histiocytic sarcoma, renal cell carcinoma, rhabdomyosarcoma, skin merkel cell carcinoma, and synovial sarcoma. The majority were stage IV. Identification of this alteration has lead to treatment with MET inhibitors such as crizotinib, and to durable partial responses or better exceeding 3 months in histiocytic sarcoma (1), sarcomatoid lung carcinoma (1), and nsclc (1+). Multiple patients (5+) have initiated treatment on either crizotinib or MET inhibitors in clinical development, and additional outcome data will be reported. One patient with locally advanced unresectable disease harbored a MET exon 14 skipping alteration. On initiation with treatment with an MET inhibitor, symptomatic relief was observed in 3 days, radiographic response was observed at two weeks, and resection was performed 8 weeks after initiation of the MET inhibitor.

      Conclusion:
      MET exon 14 alterations define a hereto unrecognized population of advanced cancer cases, particularly in NSCLC. Multiple case reports demonstrate that these alterations confer sensitivity to multiple small molecule MET inhibitors. This finding expands the population of advanced NSCLC patients who can derive benefit from MET-targeted therapies.

      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.

      Only Active 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 or select "Add to Cart" and proceed to checkout.