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B.J. Solomon



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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO07.02 - Clinical experience with crizotinib in patients with advanced <em>ALK</em>-rearranged non-small cell lung cancer and brain metastases in PROFILE 1005 and PROFILE 1007 (ID 2932)

      16:15 - 17:45  |  Author(s): B.J. Solomon

      • Abstract
      • Presentation
      • Slides

      Background
      Crizotinib is an oral tyrosine kinase inhibitor targeting ALK and is approved multinationally for the treatment of advanced ALK-rearranged non-small cell lung cancer (NSCLC) due to its efficacy in controlling systemic tumor burden. The clinical effects of crizotinib in patients with brain metastases have not been previously studied in detail. To evaluate the clinical outcomes of patients with brain metastases on crizotinib, we conducted a retrospective analysis of pooled data from PROFILE 1005 (NCT00932451; a large ongoing global open-label, single-arm phase II study of crizotinib in patients with ALK-rearranged NSCLC who have received one or more treatment regimen for advanced/metastatic disease) and PROFILE 1007 (NCT00932893; an ongoing global randomized phase III study that compared crizotinib with standard second-line chemotherapy [docetaxel or pemetrexed] for advanced ALK-rearranged NSCLC; Shaw et al, N Engl J Med 2013). Subgroup analysis in PROFILE1007 showed that progression-free survival was longer with crizotinib than with chemotherapy for both patients with brain metastases (HR 0.67) and patients without brain metastases (HR 0.43) at baseline.

      Methods
      Patients with previously treated (but ALK-inhibitor-naïve) advanced ALK-rearranged NSCLC enrolled in either PROFILE 1005 or PROFILE 1007 (and randomized to crizotinib) were included in this analysis. Patients with asymptomatic brain metastases were eligible for both studies. The starting dose of crizotinib was 250 mg twice daily. Tumor assessments were evaluated by investigators based on RECIST. Baseline brain imaging (with either computed tomography or magnetic resonance imaging) was required in both studies, and if brain metastases were detected, subsequent brain imaging was required at 6-week intervals. Otherwise, imaging to assess brain metastases on treatment was performed as clinically indicated. Brain metastases were monitored as non-target or target lesions.

      Results
      A total of 275 patients, 31% of 888 patients included in this retrospective analysis, had asymptomatic brain metastases at baseline. Of the 888 patients included, 109 patients (12%) had no prior radiotherapy and 166 patients (19%) had prior radiotherapy for their brain metastases. Among the 109 patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR; % complete responses + partial responses + stable disease) at 12 weeks was 63%, with a systemic objective response rate (ORR) of 53%, and the intracranial DCR at 12 weeks was 56%, with an intracranial ORR of 7%. Among the 166 patients with previously treated brain metastases, the systemic DCR at 12 weeks was 65%, with a systemic ORR of 46%, and the intracranial DCR at 12 weeks was 62% weeks, with an intracranial ORR of 7%. Additional data, including outcomes for patients without brain metastases at baseline, will be presented.

      Conclusion
      In this large retrospective analysis, crizotinib was associated with an initial intracranial DCR of approximately 60% at 12 weeks in patients who were ALK-inhibitor-naïve and had untreated or previously treated brain metastases identified prior to initiation of therapy. Prospective studies may help to determine if crizotinib can delay the natural occurrence or progression of brain metastases in advanced ALK-positive NSCLC.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-041 - Effect of treatment duration on incidence of adverse events (AEs) in a phase III study of crizotinib versus chemotherapy in advanced <em>ALK</em>-positive non-small cell lung cancer (NSCLC) (ID 2900)

      09:30 - 16:30  |  Author(s): B.J. Solomon

      • Abstract

      Background
      In the ongoing global randomized phase III study PROFILE 1007, the oral ALK inhibitor crizotinib improved progression-free survival, response rate, and global quality of life compared with single-agent chemotherapy in patients with advanced, previously treated ALK-positive NSCLC. While hematologic toxicities were more common with chemotherapy, a greater number of non-hematologic toxicities were reported with crizotinib. Several factors may have complicated the comparison of AEs, including longer treatment duration with crizotinib, standard use of prophylactic medications with chemotherapy but not with crizotinib, and a higher rate of continuing treatment beyond RECIST-defined progressive disease with crizotinib. Here we examine whether differences in treatment duration may have impacted the incidences of selected AEs and non-fatal serious AEs (SAEs) observed in this study.

      Methods
      In PROFILE 1007, 172 patients received crizotinib 250 mg orally BID and 171 patients received chemotherapy (pemetrexed 500 mg/m[2] or docetaxel 75 mg/m[2], both IV q3w). AEs were classified and graded using CTCAE v4.0. For this analysis, AEs of interest included those occurring in ≥10% of patients with ≥5% absolute difference between treatment groups, as well as non-fatal SAEs. To evaluate the potential impact of differential treatment duration on these AEs, exposure-adjusted incidence rates were calculated using person-years of exposure (PYE; the sum of the individual person-years at risk for a particular AE).

      Results
      Median treatment duration was almost three-fold longer with crizotinib (31 weeks) versus chemotherapy (12 weeks). Incidences and exposure-adjusted incidence rates of AEs of interest are shown in the table below. After accounting for treatment duration, the rates of nausea, constipation, elevated transaminases, edema, upper respiratory infection, dizziness, pulmonary embolism, hypokalemia, and non-fatal SAEs were comparable between the crizotinib and chemotherapy groups. The rates of diarrhea, vision disorder, vomiting, dysgeusia, and syncope were significantly higher with crizotinib. Exposure-adjusted incidence rates for other AEs, as well as additional analyses to account for treatment duration will be presented.

      Crizotinib (n=172) Chemotherapy (n=171)
      AE Incidence (%) Incidence rate/1000 PYE Incidence (%) Incidence rate/1000 PYE P value[a]
      Diarrhea 60 1848 19 592 <0.0001
      Vision disorder[b] 60 2449 9 268 <0.0001
      Nausea 55 1577 37 1527 0.842
      Vomiting 47 1083 18 561 0.001
      Constipation 42 832 23 789 0.789
      Elevated transaminases[b] 38 716 15 470 0.056
      Edema[b] 31 568 16 473 0.430
      Dysgeusia 26 463 9 269 0.045
      Upper respiratory infection[b] 26 419 13 401 0.865
      Dizziness[b] 22 346 8 236 0.195
      Pulmonary embolism[b] 6 78 2 62 0.686
      Hypokalemia 5 70 2 63 0.846
      Syncope 3 39 0 0 0.025
      Non-fatal SAEs 29 440 21 640 0.105
      [a]For differences in incidence rates, two‑sided.[b]Clustered term.

      Conclusion
      This initial analysis suggests that differences in treatment duration between two drugs may have a significant impact when comparing AE profiles. Depending on the safety profiles of the two drugs, analyses to account for treatment duration may be appropriate when a large disparity has been observed.