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D. Kim



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    MO07 - NSCLC - Targeted Therapies II (ID 114)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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      MO07.01 - Clinical benefit of continuing crizotinib beyond initial disease progression in patients with advanced <em>ALK</em>-positive non-small-cell lung cancer (ID 2843)

      16:15 - 16:20  |  Author(s): D. Kim

      • Abstract
      • Presentation
      • Slides

      Background
      Crizotinib is approved multinationally to treat advanced ALK-positive non-small-cell lung cancer (NSCLC). Most patients with crizotinib-treated ALK-positive NSCLC ultimately develop progressive disease (PD). We investigated whether continuing ALK inhibition beyond PD is clinically beneficial and the clinicopathologic characteristics associated with patients who experience clinical benefit.

      Methods
      Patients with advanced ALK-positive NSCLC enrolled in two ongoing multicenter, single-arm trials (the molecularly enriched expansion cohort of the phase I trial PROFILE 1001 and the phase II trial PROFILE 1005) who developed RECIST-defined PD were allowed to continue crizotinib if, in the investigator's opinion, they were deriving ongoing clinical benefit. In the present retrospective analyses, continuation of crizotinib beyond PD (CBPD) was defined as >3 weeks of crizotinib treatment after PD documentation. Baseline and post-progression characteristics, sites of PD, progression-free survival (PFS), and overall survival (OS) were compared in patients who continued CBPD versus those who did not. The impact of continuing CBPD on OS after adjusting for potential confounding factors was assessed.

      Results
      Among 194 crizotinib-treated patients with RECIST-defined PD, 120 (62%) continued CBPD. A higher proportion of patients who continued CBPD responded to initial crizotinib treatment (74% vs. 55%), had an ECOG performance status of 0/1 at PD (96% vs. 82%), and had brain (56% vs. 28%) and/or bone (20% vs. 9%) as sites of PD compared with patients who did not continue CBPD. CBPD patients also had numerically longer median PFS from initial crizotinib treatment (7.3 months vs. 5.7 months) and significantly longer OS from the time of PD (median 16.4 months vs. 3.9 months; HR, 0.27; 95% CI: 0.17−0.42; P<0.0001; Figure 1). Multiple-covariate Cox regression analysis revealed that CBPD remained significantly associated with improved OS post-PD after adjusting for relevant factors. Figure 1. OS of patients who continued CBPD versus those who did not, from the time of PD. Shaded areas are 95% Hall-Wellner confidence bands. Figure 1

      Conclusion
      Continuing ALK inhibition after PD may provide survival benefit to a majority of patients with advanced ALK-positive NSCLC. Prolonged PFS on initial crizotinib, good performance status at PD, and progression in brain and/or bone are characteristics that were commonly found in patients who benefited from continued ALK inhibition.

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      MO07.03 - Crizotinib therapy for patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC) (ID 2777)

      16:25 - 16:30  |  Author(s): D. Kim

      • Abstract
      • Presentation
      • Slides

      Background
      Rearrangements of the ROS1 receptor tyrosine kinase gene identify a subset of NSCLC sensitive to the small-molecule ALK and MET inhibitor crizotinib, approved multinationally for the treatment of advanced ALK-positive NSCLC. Here we present updated efficacy and safety data for crizotinib in an expanded cohort of patients with advanced ROS1-rearranged NSCLC.

      Methods
      ROS1 status was determined by break-apart FISH assays, and patients were enrolled into an expansion cohort of an ongoing phase I crizotinib study (PROFILE 1001; NCT00585195, Pfizer). Where available, samples were also tested for concurrent ALK rearrangement and MET amplification. Patients received crizotinib 250 mg BID, and responses were assessed using RECIST v1.0.

      Results
      At the data cut-off, 35 of 40 patients with ROS1-positive NSCLC were evaluable for response. Median age was 51 years (range 31–77), 80% of patients were never-smokers, and 98% had adenocarcinoma histology; 40% had received one prior regimen, and 45% had received 2–6 regimens for advanced/metastatic disease. 25 samples tested for concurrent ALK rearrangement (24 by FISH and 1 by PCR) and 12 samples tested for concurrent MET amplification (11 by FISH and 1 method not recorded) were all negative. The objective response rate (ORR) was 60% (95% CI: 42–76), with 2 complete responses, 19 partial responses, and 10 cases of stable disease. Median progression-free survival (PFS) had not been reached, with 25 patients (63%) still in follow-up for PFS; six patients (15%) experienced disease progression, and two (5%) died before progression occurred; 6-month PFS probability was 76% (95% CI: 55–88). The disease-control rate was 80% at 8 weeks and 66% at 16 weeks. The most common treatment-related adverse events (AEs) were visual impairment (80%), diarrhea (35%), and nausea (30%), with most patients (68%) reporting only AEs of grade 1 or 2 severity. Peripheral edema (28%) and elevated transaminases (18% AST, 15% ALT) were also reported, similar to previous experience with crizotinib. There were no treatment-related serious AEs and one patient discontinued treatment due to treatment-related nausea. Accrual of patients with ROS1-positive NSCLC is ongoing.

      Conclusion
      Similar to results obtained in ALK-positive NSCLC, crizotinib had marked antitumor activity with a high ORR (60%) in patients with ROS1-positive NSCLC, with a generally tolerable and manageable AE profile. These data suggest that crizotinib is an effective therapy for patients with advanced ROS1-positive NSCLC.

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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.12 - AZD9291: an irreversible, potent and selective tyrosine kinase inhibitor (TKI) of activating (EGFRm+) and resistance (T790M) mutations in advanced NSCLC (ID 2289)

      11:30 - 11:35  |  Author(s): D. Kim

      • Abstract
      • Presentation
      • Slides

      Background
      The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced EGFR mutant NSCLC but many patients ultimately develop disease progression due to acquired resistance. The EGFR T790M mutation is the most common mechanism of acquired drug resistance, detected in more than 50% of gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for NSCLC patients with EGFR T790M.

      Methods
      AZD9291 is an oral, irreversible, third generation inhibitor of both EGFR activating (EGFRm+) and resistance mutations (T790M). The mechanistic and functional activity of AZD9291 was characterised in vitro across a number of cell lines harbouring various EGFR-mutations or wild type EGFR. Efficacy of AZD9291 was further evaluated across a number of different EGFR-mutant xenograft and transgenic models in vivo. One open label, dose escalation phase I study of AZD9291 (NCT01802632) is ongoing to determine the safety and tolerability [primary measure], pharmacokinetics and preliminary efficacy profiles of AZD9291, in patients with advanced NSCLC who have progressed following EGFR TKI. Sequential cohorts of 3-6 patients with advanced NSCLC who have had at least one prior regimen containing an EGFR TKI agent (with confirmed EGFRm+ status or Jackman criteria), were treated with AZD9291 once daily. Other key inclusion criteria were PS 0-1, measurable disease, and no prior history of ILD. RECIST assessments were scheduled 6 weekly. Dose escalation can occur after ≥ 3 patients complete both single dose and the first 21-day cycle of AZD9291 multiple dosing with no DLT.

      Results
      AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (PC9; 14nM) and EGFRm+/T790M (H1975; 13nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (LoVo; 400nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 treatment caused profound growth regression across multiple EGFRm+ (PC9; 250% growth inhibition) and EGFRm+/T790M (H1975; 132% growth inhibition) tumour models in vivo, at doses as low as 5mg/kg after 14 days. Tumour growth inhibition was associated with profound inhibition of EGFR activity and key downstream signaling pathways. Chronic long-term treatment of in vivo PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response. In the phase I study, clinical activity with RECIST responses have already been observed at the starting dose level of 20mg once daily, with good tolerability, no reported events of EGFR wild-type rash, and only grade 1 diarrhoea (based on preliminary data, unvalidated and subject to change).

      Conclusion
      Preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance mutations (T790M) whilst sparing wild-type EGFR and, early clinical data have been promising. Taken together, these data support the further clinical investigation of AZD9291 in advanced EGFR mutant NSCLC.

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    O16 - NSCLC - Targeted Therapies III (ID 115)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O16.05 - Efficacy, safety, and patient-reported outcomes (PROs) with crizotinib versus chemotherapy in Asian patients in a phase III study of previously treated advanced <em>ALK</em>-positive non-small cell lung cancer (NSCLC) (ID 2818)

      11:15 - 11:25  |  Author(s): D. Kim

      • Abstract
      • Presentation
      • Slides

      Background
      Crizotinib is a potent selective ATP-competitive ALK inhibitor demonstrating a high ORR in patients with advanced ALK-positive NSCLC. The main objective of the present post hoc analyses was to compare the impact of crizotinib on efficacy, safety, and PROs with that of standard second-line chemotherapy in a subgroup of patients of Asian ethnicity from the ongoing phase III study PROFILE 1007.

      Methods
      Patients with stage IIIB/IV ALK-positive NSCLC who had received one prior platinum-based regimen were randomized to open-label crizotinib (250 mg PO BID) or chemotherapy (pemetrexed 500 mg/m[2] or docetaxel 75 mg/m[2], IV q3w). In these subgroup analyses, PFS and ORR based on independent radiologic review, OS, safety, and PROs were evaluated. PROs were assessed at baseline, on day 1 of each cycle, and at end of treatment using the validated cancer-specific questionnaire EORTC QLQ-C30 and its LC module QLQ-LC13. Time to deterioration (TTD) was defined as the time from randomization to the earliest time with a ≥10-point increase from baseline (worsening) in pain in chest, dyspnea, or cough. Repeated measures mixed-effects analyses were performed to compare change from baseline scores between the treatment arms.

      Results
      Of 347 patients randomized, 45% were of Asian ethnicity (crizotinib, n=79; chemotherapy, n=78 [pemetrexed, 50; docetaxel, 27; no treatment, 1]). At data cutoff (March 2012), 52 Asian patients (crizotinib, 41; chemotherapy, 11) were continuing on treatment. PFS was significantly longer with crizotinib than with chemotherapy (median 8.1 vs. 2.8 months; HR, 0.53; P=0003). The ORR on crizotinib (75%) was significantly higher than on chemotherapy (22%; P<0.0001). In an interim analysis, median OS had not yet been reached in the crizotinib arm and was 22.8 months in the chemotherapy arm (HR, 0.89; P=0.347, noting that in the overall study population, only 40% of planned events had occurred and 64% of patients in the chemotherapy arm subsequently received crizotinib in another study). The most common all-causality AEs with crizotinib were diarrhea (70%), vision disorder (68%), and nausea (66%) and with chemotherapy were decreased appetite (40%), nausea (39%), and fatigue (35%). Crizotinib treatment was associated with a significantly longer TTD in LC symptoms compared with chemotherapy (median 4.2 vs. 1.6 months; HR, 0.66; 95% CI, 0.44−0.98; P=0.037). A significantly greater improvement from baseline was observed with crizotinib for global QOL (P<0.05), cough (P<0.001), dyspnea (P<0.001), pain in arm or shoulder (P<0.001), pain in chest (P<0.001), pain in other parts (P<0.05), fatigue (P<0.05), insomnia (P<0.05), and pain (P<0.001). A significantly greater improvement was observed with crizotinib compared with chemotherapy for emotional functioning (P<0.05), physical functioning (P<0.05), hair loss (P<0.001), and sore mouth (P<0.05). A significantly greater deterioration was observed in the crizotinib arm for constipation (P<0.05) and diarrhea (P<0.001) compared with chemotherapy.

      Conclusion
      Consistent with previously reported results in the overall study population, crizotinib treatment showed significantly greater improvement in PFS, ORR, patient-reported LC symptoms, and global QOL compared with chemotherapy in a subgroup of patients of Asian ethnicity with previously treated advanced ALK-positive NSCLC, confirming the utility of crizotinib in this patient population.

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    O21 - SCLC II (ID 119)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O21.02 - Phase III trial comparing irinotecan plus cisplatin (IP) with etoposide plus cisplatin (EP) in Korean patients with extensive disease (ED) small cell lung cancer (SCLC) (ID 2937)

      16:25 - 16:35  |  Author(s): D. Kim

      • Abstract
      • Presentation
      • Slides

      Background
      IP showed superior survival outcomes compared with EP in Japanese patients. However, IP failed to show the superiority in subsequent studies in Western population. We conducted a multi-center randomized controlled trial to determine whether IP regimen is superior to EP regimen in Korean patients (ClinicalTrials.gov Identifier: NCT00349492)

      Methods
      Patients were randomly assigned (simple randomization, stratified by ECOG performance status and center) to IP (irinotecan 65 mg/m2 IV on D1&8 plus cisplatin 70 mg/m2 IV on D1, every 3 weeks) or EP (etoposide 100 mg/m2 IV on D1-3 plus cisplatin 70 mg/m2 IV on D1, every 3 weeks) for maximum 6 cycles, until disease progression, or until unacceptable toxicity occurred. The primary objective was to compare overall survival (OS).

      Results
      A total of 362 patients were randomized to IP (N=173) and EP (N=189) arms. Median OS was 10.9 and 10.3 months (m) for IP and EP, respectively (hazard ratio for death in the IP group, 0.879; 95% one-sided confidence interval, 0 to 1.054; P=0.1207). Objective response rate was higher with IP than with EP (62.4%, 48.2%, P=0.0064), however, there was no significant difference in median progression free survival between IP and EP (6.5 and 5.8 m, P=0.1158). In the pre-planned subgroup analyses, IP was associated with longer OS than with EP in male (11.3 vs 10.1 m, P=0.0361), <65 years old (12.7 vs 11.3 m, P=0.0240), ECOG performance status 0/1 (12.4 vs 10.9 m, P=0.0407) patients group. Grade 3/4 anemia, nausea and diarrhea were more frequent in patients treated with IP. There was no difference in the frequency of grade 3/4 neutropenia, thrombocytopenia, neutropenic fever, infection between both arms.

      Conclusion
      IP failed to show superiority in overall survival compared to EP in Korean patients with ED SCLC. However, prolongation of OS was observed with IP in pre-defined subgroup of patients with male gender, young age, or good performance status.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-027 - Phase I studies of HM781-36B, an irreversible pan-HER tyrosine kinase inhibitor (TKI) in patients with advanced solid tumor and the therapeutic potential in patients with advanced non-small cell lung cancer (NSCLC) (ID 2029)

      09:30 - 09:30  |  Author(s): D. Kim

      • Abstract

      Background
      HM781-36B is an irreversible pan-HER TKI, which showed a strong anticancer activity in many cell lines, including epidermal growth factor receptor (EGFR) TKI resistant ones in preclinical studies. Two phase I studies were conducted to determine the maximum tolerated dose (MTD) in patients with advanced solid tumor.

      Methods
      Patients with advanced malignancies refractory to standard therapies were eligible. Standard 3+3 dose escalation scheme was used in two phase I studies; a 2-weeks on / 1-week off schedule and a continuous dosing schedule.

      Results
      A total of 75 patients were enrolled; 55 patients in the 2-weeks on / 1-week off schedule and 20 patients in the continuous dosing schedule. 27 NSCLC patients were enrolled. Among 25 evaluable NSCLC patients, 3 patients achieved partial response (PR) and 10 patients had stable disease (SD). All 3 patients who achieved PR were previously treated with gefitinib, and one of them harbored EGFR T790M mutation. In addition, two of them had been treated with 4 or more regimens. Among 10 SD patients, 5 patients showed some degree of tumor shrinkage. Dose -limiting toxicity (DLT) was grade 3 diarrhea. The MTD was determined as 24 mg/day in the 2-weeks on / 1-week off schedule and 18 mg/day in the continuous dosing schedule. The recommended phase II dose was 16 mg/day (continuous) on the basis of toxicity, pharmacokinetic and pharmacodynamic profiles. Two phase II studies of HM781-36B are ongoing in NSCLC patients with previously EGFR TKI treated and EGFR TKI naive, respectively.

      Conclusion
      HM781-36B showed good safety profile and anticancer activity in NSCLC patients in two phase I studies. Effectiveness in the gefitinib refractory and heavily pretreated patients supported the potential of HM781-36B as a therapeutic agent for 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: 3
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      P2.11-010 - Phase I study of HM61713, a novel epidermal growth factor receptor (EGFR) mutant selective inhibitor, in non-small cell lung cancer (NSCLC) patients having an activating EGFR mutation but failed to prior EGFR tyrosine kinase inhibitor (TKI) therapy. (ID 1048)

      09:30 - 09:30  |  Author(s): D. Kim

      • Abstract

      Background
      NSCLC patients having an activating EGFR mutation initially responded well to EGFR TKI but most of them experienced progressive disease due to various resistance mechanisms including T790M (~50% of cases) mutation. HM61713 is an orally active, novel EGFR mutant selective inhibitor showing a strong anticancer activity in many lung cancer cell lines including T790M mutation harboring cell line. Therefore, HM61713 might provide the potential clinical benefit to those who have an activating EGFR mutation but have failed previous EGFR TKI treatment.

      Methods
      This is a phase I study using a standard 3+3 dose escalation scheme. NSCLC Patients with activating EGFR mutation and progressed after at least 2 prior chemotherapy regimens including EGFR TKI were eligible. The objective of this study is to determine the recommended phase II dose as well as to assess the preliminarily efficacy.

      Results
      To date, a total of 23 patients were treated with at doses of 75-250 mg/day. One patient at a dose of 200 mg/day experienced grade 3 drug induced idiosyncrasy and grade 4 elevation of amylase. The drug induced idiosyncrasy was skin rash of non-EGFR TKI type. The most common drug-related adverse events were desquamation, diarrhea, pruritus, and nausea; most were grade 1 or 2. The maximum tolerated dose (MTD) and recommended phase II dose were not determined yet. Plasma concentration of HM61713 reached the peak 2-4 hr after administration and declined with the half-life of 8-12 hr. Among 21 evaluable patients, 2 patients achieved partial response (PR) and one of them had confirmed T790M mutation while 12 patients had stable disease (SD) including 11 patients showed tumor shrinkage. Accrual to this study is ongoing and updated data will be presented at the meeting.

      Conclusion
      HM61713 showed good safety profile and promising anticancer activity in NSCLC patients with EGFR mutation who failed to prior EGFR TKI therapy. These results support the therapeutic potential of HM61713 for NSCLC patients with activating EGFR mutations after development of resistance to EGFR TKI therapy.

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      P2.11-032 - Patient Report of Dacomitinib (PF-00299804)-Associated Symptom and HRQoL Benefit in Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2293)

      09:30 - 09:30  |  Author(s): D. Kim

      • Abstract

      Background
      Decreasing tumor burden may reduce/delay cancer-related symptoms experienced by patients with NSCLC and favorably impact global health-related quality of life (HRQoL). Dacomitinib is an irreversible small-molecule inhibitor of all catalytically active members of the human epidermal growth factor receptor (HER) family of tyrosine kinases (EGFR/HER1, HER2, and HER4), and has shown anticancer activity and manageable toxicity in NSCLC clinical trials [Janne et al 2009; Park et al 2010; Ramalingam et al 2012; Mok et al 2012]. Qualitative assessment of the adverse event (AE) burden from the patient’s perspective helps to provide a greater understanding of the overall impact of treatment-related AEs than grading of AEs alone. Here we report the impact of dacomitinib on core lung cancer symptoms in patients with previously treated, advanced NSCLC in three phase II clinical trials [Janne et al 2009; Park et al 2010; Ramalingam et al 2012].

      Methods
      Dacomitinib was evaluated in advanced NSCLC, in patients who had received prior chemotherapy and erlotinib (study 1002; n=66) [Janne et al 2009], in Korean patients who had received prior chemotherapy and erlotinib or gefitinib (study 1003; n=43 in phase II) [Park et al 2010], and in comparison with erlotinib in patients who had received prior chemotherapy (study 1028; n=188) [Ramalingam et al 2012]. In each of the trials, HRQoL was evaluated using validated patient-reported outcome (PRO) measures. Disease/treatment‑related symptoms were recorded using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core module (EORTC QLQ-C30) and its lung cancer module (LC13). Scores were summarized using the mean (and 95% CI) for each group and plotted over time. Mean changes from baseline were also reported.

      Results
      On-study questionnaire mean completion rates were high (>90% of patients answered at least 1 question across treatment cycles) in each of the studies. Across the three trials, patients reported a rapid onset (typically ≤3 weeks of starting therapy) of improvement in key lung cancer symptoms (e.g. cough, pain in chest, and pain in arm/shoulder) relative to baseline scores, with symptomatic improvements remaining durable over the course of therapy. Diarrhea and sore mouth were the most commonly reported class-related AEs (for dacomitinib in studies 1002 and 1003, and for both dacomitinib and erlotinib in study 1028). These AEs peaked at weeks 3–6, were manageable, and remained stable or improved over time with intervention. Compared with erlotinib in study 1028, clinically meaningful improvements from baseline (>10 points difference on a 0–100-point scale) in key NSCLC symptoms (cough, dyspnea, pain in chest, pain in arm/shoulder, fatigue, and physical function) were reported by patients receiving dacomitinib. The difference in mean change from baseline was more favorable with dacomitinib at most time-points.

      Conclusion
      Dacomitinib demonstrated consistent improvements in common NSCLC symptoms across three clinical trials in pretreated patients with advanced NSCLC. PROs such as cough and pain improved within 3 weeks of initiating treatment, with benefits sustained throughout the course of therapy. Dacomitinib also demonstrated greater improvements in key NSCLC symptoms than erlotinib.

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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 - 09:30  |  Author(s): D. Kim

      • 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.