Virtual Library

 x 
My Library Virtual Library FAQ

Start Your Search

J. O'Connell



Author of

  • +

    Best of Posters - IASLC Selection - Part 1 (ID 262)

    • Event: WCLC 2013
    • Type: Exhibit Showcase Session
    • Track:
    • Presentations: 1
    • +

      P1.11-032 - Results with dacomitinib (PF-00299804), an irreversible pan-HER tyrosine kinase inhibitor, in a phase II cohort of patients with HER2-mutant or amplified lung cancers (ID 2237)

      09:55 - 10:25  |  Author(s): J. O'Connell

      • Abstract
      • Slides

      Background
      Dacomitinib is an oral, irreversible small molecule inhibitor of all active members of the HER (human epidermal growth factor receptor) family of tyrosine kinases: EGFR (HER1), HER2 and HER4. Dacomitinib has shown superior activity to the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib in preclinical studies of lung cancer cell lines with sensitive and resistant EGFR mutations, and superiority to gefitinib in cell-line models with a HER2 insertion mutation or amplified HER2. As part of dacomitinib’s phase II testing, we studied a cohort of patients with HER2-mutant or -amplified lung cancers.

      Methods
      As a cohort of a larger phase II study, we enrolled patients who had stage IIIB/IV lung cancers and either HER2 mutations or HER2 amplification ([centromere of chromosome 17]; ratio >2), any number of prior systemic chemotherapies, but no prior HER2-targeted treatment. Dacomitinib was administered at 45 mg once daily continuously, or 30 mg if the patient had no prior systemic therapy, with the option to escalate to 45 mg. Patients were evaluated every 28 days. Endpoints included progression-free survival (PFS) rate at 4 months (PFS4m), PFS, objective response rate by RECIST, duration of response, overall survival (OS), and toxicity.

      Results
      30 patients with HER2-mutant (n=26) or HER2-amplified lung cancers (n=4) were enrolled. Characteristics: 15 female; 18 never smokers (60%); 11 (37%) former smokers. 25 received a 45 mg starting dose; 5 patients received 30 mg. 10 patients had received ≥3 prior systemic therapies. 73% of patients had a PFS event. PFS4m overall was 27% (95% CI: 11%–46%; HER2-mutant subgroup: 21% [95% CI: 6%–43%]). Median overall PFS was 3 months (95% CI: 2–4; HER2-mutant subgroup: 3 months [95% CI: 2–4]). Of 25 patients in the HER2-mutant subgroup evaluable for response, 3 (12%; 95% CI: 3%–31%) experienced a partial response, all with 9 base-pair insertions in HER2 exon 20. The partial response durations were 3+, 11, and 11+ months. The preliminary estimate of median OS was 10 months (95% CI: 7–21; HER2-mutant subgroup: 10 months [95% CI: 7–21]). Among the 4 patients with HER2 amplified lung cancers, no partial responses were seen and the PFS ranged from 1–5 months. Of 29 patients evaluable for toxicity, the most common treatment-related adverse events were diarrhea (90%; grade 3/4: 21%/3%), dermatitis (72%; grade 3/4: 3%/0), fatigue (52%; grade 3/4: 3%/0), and dry skin (48%; grade 3/4: 0/0). 10% of patients discontinued treatment due to adverse events.

      Conclusion
      Dacomitinib demonstrated an overall 12% objective response rate in patients with HER2-mutant lung cancers. All 3 responding patients had 9 base-pair HER2 exon 20 insertions. No responses were seen in the 4 patients with HER2-amplified lung cancers. Dacomitinib was well tolerated with manageable toxicities, consistent with the class effects of EGFR TKIs.

      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.

  • +

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
    • +

      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 - 16:30  |  Author(s): J. O'Connell

      • 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.