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M. Cantarini



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    MA16 - Novel Strategies in Targeted Therapy (ID 407)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA16.11 - CNS Response to Osimertinib in Patients with T790M-Positive Advanced NSCLC: Pooled Data from Two Phase II Trials (ID 4920)

      14:20 - 15:50  |  Author(s): M. Cantarini

      • Abstract
      • Presentation
      • Slides

      Background:
      Brain metastases develop in 25–40% of patients with NSCLC. Osimertinib is an oral, potent, irreversible EGFR-TKI, selective for both sensitising (EGFRm) and T790M resistance mutations. Preclinical and early clinical evidence support central nervous system (CNS) penetration and activity of osimertinib. Two Phase II studies (AURA extension [NCT01802632] and AURA2 [NCT02094261]) evaluating the efficacy and safety of osimertinib are ongoing. We present a pre planned subgroup analysis assessing pooled CNS response from these two studies; data cut-off (DCO) was 1 November 2015. An earlier pooled analysis from these two studies (1 May 2015 DCO) showed the objective response rate (ORR) in patients with CNS metastases was consistent with ORR in the overall patient population.

      Methods:
      Patients with advanced NSCLC who progressed following prior EGFR-TKI therapy with centrally-confirmed T790M positive status (cobas® EGFR Mutation Test) received osimertinib 80 mg once daily (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment. CNS efficacy was assessed in an evaluable for CNS response analysis set, which included patients with at least one measurable CNS lesion on baseline brain scan (RECIST v1.1) by blinded independent central neuroradiology review (BICR). Effect of prior radiotherapy on CNS response was assessed.

      Results:
      As of 1 November 2015, 50/192 patients with baseline brain scans had at least one measurable CNS lesion identified by BICR. Baseline demographics were broadly consistent with the overall patient population. Confirmed CNS ORR was 54% (27/50; 95% CI: 39%, 68%), with 12% complete CNS response (6/50 patients). The median CNS duration of response (22% maturity) was not reached (95% CI: not calculable [NC], NC). The estimated percentage of patients remaining in response at 9 months was 75% (95% CI: 53, 88). CNS disease control rate (DCR) was 92% (46/50; 95% CI: 81%, 98%). Median time to first response was 5.7 weeks (range: 5.6–6.6). Median best percentage change from baseline in CNS target lesion size was 53% (range: -100% – +80%). Median follow up for CNS progression-free survival (PFS) was 11 months; the median CNS PFS was not reached (95% CI: 7, NC). At 12 months, 56% (95% CI: 40%, 70%) of patients were estimated to remain on study, alive and CNS progression-free. CNS response was observed regardless of prior radiotherapy to the brain.

      Conclusion:
      Osimertinib demonstrates durable efficacy in patients with T790M NSCLC and measurable CNS metastases, with a CNS response rate of 54% and a DCR of 92%.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P3.02b-096 - Osimertinib (AZD9291) in Asia-Pacific Patients with T790M Mutation-Positive Advanced NSCLC: Open-Label Phase II Study Results (ID 4282)

      14:30 - 15:45  |  Author(s): M. Cantarini

      • Abstract

      Background:
      Osimertinib (AZD9291) is an oral, potent, irreversible EGFR-TKI, selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. Following positive outcomes from recent Phase I and II trials, osimertinib is now recommended for patients with EGFR T790M mutation-positive advanced non-small cell lung cancer (aNSCLC).

      Methods:
      AURA17 (NCT02442349) is an open-label, single arm, Phase II study investigating the efficacy and safety of osimertinib in an Asia-Pacific patient population with EGFRm T790M mutation-positive locally advanced or metastatic NSCLC, who had progressed following EGFR-TKI therapy or EGFR-TKI and chemotherapy. T790M-positive status was confirmed via central testing of biopsy samples using the cobas[®] EGFR Mutation Test. Inclusion required measureable disease, performance status (PS) 0/1, and acceptable organ function; asymptomatic brain metastases were allowed. Patients received osimertinib 80 mg once daily until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (by blinded independent central review, BICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival, and safety and tolerability.

      Results:
      As of 4 March 2016 data cut-off, 171 patients were enrolled, with 166 evaluable for response: median age, 60.0 years; female, 69%; Asian, 98%; never smokers, 78%; PS 0/1, 15%/85%; EGFR Exon 19 and L858R mutations, 64% and 34% patients, respectively; second-/≥third-line, 32%/68%; median treatment exposure, 5.6 months. Confirmed ORR and DCR (95% CI) by BICR were 60% (52, 68) and 88% (82, 92), respectively. DoR and PFS are not calculable as data is immature. Causally-related adverse events (AEs) grade ≥3 were reported in eight (5%) patients. AEs leading to dose interruption or dose reduction occurred in seven (4%) and two (1%) patients, respectively. Six (4%) patients discontinued treatment due to AEs, two (1%) causally-related AEs as assessed by investigator. The most commonly reported AEs (%, [grade ≥3]) were diarrhoea (29%, [0]), rashes and acnes (grouped terms) (20%, [0]), and dry skin (grouped terms) (17%, [1%]). Interstitial lung disease-like events were reported in three (2%) patients.

      Conclusion:
      AURA17 demonstrated clinical efficacy of osimertinib in Asia-Pacific patients with EGFR T790M mutation-positive aNSCLC, with an ORR of 60% and DCR of 88% that are comparable to global Phase II trials. Osimertinib was well tolerated, with a low frequency of AEs grade ≥3. No new safety signals were seen and the pattern of AEs was consistent with global studies

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      P3.02b-099 - Pharmacokinetics of Osimertinib (AZD9291) in Chinese Patients with Advanced NSCLC: A Phase I Study (ID 4440)

      14:30 - 15:45  |  Author(s): M. Cantarini

      • Abstract

      Background:
      Osimertinib is a potent, irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), selective for EGFR-sensitising (EGFRm) and T790M resistance mutations. The Phase I AURA18 study (NCT02529995) assessed osimertinib pharmacokinetics (PK) in Chinese patients with advanced non-small cell lung cancer (aNSCLC) who progressed following prior EGFR-TKI therapy.

      Methods:
      Osimertinib is a potent, irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), selective for EGFR-sensitising (EGFRm) and T790M resistance mutations. The Phase I AURA18 study (NCT02529995) assessed osimertinib pharmacokinetics (PK) in Chinese patients with advanced non-small cell lung cancer (aNSCLC) who progressed following prior EGFR-TKI therapy.

      Results:
      31 patients were treated (Cohort 1, n=15; Cohort 2, n=16): median age, 57.0 years; female, 58%; never smokers, 74%. 26 harboured tumors with the EGFR T790M mutation (local test). The PK analysis set included 25 patients: 6 were excluded due to prior treatment with an osimertinib-like substance or a T790M-directed EGFR-TKI. Osimertinib exposure increased approximately dose-proportionally after single and multiple dosing, similar to previous global studies. 29 (94%) patients experienced at least one adverse event (AE), 3 patients experienced an AE of Grade ≥3; no patients discontinued treatment due to AEs. The most common AEs were: diarrhoea (32%), white blood cell decreased (23%), neutrophil count decreased (19%), dry mouth and erythema (19%). ORR (all partial responses) in T790M mutation-positive subgroup was 36% for Cohort 1 (4/11; 95% CI 11, 69) and 67% for Cohort 2 (10/15; 95% CI 38, 88).

      Conclusion:
      Osimertinib PK in the AURA18 Chinese patient population is consistent with the global population and supports 80 mg once-daily dosing. Clinical benefit and a tolerable safety profile were demonstrated. Figure 1