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Jeffrey Rothenstein



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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-54 - A Phase I/Ib Study of Binimetinib (MEK162), a MEK Inhibitor Plus Carboplatin/Pemetrexed in Non-Squamous NSCLC (ID 14205)

      16:45 - 18:00  |  Author(s): Jeffrey Rothenstein

      • Abstract

      Background

      MEK remains an important potential target in RAS/RAF dependent tumours. Binimetinib (MEK16) is a highly selective oral inhibitor of MEK1/2, which has shown activity in melanoma and other cancers. Data from preclinical models suggest greater activity with intermittent versus continuous dosing of MEK inhibitors when added to chemotherapy. This dose escalation study combines intermittent binimetinib with pemetrexed plus carboplatin in chemotherapy naive patients with advanced non-squamous NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A standard 3+3 dose-escalation design was used with planned dose expansion at RP2D (N=30) in genotypically defined cohorts (KRAS G12C mutant (mt), non-G12C mt and wild type). The primary endpoint was to define the RP2D of binimetinib using an intermittent dosing schedule in combination with standard doses of pemetrexed and carboplatin. Secondary objectives included safety, pharmacokinetics (PK), response and exploring potential biomarkers of response or toxicity. Binimetinib (30-45 mg BID) was commenced on day 1 cycle 1 for 5 days followed by a 48-hour washout period. If well tolerated, pemetrexed/carboplatin (500 mg/m2/AUC 5 mg*min/mL) were added on day 8 cycle 1 and binimetinib resumed from days 8-26 with a 48 hour drug washout before cycle 2. For subsequent cycles, pemetrexed/carboplatin were administered on day 1, binimetinib on days 1-19 every 21 days. Key eligibility criteria included ECOG performance status 0-1, adequate organ function, measureable disease by RECIST and no active CNS metastasis. Patients with EGFR/ALK mt lung cancer were permitted in the dose escalation phase after progression on standard TKI therapy.

      4c3880bb027f159e801041b1021e88e8 Result

      Between 03/2017 and 04/2018, 11 patients have been enrolled in 2 dose escalation cohorts (4 KRAS mt, 4 EGFR mt including 1 ex20ins). Six patients were treatment-naive, 3 received prior EGFR TKI and 2 prior pembrolizumab. To date, 7 have experienced grade 3 adverse events (AEs) deemed at least possibly related to binimetinib (anemia, neutropenia, abdominal pain, diarrhea, nausea, vomiting, fatigue, transaminitis). No grade 4/5 AEs have been seen. Related AEs seen in >20% of patients include: rash, mucositis, diarrhea, fatigue, transient visual changes, nausea, edema, neutropenia and vomiting. Antitumour activity was seen at each dose level of binimetinib. Final data on toxicity, response, PK and confirmation of RP2D will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The addition of binimetinib to pemetrexed/carboplatin appears to have manageable toxicity with evidence of activity in non-squamous NSCLC. Dose expansion in genotypically defined cohorts will continue and a cohort combining binimetinib with pembrolizumab is planned.

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      P1.01-83 - IMpower150: Impact of Chemotherapy Cycles in 1L Metastatic NSCLC in Patients Treated With Atezolizumab + Bevacizumab (ID 12180)

      16:45 - 18:00  |  Presenting Author(s): Jeffrey Rothenstein

      • Abstract
      • Slides

      Background

      In the randomized Phase III IMpower150 study, atezolizumab (anti–programmed death-ligand 1 [PD-L1]) + bevacizumab + chemotherapy (Arm B) showed statistically significant and clinically meaningful improvement in both progression-free survival (PFS) and overall survival (OS) over bevacizumab + chemotherapy (Arm C) in patients with first-line (1L) nonsquamous non-small cell lung cancer (NSCLC). The study protocol allowed investigator choice of 4 or 6 chemotherapy cycles. The objective of this exploratory analysis was to assess the impact of chemotherapy cycles on safety and efficacy outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients were categorized based on actual chemotherapy cycles received in Arm B. Landmark analysis of PFS was performed to assess the benefit of 4 vs 6 chemotherapy cycles. Sensitivity analyses were performed to adjust the numerically imbalanced baseline factors.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 356 patients were randomized in Arm B; 188 patients (53%) were planned to receive 4 cycles, and 168 patients (47%) were planned to receive 6 cycles of chemotherapy. Within these 2 groups, 143 (76%) and 98 patients (58%) completed 4 and 6 chemotherapy cycles, respectively. The demographic and baseline disease characteristics were balanced, except for race (Asian vs other), smoking status, and PD-L1 status (TC3 or IC3 vs other). The landmark PFS analysis showed no difference between patients who completed 4 vs 6 cycles (HR 0.83 [95% CI: 0.59, 1.17). The sensitivity analyses, which adjusted for race, smoking status, or PD-L1, showed comparable results (adjusted HRs of 0.80, 0.85, or 0.91, respectively).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In the atezolizumab + bevacizumab + chemotherapy arm, patients who received 4 cycles of chemotherapy appeared to have similar PFS benefit as those who received 6 cycles of chemotherapy. Detailed analyses of varying chemotherapy cycles, safety analyses, and impact on OS will be presented.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-13 - Real-World Study of Osimertinib in EGFR T790M-Mutated Non-Small Cell Lung Cancer (NSCLC): ASTRIS Canadian Cohort Analysis (ID 12986)

      16:45 - 18:00  |  Author(s): Jeffrey Rothenstein

      • Abstract
      • Slides

      Background

      ASTRIS is an open-label, single-arm, multinational, real world study of osimertinib for patients with advanced/metastatic epidermal growth factor receptor-mutated (EGFRm) T790M-positive non-small cell lung cancer (NSCLC) who previously received therapy with an EGFR tyrosine kinase inhibitor (EGFR-TKI) (NCT02474355). Data cut-off (DCO) for the second interim analysis was 20 October 2017, with 3014 patients enrolled (full analysis set), including 99 patients in Canada.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Adult patients with locally advanced/metastatic EGFRm NSCLC, not amenable to curative surgery/radiotherapy, with confirmation of T790M and prior EGFR-TKI therapy were enrolled. Patients were included with World Health Organization performance status of 0 to 2, as well as those with asymptomatic stable central nervous system (CNS) metastases. Patients received osimertinib 80 mg once daily until loss of clinical benefit. The primary efficacy outcome was overall survival (OS), with secondary outcomes of investigator-assessed response rate (RR), progression-free survival (PFS), and time to treatment discontinuation (TTD).

      4c3880bb027f159e801041b1021e88e8 Result

      From study start (14 January 2016) to DCO (20 October 2017), 99 patients were enrolled at 12 Canadian centres. Median age was 64 years (30-89 years). Patients were 68% female, 57% Asian, and had ECOG 0/1/2 of 22%/65%/13%. Twenty-five patients had CNS metastases at screening. Gefitinib was the most commonly used previous EGFR-TKI (gefitinib, erlotinib and afatinib were 80%, 14%, and 14%, respectively). Thirty-nine percent had previous chemotherapy; 6% previous immunotherapy; 46% previous radiotherapy. All patients had T790M: 75% tissue, 7% blood and 18% cytology. Biomarker testing methods varied, with the majority (61%) identified by Entrogen EGFR kit. At DCO, 45 patients had discontinued treatment. OS data were immature. Median PFS was 11.0 months (95% CI, 8.9-13.3). Median TTD was 14.9 months (95% CI, 11.2-not calculated). RR was 67.0% (95% CI, 56.7-76.2); sub-analyses showed RR of 69.9% (58.0-80.1), 66.7% (22.3, 95.7) and 55.6% (30.8, 78.5) for patients with T790M by tissue, blood and cytology, respectively. Serious adverse events (AEs) were reported for 18% of patients. AEs leading to dose modifications and discontinuations were reported for 12% and 5% of patients, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The Canadian results from this real world study of osimertinib in advanced/metastatic EGFRm T790M-positive NSCLC, which includes heavily pretreated patients and various approaches to biomarker testing, were comparable to outcomes reported in the phase III study AURA3 (NCT02151981). These findings provide further support for osimertinib as standard of care for EGFRm T790M-positive NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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