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Neal Ready



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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA04.02 - CheckMate 817: First-Line Nivolumab + Ipilimumab in Patients with ECOG PS 2 and Other Special Populations with Advanced NSCLC (Now Available) (ID 1876)

      15:15 - 16:45  |  Author(s): Neal Ready

      • Abstract
      • Presentation
      • Slides

      Background

      Data are limited for immunotherapy in patients with advanced NSCLC and poor performance status or other comorbidities. CheckMate 817 is a multi-cohort, open-label phase 3b/4 study investigating safety and efficacy of flat-dose nivolumab plus weight-based low-dose ipilimumab in advanced NSCLC. Here we evaluate this regimen as first-line treatment in special populations (cohort A1) and a reference population (cohort A; previously reported).

      Method

      Patients had previously untreated advanced NSCLC. Cohort A1 (n=198) had ECOG PS 2 or ECOG PS 0–1 with 1 of: asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV. Cohort A (n=391) had ECOG PS 0–1. Patients with known EGFR mutations or ALK translocations sensitive to available targeted therapy were excluded from both cohorts. Nivolumab 240 mg Q2W plus ipilimumab 1 mg/kg Q6W was administered for two years or until disease progression/unacceptable toxicity. Safety and efficacy endpoints were assessed; cohort A1 analyses were exploratory.

      Result

      Cohort A1 patients were grouped as: ECOG PS 2 (n=139) and all other special populations (AOSP; n=59). Baseline characteristics were generally balanced between cohorts. Rates of grade 3–4 treatment-related adverse events (TRAEs) were similar between cohorts; within cohort A1, grade 3–4 TRAEs were numerically higher in AOSP versus the ECOG PS 2 subgroup; TRAEs leading to discontinuation were similar across populations (Table). ORR was 25% in cohort A1 (patients with ECOG PS 2, 20%; AOSP, 37%) and 35% in cohort A. PFS was numerically shorter in cohort A1 than cohort A; high TMB (≥10 mut/Mb) and higher PD-L1 expression (≥1% or ≥50%) were associated with numerically longer PFS in both cohorts (Table).

      table_v3.jpg

      Conclusion

      First-line flat-dose nivolumab plus weight-based ipilimumab showed a consistent safety profile in special populations with advanced NSCLC, including those with ECOG PS 2. Patients with either high TMB or higher tumor PD-L1 expression appeared to exhibit improved efficacy.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Author(s): Neal Ready

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-89 - Neoadjuvant Pembrolizumab in Early Stage Non-Small Cell Lung Cancer (NSCLC): Toxicity, Efficacy, and Surgical Outcomes (ID 1941)

      10:15 - 18:15  |  Presenting Author(s): Neal Ready

      • Abstract

      Background

      Pembrolizumab is a programmed death receptor-1 masking antibody approved for advanced NSCLC in program death receptor ligand-1 high tumors, and in chemotherapy combinations. This trial studies the effect of neoadjuvant pembrolizumab on surgical tolerability (primary endpoint), tumor response, side effects, and immune biomarkers in blood and tumor.

      Method

      Baseline PET/CT, brain imaging, histologic diagnosis NSCLC, and surgical consultation were required for eligibility. Patients with stage T > 3 cm and N0, N1, or resectable N2 NSCLC received neoadjuvant pembrolizumab 200 mg every 21 days 2 cycles prior to pre-operative chest CT scan followed by standard surgery. Adjuvant chemotherapy was strongly encouraged but not required. After completion of standard chemotherapy, 4 cycles of adjuvant pembrolizumab 200 mg every 21 days was offered. Blood for immune profiling of circulating immune cells was collected at baseline, after cycle 2 pembrolizumab, after surgery, and after adjuvant pembrolizumab. Excess tumor was disaggregated for tumor infiltrating lymphocytes, regulatory immune cells, and tumor cells, and viably stored for later analysis. We report clinical outcomes of tumor response and surgical outcomes.

      Result

      Study activated 31/1/2017, last enrollment 6/2/2019, and last surgery 19/3/2019. 35 patients signed consent and 30 received at least 1 dose pembrolizumab: 2 withdrew consent, 3 screen failed. Characteristics of 30 treated patients (%): male 16 (53), adenocarcinoma 10 (33), squamous 17 (57), other histology 3 (10), and stages 1B 8 (27), IIA 8 (27), IIB 6 (20), IIIA 8 (27). Planned surgery completed for 25/30 (83%). Reasons for not undergoing surgery: distant metastatic disease (1 brain metastases, 2 pleural metastases), 1 would not tolerate required pneumonectomy, 1 N3 nodal disease. Surgeries performed: video-assisted thoracic surgery (VATS) lobectomy 12, thoracotomy lobectomy 9, VATS pneumonectomy 2, thoracotomy pneumonectomy 1, and VATS bilobectomy and chest wall resection 1. All surgery was performed within range 38-77 days (median 48 days) after cycle 1 day 1 pembrolizumab. Data will be presented for toxicities neoadjuvant pembrolizumab, surgical outcomes, and neoadjuvant pembrolizumab RECIST responses, and pathologic responses. Some major pathologic responses (< 10% viable tumor) and at least 2 pathologic CRs were observed.

      Conclusion

      Two doses of neoadjuvant pembrolizumab was tolerable and produced major or complete pathologic responses in some tumors. Neoadjuvant pembrolizumab is tolerable and is an ideal platform to investigate mechanisms of immune resistance and sensitivity in early stage NSCLC.