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Ryan D Gentzler



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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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      OA04.05 - KEYNOTE-021: TMB and Outcomes for Carboplatin and Pemetrexed With or Without Pembrolizumab for Nonsquamous NSCLC (Now Available) (ID 2630)

      15:15 - 16:45  |  Author(s): Ryan D Gentzler

      • Abstract
      • Presentation
      • Slides

      Background

      KEYNOTE-021 cohort C was the first study to show antitumor activity for pembrolizumab plus platinum-based chemotherapy in previously untreated advanced nonsquamous NSCLC; the combination significantly improved efficacy vs platinum-based chemotherapy alone in cohort G. We explored the relationship between TMB and outcomes in KEYNOTE-021 cohorts C and G.

      Method

      All patients in cohort C received pembrolizumab plus carboplatin and pemetrexed. Patients in cohort G were randomized 1:1 to pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone. TMB was determined by whole-exome sequencing of tumor and matched normal DNA. Association of TMB (continuous, log10 transformed) with outcomes for pembrolizumab plus chemotherapy and chemotherapy alone were assessed using logistic regression for ORR and Cox proportional hazards models for PFS and OS adjusted for ECOG PS; statistical significance was determined at the 0.05 level without multiplicity adjustment. The correlation of TMB (continuous, log10­ transformed) with PD-L1 TPS (square root scale) was assessed in the combined population. The clinical utility of TMB for ORR using a prespecified TMB cutpoint of 175 Mut/exome (~13 Mut/Mb by FoundationOne CDx) was assessed for pembrolizumab + chemotherapy.

      Result

      TMB data were evaluable for 70 patients: 12/24 (50.0%) in cohort C, 32/60 (53.3%) in the cohort G pembrolizumab plus chemotherapy arm, and 26/63 (41.3%) in the cohort G chemotherapy only arm; median age was 65 years (IQR, 57-70) and 61% were female. Baseline characteristics were generally similar in the TMB-evaluable and total populations. TMB as a continuous variable was not significantly associated with ORR, PFS, or OS for pembrolizumab plus chemotherapy (one-sided P = 0.180, 0.187 and 0.081, respectively) or chemotherapy alone (one-sided P = 0.861, 0.795 and 0.763, respectively). There was no significant correlation between TMB and TPS (r=0.12, P=0.34). ORR (95% CI) in patients treated with pembrolizumab plus chemotherapy was 60.8% (38.5-80.3) in the 23 patients with TMB <175 and 71.4% (47.8-88.7) in the 21 patients with TMB ≥175.

      Conclusion

      In this exploratory analysis, TMB was not significantly associated with efficacy of pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone as first-line therapy for metastatic nonsquamous NSCLC. TMB was not significantly correlated with PD-L1 expression. Among pembrolizumab plus chemotherapy-treated patients, ORR was high in both the TMB low and high subgroups. Sample size is a limitation of this study; exploration in larger datasets is required to understand any differential efficacy of pembrolizumab plus chemotherapy vs chemotherapy alone based on TMB status.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-67 - Ph I/II Carboplatin, Nab-Paclitaxel and Pembrolizumab for Advanced NSCLC (HCRN LUN13-175): Outcomes by Nab-Paclitaxel Dose (ID 530)

      09:45 - 18:00  |  Presenting Author(s): Ryan D Gentzler

      • Abstract
      • Slides

      Background

      Combination chemotherapy and immunotherapy have significantly improved survival for patients with treatment-naïve advanced non-small cell lung cancer (NSCLC). We sought to evaluate the safety and efficacy of adding pembrolizumab to a standard regimen at the time of study development, nab-paclitaxel and carboplatin. Safety data from phase I have been reported, and phase II commenced with the same chemotherapy doses and flat dosing of pembrolizumab at 200 mg.

      Method

      Patients with treatment-naïve, stage IIIB/IV NSCLC AJCC 7 (all histology), any PDL1, no EGFR or ALK, ECOG 0-1, received carboplatin AUC 6 day 1, nab-paclitaxel 100 mg/m2 days 1, 8, 15, and pembrolizumab 200 mg day 1 q21 days for 4 cycles followed by maintenance pembrolizumab q3wks. Co-primary endpoints were progression-free survival (PFS) and response rate (RR). PDL1 was assessed prior to treatment and from biopsies obtained after cycle 4.

      Result

      46 patients enrolled, 14 on phase I and 32 in phase II, from June 2015–July 2018. Accrual stopped after data was presented from similar phase III trials. 43 were evaluable for the primary endpoints. Median age was 65 years, 48% female, 45% adenocarcinoma, 94% current/former smokers, 9% brain metastases. PDL1 expression (TPS) by <1%, 1-49%, and ≥ 50% cutoffs was 44%, 28%, and 28%, respectively. ORR was 28%. Median PFS was 5.6 months (CI, 4.2-10.5 mo). Median OS was 15.7 mo (CI 11.1-22.3 mo). There was no statistical differences in PFS or OS outcomes by PDL1 status. Paired PDL1 results from pre- and post-treatment biopsies were available in 8 patients. PDL1 status changed categories in 4/8 samples (n=3, 0% to positive; n=1, 99% to 0%). The most common grade 3-4 adverse events (AEs) were neutropenia (64%), anemia (31%), thrombocytopenia (24%), leukopenia (16%) and fatigue (11%). Other notable AEs included rash (58%), diarrhea (47%), neuropathy (22%), arthralgia (18%), transaminitis (13%), and myalgia (11%). 18% discontinued treatment due to AEs. In an exploratory analysis, there was no difference in median PFS for those receiving total nab-paclitaxel dose of 400–799 mg/m2 compared to ≥800 mg/m2 (6.2 mo vs. 8.2 mo, p=0.62).

      Conclusion

      Although the study did not meet its pre-specified endpoints of PFS 9 months and RR of 50%, results were similar to previously reported phase III Keynote 407 (squamous histology). Despite hematologic toxicity, the combination could safely be administered, and outcomes were similar for those receiving moderate doses of nab-paclitaxel compared to those with an average of at least 200 mg/m2 per cycle.

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    P1.18 - Treatment of Locoregional Disease - NSCLC (ID 190)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.18-05 - ChemoXRT W/ Consolidation Pembrolizumab in Unresectable Stage III NSCLC:  Long-Term Survival Update and Analysis of Post-Progression Therapy (Now Available) (ID 2765)

      09:45 - 18:00  |  Author(s): Ryan D Gentzler

      • Abstract
      • Slides

      Background

      Consolidation PD-1/PD-L1 inhibition following chemoradiation is a new standard of care for patients with stage III NSCLC. 3-year survival rates in patients receiving consolidation PD-1/PD-L1 have not been previously reported. In addition, the response to subsequent chemotherapy or immunotherapy in patients who experienced disease progression following consolidation PD-1/PD-L1 has also not been previously reported.

      Method

      This is a phase II, single-arm, multi-center trial of consolidation pembrolizumab 200mg IV every 3 weeks for up to a year following concurrent chemoradiation in patients with unresectable stage III NSCLC. This analysis provides the first-ever report of 3-year overall survival (OS) estimates with consolidation PD-1. In addition, treatment details for patients who experienced progression of disease on or after consolidation pembrolizumab are described.

      Result

      Median follow is 31.1 months (range 1.2-42.4). Median OS is 35.8 months (95% CI, 24.2 -not estimable). One, two, and three-year OS estimates are 81.1%, 62%, and 49.5%. Of 37 patients reported to have progressive disease (PD), subsequent treatment data were available for 35. Twenty-four received additional systemic therapy, and 11 received no subsequent systemic treatment. Fifteen experienced PD during pembrolizumab, 18 after pembrolizumab (and 4 had missing data). The best response to any systemic therapy (n=24) was 3 partial responses (PR), 9 stable disease (SD), and 12 PD. Chemotherapy was given to 21 patients and 1 patient each received erlotinib, ponatinib, and an investigational agent. Best response to chemo was 2 PR, 6 SD, and 13 PD. 11 patients received pemetrexed with 2 SD and 9 PD; 6 patients received a single agent taxane with 1 SD and 5 PD. 5 patients received combination therapy with 1 PR, 3 SD, and 1 PD. 3 patients received gemcitabine with 1 PR and 2 PD. 6 of 24 patients received subsequent PD-1 or PD-L1 inhibitors; the best response to immunotherapy was 1 PR and 5 PD. The PR was a patient who had completed pembro consolidation 14 months prior to PD and subsequently was retreated with pembro at the time of biopsy-proven recurrence (PD-L1 TPS was 90%). He responded after 3 cycles of pembro and has maintained this response for 13+ cycles.

      Conclusion

      The 3-year OS estimate indicates that nearly half of all patients treated with consolidation pembrolizumab may be long-term survivors. For patients with disease progression after consolidation pembrolizumab, response rates with chemotherapy are similar to what is expected in the 2nd line setting with 38% experiencing disease control for a period of time. Only 1 of 6 patients re-challenged with a checkpoint inhibitor responded, but this patient has maintained a durable response lasting 13+ cycles.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-52 - Clinical Characteristics and Outcomes in NSCLC Patients Associated with Very High PD-L1 Expression (ID 1787)

      10:15 - 18:15  |  Author(s): Ryan D Gentzler

      • Abstract

      Background

      Clinical characteristics and outcomes for patients with non-small cell lung cancer (NSCLC) and very high PD-L1 expression are unknown. We sought to better characterize this subset of patients with PD-L1 ≥90% to determine any differences in clinical presentation or survival.

      Method

      We performed a retrospective analysis of patients treated at our institution between 2014 and 2018 with metastatic NSCLC and an available PD-L1 result (any assay). We assessed tumor size, location of metastasis, and presence of mediastinal invasion using continuous PD-L1 values (Wilcoxon Mann-Whitney test) and compared two subgroups based on a PD-L1 cut point of ≥90% (Fisher’s exact test). Survival comparisons used Kaplan Meier log-rank methodology.

      Result

      A total of 101 patients were included in the analysis; 16.8% had PD-L1 ≥90%. A summary of the patient demographics and clinical characteristics are summarized in Table 1. Higher PD-L1 values were associated with mediastinal invasion (median PD-L1 60% vs 5% without invasion, p=0.0268) and those with PD-L1 ≥90% were more likely to have adrenal metastasis (p=0.0266). There was no correlation between tumor size or other sites of metastasis and PD-L1 expression. OS was not significantly different when compared to those with PD-L1 50-89% or lower PD-L1 subgroups in either immunotherapy alone treatment group (p=0.6358) or for the combination chemotherapy/ immunotherapy group (p=0.2580). Patients receiving immunotherapy alone with PD-L1 expression ≥90% had a median OS of 38.0 months compared to 21.3 months for PD-L1 0-89% (p=0.8480).

      Table 1:

      table1.png

      Conclusion

      Higher PD-L1 expression was associated with mediastinal invasion, and adrenal metastasis were more common in patients with PD-L1 ≥90%. While there were no detectable survival differences in the very high PD-L1 group, differences in clinical characteristics highlight the heterogeneity of this group of patients and need for further characterization that may be predictive of treatment response and help tailor treatments for this group.

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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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      P2.04-75 - Overall Survival by IDO1 and PD-L1 Expression in NSCLC Patients Receiving an Immune Checkpoint Inhibitor (ICI) (ID 1952)

      10:15 - 18:15  |  Author(s): Ryan D Gentzler

      • Abstract
      • Slides

      Background

      Although preliminary data suggest that differential expression of the immunoregulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) may modulate clinical response to agents that target the PD-1/PD-L1 axis, little is known about the predictive value of measuring concomitant expression of both markers for patients receiving immune checkpoint inhibitor (ICI) therapy for non-small cell lung cancer (NSCLC).

      Method

      We identified patients with stage IV NSCLC who received at least one dose of an ICI alone or in combination with chemotherapy (CTX) at our institution between 2014 and 2018. Immunohistochemistry (IHC) for IDO1 (HPA023072, Sigma Prestige) and PD-L1 (SP142, Abcam) was performed on FFPE tissue. PD-L1 was scored as <1 %, 1-50%, or >50%, and IDO1 was scored as <1% or >1%. Median overall survival (OS) was calculated using proportional hazards model and groups were compared using log-rank test.

      Result

      65 eligible patients were identified. PD-L1 IHC failed in 1 patient. Patient characteristics and IHC results are detailed in Table 1. Patients with IDO1 expression had a numerically longer median OS (37.8 vs. 17.7 months, p=0.16), which was maintained regardless of PDL1 positivity. This effect was more pronounced in the ICI alone cohort (median OS of 34.4 mo vs. 17.7 mo, p=0.0995) than in the CTX+ICI cohort (p=0.92). There was no difference in OS when evaluating IDO and PDL1 expression in 4 subgroups (IDO1+/PD-L1+, +/-, -/+, -/-) using PD-L1 cutoffs of ≥1% (p=0.50) or ≥50% (p=0.49).

      Table 1:

      Characteristic - n, (%)

      ICI Alone Cohort

      n = 48 (73.8%)

      ICI + CTX Cohort

      n = 17 (26.2%)

      Patient Demographics

      Age (median in years)

      63.5

      59

      Female Gender

      22 (45.8)

      9 (52.9)

      Former/Current Smoking

      44 (91.7)

      14 (82.4)

      EGFR Mutation

      3 (6.3)

      0 (0)

      Line of Treatment

      1st line

      6 (12.5)

      15 (88.2)

      ≥2nd line

      42 (87.5)

      2 (11.8)

      IHC Results

      PD-L1 IHC

      0%

      9 (19.1)

      9 (53.0)

      1-49%

      25 (53.2)

      5 (29.4)

      ≥50%

      13 (27.7)

      3 (17.6)

      IDO1 IHC

      0%

      23 (47.9)

      11 (64.7)

      ≥1%

      25 (52.1)

      6 (35.3)

      PD-L1/IDO1

      <50% / 0%

      20 (41.7)

      10 (58.8)

      <50% / ≥1%

      15 (31.2)

      4 (23.5)

      ≥50% / 0%

      3 (6.3)

      1 (5.9)

      ≥50% / ≥1%

      10 (20.8)

      2 (11.8)

      Conclusion

      In this retrospective study of NSCLC patients receiving an ICI, our results suggest IDO positivity may be predictive of improved OS. Our ability to detect a statistically significant difference may have been limited by small sample size, particularly in the ICI+CTX cohort. Further studies examining the predictive role of IDO1 IHC would be useful to identify patients most likely to benefit from PD-1 or IDO1 inhibition.

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