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    FP13 - Immunotherapy (Phase II/III Trials) (ID 247)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP13.02 - Pembrolizumab + Pemetrexed-Platinum vs Pemetrexed-Platinum for Metastatic NSCLC: 4-Year Follow-up From KEYNOTE-189 (ID 3194)

      00:00 - 00:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Introduction

      In the randomized, double-blind, phase 3 KEYNOTE-189 trial (NCT02578680) pembrolizumab plus pemetrexed-platinum chemotherapy significantly improved OS and PFS vs placebo plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations, regardless of PD-L1 expression. We present efficacy and safety outcomes after ~4 years of follow-up.

      Methods

      Patients were randomized (2:1) to intravenous pembrolizumab 200 mg or placebo Q3W for up to 35 cycles (2 years). All patients received pemetrexed and investigator’s choice of carboplatin/cisplatin for 4 cycles, followed by maintenance pemetrexed. Treatment continued until radiographic progression/unacceptable toxicity. Crossover from placebo plus chemotherapy to pembrolizumab monotherapy was permitted after PD. Patients who experienced SD or better during initial treatment or crossover phases with pembrolizumab and then experienced PD at any time during the follow-up period could receive second-course pembrolizumab (17 cycles). The primary endpoints were OS and PFS.

      Results

      616 patients were randomized (pembrolizumab plus pemetrexed-platinum, n=410; placebo plus pemetrexed-platinum, n=206). Median (range) time from randomization to data cutoff (August 28, 2020) was 46.3 (41.8–54.1) months. 84 patients (40.8%) randomized to the control group crossed over to pembrolizumab monotherapy on-study. Efficacy outcomes are summarized in the Table. Median (95% CI) OS was 22.0 (19.5‒24.5) months with pembrolizumab plus pemetrexed-platinum vs 10.6 (8.7‒13.6) months with placebo plus pemetrexed-platinum (hazard ratio [HR], 0.60; 95% CI, 0.50‒0.72). 3-year OS rate was 31.3% vs 17.4%. Median (95% CI) PFS was 9.0 (8.1‒10.4) months vs 4.9 (4.7‒5.5) months, respectively (HR, 0.50; 95% CI, 0.41‒0.59). Grade 3‒5 AEs occurred in 72.1% patients in the pembrolizumab plus pemetrexed-platinum group and 67.3% patients in the placebo plus pemetrexed-platinum group. Among 56 patients who completed 35 cycles (2 years) of pembrolizumab, 49 (87.5%) had an objective response (CR, n=6; PR, n=43) and 7 (12.5%) had SD. 45 patients (80.4%) were alive at data cutoff (28 without PD), and 2-year OS after completion of 35 cycles was 79.6%. At data cutoff, 7 patients had initiated second-course pembrolizumab.

      Table. Efficacy Outcomes in the ITT Population and in Subgroups Defined by PD-L1 TPSa

      ITT
      N=616

      TPS ≥50%
      n=202

      TPS 1%-49%
      n=186

      TPS <1%
      n=190

      OS HR (95% CI)b

      0.60 (0.50–0.72)

      0.71 (0.50–1.00)

      0.66 (0.47–0.93)

      0.52 (0.37–0.72)

      3-yr OS rate,b %

      31.3 vs 17.4

      43.7 vs 30.0

      28.3 vs 17.2

      23.3 vs 5.3

      PFS HR (95% CI)b,c

      0.50 (0.41–0.59)

      0.36 (0.26–0.49)

      0.54 (0.39–0.76)

      0.68 (0.49–0.93)

      PFS2 HR (95% CI)b,c,d

      0.52 (0.43–0.63)

      0.55 (0.39–0.77)

      0.59 (0.42–0.83)

      0.49 (0.35–0.68)

      ORR,c %

      48.3 vs 19.9

      62.1 vs 25.7

      50.0 vs 20.7

      33.1 vs 14.3

      Median DOR,b,c mo

      12.6 vs 7.1

      15.1 vs 7.1

      13.6 vs 7.6

      10.8 vs 7.8

      DOR, duration of response; ITT, intention-to-treat; TPS, tumor proportion score
      aAll outcomes are pembrolizumab plus pemetrexed-platinum vs placebo plus pemetrexed-platinum.
      bKaplan-Meier estimate.
      cPer RECIST version 1.1 by blinded independent central review.
      dPFS2 was defined as the time from randomization to second/subsequent tumor progression on next-line treatment/death (per investigator assessment per RECIST version 1.1).

      Conclusion

      With ~4 years of follow-up, pembrolizumab plus pemetrexed-platinum continued to provide OS and PFS benefit vs pemetrexed-platinum alone in patients with previously untreated metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations, irrespective of PD-L1 expression. Patients who received 35 cycles of pembrolizumab had durable responses and most were alive at data cutoff. Toxicity was manageable. Pembrolizumab plus pemetrexed-platinum remains a standard-of-care therapy for patients with newly diagnosed metastatic nonsquamous NSCLC.

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    FP14 - Targeted Therapy - Clinically Focused (ID 252)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP14.12 - Quality of Life and Subgroup Analysis in a Phase 3 Randomized Study of Ensartinib vs Crizotinib in ALK–Positive NSCLC Patients: eXalt3. (ID 3852)

      00:00 - 00:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Introduction

      Ensartinib (X-396) is a novel second-generation ALK tyrosine kinase inhibitor (TKI). In a phase 3 study interim analysis, ensartinib showed statistically significant improvement of median PFS over crizotinib in patients with ALK+ NSCLC who were ALK TKI naive or received up to one prior chemotherapy line, including higher efficacy against brain metastases. Ensartinib was well tolerated, with low grade rash, pruritus, edema, and transaminitis as the most frequent treatment-related AEs. Here we plan to present subgroups analyses and the quality of life outputs of the phase 3 eXalt3 study (NCT02767804).

      Methods

      Patients with locally tested ALK+ NSCLC (ITT population) were randomized 1:1 to ensartinib (225 mg QD orally) or crizotinib (250 mg BID orally). No crossover was allowed. Patients were stratified by prior chemotherapy, ECOG PS, brain metastases, and geographic region. The modified ITT (mITT) population was prespecified to include all centrally ALK+ patients by Abbott FISH test. The primary endpoint was blinded independent review committee (BIRC)–assessed progression-free survival (PFS; RECIST v.1.1). Secondary endpoints included overall survival (OS), overall response rate (ORR), and time to treatment failure (TTF) in the brain and patients reported outcomes (PRO). PRO data collection included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30). A linear mixed model for repeated measures was used to analyze change from baseline in the Global Health Status/Quality of Life subscale (GHS/QOL), with a change of greater than or equal to ten points deemed meaningful. Time to symptom deterioration will be presented.

      Results

      In total, 290 patients were randomized (ensartinib [n=143]; crizotinib [n=147]).Median age was 54.1 y, 26% of patients had prior chemotherapy, and 36% of patients had baseline CNS metastases (5% had prior brain radiotherapy). The mITT population included 247 patients (ensartinib [n=121]; crizotinib [n=126]). At the July 1, 2020, data cutoff, 139 BIRC-assessed PFS events (73%) occurred in the ITT population and 119 (63%) in the mITT population. Median PFS was 25.8 months with ensartinib vs 12.7 months with crizotinib (HR, 0.52; P=.0003 by log-rank test) with a median follow-up of 23.8 and 20.2 months in the ITT population. Median PFS was not reached with ensartinib vs 12.7 months with crizotinib in the mITT population (HR, 0.48; P=.0002 by log-rank test). New subgroup analyses in mITT for ensartinib showed a trend for higher efficacy by prior chemotherapy vs no chemotherapy (mPFS NR vs 25.8). Both global health status (GHS) as well as 5 functional and 9 symptom domains within EORTC QLQ-C30 had clinical meaningful improvement over time for ensartinib. Ensartinib delays the time to worsening of GHS with HR =0.83 (95% CI [0.57, 1.20]) vs crizotinib. Complete subgroup analyses (forest plot and multivariate analyisis) will be presented at the conference as well as OS updates. Comprehenive EORTC QLQ-C30 and Lung Cancer Symptom Scale scores will also be reported at the conference.

      Conclusion

      In ALK+ NSCLC patients ensartinib represents a new option in first-line setting. QOLs data support its favorable safety profile. Relevant subgroups analyses to evaluate its clinical impact will be presented at the meeting.

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    IS07 - Industry Symposium Sponsored by Roche: Expert Perspectives on the Management of Lung Cancer (ID 284)

    • Event: WCLC 2020
    • Type: Industry Symposium
    • Track:
    • Presentations: 1
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      IS07.02 - Future Directions for Cancer Immunotherapy: Resectable NSCLC and Novel Combinations in Lung Cancer (ID 4340)

      16:45 - 17:45  |  Presenting Author(s): Martin Reck

      • Abstract

      Abstract not provided

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    OA02 - Updates in Locally Advanced NSCLC (ID 125)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Locoregional and Oligometastatic Disease
    • Presentations: 1
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      OA02.03 - Pembrolizumab Plus Platinum Chemotherapy and Radiotherapy in Unresectable, Locally Advanced, Stage III NSCLC: KEYNOTE-799 (ID 3199)

      09:15 - 10:15  |  Presenting Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Introduction

      Pembrolizumab has shown durable clinical benefit in advanced/metastatic NSCLC. The ongoing KEYNOTE-799 study (NCT03631784) is evaluating pembrolizumab plus concurrent chemoradiation therapy (cCRT) in patients with unresectable, locally advanced, stage III NSCLC. Previous interim results showed an ORR of 67.0% and 56.6% in cohorts A (squamous/non-squamous) and B (non-squamous), respectively, with ≥15 weeks of follow-up, and grade ≥3 pneumonitis reported in 8.0% and 5.5%, respectively. We report results from KEYNOTE-799 with 6 additional calendar months of follow-up.

      Methods

      This nonrandomized, open-label, phase 2 study enrolled patients aged ≥18 years with previously untreated, unresectable, pathologically confirmed stage IIIA–C NSCLC with measurable disease per RECIST v1.1. Patients in cohort A received 1 cycle of carboplatin AUC6 with paclitaxel 200 mg/m2 and pembrolizumab 200 mg; 3 weeks later patients received carboplatin AUC2 and paclitaxel 45 mg/m2 QW for 6 weeks with 2 cycles of pembrolizumab Q3W plus standard thoracic radiotherapy (TRT). Patients in cohort B (non-squamous only) received cisplatin 75 mg/m2, pemetrexed 500 mg/m2 and pembrolizumab 200 mg Q3W for 3 cycles, plus TRT in cycles 2 and 3. Both cohorts received 14 additional cycles of pembrolizumab 200 mg Q3W thereafter. The primary endpoints are ORR (per RECIST v1.1 by blinded independent central review) and the incidence of grade ≥3 pneumonitis (per NCI CTCAE v4.0). Efficacy was analyzed in all patients with first study dose prior to or on October 31, 2019. Safety was assessed in all patients in the as-treated population.

      Results

      As of July 30, 2020, 213 patients were enrolled (112 in cohort A; 101 in cohort B). The median (range) time from first dose to database cutoff was 15.5 (10.6–20.8) months for cohort A and 13.6 (9.1–20.6) months for cohort B. Efficacy outcomes are summarized in the Table. ORR (95% CI) was 69.6% (60.2%–78.0%) in cohort A and 70.5% (57.4%–81.5%) in cohort B; and was similar in each cohort regardless of PD-L1 TPS or tumor histology. Median duration of response was not reached in either cohort. Grade ≥3 pneumonitis occurred in 9/112 (8.0%) patients in cohort A and 8/101 (7.9%) in cohort B. Seventy-two (64.3%) and 47 patients (46.5%) had grade 3−5 treatment-related AEs in cohorts A and B, respectively.

      Table

      Cohort A

      Pembro + cCRT

      (Paclitaxel + Carboplatin)

      n = 112

      Cohort B

      Pembro + cCRT

      (Pemetrexed + Cisplatin)

      n = 61

      ORR, % (95% CI)

      69.6 (60.2–78.0)

      70.5 (57.4–81.5)

      Median DOR, mo (range)

      NR (1.4+ to 16.1+)a

      NR (2.0+ to 15.9+)a

      DOR ≥12 mo,b %

      82.2

      72.1

      Median PFS, mo (95% CI)

      NR (16.6−NR)

      NR (10.6−NR)

      12-mo PFS rate,b %

      67.7

      65.2

      Median OS, mo (95% CI)

      NR (NR−NR)

      NR (NR−NR)

      12-mo OS rate,b %

      81.2

      88.0

      PD-L1 TPS <1%

      n = 21

      PD-L1 TPS ≥1%

      n = 66

      PD-L1 TPS <1%

      n = 17

      PD-L1 TPS ≥1%

      n = 26

      ORR, n (%)

      14 (66.7)

      49 (74.2)

      11 (64.7)

      18 (69.2)

      Squamous

      n = 73

      Non-squamous

      n = 39

      Squamous

      n = 0

      Non-squamous

      n = 61

      ORR, n (%)

      51 (69.9)

      27 (69.2)

      NA

      43 (70.5)

      a+ indicates there was no disease progression by the time of last disease assessment. bKaplan-Meier estimate.

      Conclusion

      Pembrolizumab with standard cCRT showed promising antitumor activity and manageable safety in patients with unresectable, locally advanced, stage III NSCLC, regardless of PD-L1 TPS and tumor histology.

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    OA11 - A Symphony of Progress (ID 229)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
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      OA11.06 - IMpower133: Exploratory Analysis of Maintenance Therapy in Patients With Extensive-Stage Small-Cell Lung Cancer (ID 3127)

      15:30 - 16:30  |  Presenting Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Introduction

      Several immunotherapies are under investigation across treatment settings in extensive-stage small-cell lung cancer (ES-SCLC). However, studies of maintenance immunotherapy have not shown improved survival outcomes in patients with ES-SCLC. In the Phase I/III IMpower133 study (NCT02763579), adding atezolizumab (anti–PD-L1) to carboplatin+etoposide (CP/ET) followed by atezolizumab maintenance for the first-line treatment of ES-SCLC led to significant overall survival (OS) and progression-free survival (PFS) improvement vs placebo+CP/ET. In this analysis, we explored the benefit of atezolizumab vs placebo in the patients who reached the maintenance phase of IMpower133.

      Methods

      403 patients with untreated ES-SCLC were randomised (1:1) to four 21-day cycles of carboplatin (AUC 5 mg per mL/min IV) + etoposide (100 mg/m2 IV) with atezolizumab (1200 mg IV) or placebo, followed by maintenance atezolizumab or placebo until unacceptable toxicity, disease progression or loss of clinical benefit. The two primary endpoints were OS and investigator-assessed PFS (RECIST v1.1). Patients who received at least the first dose of maintenance atezolizumab/placebo were included in this exploratory analysis. To account for potential lead-time bias, a multivariate Cox model from the start of maintenance treatment was used to evaluate the treatment effect. A generalised linear model (GLM) was used to identify characteristics that could be predictive of reaching the maintenance phase. Baseline characteristics tested in the models included ECOG PS, sex, age, presence of brain metastases, LDH level, SLD and number of metastatic sites.

      Results

      At data cutoff (24 April 2018), the median duration of follow-up was 13.9 mo. A similar proportion of patients received maintenance treatment in the atezolizumab+CP/ET (n=154/201 [76.6%]; 95% CI: 70.2-82.3) and placebo+CP/ET arms (n=164/202 [81.2%]; 95% CI: 75.1-86.3). Baseline characteristics in the maintenance population were well balanced between arms. Median OS in maintenance patients in the atezolizumab+CP/ET and placebo+CP/ET arms was 15.7 and 11.3 mo, respectively (HR, 0.67 [95% CI: 0.49-0.90]; P=0.008); median PFS was 5.5 and 4.5 mo, respectively (HR, 0.73 [95% CI: 0.57-0.92]; P=0.008). The positive treatment effect with atezolizumab remained after adjusting for baseline characteristics (multivariate Cox regression; OS HR, 0.59 [95% CI: 0.43-0.81]; P=0.001; PFS HR, 0.64 [95% CI: 0.50-0.82]; P<0.001). The GLM identified 3 prognostics factors for reaching the maintenance phase: ECOG PS (odds ratio [OR], 0.44; P=0.004), LDH (OR, 0.59; P=0.053) and age (OR, 0.93; P=0.001). Age also appeared to have a significant treatment interaction (P=0.006). Adverse events (AEs) related to treatment with atezolizumab or placebo, respectively, occurred in 64.5% and 52.8% of safety-evaluable maintenance patients. Immune-related AEs in the atezolizumab+CP/ET and placebo+CP/ET arms occurred in 41.3% and 28.2%, respectively. No Grade 5 immune-related AEs were reported.

      Conclusion

      In this exploratory analysis of IMpower133, OS and PFS benefit in patients receiving atezolizumab vs placebo during maintenance treatment was observed. The positive treatment effect persisted after adjusting for baseline characteristics via multivariate Cox regression models. No new or unexpected safety signals were identified. Induction treatment with atezolizumab in combination with CP/ET together with continuation of maintenance therapy with atezolizumab appeared to contribute to the OS benefit observed in IMpower133.

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    P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P01.21 - ANSELMA: Antiangiogenic Second Line Lung Cancer Meta-Analysis on Individual Patient Data in Non-Small Cell Lung Cancer, Again Relevant in ICI Era (ID 721)

      00:00 - 00:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Introduction

      There is renewed interest in the efficacy of 2nd line treatments (2LT) with anti-angiogenics (AA), now that immunotherapy plus chemotherapy (CT) is one of the standard options in 1st line treatment of advanced non-small cell lung cancer (NSCLC). Antibodies (mAb) against VEGF, VEGFR2, or AA tyrosine kinase inhibitors (TKI) have inconsistently shown benefit in combination with CT or erlotinib (E). We performed an individual patient data (IPD) meta-analysis to validate efficacy of these combinations as 2LT.

      Methods

      Randomized trials of AA plus standard 2LT (CT or TKI) compared to 2LT alone that ended accrual before 2015 were identified from publication databases, abstract proceedings and trial registers. Fixed-effect models were used to compute pooled hazard ratios (HRs) for overall survival (OS, primary endpoint), progression-free survival (PFS) and subgroup analyses. Peto method was used to estimate survival benefit.

      Results

      IPD were available for 15 out of 17 eligible trials (only via remote access for 9 trials). Out of 8,502 patients (pts) enrolled, 35% were female and 64% had adenocarcinoma. At 3 years, 10.5% were alive. Addition of AA significantly prolonged OS (HR=0.93 [95% confidence interval (CI): 0.89-0.98], p=0.005) and PFS (0.80 [0.77-0.84], p<0.0001) compared with 2LT alone. Absolute 1-year OS and PFS benefit for AA were +1.9% [95% CI: -0.3%;+4.1%] and +3.6% [+2.0%;+5.2%] respectively. According to the 3 types of combinations (mAb AA + CT, TKI AA + CT, AA + E), there was no significant interaction for OS. Interaction was significant for PFS (p=0.004): HR=0.78 [0.72-0.85], 0.86 [0.80-0.91] and 0.70 [0.63-0.77] respectively. There was a significant reduction of AA benefit on OS when age increased: 0.86 [0.75-0.99], 0.89 [0.81-0.97], 0.94 [0.87-1.02] and 1.04 [0.93-1.17] for pts <50, 50-59, 60-69 and ≥70 respectively (interaction p=0.009). Effect of AA was independent of sex (p=0.98) and performance status (0, ≥1; p=0.78) and ethnicity (Asian, non-Asian, p=0.38). Subgroup results were similar for PFS.

      Conclusion

      In the 2LT of advanced NSCLC, adding AA modestly but significantly prolongs OS and PFS. This appears independent of type of AA drugs, but the observed benefit may be higher in younger pts.

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    P75 - Immunotherapy (Phase II/III Trials) - Misc. Topics (ID 248)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P75.04 - Advanced Lung Cancer Inflammation Index (ALI), Neutrophil-to-Lymphocyte Ratio (NLR), and PD-(L)1 Inhibitor Efficacy in NSCLC (ID 3415)

      00:00 - 00:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Introduction

      Improved biomarkers of immune checkpoint inhibitor (ICI) efficacy are a main objective of research in thoracic oncology currently. The neutrophil-to-lymphocyte ratio (NLR) and advanced lung cancer inflammation (ALI) index (body mass index*serum albumin/NLR) reflect systemic inflammation and are easily reproducible in clinical practice.

      Methods

      The potential value of ALI and NLR as immunotherapy (IO) biomarkers was analyzed in a discovery cohort of 348 advanced NSCLC patients treated with PD-(L)1 inhibitors in the Heidelberg University Hospital, followed by validation in an independent cohort of 590 patients with similar characteristics from 25 cancer centers in Greece (experimental cohorts). An additional control cohort of 444 therapy-naive NSCLC patients treated with first-line platinum-based chemotherapy without subsequent targeted or IO drugs from Heidelberg was also examined in order to discern predictive from prognostic effects. ALI and NLR were dichotomized at the bibliographic cut-offs of 18 and 5, respectively, which corresponded to the median value of our untreated patients (18.03 and 5.00). The relationship of overall survival from start of IO treatment (OS) with other parameters was analyzed with Cox regression models, including calculation of the Harrel’s C-index in both ICI-treated cohorts for validation of results.

      Results

      High ALI values (>18) were significantly associated with longer OS for patients receiving ICI monotherapy in both the training (hazard ratio (HR)=0.43, 95% confidence interval (CI) 0.31-0.61, p<0.0001, n=245) and validation cohorts (HR=0.70, 95% CI 0.52-0.95, p=0.0236, n=507). In contrast, no relationship between ALI and OS was observed for patients treated with chemoimmunotherapy (HR=1.10 with p=0.82, and HR=0.83 with p=0.74 in the two cohorts, respectively). In the control cohort of chemotherapy, the association between ALI and OS was less pronounced compared to the discovery cohort (HR=0.70, 95% CI 0.58-0.85, p=0.0003), and showed a significant interaction with the type of treatment (ICI vs. chemotherapy, p<0.0001) in combined analysis of the two cohorts. The relationships of NLR and PD-L1 tumor proportion score (TPS, absent vs. 1-49 vs. 50-100) with OS were significant also in case of ICI monotherapy only (HR=0.50 with p<0.0001, and HR=0.75 with p=0.013, respectively, in the training cohort), but not with chemoimmunotherapy (p>0.70 for both markers in both cohorts). Among patients treated with ICI monotherapy in both experimental cohorts (n=752), the effect of ALI on OS (HR=0.51, p=6*10‑10) was stronger than that of the NLR (HR=0.55, p=3*10-8) and PD-L1 TPS (HR=0.71, p=10-4). In a multivariable analysis for OS together with other parameters significant in univariable testing, ALI emerged as an independent predictor with the strongest impact (HR=0.48 with p=0.002 for high ALI, HR=0.62 with p=0.005 for first- vs. subsequent-line immunotherapy, HR=0.79 with p=0.023 for higher PD-L1 TPS, and HR=0.83 with p=0.45 for low NLR).

      Conclusion

      The ALI score is a powerful prognostic and predictive biomarker for patients with advanced NSCLC treated with PD-(L)1 inhibitors alone, but not in combination with chemotherapy. Its association with outcome appears to be stronger than that of other widely used parameters, such as the PD-L1 TPS and NLR, and could therefore facilitate more accurate predictions. Reliable markers for chemoimmunotherapy outcomes remain an unmet need in NSCLC.

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    P77 - Immunotherapy (Phase II/III Trials) - Combining Different Immunotherapeutic Approaches (ID 254)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immunotherapy (Phase II/III Trials)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P77.04 - PROPEL: A Phase 1/2 Trial of Bempegaldesleukin (NKTR-214) Plus Pembrolizumab in Lung Cancer and other Advanced Solid Tumors (ID 1548)

      00:00 - 00:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Introduction

      Checkpoint inhibitors (CPIs), are now part of standard treatment in many advanced solid tumors, including metastatic non-small cell lung cancer (NSCLC). However, novel, more effective CPI combinations are needed to broaden, deepen, and prolong responses, especially for patients with poor prognostic features or negative predictive clinical factors for CPI benefit, including programmed death-ligand 1-negative (PD-L1[-]) status. Bempegaldesleukin (BEMPEG; NKTR-214) is a first-in-class CD122-preferential interleukin-2 pathway agonist that directly activates and expands effector T cells and natural killer cells over immunosuppressive regulatory T cells. BEMPEG plus CPI combination has demonstrated promising efficacy and can convert PD-L1(-) tumors to PD-L1(+) in patients with various solid tumors.(1,2) Given the early efficacy data and favorable safety profile of BEMPEG plus nivolumab, PROPEL will evaluate the clinical benefit, safety and tolerability of BEMPEG combined with another CPI, pembrolizumab (PEMBRO). Here, we present the updated methodology and protocol for the enrolling PROPEL study.(3)

      Methods

      This phase 1/2 multinational trial evaluates BEMPEG plus PEMBRO in patients with locally advanced or metastatic solid tumors. During dose escalation (US only), ~40 patients with various advanced solid tumors (first- and second-line melanoma, NSCLC, urothelial carcinoma, head and neck squamous cell carcinoma, and hepatocellular carcinoma; regardless of PD-L1 status) will be treated with escalating doses of BEMPEG plus PEMBRO according to a 3+3 or step-up design. During dose expansion (global), ~58 patients with previously untreated advanced or metastatic NSCLC will be enrolled, and stratified based on PD-L1 status (<1%, 1-49%, and >50% staining on tumor cells by immunohistochemistry [for France only, patients with PD-L1 ≤49% will be excluded]). The primary objectives of the dose escalation are to evaluate safety and tolerability and determine the maximum tolerated dose/recommended phase 2 dose for BEMPEG in combination with PEMBRO. The primary objective of the dose expansion is objective response rate (by RECIST 1.1) in first-line metastatic NSCLC. Enrollment is ongoing (NCT03138889).

      References: 1. Diab A, et al. J Immunotherapy Canc 2019;7(1 suppl):3006; 2. Siefker-Radtke A, et al. J Clin Oncol 2019;37(7 suppl):388; 3. Reck M, et al. Poster presented at ESMO 2019; Poster 127TiP.

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    PS01 - Presidential Symposium (Japanese, Mandarin, Spanish Translation Available) (ID 143)

    • Event: WCLC 2020
    • Type: Plenary
    • Track: N.A.
    • Presentations: 2
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      PS01.04 - International Tailored Chemotherapy Adjuvant Trial : ITACA Trial. Final Results (ID 1820)

      07:00 - 09:00  |  Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Introduction

      Adjuvant platinum-based chemotherapy in early stage non-small cell lung cancer confers a modest 5% overall survival benefit. Different strategies have been investigated to improve these results. mRNA expression of some genes was correlated with the sensitivity or resistance to specific anticancer agents. We aimed to evaluate the predictive utility of the mRNA expression levels of molecular markers ERCC1 and TS.

      Methods

      An open label, randomized, comparative phase III investigator-initiated study (EudraCT 2008-001764-36) of adult patients (aged > 18 years), with an ECOG performance status of 0 or 1 and with a completely resected stage II-III NSCLC according to the 6th edition of the TNM staging System was planned. We enrolled patients from 17 Italian centers and 13 German Centers within 6-12 weeks after radical surgery.

      Genomic analyses were performed soon after surgery and then patients were randomly assigned in each of the 4 genomic subgroups to investigator’s choice of platinum-based chemotherapy (C1-2-3-4) or chemotherapy defined by the molecular markers. In the tailored arm patients with tumors that had high ERCC1 and high TS received single-agent docetaxel (T1); patients with high ERCC1 and low TS received single-agent pemetrexed (T2); patients with low ERCC1 and high TS received cisplatin and gemcitabine (T3); finally, patients with low ERCC1 and low TS received cisplatin and pemetrexed (T4). All anticancer drugs were administered according to standard doses and schedules. We randomly allocated patients with 1:1 ratio centrally using permuted blocks sizes and stratified by stage and smoking status. The primary end point of the study was overall survival according to an intent to treat analysis. For the final statistical analysis all the control arms were grouped in one (control arm) and all tailored chemotherapies in another one (experimental arm).

      Results

      Between December 2008 and August 2014, 773 patients were enrolled and randomly assigned to the treatment groups: 389 to arms C and 384 to arms T (T1, n=148, T2, n=43, T3, N=101, T4, N=92).

      Six hundred and ninety patients were included in the intent to treat analysis. In the control arm the following regimens were used: cisplatin /gemcitabine (n=159, 50.0%), cisplatin /viborelbine (n=123, 38.7%), cisplatin/docetaxel (n=23, 7.2%), platinum/pemetrexed (n=5, 1.6%), others (n=8, 2.5%). At a median follow up of 28.2 months (IQR: 9.9-55.8 months), 86 (24.9%) and 68 (19.8%) patients were deceased in arms C and T, respectively. The estimated median overall survival in arm C was 83.5 months (95%CI: 60.1-not defined) and in arm T was 96.4 months (95%CI: 81.8-not defined; hazard ratio (group T vs. group C) was 0.76 (95%CI: 0.55-1.04; p=0.091). Grade 3-5 toxicities that were reported more frequently in arm C (control) than in arm T (tailored) were neutropenia (18.9% vs 13.4%), leukopenia (13.3% vs 3.9%), thrombocytopenia (7.7% vs 3.3%) and anaemia (2.7% vs 0.9%).

      Conclusion

      In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy on the basis of the mRNA expression of selected genes do not confer a statistically significant survival advantage in terms of overall survival and relapse-free survival and toxicity was less commonly reported in the customization arms.

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      PS01.09 - Pembrolizumab Plus Ipilimumab vs Pembrolizumab Plus Placebo as 1L Therapy for Metastatic NSCLC of PD-L1 TPS ≥50%: KEYNOTE-598 (ID 4248)

      07:00 - 09:00  |  Author(s): Martin Reck

      • Abstract
      • Presentation
      • Slides

      Introduction

      In KEYNOTE-024, pembrolizumab monotherapy significantly improved survival versus platinum-doublet chemotherapy in patients with metastatic NSCLC with PD-L1 TPS ≥50% and no targetable EGFR or ALK aberrations. We conducted the randomized, double-blind, phase 3 KEYNOTE-598 study (NCT03302234) to determine whether adding ipilimumab to pembrolizumab improved efficacy over pembrolizumab alone in this population.

      Methods

      Eligible patients were randomized 1:1 to ipilimumab 1 mg/kg Q6W or saline placebo for up to 18 cycles; patients in both arms received pembrolizumab 200 mg Q3W for up to 35 cycles. Randomization was stratified by ECOG PS (0 vs 1), region (East Asia vs not East Asia), and histology (squamous vs nonsquamous). Treatment differences in the primary endpoints of OS and PFS (RECIST v1.1; blinded, independent central review) were assessed by the stratified log-rank test in the ITT population. The protocol-specified first interim analysis (IA1) was planned to occur when ~255 deaths occurred and ~12 months after the last participant was randomized. Nonbinding futility criteria at IA1 were differences in the restricted mean survival time (RMST) between pembro–ipi and pembro–placebo of ≤0.2 at the maximum observation time and ≤0.1 at 24 months of follow-up.

      Results

      Between 12‑January‑2018 and 22‑August‑2019, 568 participants were randomized to pembro–ipi (n=284; 282 treated) and pembro–placebo (n=284; 281 treated). As of 01‑September‑2020, median (range) study follow-up was 20.6 months (12.4-31.7), treatment was ongoing in 21.3% in the pembro–ipi arm vs 23.8% in the pembro–placebo arm, and median number of treatment cycles was 10 vs 15. Baseline characteristics were balanced between arms. With 272 deaths, median OS was 21.4 months for pembro–ipi vs 21.9 months for pembro–placebo (HR, 1.08 [95% CI, 0.85-1.37]; P = 0.74). RMST differences were –0.56 at the maximum observation time and –0.52 at 24 months, which met the futility criteria. With 372 events, median PFS was 8.2 months for pembro–ipi vs 8.4 months for pembro–placebo (HR, 1.06 [95% CI, 0.86-1.30]; P = 0.72). ORR was 45.4% in both arms; median DOR was 16.1 months for pembro–ipi vs 17.3 months for pembro–placebo. Treatment-related AEs occurred in 76.2% of pembro–ipi recipients vs 68.3% of pembro–placebo recipients, were of grade 3-5 in 35.1% vs 19.6%, led to death in 2.5% vs 0%, and led to discontinuation of any treatment in 25.2% vs 10.7%. Immune-mediated AEs and infusion reactions occurred in 44.7% of pembro–ipi recipients vs 32.4% of pembro–placebo recipients, were grade 3-5 in 20.2% vs 7.8%, led to death in 2.1% vs 0%, and led to discontinuation of any treatment in 14.9% vs 5.3%. Based on the observed efficacy and safety, the external data monitoring committee recommended that the study be stopped due to futility and that participants discontinue ipi/placebo.

      Conclusion

      Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab alone as first-line therapy for metastatic NSCLC with PD-L1 TPS ≥50% and no targetable EGFR or ALK aberrations. These data confirm pembrolizumab monotherapy as a standard-of-care for this population.

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    PS02 - Presidential Symposium (Re-Broadcast) (Japanese, Mandarin, Spanish Translation Available) (ID 275)

    • Event: WCLC 2020
    • Type: Plenary
    • Track: N.A.
    • Presentations: 2
    • +

      PS02.04 - International Tailored Chemotherapy Adjuvant Trial : ITACA Trial. Final Results (ID 4285)

      18:00 - 20:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Introduction
      Adjuvant platinum-based chemotherapy in early stage non-small cell lung cancer confers a modest 5% overall survival benefit. Different strategies have been investigated to improve these results. mRNA expression of some genes was correlated with the sensitivity or resistance to specific anticancer agents. We aimed to evaluate the predictive utility of the mRNA expression levels of molecular markers ERCC1 and TS. Methods

      An open label, randomized, comparative phase III investigator-initiated study (EudraCT 2008-001764-36) of adult patients (aged > 18 years), with an ECOG performance status of 0 or 1 and with a completely resected stage II-III NSCLC according to the 6th edition of the TNM staging System was planned. We enrolled patients from 17 Italian centers and 13 German Centers within 6-12 weeks after radical surgery.

      Genomic analyses were performed soon after surgery and then patients were randomly assigned in each of the 4 genomic subgroups to investigator’s choice of platinum-based chemotherapy (C1-2-3-4) or chemotherapy defined by the molecular markers. In the tailored arm patients with tumors that had high ERCC1 and high TS received single-agent docetaxel (T1); patients with high ERCC1 and low TS received single-agent pemetrexed (T2); patients with low ERCC1 and high TS received cisplatin and gemcitabine (T3); finally, patients with low ERCC1 and low TS received cisplatin and pemetrexed (T4). All anticancer drugs were administered according to standard doses and schedules. We randomly allocated patients with 1:1 ratio centrally using permuted blocks sizes and stratified by stage and smoking status. The primary end point of the study was overall survival according to an intent to treat analysis. For the final statistical analysis all the control arms were grouped in one (control arm) and all tailored chemotherapies in another one (experimental arm).

      Results

      Between December 2008 and August 2014, 773 patients were enrolled and randomly assigned to the treatment groups: 389 to arms C and 384 to arms T (T1, n=148, T2, n=43, T3, N=101, T4, N=92).

      Six hundred and ninety patients were included in the intent to treat analysis. In the control arm the following regimens were used: cisplatin /gemcitabine (n=159, 50.0%), cisplatin /viborelbine (n=123, 38.7%), cisplatin/docetaxel (n=23, 7.2%), platinum/pemetrexed (n=5, 1.6%), others (n=8, 2.5%). At a median follow up of 28.2 months (IQR: 9.9-55.8 months), 86 (24.9%) and 68 (19.8%) patients were deceased in arms C and T, respectively. The estimated median overall survival in arm C was 83.5 months (95%CI: 60.1-not defined) and in arm T was 96.4 months (95%CI: 81.8-not defined; hazard ratio (group T vs. group C) was 0.76 (95%CI: 0.55-1.04; p=0.091). Grade 3-5 toxicities that were reported more frequently in arm C (control) than in arm T (tailored) were neutropenia (18.9% vs 13.4%), leukopenia (13.3% vs 3.9%), thrombocytopenia (7.7% vs 3.3%) and anaemia (2.7% vs 0.9%).

      Conclusion
      In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy on the basis of the mRNA expression of selected genes do not confer a statistically significant survival advantage in terms of overall survival and relapse-free survival and toxicity was less commonly reported in the customization arms.

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      PS02.09 - Pembrolizumab Plus Ipilimumab vs Pembrolizumab Plus Placebo as 1L Therapy for Metastatic NSCLC of PD-L1 TPS ≥50%: KEYNOTE-598 (ID 4292)

      18:00 - 20:00  |  Author(s): Martin Reck

      • Abstract
      • Slides

      Introduction
      In KEYNOTE-024, pembrolizumab monotherapy significantly improved survival versus platinum-doublet chemotherapy in patients with metastatic NSCLC with PD-L1 TPS ≥50% and no targetable EGFR or ALK aberrations. We conducted the randomized, double-blind, phase 3 KEYNOTE-598 study (NCT03302234) to determine whether adding ipilimumab to pembrolizumab improved efficacy over pembrolizumab alone in this population. Methods
      Eligible patients were randomized 1:1 to ipilimumab 1 mg/kg Q6W or saline placebo for up to 18 cycles; patients in both arms received pembrolizumab 200 mg Q3W for up to 35 cycles. Randomization was stratified by ECOG PS (0 vs 1), region (East Asia vs not East Asia), and histology (squamous vs nonsquamous). Treatment differences in the primary endpoints of OS and PFS (RECIST v1.1; blinded, independent central review) were assessed by the stratified log-rank test in the ITT population. The protocol-specified first interim analysis (IA1) was planned to occur when ~255 deaths occurred and ~12 months after the last participant was randomized. Nonbinding futility criteria at IA1 were differences in the restricted mean survival time (RMST) between pembro–ipi and pembro–placebo of ≤0.2 at the maximum observation time and ≤0.1 at 24 months of follow-up. Results
      Between 12‑January‑2018 and 22‑August‑2019, 568 participants were randomized to pembro–ipi (n=284; 282 treated) and pembro–placebo (n=284; 281 treated). As of 01‑September‑2020, median (range) study follow-up was 20.6 months (12.4-31.7), treatment was ongoing in 21.3% in the pembro–ipi arm vs 23.8% in the pembro–placebo arm, and median number of treatment cycles was 10 vs 15. Baseline characteristics were balanced between arms. With 272 deaths, median OS was 21.4 months for pembro–ipi vs 21.9 months for pembro–placebo (HR, 1.08 [95% CI, 0.85-1.37]; P = 0.74). RMST differences were –0.56 at the maximum observation time and –0.52 at 24 months, which met the futility criteria. With 372 events, median PFS was 8.2 months for pembro–ipi vs 8.4 months for pembro–placebo (HR, 1.06 [95% CI, 0.86-1.30]; P = 0.72). ORR was 45.4% in both arms; median DOR was 16.1 months for pembro–ipi vs 17.3 months for pembro–placebo. Treatment-related AEs occurred in 76.2% of pembro–ipi recipients vs 68.3% of pembro–placebo recipients, were of grade 3-5 in 35.1% vs 19.6%, led to death in 2.5% vs 0%, and led to discontinuation of any treatment in 25.2% vs 10.7%. Immune-mediated AEs and infusion reactions occurred in 44.7% of pembro–ipi recipients vs 32.4% of pembro–placebo recipients, were grade 3-5 in 20.2% vs 7.8%, led to death in 2.1% vs 0%, and led to discontinuation of any treatment in 14.9% vs 5.3%. Based on the observed efficacy and safety, the external data monitoring committee recommended that the study be stopped due to futility and that participants discontinue ipi/placebo. Conclusion
      Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab alone as first-line therapy for metastatic NSCLC with PD-L1 TPS ≥50% and no targetable EGFR or ALK aberrations. These data confirm pembrolizumab monotherapy as a standard-of-care for this population.

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