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Giovanna Speranza



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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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      OA04.06 - Evaluation of TMB in KEYNOTE-189: Pembrolizumab Plus Chemotherapy vs Placebo Plus Chemotherapy for Nonsquamous NSCLC (Now Available) (ID 1936)

      15:15 - 16:45  |  Author(s): Giovanna Speranza

      • Abstract
      • Presentation
      • Slides

      Background

      First-line pembrolizumab plus chemotherapy with pemetrexed and platinum significantly improved OS (HR 0.49, P < .001), PFS (HR 0.52, P < .001) and ORR (47.6% vs 18.9%, P < .001) vs placebo plus chemotherapy with pemetrexed and platinum for metastatic nonsquamous NSCLC in the double-blind phase 3 KEYNOTE-189 study (NCT02578680); benefit was observed in all analyzed subgroups, including PD-L1 TPS <1%, 1-49%, and ≥50%. We explored the association of TMB with efficacy in KEYNOTE-189.

      Method

      616 patients were randomized 2:1 to pembrolizumab plus chemotherapy or placebo plus chemotherapy. TMB was determined by whole-exome sequencing of tumor and matched normal DNA. Association of TMB (continuous log10 transformed) with outcomes in each arm was assessed using Cox proportional hazards models (OS, PFS) and logistic regression (ORR); statistical significance was determined at the 0.05 level without multiplicity adjustment. The clinical utility of TMB on outcomes was assessed using prespecified TMB cutpoints of 175 and 150 Mut/exome (~13 and ~10 Mut/Mb by FoundationOne CDx). Data cutoff was 21 Sep 2018.

      Result

      293 (48.3%) treated patients had evaluable TMB data: 207 for pembrolizumab plus chemotherapy, 86 for placebo plus chemotherapy. Baseline characteristics and outcomes were generally similar in the TMB-evaluable and total populations. TMB as a continuous variable was not significantly associated with OS, PFS, or ORR for pembrolizumab plus chemotherapy (one-sided P = .174, .075 and .072, respectively) or placebo plus chemotherapy (two-sided P = .856, .055 and .434, respectively). Pembrolizumab plus chemotherapy improved OS, PFS, and ORR for TMB ≥175 and <175 (Table). Results were similar for TMB ≥150 and <150.

      Conclusion

      TMB was not significantly associated with efficacy of pembrolizumab plus chemotherapy or placebo plus chemotherapy as first-line therapy for metastatic nonsquamous NSCLC. Pembrolizumab plus chemotherapy had a similar OS benefit in the TMB-high and low subgroups.

      TMB ≥175 TMB <175

      Pembrolizumab plus Chemotherapy

      n = 100

      Placebo plus Chemotherapy

      n = 34

      Pembrolizumab plus Chemotherapy

      n = 107

      Placebo plus Chemotherapy

      n = 52
      Median OS (95% CI), mo 23.5
      (20.2-NE)      		 13.5
      (7.0-NE)      		 20.2
      (15.8-NE)      		 9.9
      (7.4-19.1)
      HR (95% CI) 0.64 (0.38-1.07) 0.64 (0.42-0.97)
      Median PFS (95% CI), mo 9.2
      (7.6-14.0)      		 4.7
      (4.0-5.5)      		 9.0
      (6.7-11.1)      		 4.8
      (4.5-6.6)
      HR (95% CI) 0.32 (0.21-0.51) 0.51 (0.35-0.74)
      ORR, % (95% CI) 50.0
      (39.8-60.2)      		 11.8
      (3.3-27.5)      		 40.2
      (30.8-50.1)      		 19.2
      (9.6-32.5)

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