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M.D. Hellmann



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    MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      MA 05.02 - STK11/LKB1 Loss of Function Genomic Alterations Predict Primary Resistance to PD-1/PD-L1 Axis Blockade in KRAS-Mutant NSCLC (ID 10367)

      15:45 - 17:30  |  Author(s): M.D. Hellmann

      • Abstract
      • Presentation
      • Slides

      Background:
      The genomic landscape of primary resistance to PD-1 blockade in lung adenocarcinoma (LUAD) is largely unknown. We previously reported that co-mutations in STK11/LKB1 (KL) or TP53 (KP) define subgroups of KRAS-mutant LUAD with distinct therapeutic vulnerabilities and immune profiles. Here, we present updated data on the clinical efficacy of PD-1/PD-L1 inhibitors in co-mutation defined KRAS mutant and wild-type LUAD patients and examine the relationship between genetic alterations in individual genes, tumor cell PD-L1 expression and tumor mutational burden (TMB) using cohorts form the SU2C/ACS Lung Cancer Dream Team and Foundation Medicine (FM).

      Method:
      The cohorts included 924 LUAD with NGS (FM cohort) and 188 patients with KRAS non-squamous NSCLC (SU2C cohort) who received at least one cycle of PD-1/PD-L1 inhibitor therapy and had available molecular profiling. Tumor cell PD-L1 expression was tested using E1L3N IHC (SU2C) and the VENTANA PD-L1 (SP142) assay (FM). TMB was defined as previously described and was classified as high (TMB-H), intermediate (TMB-I) or low (TMB-L).

      Result:
      188 immunotherapy-treated (83.5% nivolumab, 11.7% pembrolizumab, 4.8% anti-PD1/PD-L1 plus anti-CTLA-4) pts with KRAS-mutant NSCLC were included in the efficacy analysis. The ORR differed significantly between the KL (8.8%), KP (35.9%) and K-only sub-groups (27.3%) (P=0.0011, Fisher’s exact test). KL LUAC exhibited significantly shorter PFS (mPFS 1.8m vs 2.7m, HR=0.53, 95% CI 0.34-0.84, P<0.001, log-rank test) and OS (mOS 6.8m vs 15.6m, HR 0.53, 95% CI 0.34 to 0.84, P=0.0072, log rank test) compared to KRAS-mutant NSCLC with wild-type STK11. Loss-of function (LOF) genetic alterations in STK11 were the only significantly enriched event in PD-L1 negative, TMB-I/H compared to PD-L1 high positive (TPS≥50%), TMB-I/H tumors in the overall FMI cohort (Bonferroni adjusted P=2.38x10[-4], Fisher’s exact test) and among KRAS-mutant tumors (adjusted P=0.05, Fisher’s exact test) . Notably, PD-1 blockade demonstrated activity among 10 PD-L1-negative KP tumors, with 3 PRs and 4SDs recorded. In syngeneic isogenic murine models PD-1 blockade significantly inhibited the growth of Kras mutant tumors with wild-type LKB1 (K), but not those with LKB1 loss (KL), providing evidence that LKB1 loss can play a causative role in promoting PD-1 inhibitor resistance.

      Conclusion:
      Loss of function genomic alterations in STK11 represent a dominant driver of de novo resistance to PD-1/PD-L1 blockade in KRAS-mutant NSCLC. In addition to tumor PD-L1 status and tumor mutational burden precision immunotherapy approaches should take into consideration the STK11 status of individual tumors.

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    OA 07 - Biomarker for Lung Cancer (ID 659)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      OA 07.03a - Impact of Tumor Mutation Burden on the Efficacy of Nivolumab or Nivolumab + Ipilimumab in Small Cell Lung Cancer: An Exploratory Analysis of CheckMate 032 (ID 11063)

      15:45 - 17:30  |  Author(s): M.D. Hellmann

      • Abstract
      • Presentation
      • Slides

      Background:
      CheckMate 032 is a phase 1/2 clinical trial evaluating nivolumab ± ipilimumab in solid tumors, including small cell lung cancer (SCLC). Initial results have shown durable responses and encouraging survival, with benefit seen regardless of PD-L1 status. There is a need for improved biomarkers in SCLC. SCLC is nearly universally found in smokers and is characterized by high tumor mutation burden (TMB). The association of high TMB and clinical benefit from nivolumab ± ipilimumab in patients with SCLC was evaluated in an exploratory analysis of CheckMate 032.

      Method:
      CheckMate 032 evaluated nivolumab ± ipilimumab in non-randomized and randomized cohorts, which were pooled for this analysis. Whole exome sequencing (WES) was conducted on tumor and matched blood samples. TMB was defined as the total number of nonsynonymous somatic mutations. For the exploratory analyses, patients were equally divided into TMB tertiles (defined as low, medium, and high). Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier methods.

      Result:
      Among 401 patients in the intent-to-treat (ITT) population, 211 (53%) had an evaluable TMB result for these analyses (86% of the 246 patients with tissue available to attempt WES). Baseline characteristics and outcomes were similar between the ITT and TMB-evaluable populations. In TMB-evaluable patients treated with nivolumab (n=133), objective response rate (ORR), PFS, and OS were improved in the high TMB cohort vs the medium and low TMB cohorts (ORR: 21.3% vs 6.8% and 4.8%; 1-year PFS: 21.2% vs 3.1% and not calculable; 1-year OS: 35.2% vs 26.0% and 22.1%). Similar benefits were seen in TMB-evaluable patients treated with nivolumab + ipilimumab (n=78) in the high vs medium and low TMB cohorts (ORR: 46.2% vs 16.0% and 22.2%; 1-year PFS: 30.0% vs 8.0% and 6.2%; 1-year OS 62.4% vs 19.6% and 23.4%).

      Conclusion:
      In patients with SCLC, efficacy with nivolumab ± ipilimumab was enhanced in those with high TMB. Among patients with high TMB, ORR and 1-year OS rates were approximately double with nivolumab + ipilimumab compared with nivolumab monotherapy. TMB has a potential role as a biomarker in lung cancer. Optimization of TMB cutoff and prospective investigation are warranted.Acknowledgements: All authors contributed to and approved the abstract; writing and editorial assistance was provided by Beth Burke, PhD, CMPP, of Evidence Scientific Solutions, funded by Bristol-Myers Squibb.Trial Registration: clinicaltrials.gov, NCT01928394

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