Virtual Library

Start Your Search

Matthew Hellmann



Author of

  • +

    MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • +

      MA07.02 - Early Change of dNLR Is Correlated with Outcomes in Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 2676)

      13:30 - 15:00  |  Author(s): Matthew Hellmann

      • Abstract
      • Presentation
      • Slides

      Background

      The [neutrophils/[leucocytes-neutrophils] ratio (dNLR) correlates with immune checkpoint inhibitors (ICI) outcomes in advanced non-small cell lung cancer (aNSCLC) patients. Significance of early dNLR change after the first course of ICI is unknown.

      Method

      Patients with NSCLC treated with ICI (PD(L)1+/-CTLA4) between Nov. 2012 and Jun. 2018 at 16 EU/US centers were included. A control group treated with chemotherapy (CT) only was also evaluated (NCT02105168). dNLR was collected at baseline (B) and at cycle 2 (C2). Patients were categorized as low vs high dNLR at each timepoint (defined as < vs > 3, as previously done), and the change between B and C2 (good = low at both timepoints, poor = high at both timepoints, mixed = different at each timepoint).

      Result

      1485 patients treated with ICI were analyzed. PDL1 was negative in 162 (11%), 1-49% in 178 (12%), ≥50% in 201 (14%), and missing in 944 (64%). dNLR at B and C2 did not associate with PD-L1 status.

      At baseline, dNLR was high in 509 (34%) patients and associated with worse PFS compared to those patients with low dNLR at baseline (HR 1.56, P<0.0001) and OS (HR 2.02, P<0.0001). At C2, dNLR was high in 484 (34%) and similarly associated with worse outcomes compared to patients with low dNLR at C2 (PFS HR 1.64, P<0.0001; OS HR 2.13, P<0.0001).

      Between B and C2, dNLR remained low in 804 (56%, « good ») or high in 327 (23%, « poor ») or changed in 310 pts (22%, « intermediate »). Those with a good dNLR demonstrated mPFS 5.3, mOS 18.6 mo), followed by those intermediate with mixed dNLR (mPFS 3, mOS 9.2 mo), and finally poor dNLR (mPFS 2, mOS 5mo). Outcomes were independant of PD-L1 expression (adjusted HR for PFS 1.94 for intermediate and 3.16 for poor groups, compared to good dNLR group, P<.001; adjusted HR for OS was 2.08 for intermediate and 3.67 for poor groups, P<0.001).A bootstrap tested the stability of OS/PFS prediction (P<0.001).

      In the chemo-cohort (n=173), high C1-dNLR (n=81, 47%) was not associated with OS (P=0.84).

      Conclusion

      dNLR at baseline, at cycle 2, and the change between these two timepoints associated with outcomes in patients treated with immunotherapy independent of PD-L1, but not in patients treated with chemotherapy alone. dNLR is specifically prognostic in the context of immunotherapy.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 3
    • Now Available
    • +

      MA11.01 - Multifactorial Model to Predict Response to PD-(L)1 Blockade in Patients with High PD-L1 Metastatic Non-Small Cell Lung Cancer (Now Available) (ID 2322)

      14:00 - 15:30  |  Author(s): Matthew Hellmann

      • Abstract
      • Presentation
      • Slides

      Background

      High PD-L1 expression (≥50%) is a routine biomarker but is incompletely predictive, with response rates to PD-1 monotherapy only 35-45% in patients with lung cancer. Beyond PD-L1, additional individual pre-treatment variables, including clinical (smoking history, BMI), genomic (TMB, STK11, EGFR), and laboratory features (baseline dNLR), individually associate with response but have not been comprehensively examined in combination. We hypothesized that a multifactorial model incorporating routinely available clinical, pathologic, and genomic variables could improve prediction of response in high PD-L1 patients receiving first line anti-PD-(L)1 monotherapy.

      Method

      190 patients from MSKCC with advanced, PD-L1 high NSCLC (PD-L1 ≥50%) treated with PD-1 or PD-L1 inhibitor were identified and separated into training (n=134, 70%) and validation cohorts (n=56, 30%). In addition to PD-L1 expression, 39 variables were collected, including histology, clinical (age, gender, performance status, smoking, clinical trial vs standard of care treatment), molecular (TMB, EGFR, KRAS, STK11, KEAP1, TP53, ALK, ROS1, BRAF), and baseline CBC (including dNLR). Radiologic response assessments were performed according to RECIST 1.1. To distinguish responders vs. non-responders, a logistic regression classifier with an elastic net penalty was used to restrict the number of variables considered and to optimize generalizability to independent cohorts. The parameters of the model were optimized using only the training cohort and its performance was measured on the validation cohort.

      Result

      In PD-L1 high NSCLC patients treated with PD-(L)1 blockade, the ORR was 43%. In the training cohort, 5 features (PD-L1 expression, current smoking status, lymphocyte count, platelets, total WBC) associated with response . Three features (EGFR mutation, STK11 mutation, standard of care treatment) associated with lack of response. TMB was not predictive within this selected PD-L1 high cohort. In the training cohort, the eight identified features were used to develop a multifactorial model which improved BOR prediction (AUC 0.83) compared to PD-L1 alone (AUC 0.65), p=0.02. Improved performance of the model was confirmed in the validation cohort (AUC 0.66 for multifactorial model vs. AUC 0.52 for PD-L1 alone).

      Conclusion

      Among patients with high PD-L1 expression, multiple clinical, molecular, and baseline laboratory features impact response to PD-(L)1 monotherapy. The addition of these routinely available variables to PD-L1 in a multifactorial model improves prediction of response to PD-(L)1 blockade in patients with high PD-L1. This approach may help further stratify patients within the PD-L1 high population and identify which patients are likely to benefit from PD-(L)1 monotherapy vs those who should consider chemotherapy + immunotherapy.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA11.10 - Peripheral T Cell Repertoire Evolution in Resectable NSCLC Treated with Neoadjuvant PD-1 Blockade (Now Available) (ID 1999)

      14:00 - 15:30  |  Author(s): Matthew Hellmann

      • Abstract
      • Presentation
      • Slides

      Background

      Neoadjuvant PD-1 blockade has emerged as a promising treatment for resectable NSCLC. The neoadjuvant setting provides a unique opportunity to examine temporal-spatial dynamics of the T cell repertoire in the peripheral and tumoral compartments in response to PD-1 blockade.

      Method

      T-cell receptor (TCR) repertoire dynamics and composition were assessed in matched tumor, normal lung, and longitudinal peripheral blood from 20 NSCLC patients treated with neoadjuvant nivolumab (NCT02259621) and were correlated with major pathologic response (MPR , ≤10% viable tumor in resected specimen) at the time of resection. Treatment-induced dynamics of activated T cell clonotypes were additionally evaluated using TCR sequencing (TCRseq) of flow-sorted PD-1+ T cell populations. To focus on the phenotype of on-treatment intratumoral T cell clones that were recruited from the periphery, combined single-cell RNAseq/TCRseq was performed on post-treatment tumors of 6 patients (3 MPR and 3 non-MPR).

      Result

      MPR was associated with a more clonal intratumoral TCR repertoire and greater clonotypic sharing between pre-treatment blood and post-treatment tumor bed relative to non-MPR. Peripheral repertoire remodeling in response to anti-PD-1 treatment correlated with increased tumor infiltration. Specifically, in patients with MPR, the post-treatment tumor bed was enriched with T cell clones that were peripherally expanded between 2-4 weeks after PD-1 blockade. Clonotypic tracking of the peripherally expanded clones revealed persistence of those clones in the periphery 1+ years following surgical resection and cessation of PD-1 blockade. Single-cell RNAseq/TCRseq analyses revealed distinct phenotypes of peripherally expanded TIL for patients with MPR, with upregulated gene programs associated with cytotoxicity and cytoprotective effects against oxidative stress. Long-term peripherally-persistent TILs had significant upregulation of genes including GZMK, DUSP2, NKG7, 4-1BB and down-regulation of CTLA-4, CXCL13 and PDCD1 as compared to short-lived clones.

      Conclusion

      Our findings support the notion that neoadjuvant checkpoint blockade expands anti-tumor T cell clones in the periphery that can accumulate in tumor bed, facilitate tumor regression, and promote clonotypic persistence in the periphery. Importantly, our data demonstrate the systemic effect of neoadjuvant PD-1 blockade and indicate that the periphery may be an underappreciated originating compartment of effective anti-tumor immunity.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)

      14:00 - 15:30  |  Author(s): Matthew Hellmann

      • Abstract
      • Presentation
      • Slides

      Background

      Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.

      Method

      620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.

      Result

      Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.

      Conclusion

      In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    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
    • +

      P1.01-107 - KEYNOTE-495/KeyImPaCT: Phase 2 Biomarker-Directed Study of Pembrolizumab-Based Therapy for Non–Small Cell Lung Cancer (ID 1355)

      09:45 - 18:00  |  Author(s): Matthew Hellmann

      • Abstract

      Background

      Immune checkpoint–based therapy has revolutionized the care of patients with non–small cell lung cancer (NSCLC). Pembrolizumab-based combination therapy aims to improve clinical outcomes over pembrolizumab monotherapy. Identification of biomarkers associated with improved response to different combination therapies may improve overall outcomes and yield a more precise approach to the use of immunotherapies in NSCLC. To test the clinical usefulness of a biomarker-informed, pembrolizumab-based combination therapy, this phase 2 KEYNOTE-495 trial (NCT03516981) will be carried out in patients with treatment-naive, advanced NSCLC.

      Method

      KEYNOTE-495 is a randomized, multicenter, open-label, phase 2 trial. Tumor tissue from patients with treatment-naive, advanced NSCLC will be initially screened for 2 validated, independent, next-generation biomarkers: T cell–inflamed gene expression profile (GEP) and tumor mutational burden (TMB). Based on the results of this biomarker screening, patients will be assigned to 1 of 4 groups: TMBlowGEPlow, TMBhighGEPlow, TMBlowGEPhigh, and TMBhighGEPhigh. Within each group, patients will be randomly assigned to receive pembrolizumab combined with MK-4280 (anti–LAG-3), lenvatinib, or MK-1308 (anti–CTLA-4). This is a group-sequential, adaptive randomization trial. Patients will be randomly assigned to MK-4280 or lenvatinib first, after which MK-1308 will be introduced; randomization has been modified to accommodate the delayed introduction of MK-1308. Response will be assessed by tumor imaging every 9 weeks for the first year, then every 12 weeks thereafter using RECIST v1.1. Treatment will continue for 35 cycles (~2 years). Patients in the pembrolizumab + lenvatinib arm who complete 35 treatments may continue with lenvatinib monotherapy until disease progression or toxicity. After a patient experiences disease progression or starts new anticancer therapy, the patient will be followed up and contacted every 12 weeks until death, withdrawal of consent, or study end, whichever occurs first. Safety will be monitored throughout the study and for 30 days after treatment or before initiation of a new anticancer treatment, whichever occurs first. Treatment arms may be terminated during the interim analysis because of safety, prespecified futility criteria, or both. The primary end point is investigator-assessed objective response rate (RECIST v1.1). Secondary end points are progression-free survival, overall survival, and safety. Recruitment and screening are ongoing in more than 14 countries and will continue until ~288 patients are randomly assigned across the biomarker-defined groups to determine the optimal treatment for each subgroup.

      Result

      Section not applicable

      Conclusion

      Section not applicable

  • +

    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
    • +

      P1.04-39 - Molecular Characteristics, Immunophenotype, and Immune Checkpoint Inhibitor Response in BRAF Non-V600 Mutant Lung Cancers (ID 1529)

      09:45 - 18:00  |  Author(s): Matthew Hellmann

      • Abstract
      • Slides

      Background

      Targeted therapy for Class I BRAF mutant lung cancers (V600) is well described and there is growing literature on their response to immune checkpoint inhibitors (ICI). In contrast, the molecular characteristics, immunophenotype, and response rates of class II and III BRAF mutations are not well defined.

      Method

      Patients with BRAF Class I, II, III mutant and variants of unknown significance (VUS) lung cancers detected on NGS (MSK-IMPACT) from 1/2014-1/2018 were identified. PD-L1 by immunohistochemistry (E1L3N) was evaluated. Tumor mutation burden (TMB; mut/Mb) was determined by MSK-IMPACT. Best objective response to ICI was assessed by RECIST v1.1. Time to treatment discontinuation (TTD) and overall survival (OS) were assessed. Statistical analysis was performed with Fisher’s exact and Kaplan-Meier. BRAF V600 lung cancers were used as a comparator and analyzed separately from BRAF non-V600.

      Result

      6.0% (177/2962) of lung cancers harbored a BRAF-mutation. Median TMB of BRAF non-V600 mutant lung cancers was 10.8 mut/Mb (n=136) overall compared to 4.9 mut/Mb in V600 (n=41; p<0.0001) and 5.9 mut/Mb in BRAF wild-type patients (n=2785; p<0.0001). 69% (127/177) of BRAF-mutant cases were metastatic (29 Class I, 36 Class II, 23 Class III, and 39 VUS). 57% of patients were female, 82% were smokers, and 90% were adenocarcinoma. More smokers were seen in the BRAF V600 group than in the non-V600 group (n = 16 vs 88 respectively, p<0.0001). PD-L1 expression in 49 non-V600 cases with available tissue was 0%, 1-49%, and >50% in 59% (n=29), 31% (n=15), and 10% (n=5) respectively. 7 BRAF V600 cases with PDL1 testing had expression of 0%, 1-49%, and >50% in 2, 3, and 2 cases, respectively. No BRAF V600 cases had concurrent RAS/NF1-alterations compared to 11 non-V600 (p=0.07).

      36 patients with BRAF non-V600 mutations received ICI (nivolumab (n=25), pembrolizumab (n=5), atezolizumab (n=2), ipilimumab/nivolumab (n=4); median line of therapy=2) with an ORR of 22% (8/36). 10 BRAF V600 mutant lung cancer patients received ICI (nivolumab (n=5), pembrolizumab (n=2), atezolizumab (n=1), ipilimumab/nivolumab (n=2); median line of therapy=2) with an ORR of 10% (1/10). There was no difference in ORR between non-V600 and V600 patients that received ICI (p=0.66). TTD in BRAF non-V600 was 3.2 months compared to 1.4 months for BRAF V600 mutant lung cancer patients (HR 0.59, p=0.26). Median TMB in patients with BRAF non-V600 mutations that responded vs those who did not was 13.2 and 10.8 mut/Mb respectively (p=0.92). One response to ICI was seen in a BRAF V600 with TMB of 19.3. OS of BRAF non-V600 patients was 1.7 years compared to 2.5 years in V600 (HR 1.25, p=0.38). OS was higher in BRAF non-V600 lung cancer patients who received ICI (2.4 years) compared to those that did not (1.2 years; HR 0.60, p=0.04).

      Conclusion

      The molecular characteristics and immunophenotype of BRAF non-V600 mutant lung cancers is typified by high TMB and low PD-L1 expression, with reasonably higher response rates and improved OS to later line ICI compared to BRAF V600. Further studies of immunotherapy in this oncogene subset is warranted.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
    • +

      P2.04-24 - Transcriptional Profiling of Neoantigen Specific T Cells in Resectable NSCLC Treated with Neoadjuvant Anti-PD-1 (Now Available) (ID 2357)

      10:15 - 18:15  |  Author(s): Matthew Hellmann

      • Abstract
      • Slides

      Background

      Neoadjuvant nivolumab has a manageable safety profile and can be effective in patients with resectable non-small cell lung cancer (NSCLC). To characterize the immune response in these patients, we sought to evaluate the existence and dynamics of neoantigen specific tumor-infiltrating T cells and identify their molecular phenotype including co-inhibitory checkpoint expression.

      Method

      We evaluated peripheral blood and tumor infiltrating lymphocytes from seven patients treated with nivolumab. To identify neoantigen-specific T cell responses, we used MANAFEST (Mutation Associated Neoantigen Functional Expansion of Specific T cells), an assay we developed that links antigen specificity with unique CD8+ TCR Vβ CDR3 identities. We then carried out single cell TCRseq/RNAseq of tumor infiltrating T lymphocytes (TIL) to enumerate the genome wide digital gene expression and T cell clonotypic identity of each single cell (VDJ+DGE analysis), and particularly those with Vβ CDR3 regions identical to those identified as neoantigen-specific by MANAFEST.

      Result

      Neoantigen-specific TCRs were detected in peripheral blood in all 3 patients with major pathologic response (MPR) and in 3 of 4 patients without MPR. Several of these clonotypes were found in the resected tumor and underwent peripheral expansions upon PD-1 blockade. In one notable patient, MD043-011, MANAFEST detected a T cell clonotype specific for a CARM1 R208W mutation, despite this patient having no evidence of pathologic response. This neoantigen-specific clonotype represented 3.4% of TIL. Two years later, this patient recurred with a solitary brain metastasis. Single cell analyses of TIL in the primary lung lesion and brain metastasis revealed the same neoantigen-specific T cell clonotype was detected in the metastatic lesion. Strikingly, this clonotype exhibited a differential expression profile in the primary and recurrent lesion, with the clonotype in the primary tumor having an enrichment and upregulation of heat shock proteins indicating molecular stress and the clone in the metastatic lesion having an upregulation of checkpoint molecules, including CTLA4, TIM3, and LAG3. T cell cloning and validation experiments, as well as identification of transcriptional programs associated with MPR, are ongoing.

      Conclusion

      The coupling of MANAFEST with single cell VDJ+ DGE analysis enabled us to characterize antigen specific clonotypes after differential expansion using the TCR as a molecular barcode. The presence of alternate co-inhibitory immune checkpoints on neoantigen-specific TIL from non-responding tumors suggests a potential driver of resistance to anti-PD-1 in early stage NSCLC. Ultimately, this integrative approach may provide key insights in predicting and understanding clinical response to neoadjuvant PD-1 blockade in NSCLC.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.