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Roy S. Herbst



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    ES06 - New Approaches in Second Line Treatment In NSCLC (ID 9)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      ES06.01 - Recent Advances in Second Line Treatment (Now Available) (ID 3181)

      13:30 - 15:00  |  Presenting Author(s): Roy S. Herbst

      • Abstract
      • Presentation
      • Slides

      Abstract

      Despite advances in the treatment of cancer and reductions in smoking rates, lung cancer continues to be one of the leading causes of cancer death worldwide. Over the past decade, a handful of immune-checkpoint inhibitors (nivolumab, pembrolizumab, atezolizumab) have been shown to improve survival and changes have been made to the standard of care for first-line treatment of patients with non-small cell lung cancer (NSCLC). However, only a minority of patients respond to these treatments and even these patients acquire resistance to the therapy. Continued investigation and research for second-line therapy options are vital to provide treatment options to patients who progress. Master protocols, like LUNGMAP, are efficient trial designs used to quickly and safely investigate new therapies or combinations. LUNGMAP is the first major trial, supported by the National Cancer Institute (U.S.) to simultaneously test multiple treatments under an umbrella design. LUNGMAP was launched in 2014 to investigate new therapies for squamous cell lung cancer, enrolling over 2000 patients. In 2018, the trial underwent a major expansion to include all non-small cell lung cancer patients. Treatments being tested include immunotherapy combinations and targeted therapies that are associated with specific genomic alterations. This allows for the identification of potential biomarkers which can help identify the treatments that would most likely benefit a patient. LUNGMAP is an unprecedented public-private partnership that is more flexible and efficient and will help to speed-up the development process for new lung cancer drugs.

      References:

      RS Herbst et al. Clin Cancer Res. 2015 Apr 1;21(7):1514-24 doi: 10.1158/1078-0432.CCR-13-3473. Epub 2015 Feb 13.

      lung map schema.jpg

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

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 2
    • Now Available
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      MA11.09 - Increased Frequency of Bystander T Cells in the Lungs Is Associated with Recurrence in Localized Non-Small Cell Lung Cancer (Now Available) (ID 955)

      14:00 - 15:30  |  Author(s): Roy S. Herbst

      • Abstract
      • Presentation
      • Slides

      Background

      Non-small cell lung cancer (NSCLC) exhibits a high mutational burden. As a result, patients afflicted by this tumor type experience greater responses to immune checkpoint blockade. This is largely due to the ability of T cells to destroy tumor cells on the basis of antigens recognized by their T cell receptor (TCR). However, the lungs are exposed to carcinogens and pathogens which can also trigger a T cell response distinct from cancer. Therefore, a better understanding of the T cell repertoire in the lungs is needed to improve upon the success of current immunotherapies in NSCLC.

      Method

      We obtained peripheral blood, tumors, and adjacent uninvolved lungs from a cohort of 236 early stage NSCLC patients. Whole exome sequencing, RNA microarray, immunohistochemistry (CD3, CD4, CD8, CD57, CD68, FoxP3, CD45RO, GzmB, PD-1, and PD-L1) and T cell repertoire sequencing were performed in NSCLC patients and lungs from organ donors and COPD patients. Antigen specificity was predicted using the Grouping of Lymphocyte Interactions by Paratope Hotspot (GLIPH) algorithm. Single cell TCR and RNA sequencing as well as sequencing of the virome are underway.

      Result

      Clonality was associated with CD8 T cells (r=0.31; p=0.0003), GzmB (r=0.29; p=0.001) and IFN-γ (r=0.52; p<0.0001) production as well as with tumor mutational burden (r=0.19; p=0.015), HLA-B (r=0.29; p=0.0005) and β2-m expression (r=0.20; p=0.018). Patients with classical EGFR mutations exhibited lower T cell clonality (p=0.003) even after adjustment for TMB, highlighting the impact of this driver mutation on the T cell response. Surprisingly, clonality was higher in the adjacent uninvolved lung than tumor (p<0.0001), suggesting an active antigenic response outside the tumor. Comparison of the composition of the T cell repertoire between the uninvolved lung and tumor revealed 57% of the top 100 T cells in the tumor were also found in the adjacent normal lung, highlighting certain parallels in the ongoing antigenic responses. Deeper analysis suggested that shared T cells may have been reactive against mutations shared between the normal lung and tumor (r=0.23, p=0.028) or viruses (p<0.0001). Accordingly, patients with a more reactive T cell repertoire outside the tumor (i.e. bystanders) exhibited shorter disease-free survival (p=0.036) suggesting these responses against shared mutations and/or viruses may detract from the anti-tumor T cell response.

      Conclusion

      Our findings highlight the importance of understanding the specificity of the T cell repertoire in the lungs in patients with NSCLC treated with immunotherapy. As a high proportion of bystander T cells appear to reside in the lungs, their reactivation could contribute to the impaired responses and/or increased toxicity observed in certain patients with NSCLC treated with immunotherapy.

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      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): Roy S. Herbst

      • 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.

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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA14.07 - Phase I Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naïve Non-Small Cell Lung Cancer (JVDF) (Now Available) (ID 209)

      15:45 - 17:15  |  Presenting Author(s): Roy S. Herbst

      • Abstract
      • Presentation
      • Slides

      Background

      Emerging data suggest blockade of vascular endothelial growth factor receptor 2 (VEGFR-2) with ramucirumab (R) and programmed cell death 1 protein (PD-1) with pembrolizumab (P) has anti-tumor activity. The JVDF study (NCT02443324) evaluated the safety and efficacy of R+P in locally advanced and unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma, non-small cell lung cancer (NSCLC), urothelial carcinoma, and biliary tract cancer. Data from NSCLC patients receiving R+P as first-line therapy are reported.

      Method

      Eligible patients had treatment-naïve, PD-L1 positive, histopathologically confirmed nonsquamous or squamous NSCLC and received R 10 mg/kg and P 200 mg on Day 1 every 21 days for up to 35 cycles until confirmed disease progression or discontinuation for other reasons. Response and progression were assessed using RECIST 1.1 with confirmatory scans. PD-L1 was assessed using the PD-L1 IHC 22C3 pharmDx assay; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥1%.

      Result

      As of August 31, 2018, 26 patients were treated. Baseline characteristics were as expected for an advanced, treatment-naïve population. Median follow-up was 17.4 (13.4, 20.1) months. Adverse events were consistent with R+P, with no additive toxicities. Eleven (42.3%) patients experienced Grade ≥3 treatment-related adverse events (TRAEs), most commonly hypertension (15.4%) and myocardial infarction (7.7%). No patients discontinued because of TRAEs; the two on-study deaths were due to disease progression. Efficacy results are shown in the table.

      table.jpg

      Conclusion

      In previously untreated NSCLC, R+P has a manageable safety profile and is active in patients with PD-L1 expression. Updated results will be presented at the meeting. Randomized trials in this population are warranted.

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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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      OA04.01 - A Phase III Randomized Study of Nivolumab/Ipilimumab vs Nivolumab for Previously Treated Stage IV Squamous Cell Lung Cancer (Now Available) (ID 872)

      15:15 - 16:45  |  Author(s): Roy S. Herbst

      • Abstract
      • Presentation
      • Slides

      Background

      Lung-MAP is a master protocol for patients (pts) with stage IV previously treated SqNSCLC. S1400I enrolled pts who were not eligible for a biomarker-matched sub-study. (Lung-MAP Sub-Study S1400I, NCT02785952)

      Method

      S1400I is phase III randomized trial for immunotherapy-naïve patients with ECOG 0-1 not selected by PD-L1 expression. Pts were assigned 1:1 to nivolumab and ipilimumab (N+I) vs nivolumab (N). N was given at 3 mg/kg q 2w, I was given at 1 mg/kg q 6w. The primary endpoint was overall survival (OS). Secondary endpoints: investigator-assessed progression-free survival (IA-PFS), response by RECIST 1.1, and toxicity.

      Result

      From December 18, 2015 to April 23, 2018, 275 pts enrolled and 252 determined eligible (125 N+I and 127 N). Median follow up for patients still alive was 17.4 months. The study was closed for futility at an interim analysis. Baseline characteristics were similar across arms. mOS was 10.0 m (8.0-12.8) and 11.0 m (8.2-13.5) for N+I and N. HR 0.97 (0.71-1.31), p 0.82. mPFS was 3.8 m (2.3-4.2) and 2.9 m (1.8-3.9) for N+I and N. HR 0.84 (0.64-1.09), p 0.19. The response rate was 18% (12-25) in N+I and 17 % (11, 24) in N. Outcomes were similar across TMB subgroups and PD-L1 expression levels. Most AE were low grade. There were 5 grade 5 AE in N+I arm and 1 in N arm. Grade ≥3 treatment-related AEs occurred in 48(39%) of pts on N+I vs 38(31%) on N. irAE reported in 39% of pts on N+I and 34% of patients on N. Drug-related AEs led to discontinuation in 25% of pts on N+I and 16% of pts on N.

      OS and PFS based on TMB and PD-L1

      N+I

      Median in months

      N

      Median in months
      HR p
      OS PD-L1 ≥5 14.1 (5.8-17.5) 12.0 (8.2-19.8) 1.06 (0.58-1.92) 0.86
      OS PD-L1 <5 8.3 (6.0-10.7) 10.3 (6.3-13.5) 1.01 (0.62-1.65) 0.97
      OS TMB ≥10 13.1 (9.3-17.0) 11.4 (8.2-16.1) 0.86 (0.56-1.32) 0.48
      OS TMB <10 7.6 (5.7-10.2) 10.0 (6.3-15.2) 1.08 (0.68-1.71) 0.74
      PFS PD-L1 ≥ 5 3.9 (1.7-7.1) 2.9 (1.8-4.7) 0.65 (0.38-1.08) 0.10
      PFS PD-L1 <5 4.4 (2.1-6.0) 1.6 (1.5-3.0) 0.64 (0.41-1.01) 0.06
      PFS TMB ≥ 10 4.2 (3.4-5.9) 3.4 (1.8-5.3) 0.75 (0.52-1.10) 0.15
      PFS TMB < 10 1.9 (1.5-4.1) 2.7 (1.6-3.3) 0.92 (0.62-1.39) 0.70

      Conclusion

      S1400I failed to show improvement in outcomes with N+I. Study was closed for futility at interim analysis. Toxicities were not different between two arms. Molecular correlates will be presented at the meeting.

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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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      P1.01-107 - 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): Roy S. Herbst

      • 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

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    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
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      P1.04-28 - COAST: Durvalumab Alone or with Novel Agents for Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer (ID 174)

      09:45 - 18:00  |  Presenting Author(s): Roy S. Herbst

      • Abstract
      • Slides

      Background

      The standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) is platinum-based chemotherapy with concurrent radiotherapy, followed by durvalumab consolidation for 12 months. When administered after completion of concurrent chemoradiotherapy (cCRT) in patients with unresectable NSCLC in the PACIFIC study, durvalumab demonstrated superior clinical outcomes vs placebo in terms of progression-free survival (PFS; hazard ratio [HR] 0.51; 95% CI: 0.41, 0.63) and overall survival (OS; HR 0.68; 99.73% CI 0.47, 0.997; p=0.0025).1 Comparing durvalumab with placebo, the 24‑month OS rate (95% CI) was 66.3% (61.7, 70.4) vs 55.6% (48.9, 61.8), median PFS was 17.2 months (13.1, 23.9) vs 5.6 months (4.6, 7.7) and objective response rate was 30.0% (25.8, 34.5) vs 17.8% (13.0, 23.6).1,2 However, despite cCRT followed by durvalumab, most patients with unresectable stage III NSCLC relapse and eventually die from NSCLC. The COAST study (NCT03822351) is a platform trial that aims to identify potential combinations of durvalumab with novel agents to improve response rates over monotherapy.

      Method

      This multidrug, randomized, phase 2 trial is evaluating the clinical activity and safety of durvalumab alone or in combination with the novel agents oleclumab (MEDI9447) and monalizumab (IPH2201) in patients with unresectable, stage III NSCLC who have not progressed following definitive cCRT. New treatment arms evaluating other durvalumab combinations may be added based on emerging preclinical and clinical data. The primary endpoint is objective response per RECIST v1.1 with monotherapy and combination therapy. Secondary endpoints include safety, efficacy (duration of response, disease control, PFS, 12-month PFS rate, OS), pharmacokinetics and immunogenicity. The COAST study is open for accrual with an estimated total target enrollment of up to 60 patients per treatment arm.

      References

      1Antonia SJ, et al. N Engl J Med 2018;379:2342–50.

      2Antonia SJ, et al. N Engl J Med 2017;377:1919–29.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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