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Thomas Stinchcombe



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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): Thomas Stinchcombe

      • 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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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-04 - NCI-NRG Oncology ALK PROTOCOL (NRG-LU003): A Biomarker-Driven Protocol for Previously Treated ALK-Positive Non-Squamous NSCLC Patients      (ID 2021)

      10:15 - 18:15  |  Author(s): Thomas Stinchcombe

      • Abstract

      Background

      Currently, the 1stgeneration ALK inhibitor crizotinib and 2ndgeneration ALK inhibitors ceritinib, alectinib and brigatinib are FDA-approved for the treatment of advanced ALK-positive NSCLC. The 3rdgeneration ALK inhibitor lorlatinibrecentlyreceived accelerated approval for patients after failure of a 2ndgeneration inhibitor.

      2ndgeneration ALK inhibitors are widely used in crizotinib-resistant patients and have recently replaced crizotinib as first-line therapy for newly diagnosed patients. There is an urgent need to define the optimal therapy for patients who have become resistant to a second-generation ALK inhibitor. Pre-clinical data and small case series suggest that the presence/absence of ALK resistance mutations or the specigic ALK mutation may serve as a critical biomarker to guide selection of therapy, particularly in the setting of relapse on a 2ndgeneration ALK inhibitor when ALK resistance mutations are more common,

      Method

      NRG-LU003 proposes to study ALK-positive non-squamous NSCLC patients who develop resistance to a second-generation ALK inhibitor, in order to establish a treatment algorithm for these patients based on resistance mechanisms.Patients will undergo tissue biopsy along with blood sampling for cfDNA analysis. One of the aims of the study is to establish the concordance between tissue and liquid biopsies; liquid biopsy may replace tissue biopsy after the first 200 patients enrolled, depending on the concordance and in consultation with CDRH/FDA. Treatments will be selected based on preclinical and clinical data demonstrating activity of treatment particular inhibitor against the specific ALK mutation or resistance mechanism identified. If no ALK resistance mutations are identified, patients will be randomized to receive either a next-generation ALK inhibitor they have not previously received or pemetrexed-based therapy with cisplatin or carboplatin.

      Target accrual is 660 patients and primary objective is to assess whether ALK kinase domain mutations (e.g., G1202/C1156/I1171/L1196/V1180/F1174 mutations) associated with drug resistance are predictive of objective response to subsequent ALK inhibitor therapy, to assess whether subsequent pemetrexed based chemotherapy improves objective response compared to ALK inhibitor therapy for patients with no ALK resistance mutations, and to evaluate objective responses of patients with specific genetic alterations (e.g., ALK L1198F, compound mutations, or high-level MET amplification) treated with crizotinib.

      Mutation

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      G1202, G1202del, G1202R

      lorlatinib

      brigatinib

      C1156Y

      lorlatinib

      alectinib

      brigatinib

      I1171

      lorlatinib

      ceritinib

      brigatinib

      L1196, L1196M

      lorlatinib

      ceritinib

      alectinib

      brigatinib

      ensartinib

      V1180

      lorlatinib

      ceritinib

      brigatinib

      F1174

      lorlatinib

      alectinib

      brigatinib

      Compound mutation

      lorlatinib

      ALK L1198F (alone/ in combination with another ALK mutation)

      crizotinib

      MET amplification

      crizotinib

      No ALK-resistance mutations*

      lorlatinib

      ceritinib

      alectinib

      brigatinib

      ensartinib

      Pemetrexed

      +

      Cisplatin or Carboplatin

      Result

      "Section not applicable"

      Conclusion

      This study has been approved and is open for enrollment through the National Clinical Trials Network (NCTN).

      This project is supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC) from the National Cancer Institute (NCI)

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-89 - Neoadjuvant Pembrolizumab in Early Stage Non-Small Cell Lung Cancer (NSCLC): Toxicity, Efficacy, and Surgical Outcomes (ID 1941)

      10:15 - 18:15  |  Author(s): Thomas Stinchcombe

      • Abstract

      Background

      Pembrolizumab is a programmed death receptor-1 masking antibody approved for advanced NSCLC in program death receptor ligand-1 high tumors, and in chemotherapy combinations. This trial studies the effect of neoadjuvant pembrolizumab on surgical tolerability (primary endpoint), tumor response, side effects, and immune biomarkers in blood and tumor.

      Method

      Baseline PET/CT, brain imaging, histologic diagnosis NSCLC, and surgical consultation were required for eligibility. Patients with stage T > 3 cm and N0, N1, or resectable N2 NSCLC received neoadjuvant pembrolizumab 200 mg every 21 days 2 cycles prior to pre-operative chest CT scan followed by standard surgery. Adjuvant chemotherapy was strongly encouraged but not required. After completion of standard chemotherapy, 4 cycles of adjuvant pembrolizumab 200 mg every 21 days was offered. Blood for immune profiling of circulating immune cells was collected at baseline, after cycle 2 pembrolizumab, after surgery, and after adjuvant pembrolizumab. Excess tumor was disaggregated for tumor infiltrating lymphocytes, regulatory immune cells, and tumor cells, and viably stored for later analysis. We report clinical outcomes of tumor response and surgical outcomes.

      Result

      Study activated 31/1/2017, last enrollment 6/2/2019, and last surgery 19/3/2019. 35 patients signed consent and 30 received at least 1 dose pembrolizumab: 2 withdrew consent, 3 screen failed. Characteristics of 30 treated patients (%): male 16 (53), adenocarcinoma 10 (33), squamous 17 (57), other histology 3 (10), and stages 1B 8 (27), IIA 8 (27), IIB 6 (20), IIIA 8 (27). Planned surgery completed for 25/30 (83%). Reasons for not undergoing surgery: distant metastatic disease (1 brain metastases, 2 pleural metastases), 1 would not tolerate required pneumonectomy, 1 N3 nodal disease. Surgeries performed: video-assisted thoracic surgery (VATS) lobectomy 12, thoracotomy lobectomy 9, VATS pneumonectomy 2, thoracotomy pneumonectomy 1, and VATS bilobectomy and chest wall resection 1. All surgery was performed within range 38-77 days (median 48 days) after cycle 1 day 1 pembrolizumab. Data will be presented for toxicities neoadjuvant pembrolizumab, surgical outcomes, and neoadjuvant pembrolizumab RECIST responses, and pathologic responses. Some major pathologic responses (< 10% viable tumor) and at least 2 pathologic CRs were observed.

      Conclusion

      Two doses of neoadjuvant pembrolizumab was tolerable and produced major or complete pathologic responses in some tumors. Neoadjuvant pembrolizumab is tolerable and is an ideal platform to investigate mechanisms of immune resistance and sensitivity in early stage NSCLC.

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    P2.12 - Small Cell Lung Cancer/NET (ID 180)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.12-20 - NRG Oncology/Alliance LU005:  A Phase II/III Randomized Study of Chemoradiation Versus Chemoradiation Plus Atezolizumab in LS-SCLC   (Now Available) (ID 2670)

      10:15 - 18:15  |  Author(s): Thomas Stinchcombe

      • Abstract
      • Slides

      Background

      Clinical outcomes for limited stage small cell lung cancer (LS-SCLC) remain suboptimal. Standard of care chemoradiation with platinum/etoposide and thoracic radiation to 45 Gy delivered twice daily followed by prophylactic cranial irradiation yields a median overall survival of 30 months. LU005 is a randomized phase II/III trial designed to test the addition of atezolizumab to concurrent chemoradiation (ClinicalTrials.gov Identifier: NCT03811002).

      Method

      Patients with LS-SCLC (Tx-T4, N0-N3, M0) are randomly assigned in a 1:1 ratio to either standard chemoradiation, consisting of thoracic radiation (45 Gy twice daily or 66 Gy daily) with concurrent platinum/etoposide chemotherapy, or the experimental arm, consisting of the same chemoradiation regimen plus the addition of atezolizumab beginning concurrently with thoracic radiation, and continued every 3 weeks for 12 months duration. Thoracic radiation begins with the second cycle of chemotherapy in both treatment arms. Stratification variables include radiation schedule (once daily vs. twice daily), chemotherapy (cisplatin vs. carboplatin), sex, and performance status (PS 0/1 vs. 2). Prophylactic cranial radiation is recommended for patients who have a response to treatment. The phase II primary endpoint is progression free survival (PFS) and the phase III primary endpoint is overall survival (OS). It is hypothesized that the addition of atezolizumab will yield a hazard ratio of 0.62 for PFS, for a sample size of 280 patients in the phase II portion of this study. The overall sample size for phase II/III will be 506, with the OS analysis designed to provide at least 85% power to detect a hazard ratio of 0.71 at a 1-sided significance level of 0.025. Secondary endpoints include objective response rates, local control, distant metastases free, and quality of life. This study includes a robust translational science component including blood and tissue based assays to further understand which patients may benefit most from immunotherapy.

      Result

      This study activated in May 2019 and is currently enrolling patients.

      Conclusion

      NRG Oncology/Alliance LU005 is a randomized II/III trial testing the addition of atezolizumab to standard chemoradiation for LS-SCLC. The estimated date of study completion is May 2024.

      *Authors Higgins and Ross are co-first authors and contributed equally to this work.

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