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A. Spira
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OA20 - Immunotherapy and Markers (ID 401)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Früh, C.S. Baldotto
- Coordinates: 12/07/2016, 11:00 - 12:30, Stolz 2
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OA20.01 - Tumor Mutation Burden (TMB) is Associated with Improved Efficacy of Atezolizumab in 1L and 2L+ NSCLC Patients (ID 6149)
11:00 - 12:30 | Author(s): A. Spira
- Abstract
- Presentation
Background:
In NSCLC, atezolizumab (anti-PDL1) efficacy correlates with PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC). Here we examined the association between atezolizumab efficacy and TMB assessed by FoundationOne (F1) sequencing panel.
Methods:
Pretreatment tumor specimens from 102 1L and 465 2L+ NSCLC patients enrolled on three Ph 2 atezolizumab monotherapy trials (POPLAR: randomized 2/3L trial comparing atezolizumab vs docetaxel; BIRCH/FIR: single-arm, 1L/2L+ PD-L1‒selected trials) were available for targeted genetic sequencing using the F1 panel of 315 cancer-related genes. TMB was quantified using an updated TMB algorithm and efficacy was assessed in groups defined by the 75th (high) and 50th (median) percentile of each study-specific TMB. Atezolizumab efficacy was examined at Dec 1, 2015 (POPLAR and BIRCH); and Jan 7, 2015 (FIR) data cutoffs.
Results:
Across samples, median TMB was similar in 1L and 2L+ patients (9/MB and 9.9/MB, respectively). In 1L and 2L+ PD-L1–selected patients, atezolizumab benefit was increased in those with ≥ TMB cut-offs (Table). In unselected 2L+ patients from POPLAR, the OS, PFS, and ORR benefits of atezolizumab vs docetaxel were also enhanced in patients with increased TMB. TMB and PD-L1 expression were independently associated with improved atezolizumab efficacy. TMB associations with PD-L1 expression, tumor-infiltrating lymphocyte infiltration and T-effector cell gene expression will be presented.
Conclusion:
For the first time, we demonstrate that TMB assessed with F1 targeted sequencing is associated with improved atezolizumab outcomes in 1L and 2L+ NSCLC. Moreover, this is the first study demonstrating the association of TMB with improved anti-PD-L1/PD-1 efficacy in a randomized trial. Importantly, the association between TMB and atezolizumab efficacy occurred in both unselected and PD-L1-selected patients. Therefore, in addition to PD-L1, TMB may be an independent predictor of improved responsiveness to atezolizumab in advanced NSCLC.Atezolizumab efficacy by TMB subgroups PD-L1‒selected BIRCH+FIR 1L n=102 2L+n=371 Median (≥9/MB) High (≥13.5/MB) Median (≥9.9/MB) High (≥17.1/MB) OS,HR[a] (95% CI) 0.79 (0.39-1.58) 0.45 (0.17-1.16) 0.87 (0.65-1.16) 0.7 (0.49-1.00) PFS,HR[a] (95% CI) 0.58 (0.36-0.94) 0.54 (0.3-0.97) 0.64 (0.5-0.8) 0.5 (0.38-0.67) ORR,above/below cutoff 28%/13% 25%/20% 25%/14% 29%/16% POPLAR 2L+ unselected n=92 Biomarker- evaluable population Median (≥9.9/MB) High (≥15.8/MB) OS,HR[b ] (95% CI) 0.65 (0.38-1.12) 0.48 (0.23-1.04) 0.5 (0.15-1.67) PFS,HR[b] (95% CI) 0.98 (0.63-1.53) 0.49 (0.25-0.93) 0.49 (0.19-1.3) ORR,atezolizumab/docetaxel 13%/15% 20%/4% 20%/8% [a]HR:efficacy-evaluable patients, atezolizumab at/above cutoff vs below.[b]HR:efficacy-evaluable patients, atezolizumab vs docetaxel at/above cutoff.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-002 - G1T28, a Cyclin Dependent Kinase 4/6 Inhibitor, in Combination with Topotecan for Previously Treated Small Cell Lung Cancer: Preliminary Results (ID 5213)
14:30 - 15:45 | Author(s): A. Spira
- Abstract
Background:
Chemotherapy-induced bone marrow and immune system toxicity causes significant acute and long-term consequences. G1T28 is a potent and selective CDK4/6 inhibitor (CDK4/6i) in development to reduce chemotherapy-induced myelosuppression and preserve immune system function in small cell lung cancer (SCLC) patients. Hematopoietic stem and progenitor cells (HSPC) are dependent upon CDK4/6 for proliferation, and preclinical models demonstrated that transient G1T28-induced G~1~ cell cycle arrest renders them resistant to chemotherapy cytotoxicity, allowing faster hematopoietic recovery, preservation of long-term stem cell and immune system function, and enhancement of chemotherapy anti-tumor activity.
Methods:
Objectives of this ongoing multicenter Phase 1b/2a study are to assess the dose limiting toxicities (DLTs), safety, hematological profile, PK, and anti-tumor activity of G1T28 in combination with topotecan (NCT02514447). The study consists of a limited open-label, dose-finding portion (Part 1; up to 40 patients), and an open‑label, single-arm expansion portion (Part 2; 28 patients). Eligible patients had histologically/cytologically confirmed SCLC, adequate organ function, ECOG performance status 0-2, 1-2 prior lines of chemotherapy, and no symptomatic brain metastases. G1T28, at a starting dose of 200 mg/m[2] (derived from the Phase 1a healthy volunteer study and expected to maintain HSPC G1 arrest beyond topotecan exposure), was administered IV prior to IV topotecan on days 1-5 every 21-days.
Results:
21 patients (median age 68, 5 females, 20 white and 1 African-American) have been enrolled across 5 cohorts. DLTs due to Grade 3/4 myelotoxicity occurred in the first two cohorts and were associated with supra-therapeutic topotecan exposures due to decreased topotecan clearance by G1T28. Reducing the topotecan dose achieved exposures in the therapeutic range and was well tolerated. No episodes of febrile neutropenia or bleeding have occurred to date. For the 17 evaluable patients, there were 5 PR, 8 SD, and 4 PD. In the 6 platinum refractory patients there were 1 PR, 3 SD, and 2 PD.
Conclusion:
G1T28, a novel CDK4/6i, combined with topotecan for previously treated SCLC patients has been well tolerated, without any episodes of febrile neutropenia or bleeding. There are encouraging early signs of anti-tumor activity, with a response rate of 29% overall (36%, 4/11 in sensitive and 17%, 1/6 in refractory) and a clinical benefit rate (CR+PR+SD) of 76% overall (82%, 9/11 in sensitive and 67%, 4/6 in refractory). This novel approach, allowing the administration of chemotherapy with preservation of hematopoietic function and cellular immunity, could potentially improve treatment outcomes of patients with CDK4/6-independent tumors. Updated data will be presented.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 3
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-007 - A Phase 1/2 Trial of the Oral EGFR/HER2 Inhibitor AP32788 in Non–Small Cell Lung Cancer (NSCLC) (ID 5047)
14:30 - 15:45 | Author(s): A. Spira
- Abstract
Background:
Approximately 4%–9% of EGFR-mutated NSCLC tumors have EGFR exon 20 insertion mutations, and no targeted treatment options are currently approved for patients with these mutations. In addition, approximately 2%–4% of patients with NSCLC have HER2 mutations, the majority of which are exon 20 insertion mutations. The irreversible EGFR/HER2 inhibitor AP32788 was designed to selectively inhibit EGFR or HER2 kinases with EGFR/HER2 exon 20 mutations. In preclinical studies, investigational agent AP32788 had potent inhibitory activity against all EGFR and HER2 mutants tested, including exon 20 insertion mutants, while sparing wild-type EGFR.
Methods:
This phase 1/2 trial is a first-in-human, open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of orally administered AP32788 (NCT02716116). The study will be conducted in 2 parts: a dose-escalation phase with a 3+3 design and an expansion phase of 4 histologically and molecularly defined cohorts after the recommended phase 2 dose (RP2D) is determined. Patients (≥18 years) must have locally advanced or metastatic NSCLC. In phase 1, the dose-escalation phase, patients refractory to standard available therapies will be enrolled. The primary endpoint of phase 1 is identification of the RP2D of AP32788. Secondary endpoints include safety, dose-limiting toxicities, maximum tolerated dose, and plasma pharmacokinetics. Expected phase 1 enrollment is 20–30 patients. In phase 2, the expansion phase, 4 cohorts will be enrolled, patients with: 1. EGFR exon 20 activating insertions, without active, measurable CNS metastases; 2. HER2 exon 20 activating insertions or point mutations, without active, measurable CNS metastases; 3. EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases; 4. other targets against which AP32788 has demonstrated preclinical activity (eg, EGFR exon 19 deletions or exon 21 substitutions [with/without the T790M mutation] and other uncommon activating mutations in EGFR). The primary endpoint of phase 2 is investigator-assessed objective response rate (ORR) per RECIST v1.1 for all expansion cohorts except Expansion Cohort 3, for which the primary endpoint is intracranial ORR. Phase 2 secondary endpoints include safety, pharmacokinetics, and additional efficacy assessments (ORR per independent review committee, best overall response, best target lesion response, duration of response, disease control rate, progression-free survival, and overall survival; for Expansion Cohort 3: duration of intracranial response and intracranial progression-free survival). Expected phase 2 enrollment is 80 patients (total). The first patient was enrolled in phase 1 in June 2016.
Results:
Section not applicable.
Conclusion:
Section not applicable.
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P2.06-011 - Phase 2 Study of MM-121 plus Chemotherapy vs. Chemotherapy Alone in Heregulin-Positive, Locally Advanced or Metastatic NSCLC (ID 4158)
14:30 - 15:45 | Author(s): A. Spira
- Abstract
Background:
The role of the HER3 receptor and its ligand heregulin (HRG) in the progression of multiple cancers has been well established. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. The correlation between the level of HRG mRNA in tumor tissue and progression free survival (PFS) were retrospectively analyzed in three completed randomized Phase 2 studies of seribantumab plus standard of care (SOC) versus SOC alone (NSCLC, breast cancer and ovarian cancer). In each of these studies, high levels of HRG mRNA predicted shortened PFS for patients who received SOC treatment, while the addition of seribantumab to SOC improved PFS for patients with HRG-positive (HRG+) tumors. This is consistent with the hypothesis that HRG expression defines a drug tolerant cancer cell phenotype shielded from the effects of cytotoxic or targeted therapies and that blockade of HRG-induced HER3 signaling by seribantumab counters the effects of HRG on cancer cells, with the potential to improve outcomes for HRG+ patients. It is estimated that up to approximately 50% of cases of all solid tumor indications are HRG+. This HRG expression may contribute to rapid clinical progression in a subset of patients with poor prognosis.
Methods:
In the ongoing randomized, open-label, international, Phase 2 study, NSCLC patients with HRG+ tumors are being prospectively selected using a HRG RNA in situ hybridization assay performed on a recent tumor tissue sample collected via fine needle aspiration, core needle biopsy or excision. Approximately 560 patients will be screened to support enrollment of 280 HRG+ patients, who will be randomized in a 2:1 ratio to receive seribantumab plus investigator’s choice of docetaxel or pemetrexed, or docetaxel or pemetrexed alone. Patients will be wild-type for EGFR and ALK and will have progressed following one to three systemic therapies, one of which must be an anti-PD-1 or anti-PD-L1 therapy, for locally advanced and/or metastatic disease. Overall survival (OS) is the primary endpoint of the study and secondary endpoints include PFS, objective response rate and time to progression. Safety and health-related quality of life will also be assessed. An interim analysis is planned when 50% of final OS events have been reported. Enrollment has been initiated with approximately 80 sites expected to participate worldwide. Clinical Trials Registry number: NCT02387216
Results:
Section not applicable
Conclusion:
Section not applicable
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P2.06-014 - Phase 2 Study of Glesatinib or Sitravatinib with Nivolumab in Non-Small Cell Lung Cancer (NSCLC) after Checkpoint Inhibitor Therapy (ID 4795)
14:30 - 15:45 | Author(s): A. Spira
- Abstract
Background:
Combination therapy with agents that target the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy (CIT) is a rational approach to restoring or improving the efficacy of CIT in patients with immunotherapy resistant NSCLC. Glesatinib, a tyrosine kinase inhibitor (TKI), which targets Axl, MER and MET RTKs expressed on macrophages and antigen-presenting-cells within the tumor microenvironment (TME), may reverse the immunosuppressive TME and enhance anti-tumor T and NK cell responses by enhancing antigen presentation and T cell effector function. Sitravatinib, also a TKI, which targets VEGFR2 and KIT as well as Axl, MER and MET, may further enhance anti-tumor activity by VEGFR2 and KIT inhibition mediated reduction of regulatory T cells and myeloid-derived suppressor cells (MDSCs). Given these pleiotropic immune activating effects, the combination of glesatinib or sitravatinib with nivolumab is a rational approach to restoring or enhancing the clinical activity of CIT in patients with immunotherapy resistant NSCLC.
Methods:
This open-label Phase 2 study evaluates the tolerability and clinical activity of the investigational agents, glesatinib or sitravatinib in combination with nivolumab in separate cohorts of patients with non-squamous NSCLC who have experienced progression of disease on or after treatment with CIT. The study begins with a limited dose escalation evaluation of each investigational agent in combination with nivolumab to determine the dose levels to be used in Phase 2. The primary objective is to assess the clinical activity of the combination regimens using the Objective Response Rate (ORR) by RECIST 1.1. Other objectives include safety, tolerability, pharmacokinetics and changes in circulating and tumor cell PD-L1, circulating and tumor infiltrating immune cell populations, cytokines and gene expression signatures. Enrollment into each Phase 2 treatment arm is stratified by prior outcome of CIT (e.g., clinical benefit versus progression of disease in ≤12 weeks). The investigational agents are administered orally in continuous regimens; nivolumab is administered intravenously, 3 mg/kg every 2 weeks. The sample sizes for the treatment arms are based on two-stage Simon Optimal Designs. Status: The US IND opened in June 2016.
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-011 - A Phase 1b Open-Label Study of PEGPH20 Combined with Pembrolizumab in Patients with Selected Hyaluronan-High Solid Tumors (ID 5081)
14:30 - 15:45 | Author(s): A. Spira
- Abstract
Background:
Hyaluronan (HA) is a megadalton polysaccharide found in the tumor microenvironment (TME). HA accumulation in the TME increases tumor interstitial pressure, which promotes vascular collapse and limits access of chemotherapy and immune cells to tumor sites. In animal models, HA-High tumors exhibit increased growth and metastasis, treatment resistance, and reduced survival. PEGPH20 is a pegylated recombinant human hyaluronidase that enzymatically degrades tumor HA. Pembrolizumab (PEM) is a humanized monoclonal antibody targeting PD-1 and demonstrating tolerability and activity in patients with non-small cell lung cancer (NSCLC). This study evaluates the safety and activity of PEGPH20 plus PEM in patients with HA-High tumors.
Methods:
This is a Phase 1b study comprising a dose escalation portion (up to 30 patients without regard to HA status) followed by a cohort expansion portion in up to 51 patients with HA-High tumors, determined using a companion diagnostic assay developed in collaboration with Ventana Medical Systems. Eligible patients are ≥18 years, ECOG PS 0-1, with either relapsed/refractory stage IIIB/IV NSCLC who failed ≥1 previous platinum-based chemotherapy regimen or relapsed/refractory locally advanced or metastatic gastric adenocarcinoma who failed ≥1 previous chemotherapy regimen. Patients with NSCLC known to be epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-positive must have received an EGFR inhibitor or ALK inhibitor, respectively. PEGPH20 (1.6, 2.2, 2.6, 3.0, 4.0 μg/kg) is administered intravenously (IV) over 10 minutes on days 1, 8, and 15 of each 21-day cycle followed by PEM 2 mg/kg IV on day 1, 4 to 6 hours after PEGPH20 is completed. Piroxicam will be given prophylactically for possible musculoskeletal events. Prophylactic proton pump inhibitors will be given to all patients. The primary endpoint for the dose escalation portion is the recommended Phase 2 dose for PEGPH20 in combination with PEM. In the cohort expansion portion, the primary endpoint is objective response rate per RECIST v1.1. Secondary endpoints are duration of response, disease control rate, progression-free survival per RECIST and immune-related response criteria, pharmacokinetics, and adverse events. Exploratory endpoints in patients with HA-High NSCLC include HA levels in plasma and tumor tissue and imaging parameters of tumor blood flow (dynamic contrast-enhanced magnetic resonance imaging [DCE-MRI]) and tumor metabolic activity (positron emission tomography/computed tomography [PET/CT] scans). ClinicalTrials.gov Identifier: NCT02563548.
Results:
Section not applicable
Conclusion:
Section not applicable
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SC22 - Selection and Monitoring of Patients for Immune Checkpoint Inhibitors (ID 346)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G.V. Scagliotti, J.F. Vansteenkiste
- Coordinates: 12/06/2016, 16:00 - 17:30, Hall C8
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SC22.03 - How Do I Monitor for and Treat Immune-Related Events? (ID 6692)
16:00 - 17:30 | Author(s): A. Spira
- Abstract
- Presentation
Abstract:
Immunotherapy (IT) has become one of the most potent new treatments for all cancers, particularly non small lung cancer. However, it has a unique toxicity profile different than most therapies (chemotherapy; biologic; targeted therapy) than most oncologists are familiar with, specifically immune related adverse events; irAE. These toxicities may be acute but also can occur weeks and months after starting or even stopping therapy. Given the prolonged duration that patients may be exposed to these drugs, they become important to manage over a short and long period. Further, given the responses and the relative milder toxicity compared with traditional chemotherapy agents, the older patient population may be exposed to these agents at a somewhat higher frequency. The use of immunomodulatory drugs to counter irAE toxicity will be discussed as to how it affects efficacy of immunotherapy. This lecture will focus on: Timeframe and monitoring for immune related toxicity (with special attention paid towards pulmonary, gastrointestinal and endocrinopathies) using the appropriate immunosuppressive drugs Management of toxicities related to IT Decision making on re-exposure to drug after iRAE Patient education Toxicities associated with combination IT drugs that may be used in the future or on clinical trials
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