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N.A. Rizvi
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MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Gandhi, Y. Ohe
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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MINI03.05 - Efficacy of Pembrolizumab in Key Subgroups of Patients with Advanced NSCLC (ID 3057)
16:45 - 18:15 | Author(s): N.A. Rizvi
- Abstract
- Presentation
Background:
The humanized anti–PD-1 monoclonal antibody pembrolizumab (MK-3475) has demonstrated robust antitumor activity and a manageable safety profile in patients with advanced cancers, including NSCLC. In the first 495 patients with advanced NSCLC enrolled in multiple expansion cohorts of the phase 1b KEYNOTE-001 study (ClinicalTrials.gov, NCT01295827), pembrolizumab provided an overall response rate (ORR) of 19.4%. In a prospectively defined validation set, a relationship between tumor PD-L1 expression and pembrolizumab efficacy was demonstrated, such that patients with PD-L1 expression in ≥50% of cells had a 45.2% ORR compared with 16.5% and 10.7% in patients with PD-L1 expression in 1%-49% and <1% of cells, respectively. Using the total population of 550 patients with NSCLC treated with pembrolizumab in KEYNOTE-001, we assessed the relationship between antitumor activity and the level of PD-L1 expression in key patient subgroups.
Methods:
Patients with advanced NSCLC enrolled in the NSCLC-specific expansion cohorts of KEYNOTE-001 received pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or 10 mg/kg every 2 weeks (Q2W) until confirmed progression, intolerable toxicity, or investigator decision. Tumor PD-L1 expression was assessed by immunohistochemistry using a clinical-trial assay and scored as the proportion score (PS) (ie, percentage of tumor cells with membranous PD-L1 expression). Response was assessed every 9 weeks per RECIST v1.1 by central review. Patients evaluable for PD-L1 were those whose slides were prepared within 6 months of staining and for which a proportion score could be assigned.
Results:
ORR in the 550 patients who received ≥1 pembrolizumab dose was 18.9%. ORR was generally similar across subgroups (Table), although there may be a difference between ever and never smokers. Among the 409 patients evaluable for PD-L1 expression, ORR was highest in those with PS ≥50% as compared with PS 1%-49% or <1% (36.8%, 11.9%, and 10.0%, respectively). Within all subgroups, ORR was highest in patients with PS ≥50% (Table). Figure 1
Conclusion:
Pembrolizumab provides antitumor activity in a broad selection of subgroups of patients with advanced NSCLC. Improved response in patients whose tumors express PD-L1 in ≥50% of cells was observed for all subgroups. Ongoing analyses are investigating the interdependency between PD-L1 status, mutational status, and smoking.
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MS 04 - Harnessing the Full Potential of the Immune System (ID 22)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:C. Butts, P. Forde
- Coordinates: 9/07/2015, 14:15 - 15:45, Four Seasons Ballroom F3+F4
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MS04.02 - Other Immune Inhibitors (ID 1861)
14:15 - 15:45 | Author(s): N.A. Rizvi
- Abstract
- Presentation
Abstract not provided
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ORAL 02 - PD1 Axis Immunotherapy 2 (ID 87)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 3
- Moderators:E.B. Garon, H.J. Ross
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL02.01 - Phase 3, Randomized Trial (CheckMate 017) of Nivolumab (NIVO) vs Docetaxel in Advanced Squamous (SQ) Cell Non-Small Cell Lung Cancer (NSCLC) (ID 736)
10:45 - 12:15 | Author(s): N.A. Rizvi
- Abstract
- Presentation
Background:
Treatment options for patients with advanced SQ NSCLC who fail platinum-based doublet chemotherapy (PT-DC) are limited. NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor, demonstrates activity across NSCLC histologies and is approved in the US for treatment of metastatic SQ NSCLC with progression on or after platinum-based chemotherapy. We report results from a randomized, open-label, global phase 3 study (CheckMate 017; NCT01642004) comparing NIVO vs docetaxel in patients with previously treated SQ NSCLC and disease progression during/after one prior PT-DC regimen.
Methods:
Patients (N=272) were randomized 1:1 to receive either NIVO 3 mg/kg every 2 weeks (Q2W; n=135) or docetaxel 75 mg/m[2] Q3W (n=137) until disease progression or discontinuation due to toxicity or other reasons. For NIVO patients, treatment after initial progression was permitted at the investigator’s discretion, per protocol criteria. The primary objective was overall survival (OS). Secondary objectives included investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression (PD-L1 testing not required for enrollment), patient-reported outcomes (PRO), and safety. PRO analyses are presented in a separate abstract.
Results:
Treatment with NIVO led to 41% reduction in risk of death (hazard ratio [HR]=0.59; 95% CI: 0.44, 0.79; P=0.00025) and improved ORR (20% vs 9%; P=0.0083) and PFS (HR=0.62; 95% CI: 0.47, 0.81; P=0.0004) vs docetaxel (Table). Twenty-eight patients were treated with NIVO beyond initial progression, nine of whom demonstrated a non-conventional pattern of benefit (ie, reduction in target lesions with simultaneous appearance of new lesions, initial progression followed by tumor reduction, or no further progression for ≥2 tumor assessments). Across pre-specified cut-points (1%, 5%, and 10%), PD-L1 expression was neither prognostic nor predictive of benefit. OS HRs favored NIVO across most predefined patient subgroups. Grade 3–4 drug-related adverse events (AEs) were reported in 7% (9/131) of NIVO and 55% (71/129) of docetaxel patients. Grade 3–4 drug-related select AEs are shown below (Table). No deaths were related to NIVO vs 3 docetaxel-related deaths. Figure 1
Conclusion:
CheckMate 017 achieved its primary objective, demonstrating clinically superior and statistically significant OS with NIVO vs docetaxel in patients with advanced, previously treated SQ NSCLC. Benefit was seen regardless of PD-L1 status. The safety profile of NIVO 3 mg/kg Q2W is favorable vs docetaxel and consistent with prior studies. AEs were manageable with established guidelines. NIVO represents a new standard of care in this patient population. Updated OS and safety data will be presented.
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ORAL02.03 - Longer-Term Follow-Up of a Phase 2 Study (CheckMate 063) of Nivolumab in Patients with Advanced, Refractory Squamous Non-Small Cell Lung Cancer (ID 828)
10:45 - 12:15 | Author(s): N.A. Rizvi
- Abstract
- Presentation
Background:
Patients with advanced, refractory squamous (SQ) non-small cell lung cancer (NSCLC) have historically poor outcomes and limited treatment options. Nivolumab (NIVO), a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has activity across NSCLC histologies and is FDA-approved for treatment of metastatic SQ NSCLC with progression on or after platinum-based chemotherapy. We report efficacy, safety, and biomarker analyses from a phase 2, single-arm study of NIVO in patients with SQ NSCLC who progressed during/after prior platinum-based doublet chemotherapy and ≥1 additional systemic regimen.
Methods:
Patients (N=117) received NIVO 3 mg/kg every 2 weeks until progressive disease (PD)/unacceptable toxicity; treatment beyond PD was permitted per protocol. The primary endpoint was independent radiology review committee (IRC)-assessed objective response rate (ORR), per RECIST v1.1. Additional objectives included investigator-assessed ORR, progression-free survival (PFS), overall survival (OS), safety, ORR by patient subgroups, efficacy by tumor PD-L1 expression (PD-L1[+]: ≥5% tumor cells expressing PD-L1), and blood-based biomarker analyses (measurement of circulating microRNA and cytokines).
Results:
IRC-assessed ORR was 15% (95% CI: 9, 22), with a minimum of 11 months follow-up. Median duration of response was not reached (range, 2+–12+ months); 76% (13/17) of patients had ongoing responses. Objective responses were observed across patient subgroups and regardless of PD-L1 expression (Table). Four of 22 patients treated beyond PD demonstrated a non-conventional pattern of benefit (ie, persistent reduction in target lesions in the presence of new lesions, regression following initial progression, or no further progression for ≥2 tumor assessments); OS for these patients was 6.6, 11.6+, 12.9+, and 13.5+ months. The 1-year OS rate was 41% (95% CI: 32, 50) and median OS was 8.2 months (95% CI: 6.1, 10.9). The 1-year PFS rate was 20% (95% CI: 13, 29); median PFS was 1.9 months (95% CI: 1.8, 3.2). Peripheral increases in serum IFN-γ-stimulated cytokines, including CXCL9 and CXCL10, were observed, and preliminary microRNA analyses identified altered gene expression following NIVO treatment. Grade 3–4 treatment-related adverse events occurred in 17% of patients, including fatigue (4%), diarrhea (3%), and pneumonitis (3%). Pneumonitis was manageable with corticosteroids; median time to resolution was 3.4 weeks (range, 0.7–13.4). Two treatment-related deaths (1 hypoxic pneumonia, 1 ischemic stroke) occurred in patients with multiple comorbidities and concurrent PD. Figure 1
Conclusion:
NIVO demonstrated clinically meaningful efficacy and an acceptable safety profile in patients with advanced, refractory SQ NSCLC. Updated 18-month OS, safety, and biomarker analyses will be presented.
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ORAL02.05 - Safety and Efficacy of First-Line Nivolumab (NIVO; Anti-Programmed Death-1 [PD-1]) and Ipilimumab in Non-Small Cell Lung Cancer (NSCLC) (ID 786)
10:45 - 12:15 | Author(s): N.A. Rizvi
- Abstract
- Presentation
Background:
Combined blockade of the PD‐1 and cytotoxic T‐lymphocyte‐associated antigen‐4 (CTLA‐4) immune checkpoint pathways has shown improved responses, encouraging survival rates, and a manageable safety profile in advanced melanoma. NIVO, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has activity across NSCLC histologies and is approved in the US for treatment of metastatic squamous (SQ) NSCLC with progression on or after platinum-based chemotherapy. This phase 1 study evaluated the safety and efficacy of first‐line therapy with NIVO plus ipilimumab (IPI), an IgG1 CTLA‐4 checkpoint receptor blocking antibody, in chemotherapy‐naïve patients with advanced NSCLC.
Methods:
Patients (N=49) received NIVO plus IPI at the 1+3 mg/kg or 3+1 mg/kg combination dose, respectively (one SQ and one non‐SQ cohort per dose level), every 3 weeks for 4 cycles, followed by NIVO 3 mg/kg every 2 weeks until progression or unacceptable toxicity. Objective response rate (ORR; RECIST v1.1) was evaluated overall and by baseline tumor PD‐1 ligand 1 (PD‐L1) expression (PD‐L1[+]: ≥5% tumor cells expressing PD‐L1). Response was assessed at weeks 10, 17, and 23, and every 3 months thereafter until progression.
Results:
Median follow‐up for all patients was 50 weeks. Across histologies, confirmed ORR was 13% (3/24) for NIVO1+IPI3 and 20% (5/25) for NIVO3+IPI1. Two of 3 and 4/5 responders in the NIVO1+IPI3 and NIVO3+IPI1 arms, respectively, achieved a response by first scan. Median duration of response was not reached (NR) in either group, and responses were ongoing in 67% (2/3) and 60% (3/5) of patients treated with NIVO1+IPI3 and NIVO3+IPI1, respectively. Two patients in the NIVO3+IPI1 group exhibited an unconventional “immune-related” response with 56% and 64% maximum reductions in target lesions and simultaneous appearance of new lesions. The 24-week progression-free survival (PFS) rates and median PFS were 44% and 16.1 weeks, respectively, for NIVO1+IPI3 and 33% and 14.4 weeks, respectively, for NIVO3+IPI1. One-year overall survival (OS) rates and median OS were 65% and NR, respectively, for NIVO1+IPI3 and 44% and 47.9 weeks, respectively, for NIVO3+IPI1. Thirty-eight of 49 treated patients were evaluable for PD-L1 expression; objective responses were observed in PD‐L1[+] (19%, 3/16) and PD‐L1[-] (14%; 3/22) patients. Across arms, grade 3–4 treatment-related adverse events (AEs) were reported in 25 patients (51%); grade 3 pneumonitis was reported in 3 (6%) patients. Treatment‐related AEs led to discontinuation in 18 patients (37%); 15 (31%) patients discontinued treatment during induction. Treatment‐related deaths (n=3) were due to respiratory failure, bronchopulmonary hemorrhage, and toxic epidermal necrosis.
Conclusion:
Treatment with NIVO plus IPI was associated with durable responses and encouraging survival regardless of tumor PD-L1 expression. The safety profile was managed using established safety guidelines. Updated OS and results from additional doses and schedules will be presented.
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ORAL 13 - Immunotherapy Biomarkers (ID 104)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:D. Kim, D. Grunenwald
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL13.03 - Spatiotemporal Effects on Programmed Death Ligand 1 (PD-L1) Expression and Immunophenotype of Non-Small Cell Lung Cancer (NSCLC) (ID 1609)
16:45 - 18:15 | Author(s): N.A. Rizvi
- Abstract
Background:
PD-L1 is one of the immune-checkpoint molecules that regulates Th1 immune responses and mediates cancer immune evasion. PD-L1 can be expressed on tumor cells (TC) or tumor-infiltrating immune cells (IC) and expression in both cell types can negatively regulate T-cell function in the tumor microenvironment. The goal of this study was to evaluate the intra-patient heterogeneity and temporal changes in PD-L1 expression and overall immune phenotype in NSCLC using paired synchronous and metachronous tumor specimens.
Methods:
Thirty-nine patients (pts) with NSCLC treated at Memorial Sloan Kettering Cancer Center were evaluated as part of an IRB approved project. Most were former/current smokers (n=30, 77%) and had adenocarcinoma histology (n=36, 92%). 17 pts were KRAS mutant (45%), and 5 were EGFR mutant (13%). Paired synchronous samples were collected from 17 pts with stage IIIA-N2 resected primary lung and metastatic lymph node (met LN) tissue. Paired metachronous samples were collected from 23 pts (including one patient also with synchronous tissue) with at least two metachronous primary/metastatic (n=14) or metastatic/metastatic tissues (n=9). In pts with metachronous samples, 14 (61%) had systemic intercurrent anti-cancer therapy and 9 (39%) had none. PD-L1 expression was assessed by IHC (clone SP142) on TC and IC. CD8 expression was evaluated by IHC using the C8/144 clone. In addition, expression of ~600 immune genes was analyzed by iChip.
Results:
Twenty-five out of 39 tissue pairs were evaluable by PD-L1 IHC (14/17 synchronous, 11/23 metachronous). Among pts with synchronous samples, in the primary tumor, PD-L1 was expressed in <1% of TC or IC in 6 pts, in 1-4% of cells in 5 pts, and in ≥5% of cells in 3 pts. Among those with metachronous samples, in the first collected sample, the PD-L1 expression in <1% of TC or IC was detected in 6 pts, in 1-4% of cells in 2 pts, and in ≥5% of cells in 3 pts. PD-L1 expression was similar across all paired tissues. PD-L1 status at the TC or IC 5% cut-off remained unchanged in all evaluable paired specimens and at the TC or IC 1% cut-off remained unchanged in 80% (11/14 synchronous and 9/11 metachronous) pairs. In both synchronous and metachronous samples, CD8 expression was also similar across paired specimens. The median inter-sample difference in CD8+ T-cell infiltration was 0.5% (95% CI: -0.6% - 3.4%) in synchronous pairs; three pts had a difference >5%. In metachronous pairs, the median difference was -0.4% (95% CI: -1.4% - 0.1%); one pt had a >5% change in CD8+ T-cell infiltration.
Conclusion:
In this study, there was a high agreement in PD-L1 expression and CD8+ T-cell infiltration in both paired synchronous and metachronous NSCLC specimens. The low intra-patient heterogeneity of PD-L1 and CD8 expression in this study suggests any available tissue (e.g. primary or met) may be reliable to assess these markers in NSCLC. Overall immune characterization by gene expression analysis in paired tumor specimens will be presented.
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ORAL 41 - Immune Biology, Microenvironment and Novel Targets (ID 159)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:S.K. Padda, R. Nemenoff
- Coordinates: 9/09/2015, 18:30 - 20:00, Four Seasons Ballroom F1+F2
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ORAL41.04 - Discussant for ORAL41.01, ORAL41.02, ORAL41.03 (ID 3439)
18:30 - 20:00 | Author(s): N.A. Rizvi
- Abstract
- Presentation
Abstract not provided
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P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.01-083 - Phase 2 Study of MEDI4736 in Patients with PD-L1+ Locally Advanced or Metastatic Stage IIIb-IV NSCLC Treated with ≥ 2 Prior Regimens (ATLANTIC) (ID 2139)
09:30 - 17:00 | Author(s): N.A. Rizvi
- Abstract
Background:
The role of third and further line therapies in advanced NSCLC is contentious both for patients harboring EGFR mutations and ALK translocations and for patients without activating mutations. Recent studies have demonstrated that activation of the EGFR pathway induces PD-L1 expression, thereby facilitating evasion of the host’s anti-tumor immune response as a potential mechanism of targeted therapy resistance. This evidence suggests a promising and inadequately explored role of immunotherapy in this particular setting of patients in whom only targeted agents were considered of unique interest. For the ~85% of patients with non-squamous NSCLC without ALK/EGFR aberrations, single agent chemotherapy represents the only option with its associated poor results and chemotherapy-related toxicities. Many cancers co-opt the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway to evade immune-mediated tumor rejection. Encouraging clinical activity against several tumor types has been seen for anti-PD-L1/PD-1 monoclonal antibodies (mAbs), including the proven benefit of nivolumab in advanced refractory squamous NSCLC. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 with high affinity and selectivity. Evidence of clinical activity for MEDI4736 in NSCLC has been observed in a Phase 1 study (Study 1108, NCT01693562), with initial data indicating that PD-L1 expression is associated with a higher objective response rate (ORR). A clinical development program of MEDI4736 in NSCLC is underway. Here we describe the ATLANTIC study (NCT02087423).
Methods:
In this Phase 2, open-label, international, multicenter, non-comparative study, the efficacy and safety of MEDI4736 (10 mg/kg IV every 2 weeks for up to 12 months) is being assessed in patients with PD-L1[+] locally advanced or metastatic NSCLC (Stage IIIb–IV). The present study design includes three patient cohorts: 1) Cohort 1 (n=≥94): patients with EGFR mutations or ALK alterations; 2) Cohort 2 (n=≥94): patients with wild-type EGFR and ALK; 3) Cohort 3 (n=≥94): patients with wild-type EGFR/ALK and ≥90% of tumor cells PD-L1[+]. Cohorts 1 and 2 include patients whose tumor tissue samples have ≥25% of tumor cells with membrane staining for PD-L1. The PD-L1 status was tested according to the VENTANA proprietary assay. At the time the study was conceived, patients were initially included regardless of PD-L1 status. However, based on the observation that PD-L1 expression may enrich response to MEDI4736 (Study 1108), the trial was amended accordingly to include PD-L1[+] tumors only. Eligible patients must have an ECOG Performance Status of 0 or 1, and have received ≥2 prior systemic treatment regimens, including one platinum-based chemotherapy and a tyrosine kinase inhibitor if EGFR or ALK positive. The primary outcome measure is ORR (RECIST v1.1), based on independent central review. Secondary outcome measures will further assess efficacy (including disease control rate, duration of response, progression-free survival and overall survival), safety (CTCAE v4.03), tolerability, pharmacokinetics, and immunogenicity of MEDI4736. Patients will be recruited at ~100–150 sites across North America, Asia, and Europe.
Results:
Not applicable
Conclusion:
Not applicable
