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S. Mocci
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OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)
- Event: WCLC 2016
- Type: Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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OA03.02 - Atezolizumab as 1L Therapy for Advanced NSCLC in PD-L1–Selected Patients: Updated ORR, PFS and OS Data from the BIRCH Study (ID 4799)
11:10 - 11:20 | Author(s): S. Mocci
- Abstract
- Presentation
Background:
Atezolizumab, a humanized anti-PDL1 mAb, inhibits the PD-L1/PD-1 pathway to restore tumor-specific T-cell immunity, resulting in durable anti-tumor effects. BIRCH (NCT02031458) is a single-arm Phase II study of atezolizumab monotherapy in PD-L1–selected advanced NSCLC patients, across multiple therapy lines. Primary analyses (median follow-up, 8.5 months) demonstrated a meaningful ORR with durable response in chemotherapy-naive 1L and 2L+ PD-L1–selected patients. Here we report updated efficacy data in 1L patients.
Methods:
1L eligibility criteria included PD-L1–selected, advanced-stage NSCLC with no CNS metastases or prior chemotherapy. PD-L1 was centrally evaluated (VENTANA SP142 IHC assay). Patients expressing PD-L1 on ≥5% of tumor cells (TC) or tumor-infiltrating immune cells (IC), ie, TC2/3 or IC2/3, were enrolled. Patients with EGFR mutation or ALK rearrangement must have had prior TKI treatment. Atezolizumab 1200mg was administered IV q3w until radiographic disease progression or unacceptable toxicity. The primary endpoint was independent review facility(IRF)-assessed ORR. Secondary endpoints included investigator(INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS.
Results:
With a median follow-up of 14.6 months, median OS was not reached in TC3 or IC3 patients and was 20.1 months in TC2/3 or IC2/3 (ITT) patients; INV-assessed ORR was 32% and 24%, respectively (Table). Furthermore, ORR was 31% for mutant EGFR (n=13) vs 20% for wild-type EGFR patients (n=104), and 27% for mutant KRAS (n=33) vs 21% for wild-type KRAS patients (n=67). No new safety signals were observed. Updated efficacy (including IRF ORR), safety and exploratory biomarker analyses will be presented.
Conclusion:
With longer follow-up, atezolizumab continued to demonstrate promising efficacy in 1L NSCLC. These results indicate that atezolizumab has durable efficacy in the 1L setting, in EGFR and KRAS mutant and wild-type tumors, and support ongoing Phase III trials evaluating atezolizumab vs chemotherapy in 1L NSCLC.
NE, not estimable.[a ]TC ≥50% or IC ≥10% PD-L1–expressing cells.[b ]TC or IC ≥5% PD-L1–expressing cells.Endpoint(95% CI) TC3 or IC3[a](n=65) TC2/3 or IC2/3[b](n=139) INV ORR, % 32% (21.2–45.1) 24% (16.9–31.7) EGFR mutant/wild-type, % 25%/29% 31%/20% KRAS mutant/wild-type, % 38%/27% 27%/21% mDOR, mo 13.1 (8.5–NE) 13.1 (9.9–17.5) mOS, mo NE (12.0–NE) 20.1 (20.1–NE) 12-mo OS rate, % 61% (48.8–73.8) 66% (57.9–74.5) mPFS, mo 7.3 (4.9–12.0) 7.3 (5.6–9.1) 12-mo PFS rate, % 36% (23.8–48.8) 32% (24.0–40.7)
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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 - 11:10 | Author(s): S. Mocci
- 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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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-038 - First-Line Atezolizumab plus Chemotherapy in Chemotherapy-Naïve Patients with Advanced NSCLC: A Phase III Clinical Program (ID 4956)
14:30 - 14:30 | Author(s): S. Mocci
- Abstract
Background:
First-line treatments for patients with advanced NSCLC include targeted therapies and platinum-based doublet chemotherapy±bevacizumab and/or pemetrexed. Although immunotherapies targeting the PD-L1/PD-1 pathway are available for advanced NSCLC beyond the first line, chemotherapy is a key first-line option for patients, despite poor survival outcomes, highlighting the need for additional treatment options. Atezolizumab, a monoclonal anti–PD-L1 antibody, inhibits the binding of PD-L1 to its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Clinical efficacy has been reported with atezolizumab monotherapy in patients with squamous and nonsquamous NSCLC, with a survival benefit observed across all PD-L1 expression levels. Additionally, Phase Ib data showed the potential for chemotherapy to further enhance responses to atezolizumab, with tolerable safety, in patients with NSCLC. Bevacizumab in combination with atezolizumab may enhance efficacy in non-squamous NSCLC by inhibiting VEGF-mediated immunosuppression. Four global, Phase III, randomized, open-label trials are evaluating atezolizumab+platinum-based chemotherapy±bevacizumab in chemotherapy-naive patients with stage IV NSCLC.
Methods:
Eligible patients must have stage IV NSCLC, measurable disease (RECIST v1.1) and ECOG PS 0-1 and be chemotherapy naive. Exclusion criteria include untreated CNS metastases, autoimmune disease and prior exposure to immunotherapy. Patients will be enrolled regardless of PD-L1 expression status. Patients randomized to the experimental arm will receive atezolizumab 1200 mg with standard platinum-based chemotherapy in IMpower130 and 131 and also ±bevacizumab in IMpower150 for four or six 21-day cycles, then maintenance with atezolizumab in IMpower130 and 131 and atezolizumab+bevacizumab in IMpower150. In IMpower132, experimental-arm patients will receive atezolizumab+platinum-based chemotherapy+pemetrexed, then maintenance with atezolizumab+pemetrexed. Patients receiving atezolizumab may continue until loss of clinical benefit. Co-primary endpoints are progression-free survival and overall survival. Secondary endpoints include objective response rate and safety. Evaluation of predictive biomarkers associated with efficacy will be performed.
ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry.Trial IMpower130 IMpower131 IMpower132 IMpower150 Histology Nonsquamous Squamous Nonsquamous Nonsquamous Planned enrollment(N) 650 1025 568 1200 Experimental Atezolizuma +carboplatin +nab-paclitaxel Atezolizuma +carboplatin +paclitaxel or Atezolizumab +carboplatin +nab-paclitaxel Atezolizuma +carboplatin or cisplatin +pemetrexed Atezolizumab +carboplatin +paclitaxel or Atezolizumab +carboplatin +paclitaxel +bevacizumab Comparator Carboplatin +nab-paclitaxel Carboplatin +nab-paclitaxel Carboplatin or cisplatin +pemetrexed Carboplatin +paclitaxel +bevacizumab Stratification factors Sex Liver metastases Centrally assessed PD-L1 expression by IHC Sex Liver metastases Centrally assessed PD-L1 expression by IHC Sex ECOG PS Chemotherapy type (carboplatin vs cisplatin) Smoking status Sex Liver metastases Centrally assessed PD-L1 expression by IHC Identifier NCT02367781 NCT02367794 NCT02657434 NCT02366143
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02c-042 - IMpower110: Phase III Trial Comparing 1L Atezolizumab with Chemotherapy in PD-L1–Selected Chemotherapy-Naive NSCLC Patients (ID 5094)
14:30 - 14:30 | Author(s): S. Mocci
- Abstract
Background:
For patients with advanced NSCLC without genetic driver alterations, cisplatin/carboplatin+pemetrexed is a standard-of-care first-line (1L) treatment for non-squamous histology; and cisplatin/carboplatin+gemcitabine for squamous histology. Although immunotherapies targeting PD-L1/PD-1 are currently available for 2L+ NSCLC, chemotherapy remains the main 1L option despite poor survival and toxicities. Atezolizumab, an anti–PDL1 mAb, prevents PD-L1 from interacting with its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Clinical efficacy was demonstrated with atezolizumab in non-squamous and squamous NSCLC, with Phase I and II studies exhibiting durable responses and survival benefit that increases with higher PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC). IMpower110, a global Phase III randomized, multicenter, open-label trial, will evaluate efficacy and safety of atezolizumab vs cisplatin/carboplatin+pemetrexed or gemcitabine as 1L therapy for PD-L1–selected chemotherapy-naive patients with advanced non-squamous or squamous NSCLC, respectively.
Methods:
Eligibility criteria include stage IV non-squamous or squamous NSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, no prior chemotherapy for advanced NSCLC and centrally-assessed PD-L1 expression ≥1% on TC or IC (TC1/2/3 or IC1/2/3 with VENTANA SP142 IHC assay; expected prevalence, ≈65%). Exclusion criteria include active or untreated CNS metastases, prior immune checkpoint blockade therapy or autoimmune disease. Patients will be randomized 1:1 to receive atezolizumab or cisplatin/carboplatin+pemetrexed (non-squamous)/gemcitabine (squamous) for 4 or 6 21-day cycles. Patients in comparator arms can receive pemetrexed (non-squamous)/best supportive care (squamous) until RECIST v1.1 disease progression. Patients receiving atezolizumab may continue until loss of clinical benefit. Co-primary endpoints are PFS and OS. Key secondary efficacy endpoints include ORR, DOR, IRF-assessed PFS (RECIST v1.1) and TTD. Safety and PK will also be evaluated. Tumor biopsies at RECIST v1.1 progression will be assessed for immunologic biomarkers associated with responses to atezolizumab and to differentiate non-conventional responses from radiographic progression.Planned enrollment, N 570 Histology Non-squamous Squamous Experimental arm Atezolizumab (1200 mg q3w) Comparator arm Cisplatin (75 mg/m[2] IV q3w) + pemetrexed (500 mg/m[2] IV q3w) or Carboplatin (AUC 6 mg/mL/min IV q3w) + pemetrexed (500 mg/m[2] IV q3w) Cisplatin (75 mg/m[2] IV q3w) + gemcitabine (1200 mg/m[2] IV days 1, 8) or Carboplatin (AUC 5 mg/mL/min IV q3w) + gemcitabine (1000 mg/m[2] IV days 1, 8) Stratification factors Sex ECOG Histology (non-squamous vs squamous) PD-L1 expression by IHC ClinicalTrials.gov identifier NCT02409342
Results:
Section not applicable
Conclusion:
Section not applicable
