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W.L. Akerley
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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: 1
- Moderators:E.B. Garon, H.J. Ross
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL02.06 - Evaluation of PD-L1 Expression in Metachronous Tumor Samples and FDG-PET as a Predictive Biomarker in Ph2 Study (FIR) of Atezolizumab (MPDL3280A) (ID 2207)
10:45 - 12:15 | Author(s): W.L. Akerley
- Abstract
- Presentation
Background:
PD-L1 expression on tumor-infiltrating immune cells (IC) and/or tumor cells (TC) can inhibit antitumor immunity. Atezolizumab (MPDL3280A) is an anti-PDL1 antibody that has shown efficacy across multiple tumor types. The efficacy and safety of atezolizumab in the Phase 2 FIR study has been reported previously (Spigel et al, ASCO 2015). Efficacy appeared to correlate with PD-L1 expression on IC and/or TC, with higher ORRs observed in patients with the highest expression of PD-L1, indicating that PD-L1 may be a predictive biomarker for response to atezolizumab. FIR was also designed to address questions of potential heterogeneity and changes in tumor PD-L1 expression in metachronous tissue samples, as well as the utility of using FDG-PET as a biomarker for response to atezolizumab in PD-L1–selected patients with NSCLC.
Methods:
FIR is a 3-cohort, single-arm, Phase 2 study of atezolizumab in PD-L1–selected patients with stage IIIB/IV NSCLC. Cohort 1 included chemo-naive patients, Cohort 2 included ≥ 2L patients without a history of brain metastases, and Cohort 3 included ≥ 2L patients with asymptomatic treated brain metastases. PD-L1 expression was centrally assessed by immunohistochemistry (IHC) using the SP142 antibody assay in archival and/or fresh tumor biopsies or resections and scored as IC0, 1, 2 or 3 and TC0, 1, 2 or 3. Patients with PD-L1 IC2/3 or TC2/3 tumors were enrolled and received 1200 mg atezolizumab IV every 3 weeks (last patient entered Jun 27, 2014). Responses were measured by RECIST v1.1, modified RECIST and FDG-PET using EORTC criteria. Exploratory objectives included the evaluation of potential predictive biomarkers, including the comparison of PD-L1 expression in matched archival and fresh tumor specimens, as well as the utility of FDG-PET in assessing response to immune checkpoint blockade.
Results:
From 1009 screened patients, 95 paired archival and fresh tumor samples were obtained. In these samples, the agreement of PD-L1 expression between fresh and archival tissue at the TC3 or IC3 cutoff was 88% when the same type of tissue procurement method was used (resection or biopsy), compared with 65% when different methods of procurement were used. To date, FDG-PET response has been centrally assessed in 71 of the 138 patients enrolled in FIR. Patients with metabolic response by EORTC criteria on 6-week scans had a higher ORR per RECIST v1.1 (72% [13/18]) than metabolic non-responders (ORR 4% [2/53]).
Conclusion:
There was a high agreement in TC3 or IC3 PD-L1 expression between archival and fresh tumor specimens. This work demonstrates that intra-patient heterogeneity in PD-L1 expression is low in metachronous tissues, indicating various types of tumor samples, including fresh or archival, can be reliably used to assess PD-L1 expression. In addition, FDG-PET has potential as an early on-treatment measure of response to atezolizumab. Further analyses will be presented. (NCT01846416)
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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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P1.01-081 - Patritumab Plus Erlotinib in EGFR Wild-Type Advanced Non-Small Cell Lung Cancer: A 2-Part Phase 3 Study (HER3-Lung) (ID 2205)
09:30 - 17:00 | Author(s): W.L. Akerley
- Abstract
Background:
Patritumab (P) is a fully human monoclonal antibody directed against human epidermal growth factor receptor 3 (HER3) that blocks activation by the ligand, heregulin (HRG), and induces receptor internalization. A Phase 2 study (NCT01211483) demonstrated that addition of P to erlotinib (E) increased progression-free survival (PFS) for the subgroup of advanced non–small cell lung cancer (NSCLC) patients with high HRG mRNA expression (HRG-high); a generally similar safety profile was seen with P+E compared with E monotherapy. To confirm these results, P+E vs. E is being investigated in a 2-part Phase 3 study designed to further evaluate the predictiveness of the HRG biomarker in patients with advanced NSCLC (https://clinicaltrials.gov/ct2/show/NCT02134015).
Methods:
HER3-Lung is randomized, placebo-controlled, double-blind, 2-part (A and B), Phase 3 study. Part A will enroll subjects with any HRG expression (limited to approximately one-third of subjects with HRG-low expression) to confirm efficacy of P+E vs. E in HRG-high disease and to possibly refine the cut-off level of HRG expression. The primary endpoint of Part A is PFS and secondary endpoints are objective response rate, overall survival, and safety. Part B will enroll subjects with HRG-high disease, defined as having a cut-off based upon the results of Part A and previous Phase 2 results. Part B is designed to independently provide pivotal confirmation of the efficacy and safety of P+E vs. E in the biomarker-defined population (n=600). The primary endpoint of Part B is overall survival. For both Part A and Part B, subjects must be aged ≥20 years with advanced NSCLC previously treated with 1 or 2 systemic therapies, and if adenocarcinoma histology, wild-type for EGFR and ALK. Tissue assessable for HRG expression must be available from archival or recently collected tumor sample. For Part A, subjects will be stratified by histology subtype, Eastern Cooperative Oncology Group performance status (0, 1) and best response to the most recent systemic therapy. Within each stratum, patients will be randomized 1:1 to P (18 mg/kg intravenous loading dose, then 9 mg/kg maintenance dose every 3 weeks) + E (150 mg/day orally) or placebo + E. Patients will be treated until disease progression, unacceptable toxicity, or withdrawal of consent.
Results:
Recruitment commenced in April 2014, and enrollment of Part A is ongoing. Investigational sites are located in Europe, United States and Canada.
Conclusion:
This study employs an innovative design to confirm efficacy in HRG-selected subjects while evaluating the expression cut-off before pivotal confirmation of efficacy and safety in the HRG-high subpopulation of EGFR wild-type NSCLC.
