Dustin Smith

Results From the Phase III Randomized Trial of Onartuzumab Plus Erlotinib Versus Erlotinib in Previously Treated Stage IIIB or IV Non–Small-Cell Lung Cancer: METLung

Purpose The phase III OAM4971g study (METLung) examined the efficacy and safety of onartuzumab plus erlotinib in patients with locally advanced or metastatic non-small-cell lung cancer selected by MET immunohistochemistry whose disease had progressed after treatment with a platinum-based chemotherapy regimen. Patients and Methods Patients were randomly assigned at a one-to-one ratio to receive onartuzumab (15 mg/kg intravenously on day 1 of each 21-day cycle) plus daily oral erlotinib 150 mg or intravenous placebo plus daily oral erlotinib 150 mg. The primary end point was overall survival (OS) in the intent-to-treat population. Secondary end points included median progression-free survival, overall response rate, biomarker analysis, and safety. Results A total of 499 patients were enrolled (onartuzumab, n = 250; placebo, n = 249). Median OS was 6.8 versus 9.1 months for onartuzumab versus placebo (stratified hazard ratio [HR], 1.27; 95% CI, 0.98 to 1.65; P = .067), with a greater number of deaths in the onartuzumab arm (130 [52%] v 114 [46%]). Median progression-free survival was 2.7 versus 2.6 months (stratified HR, 0.99; 95% CI, 0.81 to 1.20; P = .92), and overall response rate was 8.4% and 9.6% for onartuzumab versus placebo, respectively. Exploratory analyses using MET fluorescence in situ hybridization status and gene expression showed no benefit for onartuzumab; patients with EGFR mutations showed a trend toward shorter OS with onartuzumab treatment (HR, 4.68; 95% CI, 0.97 to 22.63). Grade 3 to 5 adverse events were reported by 56.0% and 51.2% of patients, with serious AEs in 33.9% and 30.7%, for experimental versus control arms, respectively. Conclusion Onartuzumab plus erlotinib did not improve clinical outcomes, with shorter OS in the onartuzumab arm, compared with erlotinib in patients with MET-positive non-small-cell lung cancer.

Effect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial

Importance Dysregulation of the mesenchymal-epithelial transition (MET) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma (GEC). We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC. Objective To determine whether the addition of onartuzumab to first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative, MET-positive GEC. Design, Setting, and Participants Randomized, double-blind, multicenter trial conducted from November 2012 to March 2014. Patients were 18 years or older with an adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease not amenable for curative therapy. Tumor samples were centrally tested for MET expression using Ventana anti-Total c-MET (SP44) rabbit monoclonal antibody, HER2 status, and Lauren histologic subtype. MET-positive tumors were defined as at least 50% of tumor cells showing weak, moderate, and/or strong staining intensity (MET 1+/2+/3+, respectively) by immunohistochemistry. Interventions Patients with HER2-negative, MET-positive GEC were enrolled and randomized 1:1 to receive mFOLFOX6 with or without onartuzumab (10 mg/kg). Main Outcomes and Measures Co–primary end points: overall survival in the intent-to-treat (ITT) population and in patients with MET 2+/3+ GEC. Secondary end points: progression-free survival (PFS), overall response rate (ORR), and safety. Results Enrollment was stopped early due to sponsor decision, which was agreed with an independent data monitoring committee. At the data cutoff (April 25, 2014) there were 562 patients in the ITT population (n = 283 placebo plus mFOLFOX6 [median age, 58 y; 65% male]; n = 279 onartuzumab plus mFOLFOX6 [median age, 60 y; 67% male]); 109 (38.5%) and 105 (37.6%) of the ITT population were MET 2+/3+, respectively. Addition of onartuzumab to mFOLFOX6 did not significantly improve OS, PFS, or ORR vs placebo plus mFOLFOX6 in the ITT (OS hazard ratio [HR], 0.82; 95% CI, 0.59-1.15; P = .24; PFS HR, 0.90; 95% CI, 0.71-1.16; P = .43; ORR, 46.1% vs 40.6%) or MET 2+/3+ populations (OS HR, 0.64; 95% CI, 0.40-1.03; P = .06; PFS HR, 0.79; 95% CI, 0.54-1.15; P = .22; ORR, 53.8% vs 44.6%). Safety was as expected for onartuzumab. Conclusions and Relevance Addition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in the ITT or MET 2+/3+ populations. Trial Registration clinicaltrials.gov Identifier: NCT01662869

Randomized phase II study of two intercalated combinations of eribulin mesylate and erlotinib in patients with previously treated advanced non-small-cell lung cancer

BACKGROUND This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies. PATIENTS AND METHODS Eligible patients were randomized to eribulin mesylate 2.0 mg/m(2) on day 1 with erlotinib 150 mg on days 2-16 (21-day regimen) or eribulin mesylate 1.4 mg/m(2) on days 1 and 8 with erlotinib 150 mg on days 15-28 (28-day regimen). The primary end point was objective response rate (ORR). RESULTS One hundred and twenty-three patients received ≥ 1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%-24%] and 17% (95% CI 8%-29%), and disease control rates were 48% (95% CI 35%-61%) and 63% (95% CI 50%-75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥ 3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin. CONCLUSION Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier: NCT01104155.

Abstract B001: Development of a PD-L1 companion diagnostic IHC assay (SP142) for atezolizumab

Background: Understanding of immune tolerance mechanisms of cancer has prompted the development of cancer immunotherapies such as atezolizumab (anti-PD-L1, MPDL3280A). Robust, durable responses have been observed, leading to Breakthrough status designation by the FDA for atezolizumab for previously treated NSCLC and bladder cancer (UBC) patients. Roche/Ventana have developed a companion diagnostic (CDx) for atezoliziumab using a robust immunohistochemistry (IHC) assay and antibody clone (SP142), optimized to detect PD-L1 expression in both tumor cells (TC) and tumor-infiltrating immune cells (IC). Here we describe the characteristics of the SP142 assay, PD-L1 expression patterns observed by immunohistochemistry in TC and IC compartments, and their association with clinical efficacy for NSCLC and UBC patients. Methods: The anti-human PD-L1 rabbit monoclonal antibody SP142 was optimized for detection of both TC and IC expression of PD-L1 with the Ventana OptiView DAB IHC Detection Kit on the automated BenchMark ULTRA platform. The VENTANA PD-L1 (SP142) CDx assay was validated for use in formalin-fixed, paraffin-embedded samples of NSCLC and UBC in a series of studies addressing sensitivity, specificity, robustness, and precision. Formalin fixed, paraffin embedded tumor specimens were obtained from patients prescreened and/or enrolled into Genentech Ph I study PCD4989g, and PD-L1 expression was measured using the SP142 assay and PCR gene expression assays. Results: The SP142 assay met pre-defined acceptance criteria for TC and IC assessment of PD-L1 expression in NSCLC and UBC tumors, including >90% inter-reader concordance between pathologist readers. Rapid and durable responses were observed in the Ph I study (PCD4989g), and correlated with PD-L1 expression patterns observed by immunohistochemistry in TC and IC. In the same Ph I study (PCD4989g), PD-L1 expression as measured by PCR did not demonstrate the same predictive value as observed for IHC. Conclusions: The PD-L1 IHC (SP142) CDx is a robust assay to measure PD-L1 expression in both IC and TC. Further, the high reproducibility of results between pathologists shows that the scoring algorithms in UBC and NSCLC are precise, reproducible, and practical in the diagnostic setting. The results indicate that favorable atezolizumab efficacy for UBC is strongly associated with higher IC levels as assessed by the sensitive and specific PD-L1 IHC (SP142) CDx assay. In NSCLC, favorable atezolizumab efficacy is associated with tumors expressing either high TC or high IC levels by the PD-L1 IHC (SP142) CDx assay. These data support the predictive value of tumor PD-L1 levels by IHC for NSCLC and UBC patients receiving atezoliziumab. Citation Format: Zachary S. Boyd, Dustin Smith, Brian Baker, Bharathi Vennapusa, Hartmut Koeppen, Marcin Kowanetz, Sanjeev Mariathasan, Jean-Marie Bruey, Howard Mackey, Gregg Fine, Simonetta Mocci, Priti Hegde, J. Andrew Williams, Ian McCaffery. Development of a PD-L1 companion diagnostic IHC assay (SP142) for atezolizumab. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B001.

Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti–PD-L1)

Significance Programmed death-ligand 1 (PD-L1) expression on tumor cells and tumor-infiltrating immune cells is regulated by distinct mechanisms and has nonredundant roles in regulating anticancer immunity, and PD-L1 on both cell types is important for predicting best response to atezolizumab in non-small cell lung cancer. Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer (NSCLC) most likely to respond to single-agent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PD-L1 expression on IC was more prevalent and likely reflected IFN-γ–induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti–PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22% ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response.

Abstract A017: PD-L1 as a predictive biomarker for atezolizumab (MPDL3280A; anti-PDL1) in non-small cell lung cancer (NSCLC)

Background: Programmed death ligand-1 (PD-L1), a ligand for PD-1 and B7.1, is broadly expressed on tumor cells (TC) and tumor-infiltrating immune cells (IC) in many human cancers. PD-L1 expression on either TC or IC can negatively regulate antitumor T-cell function within the tumor microenvironment (TME). Consistent with this, the ORR, PFS and OS benefit of atezolizumab (atezo) across PhI and PhII studies appeared to correlate with increasing baseline PD-L1 expression levels on TC and/or IC. Therefore, we explored the biologic reasons for PD-L1 expression on TC and IC, the association with response to atezo and the intrapatient heterogeneity of PD-L1 expression in NSCLC. Methods: Tumor specimens were obtained from patients (pts) prescreened and/or enrolled in NSCLC atezo trials (PhI PCD4989g, PhII POPLAR and FIR [n=1360]) and from pts treated at MSKCC (n=39). Samples included 14 synchronous and 106 metachronous pairs collected in FIR or at MSKCC. Using the SP142 IHC assay, which has been optimized to detect PD-L1 on both TC and IC, PD-L1 expression was scored at 4 levels (TC0-3 and IC0-3) based on increasing expression. A subset of samples was further characterized by histopathologic review and gene expression by RNAseq. CD8 expression (clone C8/144B) was assessed in the tumor center, invasive margin and periphery by IHC. Results: PD-L1 was expressed on IC only, on TC only or on both TC and IC within the TME. Tumors with the highest (TC3 or IC3), moderate/high (TC2/3 or IC2/3) and any (TC1/2/3 or IC1/2/3) PD-L1 expression represented ≈15%, ≈38% and ≈70% of NSCLC, respectively. PD-L1 expression was similar across all paired synchronous and metachronous tissues. At the TC3 or IC3 cutoff, PD-L1 status remained unchanged in 86% of paired synchronous specimens and in 78% of metachronous pairs. Analysis of PD-L1 expression patterns revealed the existence of exclusive TC and IC subpopulations at each PD-L1 expression level, unique to NSCLC and not seen in other cancers, e.g. UBC. Strikingly, TC3 and IC3 tumors represented 2 distinct populations, with Conclusions: These data demonstrated that NSCLC has unique PD-L1 expression patterns. High expression of PD-L1 on TC and/or IC in NSCLC confers sensitivity to atezo, despite exhibiting distinct immunologic profiles. These results further our understanding of how atezo promotes responses in tumors expressing PD-L1 on TC and/or IC and emphasizes the need to assess PD-L1 on both TC and IC in NSCLC. In addition, intrapatient heterogeneity in PD-L1 expression was relatively low in both synchronous and metachronous tissues, indicating that various types of tumor samples (e.g. primary or metastatic, fresh or archival) can be reliably used to assess PD-L1 expression with the SP142 assay. Citation Format: Marcin Kowanetz, Hartmut Koeppen, Wei Zou, Sanjeev Mariathasan, Matthew Hellmann, Mark Kockx, Colombe Chappey, Edward Kadel, Dustin Smith, Natasha Miley, Vincent Leveque, Roel Funke, Alan Sandler, Ian McCaffery, Lukas Amler, Daniel Chen, Priti Hegde. PD-L1 as a predictive biomarker for atezolizumab (MPDL3280A; anti-PDL1) in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A017.

Abstract 5117: An automated 5-plex fluorescent immunohistochemistry enabled characterization of PD-L1 expression and tumor infiltrating immune cells in lung and bladder cancer specimens

Cancers may escape immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1) on tumor cells and in the tumor microenvironment. PD-L1 expression has been reported in various cell populations within the tumor, and its expression associated with prognosis for various tumors. Further, clinical studies have shown that this pathway is an important target for immunotherapy and PD-L1 expression on tumor cells and in the tumor microenvironment has been associated with enhanced response. Understanding PD-L19s complex biological function not only on tumor cells but also within the tumor microenvironment requires simultaneous interrogation of multiple biomarkers, ranging from cancer immunology checkpoint markers, tumor infiltrating immune cell markers, and tumor specific markers, etc. Multiplex immunohistochemistry (IHC) allows simultaneous detection of multiple markers to explore the potential cellular composition of immune/stromal/cancer cells in tumor microenvironment. Development of a multiplex IHC assay remains challenging due to antibody species similarity and cross reactivity, stability of fluorophores through multiple rounds of processing, balancing high and low signals and measurement of weakly expressed markers. We present here the development of a fully automated multiplex IHC assay (PD-L1, CD3, CD8, CD68 and FoxP3) using rabbit primary antibodies with a heat deactivation process between each antigen staining cycles on the BenchMark ULTRA automated slide stainer. As part of the technology validation, we compared the 5-plex IHC to the respective single-plex chromogenic IHC assays. Using the automated 5-plex fluorescent IHC assay, we tested a cohort of non-small cell lung (NSCLC) and bladder cancer tissue specimens and characterized PD-L1 and immune marker expression in both tumor and infiltrate immune cells. To provide an objective and reliable readout of the assay, image analysis tools are being developed for automated identification and quantification of the labelled biomarkers and their co-expression on a cell-by-cell basis. This automated multiplex PD-L1 5-Plex IHC assay could be utilized as a tool for further characterizing tumors and its microenvironment and gain a better understanding of which patients may benefit from immune-therapies. Citation Format: Wenjun Zhang, Antony Hubbard, Adriana Racolta, Nick Cummins, Mehrnoush Khojasteh, Liping Zhang, Karl Garsha, Joerg Bredno, Dustin Harshman, Srabani Bhaumik, Tobin Jones, Marcin Kowanetz, Sanjeev Mariathasan, Ian McCaffery, Dustin Smith, J Andrew Williams, Lidija Pestic-Dragovich, Larry Morrison, Lei Tang. An automated 5-plex fluorescent immunohistochemistry enabled characterization of PD-L1 expression and tumor infiltrating immune cells in lung and bladder cancer specimens. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5117.