Alan Pan

Biomarkers for PD-1/PD-L1 Blockade Therapy in Non–Small-cell Lung Cancer: Is PD-L1 Expression a Good Marker for Patient Selection?

Immunotherapy has emerged as a promising treatment modality in cancer therapy. With improved understanding of how to tip the balance of immune homeostasis, novel therapeutics targeting immune checkpoints have been developed, with durable responses observed in multiple solid tumors, including melanoma, renal cell carcinoma, and non-small-cell lung cancer. Clinical trials have reported favorable responses using programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) blockade as monotherapy and most impressively in combinatorial trials with cytotoxic T-lymphocyte antigen-4 protein blockade. Nonetheless, a clinical benefit has not been observed in all patients. Therefore, identifying the ideal biomarkers for patient selection would be of great value in optimizing and personalizing immunotherapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials and immunohistochemistry assays. In addition, the response to immune checkpoint inhibition has been complicated by PD-L1 expression as a marker influenced by the dynamic tumor microenvironment. No consensus has yet been reached on whether PD-L1 expression is an ideal marker for patient selection. Recent research has shown promise for alternative markers, including T-cell immunohistochemistry, other immunologic markers, T-cell receptor clonality, and somatic mutational burden. However, additional studies are needed to assess the value of these as practical predictive biomarkers for patient selection and treatment response.

Recent Advances and Future Strategies for Immune-Checkpoint Inhibition in Small-Cell Lung Cancer

Abstract Small‐cell lung cancer (SCLC) is distinguished from non–small‐cell lung cancer by its rapid growth and more frequent metastases. Although patients with SCLC are highly responsive to chemotherapy and radiation therapy, long‐term prognosis remains poor, with relapse and disease recurrence occurring in almost all cases. Whereas combination chemotherapies continue to be the standard of care in extensive‐stage SCLC, there is value in exploring whether immune‐checkpoint inhibition is an effective treatment strategy, given the durable responses in non–small‐cell lung cancer. Data from SCLC trials have shown clinical activity and response to cytotoxic T‐lymphocyte antigen‐4 protein and programmed cell death‐1 blockade, suggesting that antibodies targeting these pathways may be effective in improving survival outcome. However, data on clinical activity by programmed cell death‐1 ligand expression in SCLC are not widely available. Limited data indicate that programmed cell death‐1 ligand expression may not be an ideal biomarker for patient selection. Continued research is necessary to better optimize patient selection and response to therapy.

Abstract 658: Association of tumor mutational burden (TMB) with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer (NSCLC)

Background: Identifying optimal biomarkers for response to anti-PD-1/PD-L1 therapies in non-small cell lung cancer (NSCLC) is critical. Tumor mutational burden (TMB) is a potential biomarker of genomic instability and neoantigen binding sites to activated effector T cells. The goal of this study was to examine the association of TMB with overall survival for patients treated with checkpoint blockade and to correlate TMB with mutational status, including DNA repair mutations. Methods: We retrospectively examined TMB using next-generation sequencing (FoundationOne) for 82 patients with NSCLC in our institution. TMB included coding base substitutions and indel alterations, but excluded potentially functional mutations. TMB high versus low was stratified based on 15 mutations per megabase pair. We correlated TMB with DNA repair mutations, mutational status, and smoking history. In addition, survival data were obtained for 35 patients who were treated with anti-PD-1/PD-L1 therapy. Results: TMB was associated with significantly longer overall survival for patients treated with checkpoint blockade (Table 1, p Conclusions: Higher TMB was associated with improved survival for patients treated with anti-PD-1/PD-L1 therapies. In addition, TMB was correlated with DNA repair mutations, number of coding mutations, prior treatment, and smoking. Our results indicate that TMB can be used as a biomarker for response to checkpoint blockade in NSCLC. Citation Format: Andrew A. Davis, Young Kwang Chae, Sarita Agte, Alan Pan, Nisha Mohindra, Victoria Villaflor, Kirtee Raparia, Francis J. Giles. Association of tumor mutational burden (TMB) with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 658. doi:10.1158/1538-7445.AM2017-658

Association of tumor mutational burden with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer

Purpose: To examine clinical predictors of tumor mutational burden (TMB), to explore the association between TMB and DNA repair mutations, and to analyze TMB as a biomarker for response to immune checkpoint blockade in non–small‐cell lung cancer. Patients and Methods: TMB scores were determined retrospectively for 72 consecutive patients at our institution with next‐generation sequencing comprehensive genomic profiling testing by Foundation Medicine. TMB scores were correlated with a number of clinical variables and presence of DNA repair mutations. Thirty‐four patients were treated with anti–programmed cell death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) therapies, and survival analyses based on TMB score were performed. In addition, tissue immunohistochemical analysis was performed for a subset of patients. Results: History of smoking, but not other clinical variables, including prior treatment lines, stage of disease, and number of metastatic sites, predicted higher TMB score. Higher TMB score was significantly associated with greater number of DNA repair mutations. In the subset of patients treated with immune checkpoint blockade, higher TMB score significantly predicted overall survival, but not progression‐free survival (hazard ratio = 0.10, P = .003; hazard ratio 1.1, P = .84, respectively). In a small subset of patients, PD‐1/PD‐L1 staining did not independently predict progression‐free survival or overall survival. Conclusion: Tissue TMB was significantly associated with smoking history and number of DNA repair mutations. TMB is a promising biomarker for response to anti–PD‐1/PD‐L1 therapy, with higher TMB score predicting longer overall survival. Micro‐Abstract: Tumor mutational burden (TMB) has emerged as a biomarker for response to immune checkpoint blockade in clinical trials. We broadened the potential impact of TMB by evaluating the utility of commercial comprehensive genomic profiling in non–small‐cell lung cancer in clinical practice. We analyzed 72 patients and 34 treated with anti–programmed cell death 1/programmed death ligand 1 therapy, with higher TMB predicting longer overall survival.

Abstract 3672: Expression patterns of scavenger receptor B-1 (SR-B1) to guide biomimetic HDL gold nanoparticle therapy

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Introduction: Treatment options for many advanced cancers are fairly limited. New therapies that can open new paradigm are urgently needed. We have recently developed a novel synthetic biomimetic HDL gold nanoparticle (HDL NP) that demonstrated anti-tumor activity in cancer cells via apoptosis (Yang et al. PNAS, 2013) Its activity correlated with the expression of scavenger receptor-B1 (SR-B1) that binds to natural HDLs and HDL NPs. SR-B1 is a high-affinity HDL receptor that facilitates the bidirectional flux of free cholesterol and the transport of esterified cholesterol to cells. The mechanism of action of HDL NPs involved alterations in cholesterol flux and metabolism as well as cholesterol-based cell-signaling pathways. Understanding the expression patterns of SR-B1 in various human cancers can assist in developing HDL NP therapy to broader indications. Methods: We used Oncomine Research Edition public database to assess the gene expression levels of SR-B1 in various human cell lines, cancer tissues, and normal tissues. T test was use to compare cell line with the highest SR-B1 expression with the rest of cell lines of various tumor types. Also comparison was made between resected human cancer tissues and their counterpart normal tissues across various histologies. Each significant t test results from all publicly available array datasets within Oncomine were counted and compared among different tumor types. Results: First, we compared the mRNA levels of SR-B1 in human cancer tissues with those of normal tissues. Twenty different tumor types were included. Among 20 different datasets of renal cell carcinoma, 12 (60%) revealed statistically significant increase in SR-B1 expression in cancer compared with normal renal tissue samples. Other tumor types that showed ≥10% of databsets demonstrating the same pattern of expression were esophageal (44%, 4/9), melanoma (43%, 3/7), gastric (26%, 6/23), leukemia (21%, 6/29), lymphoma (20%, 6/30), colorectal (19%, 7/36), liver (15%, 2/13), and prostate cancer (15%, 3/20). Second, we compared the mRNA levels of SR-B1 across various human cancer cell lines. Among 17 different datasets that contain cancer cell lines including melanoma cell lines, melanoma was found to have the highest level of SR-B1 expression compared with the rest of the cell lines of various cancer types in 11 (65%) datasets. Other tumor types associated with ≥10% of datasets demonstrating the same highest level of SR-B1 expression were liver (33%, 4/12), kidney (12%, 2/17), and leukemia (11%, 2/19). Discussion: We found that renal cell carcinoma, melanoma, and hepatocellular carcinoma were among the cancers that expressed higher levels of SR-B1 compared with other cancers as well as with their normal tissues. These tumors merit further investigation as targets for HDL NP therapy either in the form of mono-therapy or in combination. Citation Format: Young Kwang Chae, Alan Pan, Denise Scholtens, Shuo Yang, Jonathan Rink, Colby S. Thaxton, Leo Gordon. Expression patterns of scavenger receptor B-1 (SR-B1) to guide biomimetic HDL gold nanoparticle therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3672. doi:10.1158/1538-7445.AM2015-3672