Development Of Pembrolizumab Research Articles

Safety of pembrolizumab in recurrent or advanced gastric cancer expressing PD-L1 refractory to platinum and fluoropyrimidine

ABSTRACT Introduction Pembrolizumab is a highly selective fully human immunoglobulin 4 monoclonal antibody against programmed death 1 (PD-1). Phase II and III trials have demonstrated that pembrolizumab has antitumor activity in previously treated patients with advanced gastric cancer (AGC). Area covered Pembrolizumab was approved by the US Food and Drug Administration in September 2017 as third-line or later treatment of AGC in patients positive for programmed death ligand 1 (PD-L1). In this article, we review the development of pembrolizumab, its pharmacology, and its safety profile as monotherapy in patients with PD-L1 positive previous treated AGC. Expert opinion Pembrolizumab has demonstrated durable response and acceptable safety profile in patients receiving two previous courses of systemic chemotherapy. It has become a treatment option in patients with AGC. Currently, there are several ongoing clinical trials of pembrolizumab in combination with cytotoxic chemotherapy or molecular targeting agents AGC.

Agnostic-Histology Approval of New Drugs in Oncology: Are We Already There?

Over the last several years, several molecular aberrations have been unevenly described across cancers, although the distinct functional relevance in each biological context is not yet fully understood. Novel discoveries have led to the development of drugs tailored to the molecular profile of patients, thus increasing the likelihood of response among biomarker-selected patients. In this context, there has been a progressive redefinition of a precision medicine framework where evidence-based development and earlier approvals might now be driven by this molecular information. Innovative trial designs have greatly facilitated the evaluation and approval of new drugs in small cohorts of orphan cancers in which histology-dependent molecularly defined trials might be logistically difficult. However, accelerated approvals based on this agnostic-histology development model have brought new clinical, regulatory, and reimbursement challenges. In this article, we will highlight many of the biologic issues and clinical trial design challenges characterizing the development of tissue-agnostic compounds. Also, we will review some of the key factors involved in the development of pembrolizumab and larotrectinib, the first two drugs that have been approved by the U.S. Food and Drug Administration in an histology-agnostic manner. Because we anticipate that agnostic-histology approvals will continue to grow, we aim to provide insight into the current panorama of targeted drugs that are following this strategy and some premises to take into consideration. Clinicians and regulators should be prepared to overcome the associated potential hurdles, ensuring that uncertainties are dealt with properly and allowing new, promising agents to arrive faster to the market.

ISY7-2 - Key roles of immune-check inhibitors for first- and second line treatment for advanced NSCLC

Early development of anti-PD-1/PD-L1 in advanced NSCLC demonstrated long lasting responses translating into long term survival for approximately 15% of patients. Five phase III studies including mainly unselected patients compared anti-PD-1/PD-L1 as single agent with docetaxel in 2nd line setting. Four studies showed a significant OS benefit, doubling 2-year survival rates and a better tolerance profile with around 10% grade 3-4 immune-related adverse events. The lack of PFS improvement and an increase in the early death rates in one trial underscored the need for a better patients selection. PD-L1 expression appears as an enrichment factor correlated with the probability of response and the magnitude of OS benefit. The development of pembrolizumab has established more than 50% of tumor cells expressing PD-L1 as the best cutoff for a high probability of response. Other predictive biomarkers are under investigation, notably the tumor mutational burden. In 1st line setting, the Keynote 024 trial compared pembrolizumab to platinum-based doublet in tumors with high PD-L1 expression and demonstrated a large OS benefit with 30 months median survival compared to 14.2 months in the control arm despite a cross over in 62% of patients, establishing pembrolizumab as the new standard of care for these patients. The 2nd lead combined anti-CTLA4 and anti-PD1/PD-L1 with an announcement of a significant PFS benefit for ipilimumab-nivolumab combination compared to 1st line chemotherapy in case of TMB > 10 mutations/Mb. The 3rd lead in 1st line setting assessed in unselected patients combinations of cytotoxic chemotherapy and anti-PD-1/PD-L1. The addition of atezolizumab to carboplatin-paclitaxel-bevacizumab provided a significant PFS improvement while the combination of pembrolizumab to a platinum-pemetrexed regimen improved both PFS and OS. These new combinations will change the NSCLC treatment algorithm, underscoring the need of predictive biomarkers for patients selection.

Abstract B114: Evaluation of the antitumor activity and molecular characterization of mouse syngeneic tumor models in response to anti-PD-1 treatment as a single agent and in combination with approved agents

Abstract Pembrolizumab (MK-3475), a humanized monoclonal IgG4 antibody against programmed death receptor 1 (PD-1), is currently being studied in clinical trials across more than 30 types of cancers. To further support the clinical development of pembrolizumab and to aid in the mechanistic understanding of anti–PD-1 immunotherapy, we generated a surrogate PD-1–blocking antibody (muDX400). We have used muDX400 to determine the antitumor activity, pharmacokinetics, and pharmacodynamics of PD-1 inhibition in multiple preclinical syngeneic tumor model systems. Response to muDX400 treatment in several syngeneic tumor models was broadly classified into 3 categories: highly responsive (ie, complete and durable tumor regressions were observed), partially responsive (ie, tumor growth inhibition was observed), and intrinsically resistant to therapy. Using a multifaceted approach, tumors from these models were extensively characterized at the molecular and cellular level by gene expression profiling, whole exome sequencing, fluorescence-activated cell sorting, and immunohistochemistry to help elucidate mechanisms of action and biology associated with response and resistance to anti-PD1 treatment. Analyses included but were not limited to the evaluation of mutational burden, immune cell activation and migration, interferon signaling, antigen presentation (major histocompatibility [MHC] class I and II), and expression of novel targets.To further evaluate mechanisms that could potentially enhance the antitumor activity of anti–PD-1 in these tumor models, muDX400 was combined with a number of different chemotherapies, targeted therapies, and other immunotherapies. In the models in which enhanced antitumor activity was evident, we evaluated the immune landscape of blood, tumors, and draining lymph nodes by molecular profiling. These data provide preclinical support to expand the clinical development of pembrolizumab into additional cancer types as both a single agent and in combination with other approved anticancer therapies. Additional studies with muDX400 are ongoing to further elucidate the mechanism of action of PD-1 blockade and to better understand the antitumor responses observed in clinical trials of pembrolizumab. Citation Format: Heather Hirsch, Ruban Mangadu, Mingmei Cai, Yanhong Ma, Uyen Phan, Yaolin Wang, Venkataraman Sriram, Joseph H. Phillips, Terri McClanahan, Brian Long, Elaine M. Pinheiro. Evaluation of the antitumor activity and molecular characterization of mouse syngeneic tumor models in response to anti-PD-1 treatment as a single agent and in combination with approved agents. [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 B114.

Abstract 269: Evaluation of the antitumor activity of anti-PD-1 immunotherapy as a single agent and in combination with approved agents in preclinical tumor models

Abstract Pembrolizumab (MK-3475), a humanized monoclonal IgG4 antibody against programmed death receptor 1 (PD-1), is currently being studied in clinical trials across more than 30 types of cancers. To further support the clinical development of pembrolizumab and to aid the mechanistic understanding of anti-PD-1 immunotherapy, we generated a surrogate PD-1-blocking antibody (muDX400). We have used muDX400 to determine the antitumor activity, pharmacokinetics, and pharmacodynamics of PD-1 inhibition in multiple preclinical syngeneic tumor model systems. Response to muDX400 treatment in several syngeneic tumor models was broadly classified into 3 categories: highly responsive (ie, complete and durable tumor regressions were observed), partially responsive (ie, tumor growth inhibition was observed), and intrinsically resistant to therapy. Gene and protein expression signatures revealed that the more responsive models expressed higher levels of both PD-1 ligand (PD-L1) and tumor-infiltrating lymphocytes compared with nonresponsive models. To further evaluate mechanisms that could potentially enhance the antitumor activity of anti-PD-1 in these tumor models, muDX400 was combined with a number of different chemotherapies, targeted therapies, and other immunotherapies. Because immune suppression is a common side effect associated with many standard-of-care therapies, we evaluated the potential abrogation of muDX400-mediated antitumor activity when combined with approved therapies by scheduling the dosing regimen to examine concurrent and sequential administration of these agents. In the models in which enhanced antitumor activity was evident, we evaluated the immune landscape of blood, tumors, and draining lymph nodes by immuno-phenotyping and molecular profiling. These data provide preclinical support to expand the clinical development of pembrolizumab into additional cancer types as both a single agent and in combination with other approved anticancer therapies. Additional studies with muDX400 are ongoing to further elucidate the mechanism of action of PD-1 blockade and to better understand the antitumor responses observed in clinical trials of pembrolizumab. Citation Format: Elaine M. Pinheiro, Ruban Mangadu, Uyen T. Phan, Mingmei Cai, Yanhong Ma, Heather A. Hirsch, Terrill K. McClanahan, Raymond J. Moniz, Ali-Samer Al-Assaad, Samik Basu, Yaolin Wang, Venkataraman Sriram, Joseph H. Phillips, Brian J. Long. Evaluation of the antitumor activity of anti-PD-1 immunotherapy as a single agent and in combination with approved agents in preclinical tumor models. [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 269. doi:10.1158/1538-7445.AM2015-269