Maintenance Avelumab Versus Continuation of First-Line Chemotherapy in Gastric Cancer: JAVELIN Gastric 100 Study Design

Moehler, Markus; Ryu, Min Hee; Dvorkin, Mikhail; Lee, Moon Hyoung; Çoşkun, Hasan Şenol; Wong, Rachel; Chung, Hyun Cheol; Poltoratsky, Artem; Tsuji, Akihito; Yen, Chia Jui; Muntean, Alina; Sourd, Samuel Le; Vaccaro, Gina M.; Overton, Lindsay; Boku, Narikazu; Wainberg, Zev A.; Patel, Manish R.; Sharma, Maitreyi; Xiong, Hua; Conti, Ilaria; Taieb, Julien; Bang, Yung Jue

doi:10.2217/fon-2018-0668

Cited by 23 publications

(14 citation statements)

References 39 publications

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“…The recent JAVELIN Ovarian 100 trial, which evaluated a αPD-1 antibody (avelumab) in combination with and/or following platinum-based chemotherapy in 998 previously untreated patients, found a poor overall response. Similar outcomes have been also reported in gastric, and brain malignancies (24,25,34,35). The immunosuppressive TME in these cancer types is particularly challenging to overcome.…”

Section: Discussionsupporting

confidence: 68%

Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer

Miao

Thakkar

Qian

et al. 2020

Preprint

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One Sentence Summary: Dual Inhibition of PD-L1 and PD-L2 using an affinity enhanced sPD-1 decoy molecule delivers superior antitumor activity when compared with αPD-1 and αPD-L1 antibodies in ovarian cancer. Abstract:Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have improved for a number of solid tumors. Unfortunately, ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB) with reported low patient response rates. Using IHC staining, we find that PD-L2 is highly expressed in ovarian cancers and other malignancies with sub-optimal response to ICB, and is expressed at low levels in cancers responsive to ICB. Based on this observation, we hypothesized that the elevated expression of PD-L2 produced by both tumor and surrounding stromal cells contributes to immune-suppression. Since PD-L2 has been reported to have a 6-to10-fold higher native binding affinity to PD-1 compared with PD-L1, we hypothesized that high levels of PD-L2 can lead to insufficient blockade of the PD-1 signaling pathway. To overcome the immune repressive activity of PD-L2, we engineered a soluble PD-1 decoy molecule (sPD-1 mutant) that binds and neutralizes both PD-L1 and PD-L2 with a 10,000-and 200-fold improvement in binding affinity, respectively, when compared to wild-type binding to these same molecules. Such enhancement in binding affinity is facilitated by amino acid mutations both within and outside of the binding interface. Furthermore, this high affinity sPD-1 mutant molecule demonstrates superior in vivo efficacy in multiple cancer models including ovarian cancer where PD-L2 is highly expressed on the cell surface.

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Section: Discussionsupporting

confidence: 68%

Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer

Miao

Thakkar

Qian

et al. 2020

Preprint

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“…There are many other ongoing clinical trials to evaluate the safety and efficacy of a variety of immune checkpoint inhibitors in patients with advanced G/GEJ cancer. These include tremelimumab (anti-CTLA-4) [56], avelumab (anti-PD-L1) [57,58], durvalumab (anti-PD-L1) [56,59], and relatlimab (anti-LAG3) [60]. Most of the trials are currently ongoing.…”

Section: Current Status Of Immunotherapy For Gastric Cancermentioning

confidence: 99%

Tumor immune response and immunotherapy in gastric cancer

Kwak

Seo

Lee

et al. 2020

J Pathol Transl Med

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Recent studies have reported the promising results of immunotherapy in many solid tumors [1]. Unlike traditional cancer therapy, which targets the tumor directly, immunotherapy offers a different approach and is an alternative treatment option for patients with cancer. Because immunotherapy generally engages immune reactions to recognize and eliminate tumor cells, demand for understanding the tumor immune response has increased. Resulting from increased study, novel biomarkers associated with the tumor immune reaction have emerged. These biomarkers may allow innovative approaches in patient selection for immunotherapy and lead to advanced treatment response, expanding the potential impact of immunotherapy. After the advent of U.S. Food and Drug Administration (FDA)-approved anti-programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy agents, the importance of immunotherapy in gastric cancer (GC) has continuously increased. In this review article, we recapitulate the general concept of immuno-oncology and discuss its clinical application while focusing on historical and current clinical trials.

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“…74 Results of the phase III JAVELIN Gastric 100 trial evaluating avelumab as first-line maintenance therapy following induction chemotherapy in gastric or GEJ cancer are awaited. 75 In the perioperative setting, encouraging safety and activity results have been recently reported from the interim analysis of a phase II trial testing avelumab plus chemotherapy in locally advanced gastric and esophagogastric adenocarcinoma (NCT03288350). 76…”

Section: Gastric Cancermentioning

confidence: 99%

Overcoming resistance to anti-PD1 and anti-PD-L1 treatment in gastrointestinal malignancies

Puccini

Battaglin

Iaia

et al. 2020

J Immunother Cancer

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In the last few years, the unprecedented results of immune checkpoint inhibitors have led to a paradigm shift in clinical practice for the treatment of several cancer types. However, the vast majority of patients with gastrointestinal cancer do not benefit from immunotherapy. To date, microsatellite instability high and DNA mismatch repair deficiency are the only robust predictive biomarkers of response to immune checkpoint inhibitors. Unfortunately, these patients comprise only 5%–10% of all gastrointestinal cancers. Several mechanisms of both innate and adaptive resistance to immunotherapy have been recognized that may be at least in part responsible for the failure of immune checkpoint inhibitors in this population of patients. In the first part of this review article, we provide an overview of the main clinical trials with immune checkpoint inhibitors in patients with gastrointestinal cancer and the role of predictive biomarkers. In the second part, we discuss the actual body of knowledge in terms of mechanisms of resistance to immunotherapy and the most promising approach that are currently under investigation in order to expand the population of patients with gastrointestinal cancer who could benefit from immune checkpoint inhibitors.

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Maintenance Avelumab Versus Continuation of First-Line Chemotherapy in Gastric Cancer: JAVELIN Gastric 100 Study Design

Cited by 23 publications

References 39 publications

Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer

Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer

Tumor immune response and immunotherapy in gastric cancer

Overcoming resistance to anti-PD1 and anti-PD-L1 treatment in gastrointestinal malignancies

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