Abstract B049: Hyperprogressive disease after two cycles of immunotherapy in HER-2 positive metastatic gastric cancer
Authors: Lee Jii Bum , Lee Garden , Kwon Woo Sun , Heo Jun Hyeok , Jung Seung-Hyun , Chung Yeun-Jun , Kang Beodul , Kim Hyo Song , Chung Hyun Cheol , Rha Sun Young 
Published: March 2020

Abstract
Background: Recent advancements in immune checkpoint inhibitors (ICIs) have revolutionized treatment options in many solid cancers. Pembrolizumab and nivolumab, an anti-programmed death ligand 1 (anti PD-L1) agent, has approved in treatment of advanced or metastatic gastric cancer previously treated with two or more therapies. Although immunotherapy has shown durable response in selective patients, there are also growing evidences of hyperprogression (HPD) in a subset of patients treated with ICIs. Here, we report a patient who hyper-progressed after two cycles of pembrolizumab containing regimen. Methods: Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, HPD is defined as time to treatment failure (TTF) &lt;2 months and minimum increase of measurable lesions of 10mm plus one of the following: 1) increase of &gt;40% of target lesion compared with baseline or 2) increase of &gt;20% and appearance of multiple new lesions. Medical records of the patient were retrieved from electronic medical record (EMR). Tumor samples were obtained from stomach and liver before and after anti-PD1 treatment. Serial blood was collected to evaluate circulating tumor cells (CTC), targeted NGS of circulating free DNA (cfDNA) and immune phenotyping to identify possible underlying mechanism. To identify the mechanisms of HPD, Next-Generation Sequencing (NSG) of tissue and cfDNA of FoundationOne Liquid was utilized to analyze genomic alterations such as copy number alterations, rearrangements somatic mutations. Results: The 57 year old female, was initially diagnosed with HER2 positive advanced gastric cancer (AGC) with multiple liver metastases. Before treatment, immunohistochemistry (IHC) from stomach revealed amplification of human epidermal growth factor receptor 2 (HER2, ERbB2) with combined positive score (CPS) of 10% using PD-L1 IHC 22C3 pharmDx. She was then enrolled in the currently ongoing, investigator-initiated PANTHERA trial (NCT02901301), a phase Ib/II study of first line pembrolizumab in combination with trastuzumab, capecitabine and cisplatin. However, rapid progression was noted after two cycles. Target lesions increased by 27.1%, and several new liver metastasis as well as non-targetable lesions such as stomach and peritoneal seeding, increased. Tumor markers including CA 72-4, CA 125 and aFP also increased. Since the patient’s condition deteriorated rapidly, she was immediately started with a different chemotherapy and response evaluation with immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) was not evaluated. IHC of re-biopsied stomach revealed that CPS was 30%. Notably, there were no differences in IHC of liver before and after treatment, which were both HER2 and CPS negative. Interestingly, baseline cfDNA analysis showed the amplification of EGFR, which were known to be related to HPD. Also, high level of TP53, APC mutations and Rb amplification were observed. CTC (EpCAM+CK+CD45) was initially 2 at baseline and increased to 7 after hyperprogression. Conclusion: Among 41 patients enrolled in ongoing PANTHERA trial, only one patient progressed after 2 cycles of treatment . To our knowledge, this is the first documented hyperprogression in advanced or metastatic gastric cancer after treatment with pembrolizumab. Although mechanisms behind HPD remain to be elucidated, the discrepancy in pre and post IHC results points out that tumor heterogeneity may play a role. NGS results and immune phenotyping results are pending.
Citation Format: Jii Bum Lee, Garden Lee, Woo Sun Kwon, Jun Hyeok Heo, Seung-Hyun Jung, Yeun-Jun Chung, Beodul Kang, Hyo Song Kim, Hyun Cheol Chung, Sun Young Rha. Hyperprogressive disease after two cycles of immunotherapy in HER-2 positive metastatic gastric cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B049. doi:10.1158/1535-7163.TARG-19-B049