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Positive Gastric Cancer with Sequential Genomic Profiling First-line pembrolizumab, trastuzumab, and chemotherapy in advanced HER2-positive gastric cancer with sequential genomic proling Hyun Cheol Chung ( [email protected] ) Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine Choong-kun Lee Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine https://orcid.org/0000-0001-5151-5096 Sun Young Rha Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University Health System https://orcid.org/0000-0002-2512-4531 Hyo Song Kim Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University Health System Minkyu Jung Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University Health System Beodeul Kang Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University Jingmin Che Sondang Institute for Cancer Research, Yonsei University College of Medicine Woo Sun Kwon Sondang Institute for Cancer Research, Yonsei University College of Medicine Woo Kyun Bae Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Medical School and Hwasun Hospital Dong-Hoe Koo Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine Su-Jin Shin Department of Pathology, Yonsei University College of Medicine Hyunki Kim Yonsei University, College of Medicine Hei-Cheul Jeung Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine Dae Young Zang Hallym University Medical Center, Hallym University College of Medicine Sang Kil Lee Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine Chung Mo Nam Department of Biostatistics, Yonsei University College of Medicine Article Keywords: Programmed Cell Death, Human Epidermal Receptor, Next-generation Panel Sequencing, Quadruplet Regimen Posted Date: February 23rd, 2021 DOI: https://doi.org/10.21203/rs.3.rs-254208/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License 1st-Line anti-PD-1 and anti-HER2 with chemotherapy for HER2-positive AGC Lee et al. 1 First-line pembrolizumab, trastuzumab, and chemotherapy in advanced HER2- 2 positive gastric cancer with sequential genomic profiling 3 4 Choong-kun Lee1,2†, Sun Young Rha1,2†, Hyo Song Kim1,2, Minkyu Jung1,2, Beodeul Kang3, 5 Jingmin Che2, Woo Sun Kwon2, Woo Kyun Bae4, Dong-Hoe Koo5, Su-Jin Shin6, Hyunki 6 Kim6, Hei-Cheul Jeung7, Dae Young Zang8, Sang Kil Lee9, Chung Mo Nam10, Hyun Cheol 7 Chung1,2* 8 9 1Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, 10 Yonsei University College of Medicine, Seoul, South Korea 11 2Sondang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, 12 South Korea 13 3CHA Bundang Medical Center, CHA University, Seongnam, South Korea 14 4Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National 15 University Medical School and Hwasun Hospital, Jeollanam-do, South Korea 16 5Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South 17 Korea 18 6Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea 19 7Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College 20 of Medicine, Seoul, South Korea 21 8Hallym University Medical Center, Hallym University College of Medicine, Anyang, South 22 Korea 23 9Division of Gastroenterology, Department of Internal Medicine, Yonsei University College 24 of Medicine, Seoul, South Korea 25 10Department of Biostatistics, Yonsei University College of Medicine, Seoul, South Korea 1 1st-Line anti-PD-1 and anti-HER2 with chemotherapy for HER2-positive AGC Lee et al. 26 27 †These authors contributed equally. 28 * Correspondence and requests for materials should be addressed to H.C.C. 29 ([email protected]). 30 31 2 1st-Line anti-PD-1 and anti-HER2 with chemotherapy for HER2-positive AGC Lee et al. 32 ABSTRACT 33 Combining programmed cell death 1 (PD-1) and human epidermal receptor 2 (HER2) 34 targeting agents has shown synergy in HER2-positive preclinical cancer models. Here, we 35 describe a single-arm multi-institutional phase Ib/II trial combining pembrolizumab, 36 trastuzumab, and chemotherapy (capecitabine plus cisplatin) as first-line therapy for HER2- 37 positive advanced gastric cancer (AGC). With a median follow-up of 18.2 months, 3 out of 38 43 enrolled patients remained in the treatment and 7 finished 2-year treatment without 39 progression. Objective response rate was 76.7% (complete response 16.3%, partial response 40 60.5%, conversion surgery 4.6%), with 26 patients (56.6%) showing tumor reduction of more 41 than 50%. Median progression-free survival was 8.6 months (95% confidence interval [CI] 42 7.2–16.4) and median overall survival was 19.3 months (95% CI 16.5–not reached). There 43 was no patient with microsatellite instability-high or Epstein–Barr virus-positive tumor. No 44 patient discontinued pembrolizumab because of immune-related adverse events. Programmed 45 death ligand-1 (PD-L1) status, metastatic organ, or baseline tumor burden were not related to 46 survival. Molecular analyses of pre-treatment tumor samples using next-generation panel 47 sequencing (NGS) showed that HER2 amplification, RTK/RAS pathway alteration, and 48 neoantigen load corrected by HLA-B were related to survival. Comparison analyses of 49 sequentially biopsied samples identified sensitive and resistant sub-clones with spatial and 50 longitudinal tumor heterogeneity. This study provided insight into potentially relevant NGS- 51 based genomic changes to identify patients who may benefit from quadruplet regimen 52 (pembrolizumab, trastuzumab, capecitabine, and cisplatin), which was active and safe for 53 HER2-positive AGC. 54 3 1st-Line anti-PD-1 and anti-HER2 with chemotherapy for HER2-positive AGC Lee et al. 55 INTRODUCTION 56 Gastric cancer is the third leading cause of cancer-related deaths and the fifth most common 57 cancer worldwide1,2. Human epidermal growth factor receptor 2 (HER2; erythroblastic 58 oncogene B2, ERBB2) is a transmembrane tyrosine kinase receptor and is overexpressed or 59 amplified in 10-20% of gastric cancer patients3. First-line anti-HER2 antibody trastuzumab in 60 combination with cytotoxic chemotherapy is the standard treatment for HER2-positive gastric 61 cancer patients after the Trastuzumab for Gastric Cancer (ToGA) study4. However, because 62 the majority of patients develop intrinsic or acquired resistance within the first year, 63 elucidating the molecular mechanisms for trastuzumab resistance is warranted to improve the 64 survival outcome in these patients. One strategy expected to overcome intrinsic or acquired 65 resistance to anti-HER2 treatment is by combining it with immune checkpoint inhibitors, 66 such as anti-PD-1 antibodies. Although the mechanism underlying anti-PD-1 and anti-HER2 67 treatment synergies has not been clearly identified, preclinical and clinical evidence support 68 combining anti-PD-1 antibody with anti-HER2 agents for HER2-positive cancers5-7. 69 In the present study, we report the results from a single-arm multi-institutional phase Ib/II 70 trial of a quadruplet regimen of pembrolizumab, trastuzumab, capecitabine, and cisplatin as 71 first-line therapy for HER2-positive advanced gastric and gastroesophageal junction 72 (AGC/GEJ) cancer (PANTHERA trial, NCT02901301). The primary endpoint was objective 73 response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 74 1.1, and secondary endpoints included progression-free survival (PFS), overall survival (OS), 75 duration of response (DOR), disease control rate (DCR), safety, and biomarker exploration in 76 relation with anti-HER2- or immune checkpoint-related pathway (see Online Methods). 77 78 RESULTS 79 4 1st-Line anti-PD-1 and anti-HER2 with chemotherapy for HER2-positive AGC Lee et al. 80 Clinical efficacy and safety of pembrolizumab, trastuzumab, and chemotherapy 81 82 Forty-three patients were enrolled in this study between February 2017 to March 2019 (Table 83 1). Full schedule and combination doses of pembrolizumab 200 mg on the day (D) 1, 84 trastuzumab 6 mg/kg (after 8 mg/kg load) D1, capecitabine 1,000 mg/m2 bid D1-14, and 85 cisplatin 80 mg/m2 D1 every 3 weeks were tested as a starting dose in phase Ib, and no dose- 86 limiting or unexpected toxicities were observed. The starting phase Ib doses were chosen as 87 recommended phase II dose, and three patients of the phase Ib cohort were included in the 88 final analyses of phase II part (Extended Data Fig. 1). At the time of data lock on Aug 31, 89 2020, the median follow-up duration was 18.2 months (95% confidence interval [CI] 16.5– 90 23.1). The median age of the patients was 63 years (range, 34–82), and the majority were 91 men (n=33, 76.7%). The lymph node (n=36, 83.7%) and liver (n=21, 48.8%) were 92 metastasized with highest frequencies. All the patients were HER2-positive, detected either 93 through immunohistochemistry (IHC) 3+ (n=30, 69.8%) or IHC 2+ with silver in situ 94 hybridization (SISH)-positive (n=13, 30.2%; median amplification index=2.74; range, 2.05– 95 4.07). Thirty-eight patients had pretreatment PD-L1 status evaluated with 22C3 antibody, and 96 21 (48.8%) were PD-L1 positive (combined positive score [CPS] 1 or higher) and 5 (11.6%) 97 were CPS 10 or higher. There was no patient with Epstein–Barr virus (EBV) positivity (based 98 on EBV-encoded small RNA in situ hybridization) or mismatch repair deficiency (based on 99 IHC for MLH1, MSH2, PMS2, and MSH6). At the time of the data lock, three patients 100 remained on the treatment, and seven finished the 2-year treatment without progression (six 101 patients still showing no evidence of disease progression). Two patients underwent 102 conversion surgery with curative intent after a remarkable tumor shrinkage (Fig.
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