Phase II study of multidisciplinary therapy combined with pembrolizumab for patients with synchronous oligometastatic nonsmall cell lung cancer TRAP OLIGO study (WJOG11118L)
- Phase II study of multidisciplinary therapy combined with pembrolizumab for patients with synchronous oligometastatic non-. - Several clinical trials have shown that local ablative therapy (LAT) at all sites of the disease might be beneficial for patients with oligometastatic NSCLC. - In recent years, the combination of programmed cell death 1 (PD-1) inhibitors or programmed cell death ligand 1 with cytotoxic chemotherapy has become a new standard treatment for patients with metastatic NSCLC. - Few studies have evaluated the efficacy of the combination of PD-1 inhibitors with LAT at all sites of disease. - The aim of the present multicentre single-arm phase II study is to evaluate the efficacy of LAT at all sites of disease following standard platinum doublet chemotherapy with pembrolizumab in patients with oligometastatic NSCLC.. - Methods: Thirty patients with synchronous oligometastatic NSCLC will be enrolled in the trial. - LAT will be administered at all sites of disease within 21 – 56 days of the last dose of induction therapy and will be followed by maintenance therapy within 42 days of the last day of LAT. - 1 Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan Full list of author information is available at the end of the article. - Discussion: This study will provide novel data on the efficacy and safety profile of the combination of LAT and chemotherapy plus immune-checkpoint inhibitors in patients with synchronous oligometastatic NSCLC. - Synchronous oligometastatic non-small cell lung cancer (NSCLC) is generally characterised by the limited num- ber of metastases at the time of diagnosis [1]. - Predominant patterns of initial progressive disease (PD) after first-line systemic therapy suggested the utility of LAT for all sites in patients with oligometastatic NSCLC. - Furthermore, a randomised phase II trial in patients with oligometastatic NSCLC (1–3 metastases) has shown that LAT at all sites of the disease is associated with a significant improvement in overall survival (OS) and progression-free survival (PFS) compared with maintenance therapy alone [4, 5]. - An- other randomised phase II trial in oligometastatic NSCL C patients with 1–5 metastases also showed that LAT to all sites of disease after systemic therapy is associated with a significant improvement in PFS compared with maintenance therapy alone [6]. - The KEYNOTE-189 and KEYNOTE-407 studies showed that the addition of pembrolizumab to platinum doublet chemotherapy im- proved OS in patients with non-squamous and squa- mous NSCLC, regardless of programmed cell death ligand 1 expression [7, 8].. - LAT to all sites of disease that reduce tumour burden as much as possible might maximise synergy effects with PD-1 in- hibitors in patients with oligometastatic NSCLC. - However, the optimal treatment for patients with untreated synchronous oligometastatic. - NSCLC remains unclear because 70% of the participants in the previously mentioned study were patients with metachronous oligometastatic NSCLC, and over 50% of the participants were previously treated with systemic therapy [12]. - Thus, we are conducting a multicentre single-arm phase II study to evaluate the efficacy of LAT at all disease sites following therapy with a combination of pembrolizumab and platinum doublet for patients with untreated synchronous oligometastatic NSCLC.. - Patients with an activating driver mutation (epidermal growth factor receptor [ EGFR. - The protocol will be amended to exclude patients with new potential activating driver mutation if approved during the period of this study. - Potential participants will be enrolled in this study after receiving a full explanation and obtaining consent of the study.. - Because of the lack of defini- tive data on efficacy and safety, this study was conducted as an exploratory single-arm phase II trial. - Should this study achieve its primary endpoint, we will conduct a phase III trial to evaluate the effect of adding LAT to platinum-doublet chemotherapy plus pembrolizumab for patients with synchronous oligometastatic NSCLC.. - Patients with non-squamous histology will receive pembrolizumab (200 mg/body. - Patients with squamous histology will receive pembrolizumab (200 mg/body. - Patients will receive LAT at all sites of disease within 21–56 days of the last dose of induction therapy. - LAT eligi- bility will be evaluated based on the comorbidity of the Table 1 Key Inclusion and Exclusion Criteria. - a EGFR / ALK / ROS-1 / BRAF / MET testing is not mandatory for patients with squamous carcinoma. - patient and the status of the tumour, including the tumour size and location, by a multidisciplinary tumour board. - Maintenance therapy will start within 42 days of the last day of LAT. - Patients with squamous histology will receive pembro- lizumab (200 mg/body) by intravenous infusion on the first day.. - The prescribed adverse events and any se- vere adverse events will be recorded on the basis of the National Cancer Institute Common Terminology Cri- teria for Adverse Events (version 5.0). - Therefore, we set the threshold of the 24-month PFS rate at 25%. - In a previous phase II trial, approximately 30% of the enrolled patients did not receive LAT, owing to disease progression during induc- tion systemic therapy [5, 6]. - This phase II study aims to evaluate the efficacy of LAT at all sites of the disease following standard platinum doublet chemotherapy and pembrolizumab therapy in patients with synchronous oligometastatic NSCLC. - LAT at all sites of the disease would inherently reduce the overall tumour burden, and this could promote T cell reinvigoration to enhance the efficacy of pembrolizumab [9 – 11], not just provide local control [2]. - The ongoing phase III study might establish LAT at all disease sites following standard platinum doublet chemotherapy as a new standard therapy in patients with oligometastatic NSCLC [14]. - This study will provide novel data on the efficacy and safety profile of the combination of LAT and chemotherapy plus immune-checkpoint inhibitors in patients with synchronous oligometastatic NSCLC.. - If the results of this study meet the primary endpoint, we will recommend that the integrated strategy of LAT at all sites of disease following chemotherapy and pem- brolizumab for patients with synchronous oligometa- static NSCLC be assessed further in more extensive phase III studies.. - NSCLC: Non-small cell lung cancer. - TM, HK, HH, YO, YC, KH, TO, TS, KW, KI, TU, SS, YK, YN, KN and NY contributed to the design of the study. - of the study. - The WJOG 11118 L study is being conducted in compliance with the principles of the Declaration of Helsinki, and it was approved by the central review board of Shizuoka Cancer center. - Kenmotsu reports grants and personal fees from AstraZeneca K.K., grants and personal fees from Chugai Pharmaceutical Co, Ltd., personal fees from Ono Pharmaceutical Co, Ltd., grants and personal fees from Boehringer Ingelheim, personal fees from Eli Lilly K. - K, personal fees from Kyowa Hakko Kirin Co., Ltd., personal fees from Bristol-Myers Squibb, personal fees from MSD, grants and personal fees from Novartis Pharma K.K., grants and per- sonal fees from Daiichi-Sankyo Co., Ltd., personal fees from Pfizer, and per- sonal fees from Taiho Pharma, outside the submitted work.. - Harada reports personal fees from Daiichi Sankyo pharmaceutical Co., during the conduct of the study. - personal fees from Daiichi Sankyo pharmaceutical co., personal fees from AstraZneca pharmaceutical co., personal fees from Brain labo co., personal fees from Chugai Pharmaceutical Co., grants from Japan Agency for Medical Research and Development, grants from The National Cancer Center Research and Development fund, outside the submitted work.. - Chiba reports personal fees from Chugai Pharmaceutical Co., Ltd., outside the submitted work.. - Haratani reports personal fees from AS ONE Corporation, grants and personal fees from AstraZeneca K.K., personal fees from Bristol-Myers Squibb Co.. - Ltd., personal fees from Chugai Pharmaceutical Co. - Ltd., grants and personal fees from MSD K.K. - 2018/11, personal fees from Ono Pharmaceutical Co. - Ltd., and personal fees from Pfizer Japan Inc., outside the submitted work.. - Sakamoto reports personal fees from AstraZeneca K.K., personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Merck KGaA, personal fees from Eli Lilly Japan K.K., personal fees from Novartis Pharma K.K., and personal fees from Kyowa Kirin Co., Ltd., outside the submitted work.. - Wakuda reports grants and personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from Taiho Pharmaceutical, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly K.K., personal fees from Ono Pharmaceutical, personal fees from MSD, grants from Novartis, grants from AbbVie, grants and personal fees from AstraZeneca, outside the submitted work.. - Ito reports personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from Pfizer, Eli Lilly, personal fees from Chugai Pharmaceutical, personal fees from Merk Sharp &. - Dohme (MSD), personal fees from Ono Pharmaceutical, personal fees from Taiho Pharmaceutical, during the conduct of the study.. - Uemura reports personal fees from Chugai Pharmaceutical Co., Ltd., outside the submitted work.. - Kogure reports personal fees from AstraZeneca K.K., Chugai. - Pharmaceutical Co, Ltd., Eli Lilly K. - K, and Boehringer Ingelheim., grants and personal fees from MSD, which are unrelated to the submitted work.. - Nakagawa reports grants and personal fees from AstraZeneca K.K., grants and personal fees from Astellas Pharma Inc., grants and personal fees from MSD K.K., grants, personal fees and other from Ono Pharmaceutical Co., Ltd., grants and personal fees from Nippon Boehringer Ingelheim Co., Ltd., grants and personal fees from Novartis Pharma K.K., grants, personal fees and other from Pfizer Japan Inc., grants and personal fees from Bristol-Myers Squibb Company, grants, personal fees and other from Eli Lilly Japan K.K., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees. - from Daiichi Sankyo Co., Ltd., grants and personal fees from Merck Serono Co., Ltd./ Merck Biopharma Co., Ltd., during the conduct of the study;. - personal fees from Clinical Trial Co., Ltd., personal fees from MEDICUS SHUPPAN, Publishers Co., Ltd., personal fees from Care Net, Inc., personal fees from Reno. - Medical K.K., personal fees and other from KYORIN Pharmaceutical Co., Ltd., personal fees from Medical Review Co., Ltd., personal fees from Roche Diagnostics K.K., personal fees from Bayer Yakuhin, Ltd., personal fees from Medical Mobile Communications co., Ltd., personal fees from 3H Clinical Trial Inc., personal fees from Nichi-Iko Pharmaceutical Co., Ltd., grants, personal fees and other from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants and personal fees from SymBio Pharmaceuticals Limited., personal fees from NANZANDO Co., Ltd., personal fees from YODOSHA CO., LTD., personal fees from Nikkei Business Pub- lications, Inc., personal fees from Thermo Fisher Scientific K.K., personal fees from YOMIURI TELECASTING CORPORATION., personal fees from Nippon Kayaku Co., Ltd., grants and personal fees from AbbVie Inc., grants from inVentiv Health Japan, grants from ICON Japan K.K., grants from GRITSONE ONCOLOGY.INC, grants from PAREXEL International Corp., grants from Kissei Pharmaceutical Co., Ltd., grants from EPS Corporation., grants from Syneos Health., grants from Pfizer R&D Japan G.K., grants from A2 Healthcare Corp., grants from Quintiles Inc. - IQVIA Services JAPAN K.K., grants from EP-CRSU CO., LTD., grants from Linical Co., Ltd., grants from Eisai Co., Ltd., grants from CMIC Shift Zero K.K., grants from Kyowa Hakko Kirin Co., Ltd., grants from Bayer Yakuhin, Ltd., grants from EPS International Co., Ltd. - grants from Otsuka Pharmaceutical Co., Ltd., outside the submitted work.. - Yamamoto reports grants and personal fees from MSD K.K., grants and personal fees from AstraZeneca, grants and personal fees from ONO PHARMACEUTICAL CO., LTD., personal fees from Thermo Fisher Scientific, grants and personal fees from Daiichi Sankyo Co., Ltd., grants and personal fees from TAIHO PHARMACEUTICAL CO., LTD., grants and personal fees from Takeda Pharmaceutical CO., LTD., grants and personal fees from Chugai Pharmaceutical Co., LTD., grants and personal fees from Eli Lilly Japan K.K., grants and personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, grants and personal fees from Pfizer Inc., personal fees from Bristol-Myers Squibb, personal fees from Life Technologies Japan Ltd., personal fees from NIPPON KAYAKU, personal fees from Merk Biopharma, grants from Astellas Pharma Inc., grants from TSUMURA &. - CO., grants from SHIONOGI Co., Ltd., grants from AbbVie G.K., grants from Amgen Inc., grants from KYORIN Pharmaceutical Co., Ltd., grants from Eisai Co., Ltd., grants from TERUMO CORPORATION, grants from Toppan Printing Co., Ltd., grants from TOSOH, outside the submitted work.. - Role of local ablative therapy in patients with oligometastatic and oligoprogressive non – small cell lung cancer. - maintenance therapy or observation for patients with oligometastatic non – small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. - Local consolidative therapy versus maintenance therapy or observation for patients with. - Progression- free survival at 2 years is a reliable surrogate marker for the 5-year survival rate in patients with locally advanced non-small cell lung cancer treated with chemoradiotherapy
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