PMID- 32276948 OWN - NLM STAT- MEDLINE DCOM- 20210629 LR - 20210629 IS - 2059-7029 (Electronic) IS - 2059-7029 (Linking) VI - 5 IP - 2 DP - 2020 Apr TI - Infection risk with PI3K-AKT-mTOR pathway inhibitors and immune checkpoint inhibitors in patients with advanced solid tumours in phase I clinical trials. LID - 10.1136/esmoopen-2019-000653 [doi] LID - e000653 AB - BACKGROUND: Patients undergoing chemotherapy are known to be at risk for infection from myelosuppression by cytotoxic agents (CTAs) or immunosuppressive effects from mTOR inhibitors. The infection risk of newly developed anticancer agents has not been fully evaluated. It remains unknown how T-cell activation induced by immune checkpoint inhibitors (ICIs) relates to infection. METHODS: We retrospectively examined infection risk in patients with cancer treated with investigational agents in a phase I study. The investigational agents were classified into four groups: CTA, phosphatidylinositol 3 kinase/Akt/mammalian target of rapamycin inhibitor (PAM), molecular targeted agent (MTA) and ICI. All infection-related adverse events (AEs) during treatment were recorded. We compared the CTA, PAM and ICI with MTA, because MTA are already considered low risk and were used in the largest number of patients. RESULTS: A total of 641 patients were enrolled: 35 CTAs (5.5%), 61 PAMs (9.5%), 445 MTAs (69.4%) and 100 ICIs (15.6%). Among all patients, 132 (20.6%) experienced infection-related AEs and 46 (7.2%) developed 50 >/=grade 3 infection-related AEs. In any infection-related AEs, the ORs compared with MTAs were 2.19 (95% CI 1.03 to 4.66) for CTAs, 3.55 (95% CI 2.02 to 6.24) for PAMs and 1.05 (95% CI 0.60 to 1.85) for ICIs, respectively. In time to the first infection-related AE analysis, the risks for any infection-related AE from CTAs and PAMs were higher than those from MTAs (HR 1.84 (95% CI 0.82 to 4.11); p=0.05 and 3.96 (95% CI 2.18 to 7.22); p<0.001). The risk from ICIs was not significantly different from that of MTAs (HR 0.71 (95% CI 0.46 to 1.10); p=0.19). CONCLUSION: Our results validate that PAMs and CTAs carry a higher infection risk in patients with advanced solid tumours compared with MTAs. We suggest that the infection risk of ICIs is a similar infection risk to MTAs. CI - (c) Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology. FAU - Fujiwara, Yutaka AU - Fujiwara Y AUID- ORCID: 0000-0001-6981-0800 AD - Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan yutakafu@ncc.go.jp. AD - Department of Respiratory Medicine, Mitsui Memorial Hospital, Chiyoda-ku, Tokyo, Japan. FAU - Kuchiba, Aya AU - Kuchiba A AD - Biostatistics Division, Centre for Research Administration and Support, National Cancer Center Japan, Chuo-ku, Tokyo, Japan. FAU - Koyama, Takafumi AU - Koyama T AD - Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan. FAU - Machida, Ryunosuke AU - Machida R AD - Biostatistics Division, Centre for Research Administration and Support, National Cancer Center Japan, Chuo-ku, Tokyo, Japan. FAU - Shimomura, Akihiko AU - Shimomura A AD - Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan. FAU - Kitano, Shigehisa AU - Kitano S AD - Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan. FAU - Shimizu, Toshio AU - Shimizu T AD - Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan. FAU - Yamamoto, Noboru AU - Yamamoto N AD - Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PL - England TA - ESMO Open JT - ESMO open JID - 101690685 RN - 0 (Immune Checkpoint Inhibitors) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Female MH - Humans MH - Immune Checkpoint Inhibitors/*adverse effects MH - Male MH - Middle Aged MH - Neoplasms/*complications MH - Phosphatidylinositol 3-Kinases/*adverse effects MH - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors MH - Retrospective Studies MH - Young Adult PMC - PMC7174012 OTO - NOTNLM OT - AKT OT - PI3K OT - immune checkpoint inhibitor OT - infection OT - mTOR COIS- Competing interests: All authors do not have any relevant conflicts of interest with the submitted work. But authors have the relevant conflict of interest outside the submitted work as follows:YF reports research grants from AbbVie, research grants and personal fees from AstraZeneca, research grants and personal fees from Daiichi Sankyo, research grants from Eisai, research grants from Incyte, research grants from Novartis, outside the submitted work; AK reports personal fees from Chugai, outside the submitted work; TK reports personal fees from Chugai, personal fees from Sysmex, outside the submitted work; AS reports personal fees from Chugai, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Eli-Lilly, personal fees from Eisai, personal fees from Mundipharma, personal fees from Taiho, personal fees from Daiichi Sankyo, personal fees from Novartis, outside the submitted work; SK reports personal fees from AstraZeneca, personal fees from Chugai, personal fees from Pfizer, personal fees from Sanofi, personal fees from Nippon Kayaku, research grants and personal fees from Boehringer Ingelheim, personal fees from Taiho, personal fees from Novartis, research grants and personal fees from Daiichi Sankyo, personal fees from MSD, personal fees from Kyowa Hakko Kirin, personal fees from Celgene, personal fees from Sumitomo Dainippon Pharma, research grants and personal fees from Eisai, research grants from Astellas, research grants from Gilead Sciences, personal fees from ONO, personal fees from Bristol-Myers Squibb, research grants and personal fees from REGENERON, personal fees from GlaxoSmithKline, outside the submitted work; TS reports research grants from Novartis, research grants from Eli Lilly, research grants from Bristol-Myers Squibb, research grants from Daiichi Sankyo, research grants from Millenium-Takeda, research grants from AstraZeneca, research grants from Eisai, research grants from AbbVie, research grants from Incyte, research grants from Astellas Pharma, research grants from Symbio Pharmaceuticals, research grants from 3D-Medicine, research grants from Five Prime, research grants from PharmaMar, research grants from Chordia Therapeutics, outside the submitted work; NY reports research grants and personal fees from Chugai, research grants from Taiho, research grants and personal fees from Eisai, research grants and personal fees from Eli Lilly, research grants from Quintiles, research grants from Astellas, research grants and personal fees from BMS, research grants from Novartis, research grants from Daiichi Sankyo, research grants and personal fees from Pfizer, research grants and personal fees from Boehringer Ingelheim, research grants from Kyowa-Hakko Kirin, research grants from Bayer, research grants and personal fees from ONO, research grants and personal fees from Takeda, personal fees from Otsuka, personal fees from Cimic, research grants from Janssen Pharma, research grants from MSD, research grants from Merck, research grants from GSK, outside the submitted work. EDAT- 2020/04/12 06:00 MHDA- 2021/06/30 06:00 PMCR- 2020/04/09 CRDT- 2020/04/12 06:00 PHST- 2019/12/03 00:00 [received] PHST- 2020/01/17 00:00 [revised] PHST- 2020/01/23 00:00 [accepted] PHST- 2020/04/12 06:00 [entrez] PHST- 2020/04/12 06:00 [pubmed] PHST- 2021/06/30 06:00 [medline] PHST- 2020/04/09 00:00 [pmc-release] AID - S2059-7029(20)30063-6 [pii] AID - esmoopen-2019-000653 [pii] AID - 10.1136/esmoopen-2019-000653 [doi] PST - ppublish SO - ESMO Open. 2020 Apr;5(2):e000653. doi: 10.1136/esmoopen-2019-000653.