Background/ObjectiveInadvertent intraoperative hypothermia (core temperature <36°C) is a frequently preventable complication with several adverse consequences. Our study aimed to determine the overall incidence of inadvertent intraoperative hypothermia and its risk factors associated with clinical outcomes in this national survey in China.MethodsWe conducted a national cross-sectional study with 30 days postoperative follow-up from November 2014 through August 2015. A total of 3132 eligible patients underwent general anesthesia were randomly selected from 28 hospitals in the nationwide of China.ResultsThe overall incidence of intraoperative hypothermia was as high as 44.3%, in which cumulative incidence rates of hypothermia being 17.8%, 36.2%, 42.5% and 44.1% within 1 h, 2 h, 3 h and 4 h respectively following induction of anesthesia. All patients were warmed passively by covering of surgical draping, sheets or cotton blankets, whereas only 14.2% of patients received active warming with space heaters or electric heater or electronic blankets. Compared to normothermic patients, patients with hypothermia is associated with more postoperative ICU admit, longer PACU and more postoperative hospital days, but no difference in surgical site infection (SSI) rates or 30-day mortality. Several factors were shown to be associated with decreased risk of hypothermia. They are active warming (OR = 0.46, 95% CI 0.26–0.81), BMI ≥ 25 (OR = 0.54, 95% CI 0.45–0.65), higher baseline core temperature (OR = 0.04, 95% CI 0.03–0.06), and higher ambient temperature (OR = 0.83, 95% CI 0.78–0.88). Risk factors associated with an increased risk of hypothermia included major-plus surgery (OR = 1.49, 95% CI 1.23–1.79), and long anesthesia (>2 h) (OR = 2.60, 95% CI 2.09–3.24).ConclusionsThe incidence of intraoperative hypothermia in China is high, and the rate of active warming of patients during operation is low. Hypothermia is associated with more postoperative shivering, increased ICU admissions, and longer postoperative hospital days.

Background/ObjectiveInadvertent intraoperative hypothermia (core temperature <360 C) is a recognized risk in surgery and has adverse consequences. However, no data about this complication in China are available. Our study aimed to determine the incidence of inadvertent intraoperative hypothermia and its associated risk factors in a sample of Chinese patients.MethodsWe conducted a regional cross-sectional survey in Beijing from August through December, 2013. Eight hundred thirty patients who underwent various operations under general anesthesia were randomly selected from 24 hospitals through a multistage probability sampling. Multivariate logistic regression analyses were applied to explore the risk factors of developing hypothermia.ResultsThe overall incidence of intraoperative hypothermia was high, 39.9%. All patients were warmed passively with surgical sheets or cotton blankets, whereas only 10.7% of patients received active warming with space heaters or electric blankets. Pre-warmed intravenous fluid were administered to 16.9% of patients, and 34.6% of patients had irrigation of wounds with pre-warmed fluid. Active warming (OR = 0.46, 95% CI 0.26–0.81), overweight or obesity (OR = 0.39, 95% CI 0.28–0.56), high baseline core temperature before anesthesia (OR = 0.08, 95% CI 0.04–0.13), and high ambient temperature (OR = 0.89, 95% CI 0.79–0.98) were significant protective factors for hypothermia. In contrast, major-plus operations (OR = 2.00, 95% CI 1.32–3.04), duration of anesthesia (1–2 h) (OR = 3.23, 95% CI 2.19–4.78) and >2 h (OR = 3.44, 95% CI 1.90–6.22,), and intravenous un-warmed fluid (OR = 2.45, 95% CI 1.45–4.12) significantly increased the risk of hypothermia.ConclusionsThe incidence of inadvertent intraoperative hypothermia in Beijing is high, and the rate of active warming of patients during operation is low. Concern for the development of intraoperative hypothermia should be especially high in patients undergoing major operations, requiring long periods of anesthesia, and receiving un-warmed intravenous fluids.

Background: KRASG12C mutation acts as an oncogenic driver and occurs in ~15% of NSCLC. D-1553 is a novel and potent small molecule inhibitor of KRASG12C. Here we present the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of D-1553 in KRASG12C mutated NSCLC. Methods: Key inclusion criteria: KRASG12C identified by molecular testing, and after progression of standard therapy. Oral daily (QD) doses of 600, 800 and 1200 mg, and twice daily (BID) doses of 400 and 600 mg were assessed in dose escalation part; 600 mg BID was assessed in dose expansion part. Endpoints included safety, PK parameters, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and duration of response (DOR), evaluated by RECIST 1.1. Efficacy results included 6 NSCLC pts from dose escalation part of another Phase I study of D-1553 [NCT04585035] with similar inclusion/exclusion criteria as this study. Results: As of Dec 27, 2021, 16 pts with NSCLC (15 [93.8%] male, median age 61 [range: 30-74]) were enrolled in dose escalation part and 8 pts were evaluated in dose expansion part. D-1553 was well absorbed, with a median time to reach tmax in 1-4 hours. The Cmax and AUC of each dose group tested (400 mg and 600 mg, BID) increased linearly as the dose increased. However, the changes of Cmax and AUC in 600, 800 and 1200 mg (QD) group were not dose-dependent. No DLTs had been reported in dose escalation part. 15 pts (93.8%) had treatment-related adverse events (TRAEs), most of which were grade 1-2. The most frequently reported TRAEs (frequency ≥ 15%) were elevated alanine aminotransferase, aspartate aminotransferase and conjugated bilirubin, rash, anemia, asthenia, decreased appetite, hyperuricemia, and increased γ-glutamyltransferase. Among the 28 pts (including 14 pts from dose escalation, 8 pts from dose expansion, and 6 pts with NSCLC from another D-1553 study) evaluable for tumor response, 12 pts had partial response (PR), and 14 had stable disease (SD). ORR and DCR were 42.9% (12/28) and 92.9% (26/28), respectively. Among the 11 pts in 600 mg BID group, 6 pts had PR, and 3 had SD. ORR and DCR were 54.5% (6/11,) and 81.8% (9/11), respectively. Most of the patients with PR or SD were continuing on study at the time of the data cut-off. Conclusion: D-1553 is well tolerated with no DLTs at studied doses. Early results demonstrate significant anti-tumor activity of single-agent D-1553 in pts with KRASG12C mutated NSCLC. This study is ongoing. More results will be presented at the meeting. Citation Format: Hong Jian, Zhenbo Song, Yiping Zhang, Kunyan Li, Nong Yang, Melissa Moore, Pingli Wang, Yanqiu Zhao, Yi Gong, Craig Underhill, Sang-We Kim, Cheng-Ta Yang, Ziyong Xiang, Zhe Shi, Ling Zhang, Yaolin Wang, Shun Lu. Phase I study of D-1553 to assess safety and efficacy in patients with non-small cell lung cancer (NSCLC) harboring KRASG12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT505.

Background: KRASG12C mutation is an oncogenic driver that occurs in approximately 15% of non-small cell lung cancer (NSCLC), 3% of colorectal cancer (CRC), and ~1% of several other solid tumors. D-1553 is a novel, potent and orally bioavailable KRASG12C inhibitor. Here we present the safety, tolerability and PK and preliminary efficacy of D-1553 from a phase I trial in patients (pts) with advanced or metastatic solid tumors harboring KRASG12C mutation. Method: Key inclusion criteria: KRASG12C identified by molecular testing, measurable disease, and refractory to or intolerant of standard therapy. D-1553 dose escalation included oral daily (QD) doses of 150, 300, 600, 800, and 1200 mg, and twice daily (BID) doses of 400, 600, and 800 mg. Primary endpoint: safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary endpoints: PK parameters, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and duration of response (DOR), evaluated per RECIST 1.1. Results: As of Dec 27, 2021, 22 pts (12 [54.5%] male, median age 65 [range: 49-90]), including 14 pts with CRC, 6 pts with NSCLC, and 2 pts with other solid tumors, were enrolled. D-1553 was well absorbed, with a median time to reach maximum plasma concentration (Tmax) of 1-4 hours. The Cmax and AUC of each dose group (150-600 mg, QD; 400-600 mg, BID) increased linearly as the dose increased. However, the changes of Cmax and AUC in 600-1200 mg (QD), 600-800 mg (BID) groups were not in a dose-dependent manner. The most frequently reported treatment-related adverse events (TRAEs) (frequency ≥ 10%) were diarrhea, nausea, vomiting, headache, and lethargy, all grade ≤ 2. Thirteen pts (59.1%) had TRAEs: 11 pts (52.4%) had grade 2 or lower TRAEs; 2 (9.1%) had three grade ≥3 TRAEs (hypokalemia, hypertension, anaemia). No DLT has been reported. MTD was not reached. One pt (4.5%) discontinued the D-1553 therapy due to cerebral hemorrhage. This event was evaluated by investigator as unlikely related to the drug. Among 21 evaluable pts (including 14 CRC, 6 NSCLC, and 1 endometrial carcinoma (EC), confirmed ORR and DCR were 19.0% (4/21) and 85.7% (18/21), respectively. One pt with EC achieving PR had the best tumor burden reduction of 80%. Conclusion: In patients with KRASG12C mutated solid tumor, D-1553 is well tolerated with no DLTs at studied doses. The RP2D has been determined to be 600 mg BID. Preliminary efficacy results demonstrate promising clinical activity of single-agent D-1553 in pts with KRASG12C mutated solid tumor. This study is ongoing (NCT04585035) and more results will be presented at the meeting. Citation Format: Timothy Price, Jaspreet Grewal, Afaf Abed, Melissa Moore, Yu-Min Yeh, Shirish Gadgeel, Gary Richardson, Craig Underhill, Vinod Ganju, Keun-Wook Lee, Seok Jae Huh, Sang-We Kim, Chih-Hsin Yang, Yuh-Min Chen, Ziyong Xiang, Zhe Shi, Yaolin Wang, Ling Zhang, Michael Millward. A phase 1 clinical trial to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of D-1553, a novel KRASG12C inhibitor, in patients with advanced or metastatic solid tumor harboring KRASG12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT504.

e21702 Background: Aberrant activation of the MET pathway is associated poor prognosis and poor response to standard therapies in cancer patients. Glumetinib (SCC224) is an oral potent and highly selective MET inhibitor. This is an open label, dose-escalation, phase I clinical study to determine the safety, pharmacokinetics and anti-tumor activity in patients with advanced NSCLC regardless of MET status. Methods: Patients with advanced NSCLC failed standard treatments received glumetinib orally according to one of four dose escalation regimens on a 28-day cycle: 100 mg, 200 mg, 300mg and 400 mg once daily, in a Pharmacologically Guided Dose Escalation (PGDE) design (a variation of the standard 3+3 design). The primary endpoints are the incidence of dose limit toxicity (DLT), maximally tolerated dose (MTD), biologically effective dose (BED). The secondary endpoints are treatment-emergent adverse events (TEAE), safety and tolerability, anti-tumor efficacy, pharmacokinetics, and its metabolites. Results: As of Feb 7, 2020, a total of eighteen eligible (18) patients were enrolled into this study: 3 at 100 mg, 3 at 200 mg, 6 at 300 mg and 6 at 400 mg. Only one patient among 6 evaluable patients at 400mg cohort reported one DLT of grade 3 vomiting. Treatment-related adverse events mostly were grade 1 or 2 nausea, vomiting, elevated alkaline phosphatase, elevated conjugated bilirubin, edema, headache, asthenia and decreased appetite. Non-DLT treatment related G3/4 adverse events were peripheral edema (n = 1, 5.5%), hypothyroidism (n = 1, 5.5%). Absorption was rapid after dosing and the median time to reach maximum plasma drug concentration ( Tmax) was 2.0‐6.0 hours. The mean value of half-life(t1/2) in each dose group ranged from 20.43h to 35.36 h. In response to glumetinib, one patient with MET overexpression at 200mg dose level had a best of response of partial response and completed 44 weeks glumetinib treatment, 4 patients (3 with MET amplification) had a best of response of stable disease. Conclusions: Glumetinib was well tolerated at doses up to 400 mg once daily and demonstrated clinical activity in advanced NSCLC with MET alterations. Glumetinib is used in ongoing clinical trials to further explore safety and efficacy in NSCLC. Clinical trial information: NCT03466268.