A Pilot Study for a Randomized Controlled Trial to Prevent Gastric Cancer in High-risk Japanese Population: Study Design and Feasibility Evaluation

Observational epidemiological studies suggest that some nutrients reduce the risk of gastric cancer and that individuals with atrophic gastritis are at high risk of developing gastric cancer. One possible measure for gastric cancer prevention is therefore nutritional supplementation for the high risk group. Before recommending this strategy for the general public, however, a randomized controlled trial (RCT) is necessary. To evaluate the feasibility of an RCT, the authors conducted a pilot study using recipients of a health check-up program in a general hospital in Japan. The subjects who were asked to participate in the trial had been diagnosed as having atrophic gastritis on the basis of serum pepsinogen I <70 ng/ml and the ratio of pepsinogen I to II <3.0. They were requested to ingest double-blinded capsules containing different levels of vitamin C and β-carotene every day. Out of the 219 subjects (118 males, 101 females) who were eligible for the study and had the required pepsinogen measurement, 90 (41%) met the criteria for atrophic gastritis. Among them, 55 (61%) (35 males, 20 females) gave their informed consent to participate in the RCT. Fifty-four participants completed a 3-month course of supplementation, and all of them agreed to a 5-year supplementation period. The authors concluded that an RCT using double-blinded nutritional supplements and targeting apparently healthy individuals is feasible in an intervention study for cancer prevention in Japan.     

Effects of Three-month Oral Supplementation of β-Carotene and Vitamin C on Serum Concentrations of Carotenoids and Vitamins in Middle-aged Subjects: A Pilot Study for a Randomized Controlled Trial to Prevent Gastric Cancer in High-risk Japanese Population

Prior to a randomized controlled trial to prevent gastric cancer by oral supplementation of β-carotene and vitamin C in a high-risk Japanese population, we examined the serum response to threemonth oral supplementation of β-carotene (0, 3, 30 mg/day) and vitamin C (0, 50, 1000 mg/day) by a three-by-three factorial design using 54 subjects (age range=40–69 years). Serum concentrations of carotenoids, α-tocopherol, and ascorbic acid were examined at baseline, and one, two, and threemonth points. Both serum β-carotene and ascorbic acid were significantly higher in high-dose groups than in each placebo group during the supplementation. The serum β-carotene increased gradually (597–830% increase) during the study, whereas the serum ascorbic acid reached nearly a steady-state at the one-month point and remained stable thereafter (88–95% increase). No statistically significant interaction between β-carotene and vitamin C supplementations was observed either for serum β-carotene or for serum ascorbic acid. Among carotenoids and α-tocopherol examined, serum lycopene in the high-dose β-carotene group was significantly higher than in the placebo group at all points. No unfavorable change in carotenoids and α-tocopherol was observed in any group.     

A Prospective Study of Atrophic Gastritis and Stomach Cancer Risk

The relation of atrophic gastritis, other gastric lesions and lifestyle factors to stomach cancer risk was prospectively studied among 3,914 subjects who underwent gastroscopic examination and responded to a questionnaire survey at the Aichi Cancer Center Hospital. During 4.4 years of follow-up on average, 45 incident cases of stomach cancer were identified at least three months after the initial examination. If the baseline endoscopic findings indicated the presence of atrophic gastritis, the risk of developing stomach cancer was increased 5.73-fold, compared with no indication at the baseline. The risk further increased with advancing degree of atrophy and increasing extension of atrophy on the lesser curvature. These trends in the relative risks were statistically significant ( P = 0.027 and P = 0.041, respectively). The risk of developing stomach cancer was statistically significantly increased among subjects with gastric polyps, but not among those with gastric ulcer. Stomach cancer cases tended to consume more cigarettes, alcohol, rice, pickles and salted fish gut/cod roe and less fruits and vegetables and to have more family histories of stomach cancer than noncases, although these differences were not statistically significant. The results of the present study provide additional evidence on the relation between atrophic gastritis and stomach cancer and suggest a need for intensive follow-up of patients with atrophic gastritis and gastric polyps.     

生长抑素对胃癌VEGFs和VEGF受体影响的实验研究

目的探讨VEGFs/VEGFRs与胃癌的恶化及不良预后的关系。方法将60例患者随机分成生长抑素预处理组和安慰剂组,采用酶联免疫法、实时定量PCR法和免疫组化法检测VEGF水平。结果生长抑素预处理组血清VEGF水平明显下降,但mRNA水平并无明显变化,并且血清VEGF水平下降是由于蛋白降解而非mRNA转录下降引起的。同时,预处理组VEGF受体-3蛋白明显下降。结论生长抑素通过下调血清VEGF水平和VEGF受体-3的表达,从而达到抗血管生成作用,为应用生长抑素治疗胃癌提供实验依据。     

A Cooperative Randomized Study on Tegafur plus Mitomycin C versus Combined Tegafur and Uracil plus Mitomycin C in the Treatment of Advanced Gastric Cancer

A randomized controlled trial involving 13 institutions in Japan was conducted in order to compare the efficacy of tegafur plus mitomycin C (MMC) (Regimen A) and UFT (a combination of uracil and tegafur at a molar ratio of 4 to 1) plus MMC (Regimen B) for patients with advanced gastric cancer, who had not received any prior cancer chemotherapy. Regimen A (tegafur+MMC) consisted of 5 mg of MMC/m²/week given intravenously, and 500 mg of tegafur/m²/day given orally. Regimen B consisted of the same schedule of MMC and 375 mg of UFT/m²/day given orally. One hundred and eighty-six patients with primary gastric cancer were entered; 183 were eligible and 3 were ineligible for the study. A total of 169 were evaluable for efficacy of the treatment, including 90 patients with Regimen A and 79 with Regimen B. A response rate of 7.8% (7/90 cases) for Regimen A and one of 25.3% (20/79 cases) for Regimen B were obtained, indicating a significantly higher response rate for Regimen B according to the Criteria for Evaluating Efficacy of Chemotherapy /Radiation Therapy in the Treatment of Gastric Cancer ( P = 0.004), Regarding side effects, no marked differences in either severity or incidence were observed between the two groups. The group assigned to Regimen B showed a significant survival advantage after adjustment for major prognostic factors using a proportional hazards model ( P =0.0398). Moreover, a close correlation of antitumor effect and survival duration was found when the above criteria were used.     

The Efficacy and Safety of Modified Docetaxel,Cisplatin, and 5-Fluorouracil Vs. Epirubicin,Oxaliplatin, and Capecitabine Regimen in the Advanced Gastric Cancer: A Randomized Controlled Clinical Trial

Introduction: One of the major challenges of advanced gastric cancer treatment is the lack of a standard regimen for patients. However, several clinical trials have shown that modified docetaxel, cisplatin, and 5-fluorouracil (m-DCF) and epirubicin, oxaliplatin, and capecitabine (EOX) regimens are superior to other regimens. Methods: This randomized, single-center clinical trial was performed on 40 patients with advanced gastric cancer. The first group received the m-DCF regimen as follows: docetaxel (40 mg/m2) on the first day; cisplatin (40 mg/m2) on the first and second days; and 5-fluorouracil (400 mg/m2) from the first to fourth day. The second group received the EOX regimen, including epirubicin (50 mg/m2) and oxaliplatin (130 mg/m2) i.v on the first day and capecitabine at a twice-daily dose of 625 mg/m2 p.o for 21 days. Treatment was applied every three weeks for a total of eight cycles in both groups. In each group, the overall and progression-free survival rates and toxicity were assessed. Results: A total of 40 patients were enrolled in this study (21 samples in the m-DCF group and 19 samples in the EOX group), 62.5% of whom were male. The median survival rate was 14.00 (95% CI: 11.82-16.18) months in the m-DCF group and 15.00 (95% CI: 9.56-20.43) months in the EOX group; however, differences between the groups were not significant. The progression-free survival rate was higher in the EOX group, although there was no significant difference between the two groups. Also, there was no significant difference regarding the side effects (e.g., toxicity) or need for supportive care between the groups. Conclusion: It seems that both m-DCF and EOX regimens are similar in terms of survival and toxicity and are recommended as first-line treatment for advanced gastric cancer with respect to the patient’s status.     

Helicobacter pylori Infection, Serum Pepsinogen Level and Gastric Cancer: A Case-Control Study in Japan

We conducted a case-control study to evaluate the effect of Helicobacter pylori (HP) infection on the risk of gastric cancer in Tokyo, Japan. The sera at the time of diagnosis from 282 gastric cancer cases and 767 sex- and age-matched cancer-free controls were tested for the presence of anti-HP IgG antibody (HM-CAP ELISA kit) and serum pepsinogen (PG) level (PG I and PG II Riabead). No significant association was observed in all sets [matched odds ratio (OR)=1.04, 95% confidence interval: 0.73–1.49]. In subgroup analyses, however, an association was suggested in females [OR=1.57], a younger population (<50 years) [OR=1.86], early cancer [OR=1.53] and small cancer (<40 mm) [OR=1.55]. Furthermore, we observed a tendency for odds ratios to decrease with an increase in age or cancer growth (depth of tumor invasion and tumor size). Considering that the spontaneous disappearance of HP due to extended mucosal atrophy may lead to these decreasing odds ratios, we applied the conditional logistic model adjusted for the PG I/II ratio as a measure of atrophic gastritis. This analysis showed a positive association with HP infection in all sets [OR=1.69; 1.01–2.81], distal cancer [OR=1.88; 1.07–3.31] and intestinal-type cancer [OR=3.76; 1.39–10.18]. We concluded that the risk of cancer associated with HP infection may be underestimated in studies with cross-sectional exposure because of spontaneous disappearance of HP due to extended mucosal atrophy.     

胃癌组织中Sonic Hedgehog表达及其与NF-kappaB的关系研究

目的探讨Hedgehog在胃癌及其癌前病变中的表达及与NF-kappaB的关系。方法选择50例萎缩性胃炎、46例肠化生和57例胃癌患者的胃黏膜内镜活检样本,同时选择30例正常人作为对照;分为萎缩性胃炎组、肠化生组、胃癌组和正常黏膜组。通过病理学检测患者Hpylori感染状况。免疫组化法检测Hedgehog和NF-kappaB在不同阶段胃癌组织中的表达差异。流式细胞仪分析各组胃黏膜细胞的周期分布和凋亡率。Western blot检测Hedgehog表达。结果在胃癌的发展过程中,胃黏膜组织中Hedgehog表达水平先降低后升高。NF-kappaB表达水平在正常胃组织、萎缩性胃炎和肠化生组织中无明显变化,但在胃癌组织中表达显著增强。与正常胃黏膜组织比较,萎缩性胃炎、肠化生和胃癌组织中的S期细胞比例更高。细胞凋亡率萎缩性胃炎组和肠化生组较高,而胃癌组较低。抑制NF-kappaB后,Hedgehog蛋白在胃癌组织中的表达降低。结论在胃癌的发展过程中,Hedgehog蛋白表达水平先降低后升高。H pylori感染可能通过激活NF-kappaB,继而增强Hedgehog表达,同时赋予胃癌细胞凋亡抵抗。     

454例自然人群的3432份胃粘膜活检观察

自胃癌高发区454例自然人群的3432份胃粘膜活检,检出胃癌5例,慢性浅表性胃炎(CSG)67.28％,慢性萎缩性胃炎(CAG)3.88％,肠上皮化生(IM)14.28％。CSG在胃体部高于窦部,CAG与IM则胃窦部明显高于体部(P<0.05)。支持CAG、IM为癌前状态之观点。     

A Case-Control Study of Gastric Cancer and Diet in Northern Kyushu, Japan

A case-control study of gastric cancer was done in a rural area of northern Kyushu, Japan, in relation to dietary habits especially focusing on the relationship with the consumption of broiled fish. The study was based upon 139 cases of newly diagnosed gastric cancer at a single institution, 2,574- hospital controls and 278 controls sampled randomly from the residents of the study area (with sex and year of birth matched). No association was observed between the consumption of broiled fish and gastric cancer risk whether three types of broiled fish (raw fish, dried fish and salted fish) were analyzed separately or as a single category. However, consistently in the comparisons with both sets of controls, the risk of gastric cancer was inversely related with the consumption of fruits and positively associated with cigarette smoking. A decreased risk of gastric cancer was also noted among those with high consumption of green tea (10 or more cups per day).     

Quality of Life in the Trastuzumab for Gastric Cancer Trial

Background.

The Trastuzumab for Gastric Cancer phase III trial demonstrated that combining trastuzumab with chemotherapy significantly improved overall survival compared with chemotherapy alone in HER2-positive advanced gastric or gastroesophageal junction cancer. We report health-related quality of life (HRQoL) and quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) results from this trial.

Patients and Methods.

Patients were randomized to receive six cycles of chemotherapy given every 3 weeks (capecitabine or fluorouracil, plus cisplatin) either alone or combined with administration of trastuzumab every 3 weeks until disease progression. At each clinical visit, HRQoL was assessed using two European Organization for Research and Treatment of Cancer quality of life questionnaires, QLQ-C30 and QLQ-STO22. Q-TWiST methodology was applied retrospectively using the clinical data and utility coefficients.

Results.

Trastuzumab plus chemotherapy prolonged time to 10% definitive deterioration in all QLQ-C30 and QLQ-STO22 scores, including QLQ-C30 global health status versus chemotherapy alone, from 6.4 months to 10.2 months. In addition, trastuzumab plus chemotherapy extended Q-TWiST by 2.42 months compared with chemotherapy alone.

Conclusion.

Compared with chemotherapy alone, trastuzumab plus chemotherapy prolongs time to deterioration of HRQoL and increases quality-adjusted survival in patients with HER2-positive gastric or gastroesophageal junction cancer.     

Determination of Prognostic Factors in Japanese Patients With Advanced Gastric Cancer Using the Data From a Randomized Controlled Trial,Japan Clinical Oncology Group 9912

Background.

In advanced gastric cancer (AGC), no globally accepted prognostic scoring system has been developed. Therefore, we explored baseline prognostic factors in Japanese AGC patients using the data from a randomized controlled trial, Japan Clinical Oncology Group (JCOG) 9912, which investigated the efficacy of systemic chemotherapy as a first-line treatment.

Patients and Methods.

Prognostic factors and prognostic indices for overall survival were screened and evaluated in patients enrolled in JCOG9912 using the Cox proportional hazard model. The Royal Marsden Hospital prognostic model was also applied to the JCOG9912 trial.

Results.

A total of 650 (92.3%) of the 704 patients randomized in the JCOG9912 trial, for whom complete data were available for multivariate analyses, was included in the present study (5-fluorouracil arm, n = 215; irinotecan plus cisplatin arm, n = 216; S-1 arm, n = 219). The median survival time (MST) for all patients was 11.8 months. To construct a prognostic index, we selected four risk factors by multivariate analysis: performance status ≥ 1, number of metastatic sites ≥ 2, no prior gastrectomy, and elevated alkaline phosphatase. MSTs were 17.0 months for patients categorized into the low-risk group, who had zero or one risk factor (n = 225); 10.4 months for patients in the moderate-risk group, who had two or three risk factors (n = 368); and 5.0 months for patients in the high-risk group, who had all four risk factors (n = 57).

Conclusion.

In the present study, we propose a new prognostic index for patients with AGC. This can be used for more appropriate patient stratification in future clinical trials.     

Smoking Behavior and Risk of Helicobacter Pylori Infection,Gastric Atrophy and Gastric Cancer in Japanese

Although many studies have shown that smoking is an established risk factor for gastric cancer, relativelyfew studies have investigated on which step smoking has effects in Helicobacter pylori (H. pylori) related gastriccarcinogenesis. In this study we investigated the association of smoking with risk of three steps leading to gastriccancer: H. pylori infection, gastric atrophy, and gastric cancer. Among the participants who visited Aichi CancerCenter Hospital from year 2001 to 2005, 583 cases diagnosed as gastric cancer and age-and sex-frequency-matched1,742 cancer free controls were sampled, from whom those without serum samples or without information aboutsmoking habit were excluded, leaving 576 cases and 1,599 controls eligible for the analyses. Anti- H. pylori IgGantibody and serum pepsinogens (PG) were measured to detect H. pylori infection and gastric atrophy. Smokingstatus was asked by a self-administered questionnaire. The odds ratio (OR) of H. pylori infection, as well as theOR of gastric atrophy among the H. pylori seropositive controls was not significant for smokers. The age- andsex-adjusted OR of gastric cancer was significantly elevated relative to the subjects with gastric atrophy: OR=1.62(95% confidence interval (CI), 1.19-2.22; P=0.002) for ever smokers and 2.52 (1.75-3.64; P<0.001) for currentsmokers, relative to never smokers. This study revealed that smoking behavior contributed to the increased riskof gastric carcinogenesis from gastric atrophy, and had little influence on H. pylori infection or gastric atrophydevelopment.     

Smoking Behavior and Risk of Helicobacter Pylori Infection,Gastric Atrophy and Gastric Cancer in Japanese

Although many studies have shown that smoking is an established risk factor for gastric cancer, relatively few studies have investigated on which step smoking has effects in Helicobacter pylori (H. pylori) related gastric carcinogenesis. In this study we investigated the association of smoking with risk of three steps leading to gastric cancer: H. pylori infection, gastric atrophy, and gastric cancer. Among the participants who visited Aichi Cancer Center Hospital from year 2001 to 2005, 583 cases diagnosed as gastric cancer and age-and sex-frequency-matched 1,742 cancer free controls were sampled, from whom those without serum samples or without information about smoking habit were excluded, leaving 576 cases and 1,599 controls eligible for the analyses. Anti- H. pylori IgG antibody and serum pepsinogens (PG) were measured to detect H. pylori infection and gastric atrophy. Smoking status was asked by a self-administered questionnaire. The odds ratio (OR) of H. pylori infection, as well as the OR of gastric atrophy among the H. pylori seropositive controls was not significant for smokers. The age- and sex-adjusted OR of gastric cancer was significantly elevated relative to the subjects with gastric atrophy: OR=1.62 (95% confidence interval (CI), 1.19-2.22; P=0.002) for ever smokers and 2.52 (1.75-3.64; P<0.001) for current smokers, relative to never smokers. This study revealed that smoking behavior contributed to the increased risk of gastric carcinogenesis from gastric atrophy, but had little influence on H. pylori infection or gastric atrophy development.     

Study Protocol of the Bladder Adjuvant RadioTherapy (BART) Trial: A Randomised Phase III Trial of Adjuvant Radiotherapy Following Cystectomy in Bladder Cancer

AimsTo assess the efficacy and safety of adjuvant radiotherapy in patients with high-risk muscle-invasive bladder cancer (MIBC) following radical cystectomy (RC) and chemotherapy.Materials and methodsThe BART (Bladder Adjuvant RadioTherapy) trial is an ongoing multicentric, randomised, phase III trial comparing the efficacy and safety of adjuvant radiotherapy versus observation in patients with high-risk MIBC. The key eligibility criteria include ≥pT3, node-positive (pN+), positive margins and/or nodal yield <10, or, neoadjuvant chemotherapy for cT3/T4/N+ disease. In total, 153 patients will be accrued and randomised, in a 1:1 ratio, to either observation (standard arm) or adjuvant radiotherapy (test arm) following surgery and chemotherapy. Stratification parameters include nodal status (N+ versus N0) and chemotherapy (neoadjuvant chemotherapy versus adjuvant chemotherapy versus no chemotherapy). For patients in the test arm, adjuvant radiotherapy to cystectomy bed and pelvic nodes is planned with intensity-modulated radiotherapy to a dose of 50.4 Gy in 28 fractions using daily image guidance. All patients will follow-up with 3-monthly clinical review and urine cytology for 2 years and subsequently 6 monthly until 5 years, with contrast-enhanced computed tomography abdomen pelvis 6 monthly for 2 years and annually until 5 years. Physician-scored toxicity using Common Terminology Criteria for Adverse Events version 5.0 and patient-reported quality of life using the Functional Assessment of Cancer Therapy – Colorectal questionnaire is recorded pre-treatment and at follow-up.Endpoints and statisticsThe primary endpoint is 2-year locoregional recurrence-free survival. The sample size calculation was based on the estimated improvement in 2-year locoregional recurrence-free survival from 70% in the standard arm to 85% in the test arm (hazard ratio 0.45) using 80% statistical power and a two-sided alpha error of 0.05. Secondary endpoints include disease-free survival, overall survival, acute and late toxicity, patterns of failure and quality of life.ConclusionThe BART trial aims to evaluate whether contemporary radiotherapy after standard-of-care surgery and chemotherapy reduces pelvic recurrences safely and also potentially affects survival in high-risk MIBC.     

Effects of a Self-Monitoring Quality of Life Intervention for Patients with Cancer Receiving Palliative Care in Japan: Study Protocol for a Randomized Controlled Trial

Background: Previous studies suggest the use of patient-reported outcome measures in routine clinical practice hasimportant benefits for patients with cancer, particularly as feedback regarding patients’ quality of life (QOL) improvesdoctor-patient communication and clinical decision making. This study aimed to examine the effect of using the CareNotebook as a routine self-monitoring QOL intervention in clinical practice for patients with cancer receiving palliativecare. The results are expected to clarify the practical use of the Care Notebook in this population. Methods: Thisprospective randomized study is being undertaken at Toshima Hospital, Japan. Participating patients who are randomlyassigned to the intervention group will be asked to complete the shortened Care Notebook booklet for patients withcancer in palliative care once each day. A control group will receive usual care. The primary outcome is global healthstatus/QOL (Global QOL), as assessed by the European Organization for Research and Treatment of Cancer Quality ofLife Questionnaire Core 15 Palliative. Data will be collected at baseline (after allocation), and at 1 week and 3 weeksin both the control and intervention groups. The effects of the intervention will be evaluated with a mixed randomeffects model. The required sample size is 200 patients. We obtained approval from Toshima Hospital (No 26-11) andthe Tokyo Medical and Dental University Ethics Committee (No 1756). The findings will be disseminated throughpublications in peer-reviewed journals and attendance at domestic and international conferences. The trial was registeredwith the UMIN clinical trials registry (Trial registration number: UMIN000025322). Conclusions: This study willprovide evidence on whether medical staff can use the Care Notebook as a routine self-monitoring QOL intervention inclinical practice for patients with cancer receiving palliative care. We expect that a routine Care Notebook interventionfor patients with cancer will be recommended in healthcare facilities.     

Antiemetic Efficacy of High-Dose Intravenous Metoclopramide and Dexamethasone in Patients Receiving Cisplatin-Based Chemotherapy: A Randomized Controlled Trial

High-dose intravenous (IV) metoclopramide has shown efficacywith few side effects for the treatment of nausea and vomitingon the day of cisplatin administration. From November 1984 toJanuary 1986, two randomized trials in an antiemetic study wereconducted. In trial I, the antiemetic effect of a short courseof high-dose dexamethasone was compared with that of high-dosemetoclopramide in 29 patients with lung cancer receiving chemotherapycon taining cisplatin (80 mg/m² IV) in a randomized controlledtrial. Dexamethasone was given IV at a dose of 16 mg 1/2 hrbefore and 8 mg, 1 1/2, 3 1/2 and 5 1/2 hr after cisplatin.Metoclopramide was given IV at a dose of 2 mg/kg, 1/2 hr beforeand 1 1/2, 3 1/2 and 5 1/2 hr after cisplatin. Major emeticcontrol (0–2 episodes of vomiting) during the 24 hr aftercisplatin administration was achieved in 55% (6/11) and 67%(12/18) of the patients receiving dexa methasone and metoclopramide,respectively, without serious toxicity. The dura tion of nauseaor anorexia was similar for the two treatment groups. In trial11, the combination of metoclopramide and dexamethasone wascompared with metoclopramide alone to assess the additive antiemeticeffect of the two drugs in 23 patients with lung cancer receivingcisplatin at a dose of 120 mg/m IV in a randomized cross-overstudy. A major antiemetic response was observed in 27% (3/11)and 92% (11/12) of the patients receiving metoclopramide aloneand metoclopramide plus dexamethasone, respectively (p <0.005). The duration of nausea and anorexia was similar forthe two treatment groups. Pa tients tended to prefer the combinationof metoclopramide and dexamethasone; however, the differencewas not statistically significant (p = 0.14) in the small numberof patients entered in this study. Despite excellent controlof acute chemotherapy-induced emesis, 45% of 52 patients experienceddelayed nausea and vomiting more than 24 hr after cisplatinadministration even among those who had had an excellent short-termresponse to the antiemetic agents.     

Tislelizumab Versus Docetaxel in Patients With Previously Treated Advanced NSCLC (RATIONALE-303): A Phase 3, Open-Label,Randomized Controlled Trial

IntroductionThe phase 3 RATIONALE-303 trial (NCT03358875) investigated the efficacy and safety of tislelizumab versus docetaxel in pretreated patients with advanced NSCLC. Here, we report the efficacy and safety results and describe the exploratory biomarker analyses.MethodsA total of 805 patients aged more than or equal to 18 years with locally advanced or metastatic squamous or nonsquamous NSCLC were randomized 2:1 to intravenous tislelizumab 200 mg or docetaxel 75 mg/m² every 3 weeks. Co-primary end points were overall survival (OS) in the intent-to-treat (ITT) and programmed death-ligand 1 (PD-L1) tumor cell expression greater than or equal to 25% populations. The exploratory biomarker analyses included PD-L1 expression, tumor mutation burden, and gene expression profile.ResultsAt the prespecified interim analysis (August 10, 2020), the co-primary end point of OS in the ITT population was met, with a statistically significant and clinically meaningful improvement in OS with tislelizumab versus docetaxel (median 17.2 versus 11.9 mo, respectively; hazard ratio [HR] = 0.64, p < 0.0001). At the final analysis (July 15, 2021), the other co-primary end point of OS in the PD-L1 tumor cell greater than or equal to 25% population was further met (median 19.3 versus 11.5 mo, respectively; HR = 0.53, p < 0.0001), and OS continued to improve in the ITT population (median 16.9 versus 11.9 mo, respectively, HR = 0.66). Exploratory biomarker analyses revealed the potential association of NOTCH1–4 mutations with improved tislelizumab efficacy for both OS and progression-free survival, whereas tissue tumor mutation burden correlated with progression-free survival benefit, but not OS benefit. No new safety signals were identified.ConclusionsTislelizumab was found to have a significantly improved and long-term clinical benefit in OS versus docetaxel in pretreated patients with advanced NSCLC, regardless of PD-L1 expression.