Phase III,randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300

BackgroundThere currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.Patients and methodsPatients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician’s choice of chemotherapy (paclitaxel 80 mg/m² on days 1, 8, and 15 or irinotecan 150 mg/m² on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.ResultsA total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0 months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9–1.4]; P = 0.81} or the secondary end points of PFS [median, 1.4 versus 2.7 months; HR=1.73 (95% CI 1.4–2.2); P > 0.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.ConclusionsTreatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.Trial registrationClinicalTrials.gov: NCT02625623.     

First-Line Nivolumab Plus Ipilimumab With Chemotherapy Versus Chemotherapy Alone for Metastatic NSCLC in CheckMate 9LA: 3-Year Clinical Update and Outcomes in Patients With Brain Metastases or Select Somatic Mutations

IntroductionIn the phase 3 CheckMate 9LA study, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy alone. We report updated efficacy and safety (≥3 y of follow-up), clinical outcomes in patients with baseline brain metastases, and exploratory somatic mutation analyses.MethodsAdults with stage IV or recurrent NSCLC, no known sensitizing EGFR or ALK alterations, and Eastern Cooperative Oncology Group performance status less than or equal to 1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy alone (four cycles). Assessments included OS, progression-free survival (PFS), and objective response rate. Exploratory analyses included systemic and intracranial efficacy in patients with or without baseline brain metastases, in addition to OS and PFS by KRAS, TP53, STK11, and KEAP1 somatic mutation status in patients with nonsquamous NSCLC.ResultsWith a minimum follow-up of 36.1 months, nivolumab plus ipilimumab with chemotherapy continued to prolong OS versus chemotherapy alone in the intent-to-treat population (median [hazard ratio; 95% confidence interval] OS: 15.8 versus 11.0 mo [0.74; 0.62–0.87]; 3-y OS: 27% versus 19%). Efficacy outcomes were improved in patients with pretreated baseline brain metastases (median [hazard ratio; 95% confidence interval] OS: 19.3 versus 6.8 mo [0.45; 0.29–0.70]; systemic PFS: 9.7 versus 4.1 mo [0.44; 0.28–0.69]; intracranial PFS: 11.4 versus 4.6 mo [0.42; 0.26–0.68]). A trend of OS benefit was observed in patients treated with nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone, despite KRAS, TP53, and STK11 tumor mutations. Extended follow-up revealed no new safety signals.ConclusionsWith a 3-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy continued to have long-term, durable efficacy versus chemotherapy alone; a manageable safety profile; and survival benefit in patients with or without baseline brain metastases or select somatic mutations, further supporting the regimen as first-line treatment for patients with metastatic NSCLC.     

Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort

IntroductionNivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort.MethodsPatients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review.ResultsOverall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06–4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8–7.6) versus 4.7 months (3.1–8.3). Twenty-four–month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively.ConclusionsWhereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy.     

Quality-adjusted time without symptoms or toxicity analysis of nivolumab plus chemotherapy versus chemotherapy alone for the management of previously untreated patients with advanced gastric cancer,gastroesophageal junction cancer,or esophageal adenocarcinoma

Background

The phase 3 CheckMate 649 established superior overall survival of nivolumab in combination with chemotherapy (NIVO + chemo) compared with chemotherapy (chemo) alone as a first-line treatment for patients with Her2-negative advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC). This post hoc trial analysis aimed to evaluate the benefit of NIVO + chemo using quality-adjusted time without symptoms or toxicity (Q-TWiST) to further account for quality of life (QoL) in different health states depending on disease progression and treatment toxicity.

Methods

Using data from CheckMate 649, we evaluated the quality-adjusted survival gain associated with NIVO + chemo compared with chemo alone among all randomized patients and repeated similar analyses among those with programmed cell death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5. Relative Q-TWiST gains of ≥ 10% were predefined as clinically important.

Results

In all randomized patients, those receiving NIVO + chemo had a mean Q-TWiST gain of 1.8 (95% CI 0.9, 2.7) months compared with those receiving chemo alone. The relative Q-TWiST gain was estimated to be 12.8%. Patients with PD-L1 CPS ≥ 5 had greater quality-adjusted survival gain from NIVO + chemo with an estimated Q-TWiST gain of 2.8 (95% CI 1.5, 4.1) months, representing a relative gain of 20.6%. Subgroup analyses and sensitivity analyses with various QoL utility values yielded consistent findings in favor of NIVO + chemo compared with chemo alone. Q-TWiST gain from NIVO + chemo increased with longer duration of follow-up.

Conclusions

NIVO + chemo was associated with a statistically significant and clinically important gain in quality-adjusted survival compared with chemo alone among previously untreated patients with advanced GC/GEJC/EAC.

     

Safety and Efficacy of Nivolumab in Patients With Advanced Non–Clear Cell Renal Cell Carcinoma: Results From the Phase IIIb/IV CheckMate 374 Study

BackgroundThe open-label phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma. Three cohorts included patients with predominantly clear cell histology, non–clear cell histologies, or brain metastases. We report safety and efficacy from the advanced non–clear cell RCC (nccRCC) cohort of CheckMate 374.MethodsEligible patients received 0 to 3 prior systemic therapies. Patients received nivolumab 240 mg Q2W for ≤24 months or until confirmed progression or unacceptable toxicity. The primary endpoint was incidence of high-grade (grade 3-5) immune-mediated adverse events (IMAEs). Exploratory endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsForty-four patients had advanced nccRCC (papillary [n = 24], chromophobe [n = 7], unclassified [n = 8], other [n = 5]); 34.1% received ≥1 prior systemic regimen in the advanced/metastatic setting. With median follow-up of 11 (range, 0.4-27) months, no all-cause grade 3-5 IMAEs or treatment-related grade 5 adverse events were reported. ORR was 13.6% (95% confidence interval [CI], 5.2-27.4), with 1 complete response (chromophobe) and 5 partial responses (papillary [n = 2], chromophobe [n = 1], collecting duct [n = 1], and unclassified [n = 1] histology). Median PFS was 2.2 months (95% CI, 1.8-5.4). Median OS was 16.3 months (95% CI, 9.2-not estimable).ConclusionsSafety of flat-dose nivolumab 240 mg Q2W was consistent with previous results. Clinically meaningful efficacy was observed with responses in several histologies, supporting nivolumab as a treatment option for patients with advanced nccRCC, a patient population with high unmet need.     

西妥昔单抗联合化疗治疗K-ras基因不明的晚期结直肠癌

目的 探讨西妥昔单抗联合化疗对K-ras基因状态不明的晚期结直肠癌患者的疗效和安全性.方法 收集2005年3月至2008年12月间在中山大学肿瘤防治中心接受西妥昔单抗联合化疗的102例晚期结直肠癌患者的资料,统计患者的有效率(ORR)、疾病控制率(DCR)、无进展生存时间(PFS)和总生存期(OS).比较一线与非一线化疗联合应用西妥昔单抗、含奥沙利铂方案与含伊立替康方案的ORR、DCR、PFS和OS的差异.结果 102例患者的ORR和DCR分别为43.1%和74.5%,中位PFS和OS分别为4.0个月和28.5个月,1、3和5年生存率分别为89.2%、50.9%和27.5%.一线与非一线应用西妥昔单抗联合化疗患者的ORR(50.0%和40.0%,P=0.344)、DCR(78.1%和72.9%,P=0.571)和OS(51.0和35.0个月,P=0.396)差异均无统计学意义,但一线应用西妥昔单抗联合化疗患者的PFS(5.5个月)较非一线者显著延长(3.0个月,P=0.001).应用含奥沙利铂方案治疗与应用含伊立替康方案治疗患者的ORR(54.2%和40.0%,P=0.223)、DCR(79.2%和74.7%,P=0.654)、PFS(5.0个月和3.0个月,P=0.726,)和OS(36.0个月和40.0个月,P=0.759)比较,差异均无统计学意义.常见的不良反应有痤疮样皮疹(80.4%,3～4级9.8%)、中性粒细胞下降(66.7%,3～4级18.6%)、腹泻(19.6%,3～4级5.9%),无与治疗相关性死亡病例.结论 西妥昔单抗联合化疗治疗K-ras基因状况不明的晚期结直肠癌患者的有效率较高,中位生存时间较长,不良反应少且程度轻.比较一线与非一线应用西妥昔单抗治疗、含奥沙利铂方案与含伊立替康方案间的疗效均无明显差异.     

FOLFOXIRI改良方案一线治疗晚期胃癌疗效及安全性分析

  目的   分析FOLFOXIRI改良方案一线治疗晚期胃癌的疗效及安全性。   方法   选取2016年7月至2019年3月于中国医学科学院肿瘤医院采用FOLFOXIRI改良方案一线治疗的晚期胃癌20例。药物用法:奥沙利铂85 mg/m2静点d1，伊立替康120 mg/m2静点d1，亚叶酸钙200 mg/m2静点d1，氟尿嘧啶2 400 mg/m2持续静点44 h，每14天为1个周期。主要终点为客观缓解率（objective response rate，ORR）。次要终点包括无进展生存时间（progression free survival，PFS）、总生存时间（overall survival，OS）、疾病控制率（disease control rate，DCR）、缓解持续时间（duration of response，DOR）、安全性。   结果   中位治疗8个周期，ORR为50%，DCR为95%。中位起效时间为1.6个月，中位DOR为8.7个月。中位随访时间19.5个月，中位PFS为9.5个月（95% CI:7.309~11.691），中位OS为19.9个月（95% CI:9.754~30.046）。常见不良反应包括中性粒细胞减少、肝功能异常、腹泻等。主要3级不良反应为中性粒细胞减少（50%）、腹泻（10%）、ALT升高（10%），无≥ 4级不良反应。   结论   降低伊立替康剂量的FOLFOXIRI改良方案在晚期胃癌一线治疗中初步显示出良好的疗效和耐受性，值得进一步开展临床研究。      

Pembrolizumab plus pemetrexed-platinum for metastatic nonsquamous non–small-cell lung cancer: KEYNOTE-189 Japan Study

Pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) with manageable safety compared with placebo plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous non–small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double-blind, phase 3 KEYNOTE-189 study. We present results of Japanese patients enrolled in the KEYNOTE-189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m² plus the investigator’s choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m² Q3W (all intravenous). Co–primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7‒38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed-platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9‒29.0) months in the placebo plus pemetrexed-platinum arm (hazard ratio [HR] .29; 95% CI, .07‒1.15). The median (95% CI) PFS was 16.5 (8.8‒21.1) compared with 7.1 (4.7‒21.4) months (HR, .62; 95% CI, .27‒1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune-mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first-line therapy with pembrolizumab plus pemetrexed-platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.     

Outcomes of long-term nivolumab and subsequent chemotherapy in Japanese patients with head and neck cancer: 2-year follow-up from a multicenter real-world study

Background

We have previously reported the effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) in real-world clinical practice in Japan. Here, we report long-term outcomes from this study in the overall population and subgroups stratified by subsequent chemotherapy.

Methods

In this multicenter, retrospective observational study, Japanese patients with recurrent or metastatic (R/M) HNC receiving nivolumab were followed up for 2 years. Effectiveness endpoints included overall survival (OS), OS rate, progression-free survival (PFS), and PFS rate. Safety endpoints included the incidence of immune-related adverse events (irAEs).

Results

Overall, 256 patients received a median of 6.0 doses (range: 1–52) of nivolumab over a median duration of 72.5 days (range: 1–736). Median OS was 9.5 months [95% confidence interval (CI) 8.2–12.0] and median PFS was 2.1 months (95% CI 1.8–2.7). A significant difference between 2-year survivors (n = 62) and non-2-year survivors was observed by median age (P = 0.0227) and ECOG PS (P = 0.0001). Of 95 patients who received subsequent chemotherapy, 54.7% received paclitaxel ± cetuximab. The median OS and PFS from the start of paclitaxel ± cetuximab were 6.9 months (95% CI 5.9–11.9) and 3.5 months (95% CI 2.3–5.5), respectively. IrAEs were reported in 17.2% of patients. Endocrine (7.0%) and lung (4.3%) disorders were the most common irAEs; kidney disorder (n = 1) was newly identified in this follow-up analysis.

Conclusions

Results demonstrated the long-term effectiveness of nivolumab and potential effectiveness of subsequent chemotherapy in patients with R/M HNC in the real-world setting. Safety was consistent with that over the 1-year follow-up.

     

奈达铂为基础化疗联合同步放疗治疗II-III期食管鳞状细胞癌的疗效观察

目的:探索在II-III期食管鳞癌同步放化疗中多西他赛联合奈达铂方案、S-1联合奈达铂方案与单药奈达铂化疗的疗效和安全性。方法:回归性纳入2016年1月至2017年1月就诊于我院的106例行同步放化疗的II-III期食管鳞癌患者。所有患者根据化疗方案分为三组,分别为:S-1联合奈达铂治疗组、多西他赛联合奈达铂治疗组和奈达铂单药治疗组。通过电子病历系统及随访获取患者相关信息,比较三种不同化疗方案疗效和安全性。结果:106例患者中41例为S-1联合奈达铂化疗、45例接受多西他赛联合奈达铂化疗、20例为单药奈达铂化疗。总体ORR为79.25%,三组不同化疗方案患者在CR、PR、SD、PD和ORR方面均无显著统计学差异。患者中位OS和PFS分别为25.3月和17.1月,三组患者在OS和PFS之间均无显著性差异。多西他赛联合奈达铂患者3度以上白细胞减少发生率显著高于S-1联合奈达铂和奈达铂单药（29/45 vs 12/41 vs 6/20,P=0.002）,S-1联合奈达铂患者腹泻发生率显著高于多西他赛联合奈达铂和奈达铂单药组（8/41 vs 3/45 vs 0/20,P=0.031）。结论:奈达铂为基础化疗联合同步放疗是II-III期食管鳞癌的有效治疗方法,多西他赛联合奈达铂、S-1联合奈达铂化疗和奈达铂单药化疗之间疗效接近,但S-1联合奈达铂化疗和奈达铂单药化疗不良反应优于多西他赛联合奈达铂化疗。     

免疫检查点抑制剂治疗晚期胃癌或食管胃结合部癌的有效性和安全性Meta分析

目的 系统评价免疫检查点抑制剂治疗晚期GC/GEJC患者的疗效及安全性。方法 通过计算机检索CNKI、万方、PubMed、EMBASE、ClinicalTrials、Cochrane Library等数据库收集免疫检查点抑制剂治疗晚期GC/GEJC的临床试验,检索时间从建库至2019年11月,结局指标主要包括客观缓解率、疾病控制率、无进展生存期、总生存期以及安全性;采用率差和风险比为效应量,采用RevMan5.3软件进行Meta分析。结果 共纳入7篇文献1 949例患者。结果显示：晚期GC/GEJC患者≥二线免疫检查点抑制剂治疗比化疗/安慰剂治疗提高了患者12月和18月的总生存率（均P<0.05）,延长了患者的总生存期（P<0.05）。免疫检查点抑制剂治疗引起的任何级别或≥3级不良反应的发生率均低于化疗/安慰剂治疗。结论 免疫检查点抑制剂治疗可改善部分晚期GC/GEJC患者生存终点,且常见不良反应发生率较低。     

Pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous non-small-cell lung cancer in KEYNOTE-407

The global phase III KEYNOTE-407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression-free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non-small-cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE-407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m² every 3 weeks (Q3W) or nab-paclitaxel 100 mg/m² (weekly) plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end-points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow-up time at data cut-off (May 9, 2019) was 15.1 (range, 0.5–24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5–not reached) versus 11.0 (8.6–19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27–1.15). Median PFS (95% CI) was 8.3 (6.1–13.0) versus 7.2 (3.9–8.8) months (HR 0.65; 95% CI, 0.35–1.23). Grade 3–5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment-related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC.     

IO-IO vs IO-TKI efficacy in metastatic kidney cancer patients: A structured systematic review over time

Multiple systemic immune-oncology (IO) combination therapies have demonstrated overall survival (OS) benefits in metastatic renal clear cell carcinoma (mRCC). However, the magnitude of benefits over time has not been compared in a structured fashion. To assess OS and progression free survival (PFS) efficacy as reflected by hazard ratios [HR]) according to the duration of follow-up over time for each of four IO combination therapies. A systematic PubMed (MEDLINE) literature review was performed (January, 1, 2016 to February, 20, 2022). Only phase III randomized clinical trials with proven OS benefit relative to sunitinib were included. These search criteria yielded four eligible RCTs: CheckMate 214 (nivolumab plus ipilimumab), Keynote 426 (pembrolizumab plus axitinib), CheckMate 9ER (nivolumab plus cabozantinib), CLEAR (lenvatinib plus pembrolizumab). OS and PFS HRs were tabulated for all four studies including all reported timepoints. Median follow-up ranged from 25–68 months for CheckMate 214 (5 timepoints), 13–43 months for Keynote 426 (3 timepoints), 18–33 months for CheckMate 9ER (3 timepoints) and 27–34 months for CLEAR (2 timepoints). Respective OS and PFS HRs were 0.68–0.72 and 0.98–0.86, 0.53–0.73 and 0.69–0.68, 0.60–0.70 and 0.51–0.56, 0.66–0.72 and 0.39–0.47 for CheckMate 214, Keynote 426, CheckMate 9ER and CLEAR. Regarding OS HRs virtually no change was recorded over time for CheckMate 214, but a decrease in magnitude occurred in the three IO-TKI remaining studies. Regarding PFS HRs, no benefit was recorded for CheckMate 214. Statistically significant benefit was recorded in the remaining IO-TKI studies. However, it also decreased with longer follow-up. It remains to be seen, whether further ‘slippage’ of efficacy will persist as the data matures further for all IO-TKI combinations.     

Phase 1 trial of zolbetuximab in Japanese patients with CLDN18.2+ gastric or gastroesophageal junction adenocarcinoma

Zolbetuximab is a chimeric monoclonal antibody that targets claudin-18.2, a candidate biomarker in patients with advanced gastric/gastroesophageal cancer. This nonrandomized phase 1 study (NCT03528629) enrolled previously treated Japanese patients with claudin-18.2–positive locally advanced/metastatic gastric/gastroesophageal cancer in two parts: Safety (Arms A and B, n = 3 each) and Expansion (n = 12). Patients received intravenous zolbetuximab 800 mg/m² on cycle 1, day 1 followed by 600 mg/m² every 3 weeks (Q3W; Safety Part Arm A and Expansion) or 1000 mg/m² Q3W (Safety Part Arm B). For the Safety Part, the primary endpoint was safety (i.e., dose-limiting toxicities [DLTs]) and a secondary endpoint was objective response rate (ORR) by investigator. For the Expansion Part, the primary endpoint was ORR by investigator and secondary endpoints included ORR by central review and safety. Additional secondary endpoints for both the Safety and Expansion Parts were disease control rate (DCR), overall survival (OS), progression-free survival (PFS), duration of response, pharmacokinetics, and immunogenicity. In 18 patients, no DLTs (Safety Part) or drug-related treatment-emergent adverse events (TEAEs) grade ≥3 were observed. Most TEAEs were gastrointestinal. In 17 patients with measurable lesions, best overall response was stable disease (64.7%) or progressive disease (35.3%). The DCR was 64.7% (95% confidence interval 38.3–85.8). In Arm A and Expansion combined (n = 15), median OS was 4.4 months (2.6–11.4) and median PFS was 2.6 months (0.9–2.8). In Arm B (n = 3), median OS was 6.4 months (2.9–6.8) and median PFS was 1.7 months (1.2–2.1). Zolbetuximab exhibited no new safety signals with limited single-agent activity in Japanese patients.     

Long‐term efficacy and predictive correlates of response to nivolumab in Japanese patients with esophageal cancer

The long‐term efficacy of nivolumab in esophageal squamous cell carcinoma and its association with disease biomarkers are currently not well known. Therefore, we investigated the association in Japanese patients with treatment‐refractory advanced esophageal cancer who participated in an open‐label, single‐arm, multicenter phase II study. Patients received nivolumab 3 mg/kg i.v. every 2 weeks until disease progression or unacceptable toxicity, and were followed up for 2 years after the initial dosing of the last patient. Archival tissue samples were collected before treatment and analyzed for programmed death ligand‐1 (PD‐L1) and CD8⁺ status of tumors and tumor‐infiltrating lymphocytes (TILs) and human leukocyte antigen class 1. Efficacy end‐points included objective response rate (ORR), overall survival (OS), progression‐free survival (PFS), time to response, and duration of response. Of 65 enrolled patients (83% male), 64 were evaluable for efficacy and 41 (63%) for biomarkers. The ORR, median OS, and survival rate were 17.2%, 10.78 months, and 17.2%, respectively. Time to response was 1.45 months and duration of response was 11.17 months. The PD‐L1 positivity of tumor cells was possibly associated with better PFS (2.04 vs 1.41 months, cut‐off 1%) and OS (11.33 vs 6.24 months, cut‐off 1%). Median OS was prolonged in patients with a median number of TILs greater than 63.75% vs 63.75% or less (11.33 vs 7.85 months). Nivolumab showed continued long‐term efficacy, as seen by the stability of PFS and OS, in Japanese patients with esophageal squamous cell carcinoma. Further investigation of PD‐L1 tumor expression and TILs as potential biomarkers for predicting patients likely to benefit from nivolumab therapy is warranted.     

奥沙利铂联合紫杉醇脂质体治疗晚期胃癌的疗效分析

目的 探讨奥沙利铂联合紫杉醇脂质体或替吉奥治疗晚期胃癌的临床疗效及不良反应.方法 选取46例晚期胃癌患者作为研究对象.按照随机数字表法将46例晚期胃癌患者随机分为A组和B组,每组23例.其中,A组患者接受奥沙利铂联合紫杉醇脂质体方案化疗,B组患者接受奥沙利铂联合替吉奥方案化疗.比较两组患者的客观缓解率(ORR)、疾病控制率(DCR)、无进展生存期(PFS)、总生存期(OS)和不良反应发生情况.结果 A组患者的ORR为47.8%,DCR为78.3%;B组患者的ORR为43.5%,DCR为69.6%;两组患者的ORR和DCR比较,差异均无统计学意义(P=0.767、0.502).A组和B组患者的中位OS分别为9.4个月和9.5个月,两组比较,差异无统计学意义(P=0.911).A组患者的中位PFS为6.9个月(95%CI:6.2~7.8个月),长于B组患者的5.4个月(95%CI:4.0~5.9个月),差异有统计学意义(P=0.048).两组患者的中性粒细胞减少、血小板减少、贫血、疲劳乏力、腹泻、关节肌肉疼痛、恶心呕吐以及神经毒性的发生率比较,差异均无统计学意义(P﹥0.05).结论 奥沙利铂联合紫杉醇脂质体方案和奥沙利铂联合替吉奥方案治疗晚期胃癌的临床疗效接近,但在晚期胃癌患者的无进展生存期方面,奥沙利铂联合紫杉醇脂质体方案可能优于奥沙利铂联合替吉奥方案.     

Alpha-fetoprotein response at different time-points is associated with efficacy of nivolumab monotherapy for unresectable hepatocellular carcinoma

Nivolumab monotherapy has a modest objective response rate (ORR) in hepatocellular carcinoma (HCC). To overcome the lack of biomarkers that predict delayed alpha-fetoprotein (AFP) response beyond 4 weeks, we applied a novel 50-10 rule of AFP response for unresectable HCC patients under nivolumab monotherapy and proposed an algorithm based on on-treatment AFP reduction at different time-points. Ninety unresectable HCC patients who underwent nivolumab monotherapy in 2015-2019 were retrospectively recruited and divided into four classes: rapid AFP decrease of ≥ 50% of baseline at week 4 (class I), AFP changes within ± 50% of baseline at week 4 that later decreased to ≥ 10% of baseline (class II) or not (class III) at week 12, and rapid AFP increase of ≥ 50% of baseline at week 4 (class IV). ORR was 47.4%, 36.0%, 7.7%, and 5.0% in class I-IV patients, respectively. Rapid (class I) and delayed (class II) AFP responders had significantly higher ORR, overall survival (OS) and progression-free survival (PFS) than non-responders (class III and IV) (ORR: 40.9% vs. 6.5%, P<0.001; median OS: not reached vs. 9.6 months, log-rank P<0.001; median PFS: 9.6 vs. 2.8 months, log-rank P<0.001). In multivariate analysis, AFP response was an independent factor associated with good OS (hazard ratio [HR]=0.301, P=0.001) and PFS (HR=0.332, P<0.001). Moreover, AFP responders had higher ORR and better OS as well as PFS than non-responders, regardless of nivolumab as a first- or more than a second-line therapy (all P<0.05). In conclusion, the novel 50-10 rule of AFP response provides practical guidance for nivolumab monotherapy in unresectable HCC patients. However, this algorithm remains to be verified in a large prospective cohort.     

A randomised,double-blind,placebo-controlled trial of trametinib,an oral MEK inhibitor,in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas

BackgroundTrametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed.MethodsAdults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m² (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2 mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups.ResultsBaseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67–1.44; P = .453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n = 103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia.ConclusionsThe addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.     

Ixabepilone plus capecitabine in metastatic breast cancer patients with reduced performance status previously treated with anthracyclines and taxanes: a pooled analysis by performance status of efficacy and safety data from 2 phase III studies

Patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes often have decreased performance status secondary to extensive tumor involvement. Here, we report the pooled analysis of efficacy and safety data from two similarly designed phase III studies to provide a more precise estimate of benefit of ixabepilone plus capecitabine in MBC patients with Karnofsky’s performance status (KPS) 70–80. Across the studies, anthracycline/taxane-pretreated MBC patients were randomized to receive ixabepilone plus capecitabine or capecitabine alone. Individual patient data for KPS 70–80 subset (n = 606) or KPS 90–100 subset (n = 1349) from the two studies were pooled by treatment. Analysis included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety. In patients with reduced performance status (KPS 70–80), ixabepilone plus capecitabine was associated with improvements in OS (median: 12.3 vs. 9.5 months; HR, 0.75; P = 0.0015), PFS (median: 4.6 vs. 3.1 months; HR, 0.76; P = 0.0021) and ORR (35 vs. 19%) over capecitabine alone. Corresponding results in patients with high performance status (KPS 90–100) were median OS of 16.7 versus 16.2 months (HR, 0.98; P = 0.8111), median PFS of 6.0 versus 4.4 months (HR, 0.58; P = 0.0009), and ORR of 45 versus 28%. The safety profile of combination therapy was similar between the subgroups. Ixabepilone plus capecitabine appeared to show superior efficacy compared to capecitabine alone in MBC patients previously treated with anthracyclines and taxanes, regardless of performance status, with a possible OS benefit favoring KPS 70–80 patients (ClinicalTrials.gov identifiers: NCT00080301 and NCT00082433).