Background.
The phase II YO28252 study (01590719) examined first‐line onartuzumab plus mFOLFOX6 in patients with metastatic, human epidermal growth factor receptor 2‐negative adenocarcinoma of the ...stomach or gastroesophageal junction. MET immunohistochemistry expression as a biomarker of onartuzumab activity was also examined.
Patients and Methods.
Patients were randomized 1:1 to receive standard mFOLFOX6 plus onartuzumab (10 mg/kg) or placebo in 2‐week cycles for 12 cycles, followed by onartuzumab or placebo until disease progression. Coprimary endpoints were progression‐free survival (PFS) in intent‐to‐treat (ITT) and MET‐positive populations. The target hazard ratio (HR) was 0.70 for patients in the ITT group and 0.60 in the MET‐positive population. Secondary endpoints were overall survival (OS), overall response rate (ORR), and safety.
Results.
Overall, 123 patients were enrolled (n = 62 onartuzumab, n = 61 placebo). Median PFS was 6.77 versus 6.97 months for onartuzumab versus placebo, respectively (HR, 1.08; 95% confidence interval CI, 0.71–1.63; p = .71). In the MET‐positive population, median PFS was 5.95 versus 6.80 months, onartuzumab versus placebo (HR, 1.38; 95% CI, 0.60–3.20; p = .45). Median OS was 10.61 months for onartuzumab versus 11.27 months for placebo) (HR, 1.06, 0.64–1.75; p = .83). In the MET‐positive population, median OS was 8.51 versus 8.48 months for onartuzumab versus placebo, respectively (HR, 1.12, 95% CI, 0.45–2.78; p = .80). ORR was 60.5% for the onartuzumab group and 57.1% for placebo. Grade 3–5 adverse events (AEs) were seen in 88.3% of patients receiving onartuzumab and in 78.3% of patients receiving placebo, with serious AEs in 55% and 40%, respectively.
Conclusion.
The addition of onartuzumab to mFOLFOX6 in gastric cancer did not improve efficacy in an unselected population or in a MET immunohistochemistry‐positive population.
Implications for Practice:
The YO28252 study demonstrated that the addition of the anti‐MET agent onartuzumab to mFOLFOX6 for treatment of gastric cancer did not improve efficacy in an overall study population or those selected for positive MET status by immunohistochemistry. This highlights the importance of correctly selecting biomarkers for targeted therapies. A multivariate analysis suggested that MET positivity may still be prognostic for worse median overall survival in gastric cancer; therefore, it is important to continue investigation into the optimal approach to inhibit MET signaling in gastric cancer.
摘要
背景. II 期 YO28252 研究 (01590719) 对 onartuzumab 联合 mFOLFOX6 一线治疗人类表皮生长因子受体 2 (HER2) 阴性的转移性胃或胃食道结合部腺癌患者进行了检验。同时还对 MET 免疫组化表达作为 onartuzumab 的生物标记物进行了检验。
患者与方法. 患者按 1:1 随机分配接受标准 mFOLFOX6 联合 onartuzumab (10 mg/kg) 或安慰剂治疗, 每 2 周为一周期, 共 12 周期; 后继以 onartuzumab 或安慰剂治疗直至发生疾病进展。联合主要终点为意向性治疗 (ITT) 人群和 MET 阳性人群的无进展生存 (PFS)。ITT人群的目标风险比 (HR) 为 0.70, MET 阳性人群为 0.60。次要终点包括总生存 (OS)、总缓解率 (ORR) 和安全性。
结果. 共纳入 123 例患者 (onartuzumab 组 62 例, 安慰剂组 61 例)。Onartuzumab 组中位 PFS 为 6.77 个月, 安慰剂组为 6.97 个月HR: 1.08, 95%置信区间 (CI): 0.71∼1.63, P=0.71。在 MET 阳性人群中, onartuzumab 组和安慰剂组的中位 PFS 分别为 5.95 个月和 6.80 个月 (HR: 1.38, 95%CI: 0.60∼3.20, P=0.45)。Onartuzumab 组和安慰剂组的中位 OS 分别为 10.61 个月和 11.27 个月 (HR: 1.06, 95%CI: 0.64∼1.75, P=0.83)。MET 阳性人群的中位 OS 分别为onartuzumab组 8.51 个月和安慰剂组 8.48 个月 (HR: 1.12, 95%CI: 0.45∼2.78, P=0.80)。Onartuzumab 组的 ORR 为 60.5%, 安慰剂组为 57.1%。Onartuzumab 组的 3∼5 级不良事件 (AE) 发生率为 88.3%, 安慰剂组为 78.3%, 严重 AE 发生率分别为 55% 和 40%。
结论. 在未经选择及MET免疫组化阳性的胃癌患者中, mFOLFOX6联合onartuzumab均未能改善有效性。The Oncologist 2016;21:1085–1090
对临床实践的提示: YO28252 研究证实在 mFOLFOX6 基础上联合抗 MET 制剂 onartuzumab 用于治疗胃癌, 未能在总人群及经选 MET 免疫组化阳性患者中改善有效性。这提出了正确选择靶向治疗的生物标记物的重要性。多变量分析提示 MET 阳性可能仍然是胃癌中位总生存较差的预后因素, 因此对抑制胃癌中 MET 信号转导的最佳方案继续开展研究非常重要。
Patients with metastatic, HER2‐negative adenocarcinoma of the stomach or gastroesophageal junction, including those with MET‐positive immunohistochemistry, were randomized 1:1 to receive standard mFOLFOX6 plus onartuzumab or placebo, followed by onartuzumab or placebo until disease progression. Median progression‐free and overall survival did not differ between groups. The addition of onartuzumab to mFOLFOX6 in gastric cancer did not improve efficacy.
Abstract
Background
Estimating prognosis on the basis of clinicopathologic factors can inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic ...nomograms for one-year overall survival and six-month progression-free survival in metastatic colorectal carcinoma by using the ARCAD database.
Methods
Data from 22 674 patients in 26 randomized phase III clinical trials since 1997 were used to construct and validate Cox models, stratified by treatment arm within each study. Candidate variables included baseline age, sex, body mass index, performance status, colon vs rectal cancer, prior chemotherapy, number and location of metastatic sites, tumor mutation status (BRAF, KRAS), bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil-to-lymphocyte ratio. Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions tested if P values were less than .001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated on a 10% holdout sample from each trial (n = 2257).
Results
In final models, all included variables were associated with overall survival except for lung metastases, and all but total white cell count associated with progression-free survival. No clinically relevant pairwise interactions were identified. Final nomogram calibration was good (C = 0.68 for overall and C = 0.62 for progression-free survival), as was external validity (concordance between predicted >50% vs < 50% probability) and actual (yes/no) survival (72.8% and 68.2% concordance, respectively, for one-year overall and six-month progression-free survival, between predicted >50% vs < 50% probability and actual yes/no overall and progression-free survival). Median survival predictions fell within the actual 95% Kaplan-Meier confidence intervals.
Conclusions
The nomograms are well calibrated and internally and externally valid. They have the potential to aid prognostication and patient-physician communication and balance risk in colorectal cancer trials.
Advanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted ...tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO).
INTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator's choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation.
INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC.
INTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC).
The activity and mechanism of action of the ...combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m(2) as a loading dose and then weekly cetuximab 250 mg/m(2) with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design.
Preclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the epidermal growth factor receptor pathway and differential effects on STAT3. In the clinical study, 50 patients were enrolled, with 48 patients evaluable for response. The overall RR was 31% (95% CI, 26% to 57%), with a median PFS of 4.6 months (95% CI, 2.8 to 5.6 months). RR was 41% (95% CI, 26% to 57%) in KRAS WT tumors, with a median PFS of 5.6 months (95% CI, 2.9 to 5.6 months). There was no response in 11 patients with KRAS mutations. Frequent grade 3 and 4 toxicities were rash (48%), hypomagnesaemia (18%), and fatigue (10%).
The combination of cetuximab and erlotinib synergistically inhibits growth of colon cancer cell lines, achieves promising efficacy in patients with KRAS WT mCRC, and merits evaluation in further randomized studies.
Abstract Introduction Although contact days—days with health-care contact outside home—are increasingly adopted as a measure of time toxicity and treatment burden, they could also serve as a ...surrogate of treatment-related harm. We sought to assess the association between contact days and patient-reported outcomes and the prognostic ability of contact days. Methods We conducted a secondary analysis of CO.17 that evaluated cetuximab vs supportive care in patients with advanced colorectal cancer. CO.17 collected European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 instrument data. We assessed the association between number of contact days in a window and changes in physical function and global health status and the association between number of contact days in the first 4 weeks with overall survival. Results There was a negative association between the number of contact days and change in physical function (per each additional contact day: at 4 weeks, 1.50-point decrease; 8 weeks, 1.06-point decrease; P < .0001 for both) but not with global health status. This negative association was seen in patients receiving cetuximab but not supportive care. More contact days in the first 4 weeks was associated with worse overall survival for all participants and patients receiving cetuximab (per each additional contact day: all participants, adjusted hazard ratio HR = 1.07, 95% confidence interval CI = 1.05 to 1.10; and cetuximab, adjusted HR = 1.08, 95% CI = 1.05 to 1.11; P < .0001 for both). Conclusions In this secondary analysis of a clinical trial, more contact days early in the course were associated with declines in physical function and worse survival in all participants and in participants receiving cancer-directed treatment. Trial registration ClinicalTrials.gov number, NCT00079066.
Open-label phase II study (RELATIVITY-060) to investigate the efficacy and safety of first-line nivolumab, a PD-1-blocking antibody, plus relatlimab, a lymphocyte-activation gene 3 (LAG-3)-blocking ...antibody, plus chemotherapy in patients with previously untreated advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC).
Patients with unresectable, locally advanced or metastatic GC/GEJC were randomly assigned 1:1 to nivolumab + relatlimab (fixed-dose combination) + chemotherapy or nivolumab + chemotherapy. The primary end point was objective response rate (ORR; per RECIST v1.1 by blinded independent central review BICR) in patients whose tumors had LAG-3 expression ≥1%.
Of 274 patients, 138 were randomly assigned to nivolumab + relatlimab + chemotherapy and 136 to nivolumab + chemotherapy. Median follow-up was 11.9 months. In patients with LAG-3 expression ≥1%, BICR-assessed ORR (95% CI) was 48% (38 to 59) in the nivolumab + relatlimab + chemotherapy arm and 61% (51 to 71) in the nivolumab + chemotherapy arm; median progression-free survival (95% CI) by BICR was 7.0 months (5.8 to 8.4) versus 8.3 months (6.9 to 12.1; hazard ratio HR, 1.41 95% CI, 0.97 to 2.05), and median overall survival (95% CI) was 13.5 months (11.9 to 19.1) versus 16.0 months (10.9 to not estimable; HR, 1.04 95% CI, 0.70 to 1.54), respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 69% and 61% of all treated patients, and 42% and 36% of patients discontinued because of any-grade TRAEs in the nivolumab + relatlimab + chemotherapy and nivolumab + chemotherapy arms, respectively.
RELATIVITY-060 did not meet its primary end point of improved ORR in patients with LAG-3 expression ≥1% when relatlimab was added to nivolumab + chemotherapy compared with nivolumab + chemotherapy. Further studies are needed to address whether adding anti-LAG-3 to anti-PD-1 plus chemotherapy can benefit specific GC/GEJC patient subgroups.
Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab ...and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC.
Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work.
In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints.
Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC.
Background
The Victorian Government convened the second Pancreas Cancer Summit in 2021 to identify unwarranted variation in care 2016–2019, and to assess trends compared with the first Summit 2017 ...(reporting 2011–2015). State‐wide administrative data were assessed at population level in alignment with optimal care pathways across all stages of the cancer care continuum.
Methods
Data linkage performed by Centre for Victorian Data Linkage combined data from Victorian Cancer Registry with other administrative data sets including Victorian Admitted Episodes Dataset, Victorian Radiotherapy Minimum Data Set, Victorian Emergency Minimum Dataset and Victorian Death Index. A Cancer Service Performance Indicator audit was carried out providing an in‐depth analysis of identified areas of interest.
Results
Of 3138 Victorians diagnosed with pancreas ductal adenocarcinoma 2016–2019, 63% were metastatic at diagnosis. One‐year survival increased between time periods, from 29.7% overall 2011–2015 (59.1% for non‐metastatic, and 15.1% metastatic) to 32.5% overall 2016–2019 (P < 0.001), 61.2% non‐metastatic (P = 0.008), 15.7% metastatic (P = NS). A higher proportion of non‐metastatic patients progressed to surgery (35% vs. 31%, P = 0.020), and more received neoadjuvant therapy (16% vs. 4%, P < 0.001). Postoperative mortality following pancreatectomy at 30 and 90 days remained low at 2%. Utilization of 5FU‐based chemotherapy regimens increased between 2016 and 2020. Multidisciplinary Meeting (MDM) presentation was still below the 85% target (74%) as was supportive care screening (39%, target 80%).
Conclusions
Surgical outcomes remain world‐class and there has been an appropriate shift in chemotherapy administration towards neoadjuvant timing with increasing use of 5FU‐based regimens. MDM presentation rates, supportive care and overall care coordination remain areas of deficiency.
Outcomes of Pancreas Cancer Summit in Victoria 2022 compared with previous Pancreas Summit 2017 demonstrating changing practices.
Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to ...investigate the impact of PTS on outcomes of mCRC patients.
PTS data of 9277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemotherapy, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs chemotherapy alone). All statistical tests were 2-sided.
Compared with right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 vs 15.9 months; adjusted hazard ratio HRadj = 0.71, 95% confidence interval CI = 0.67 to 0.76; P < .001) and PFS (median = 8.6 vs 7.5 months; HRadj = 0.80, 95% CI = 0.75 to 0.84; P < .001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction < .001); left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53 to 0.66; PFS HRadj =0.68, 95% CI = 0.61 to 0.75) but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75 to 0.97; P = .01; PFS HRadj = 0.77, 95% CI = 0.67 to 0.88; P < .001) but not for right-sidedness.
The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.
Advanced biliary tract cancers (BTCs) have a poor prognosis and limited treatment options. This exploratory phase II study aimed to evaluate the activity of the mTOR inhibitor everolimus in advanced ...BTC and explore prognostic biomarkers.
Patients with advanced BTCs, who had not received chemotherapy for advanced disease, were enroled to receive everolimus (10 mg daily). The primary endpoint was disease control rate (DCR) at 12 weeks. Secondary endpoints included overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events. Activation status of the RAS and phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathways was assessed by DNA sequencing and immunohistochemistry on archival tumour tissue.
The study enroled 27 patients and the DCR at 12 weeks was 48%. Median PFS was 5.5 months (95% confidence interval (CI): 2.1-10.0 months) and median OS was 9.5 months (95% CI: 5.5-16.6 months). DCR at 12 weeks was significantly worse for gall bladder carcinoma compared to other anatomical sites, and there was a trend towards a worsened PFS and OS. Treatment was well tolerated. KRAS (12%) and PIK3CA mutations (12%) were uncommon. Immunohistochemical staining for PI3K/AKT/mTOR pathways did not significantly correlate with outcome.
In unselected patients, everolimus demonstrated clinical activity as first-line monotherapy in advanced BTC.
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