Adjuvant chemotherapy has not improved disease-free survival among patients with resected esophageal or gastroesophageal junction cancer. In this trial, after neoadjuvant chemoradiotherapy and ...resection, patients with residual disease were randomly assigned to receive nivolumab or placebo. Nivolumab doubled the median disease-free survival from 11.0 to 22.4 months.
Colorectal cancer is genetically heterogeneous. Tumors in some patients have defects in mismatch DNA repair. These tumors have a high level of mutations that can lead to immune recognition. In a ...group of patients with microsatellite-unstable tumors, pembrolizumab led to longer progression-free survival and was less toxic than standard chemotherapy.
Approximately 7% of pancreatic cancers occur in patients with a germline mutation in
BRCA1
or
BRCA2
, an alteration that compromises DNA repair. In a randomized trial in patients with metastatic ...pancreatic cancer that had responded to platinum-based chemotherapy, progression-free survival was nearly twice as long with olaparib than with placebo (7.4 months vs. 3.8 months).
Gastric cancer Van Cutsem, Eric, Prof; Sagaert, Xavier, MD; Topal, Baki, Prof ...
The Lancet (British edition),
11/2016, Volume:
388, Issue:
10060
Journal Article
Peer reviewed
Summary Gastric cancer is one of the leading causes of cancer-related death worldwide. Many patients have inoperable disease at diagnosis or have recurrent disease after resection with curative ...intent. Gastric cancer is separated anatomically into true gastric adenocarcinomas and gastro-oesophageal-junction adenocarcinomas, and histologically into diffuse and intestinal types. Gastric cancer should be treated by teams of experts from different disciplines. Surgery is the only curative treatment. For locally advanced disease, adjuvant or neoadjuvant therapy is usually implemented in combination with surgery. In metastatic disease, outcomes are poor, with median survival being around 1 year. Targeted therapies, such as trastuzumab, an antibody against HER2 (also known as ERBB2), and the VEGFR-2 antibody ramucirumab, have been introduced. In this Seminar, we present an update of the causes, classification, diagnosis, and treatment of gastric cancer.
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In the KEYNOTE-177 study, pembrolizumab monotherapy provided statistically significant and clinically meaningful improvements in progression-free survival versus chemotherapy as first-line treatment ...in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. To further support the efficacy and safety findings of the KEYNOTE-177 study, results of the health-related quality of life (HRQOL) analyses are reported here.
KEYNOTE-177 is an open-label, randomised, phase 3 trial being done at 192 cancer centres in 23 countries, in patients aged 18 years and older with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had not received previous systemic therapy for metastatic disease. Eligible patients were randomly assigned (1:1) centrally by use of interactive voice response or integrated web response technology to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator's choice chemotherapy (mFOLFOX6 leucovorin, fluorouracil, and oxaliplatin or FOLFIRI leucovorin, fluorouracil, and irinotecan intravenously every 2 weeks with or without intravenous bevacizumab or cetuximab). Patients and investigators were not masked to treatment assignment. The primary endpoints were progression-free survival (previously reported) and overall survival (data to be reported at the time of the final analysis). HRQOL outcomes were evaluated as prespecified exploratory endpoints. The analysis population comprised all randomly assigned patients who received at least one dose of study treatment and completed at least one HRQOL assessment. HRQOL outcomes were mean change from baseline to prespecified week 18 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29) scale and item scores, and in the EuroQoL 5 Dimensions 3 Levels (EQ-5D-3L) visual analogue scale and health utility scores; the proportion of patients with improved, stable, or deteriorated scores from baseline to prespecified week 18 in EORTC QLQ-C30 scales and items; and time to deterioration in EORTC QLQ-C30 global health status/quality of life (GHS/QOL), physical functioning, social functioning, and fatigue scores and EORTC QLQ-CR29 urinary incontinence scores. The threshold for a small and clinically meaningful mean difference in EORTC QLQ-C30 score was 5–8 points. This study is registered with ClinicalTrials.gov, NCT02563002 and is ongoing; recruitment is closed.
Between Feb 11, 2016, and Feb 19, 2018, 307 patients were enrolled and randomly assigned to receive pembrolizumab (n=153) or chemotherapy (n=154). The HRQOL analysis population comprised 294 patients (152 receiving pembrolizumab and 142 receiving chemotherapy). As of Feb 19, 2020, median time from randomisation to data cutoff was 32·4 months (IQR 27·7–37·8). Least squares mean (LSM) change from baseline to prespecified week 18 showed a clinically meaningful improvement in EORTC QLQ-C30 GHS/QOL scores with pembrolizumab versus chemotherapy (between-group LSM difference 8·96 95% CI 4·24–13·69; two-sided nominal p=0·0002). Median time to deterioration was longer with pembrolizumab versus chemotherapy for GHS/QOL (hazard ratio 0·61 95% CI 0·38–0·98; one-sided nominal p=0·019), physical functioning (0·50 95% CI 0·32–0·81; one-sided nominal p=0·0016), social functioning (0·53 95% CI 0·32–0·87; one-sided nominal p=0·0050), and fatigue scores (0·48 95% CI 0·33–0·69; one-sided nominal p<0·0001).
Pembrolizumab monotherapy led to clinically meaningful improvements in HRQOL compared with chemotherapy in patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These data, along with the previously reported clinical benefits, support pembrolizumab as a first-line treatment option for this population.
Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.
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Summary Background Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line ...setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction). Methods This is the final analysis from GATSBY, a randomised, open-label, adaptive, phase 2/3 study, done at 107 centres (28 countries worldwide). Eligible patients had HER2-positive advanced gastric cancer and progressed during or after first-line therapy. In stage one of the trial, patients were randomly assigned to treatment groups (2:2:1) to receive intravenous trastuzumab emtansine (3·6 mg/kg every 3 weeks or 2·4 mg/kg weekly) or physician's choice of a taxane (intravenous docetaxel 75 mg/m2 every 3 weeks or intravenous paclitaxel 80 mg/m2 weekly). In stage two, patients were randomly assigned to treatment groups (2:1) to receive the independent data monitoring committee (IDMC)-selected dose of trastuzumab emtansine (2·4 mg/kg weekly) or a taxane (same regimen as above). We used permuted block randomisation, stratified by world region, previous HER2-targeted therapy, and previous gastrectomy. The primary endpoint (overall survival) was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01641939. Findings Between Sept 3, 2012, and Oct 14, 2013, 70 patients were assigned to receive trastuzumab emtansine 3·6 mg/kg every 3 weeks, 75 to receive trastuzumab emtansine 2·4 mg/kg weekly, and 37 to receive a taxane in the stage 1 part of the trial. At the pre-planned interim analysis (Oct 14, 2013), the IDMC selected trastuzumab emtansine 2·4 mg/kg weekly as the dose to proceed to stage 2. By Feb 9, 2015, a further 153 patients had been randomly assigned to receive trastuzumab emtansine 2·4 mg/kg weekly and a further 80 to receive a taxane. At data cutoff, median follow-up was 17·5 months (IQR 12·1–23·0) for the trastuzumab emtansine 2·4 mg/kg weekly group and 15·4 months (9·2–18·1) in the taxane group. Median overall survival was 7·9 months (95% CI 6·7–9·5) with trastuzumab emtansine 2·4 mg/kg weekly and 8·6 months (7·1–11·2) with taxane treatment (hazard ratio 1·15, 95% CI 0·87–1·51, one-sided p=0·86). The trastuzumab emtansine 2·4 mg/kg group had lower incidences of grade 3 or more adverse events (134 60% of 224 patients treated with trastuzumab emtansine vs 78 70% of 111 patients treated with a taxane), and similar incidences of adverse events leading to death (eight 4% vs four 4%), serious adverse events (65 29% vs 31 28%), and adverse events leading to treatment discontinuation (31 14% vs 15 14%) than did taxane treatment. The most common grade 3 or more adverse events in the trastuzumab emtansine 2·4 mg/kg weekly group were anaemia (59 26%) and thrombocytopenia (25 11%) compared with neutropenia (43 39%), and anaemia (20 18%), in the taxane group. The most common serious adverse events were anaemia (eight 4%), upper gastrointestinal haemorrhage (eight 4%), pneumonia (seven 3%), gastric haemorrhage (six 3%), and gastrointestinal haemorrhage (five 2%) in the trastuzumab emtansine 2·4 mg/kg weekly group compared with pneumonia (four 4%), febrile neutropenia (four 4%), anaemia (three 3%), and neutropenia (three 3%) in the taxane group. Interpretation Trastuzumab emtansine was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer. There is still an unmet need in this patient group and therapeutic options remain limited. Funding F Hoffmann-La Roche.
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TAS-102, a combination of trifluridine and tipiracil in which tipiracil interferes with the deactivation of trifluridine, improved overall and progression-free survival in patients whose disease had ...progressed after treatment with fluorouracil-containing drug combinations.
Fluoropyrimidines have long represented the cornerstone of treatment for colorectal cancer.
1
Such compounds act primarily as inhibitors of thymidylate synthase, the rate-limiting enzyme in the synthesis of pyrimidine nucleotides.
2
Fluorouracil has been combined with folinic acid (also known as leucovorin) to enhance the capacity of fluorouracil to bind to thymidylate synthase.
2
The addition of irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) to fluorouracil and folinic acid, in combination with either a vascular endothelial growth factor inhibitor (bevacizumab) or an epidermal growth factor inhibitor (e.g., cetuximab or panitumumab) if the tumor contains a wild-type
RAS
gene, represents contemporary standard therapy and has extended . . .
Summary Background No treatment options are available for patients with metastatic colorectal cancer that progresses after all approved standard therapies, but many patients maintain a good ...performance status and could be candidates for further therapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients. Methods We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and progression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computer-generated randomisation list and interactive voice response system; preallocated block design (block size six); stratified by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and geographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat. This trial is registered at ClinicalTrials.gov , number NCT01103323. Findings Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6·4 months in the regorafenib group versus 5·0 months in the placebo group (hazard ratio 0·77; 95% CI 0·64–0·94; one-sided p=0·0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%). Interpretation Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population. Funding Bayer HealthCare Pharmaceuticals.
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Summary Background Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to ...assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). Methods We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov , number NCT00412061. Findings 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7–21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4–14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59–1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62% vs 14%), rash (37% vs 12%), fatigue (31% vs 23%), and diarrhoea (27% vs 16%). Interpretation Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome. Funding Novartis Pharmaceuticals.
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Summary Background Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and bevacizumab-naive second-line metastatic colorectal cancer. We assessed continued use ...of bevacizumab plus standard second-line chemotherapy in patients with metastatic colorectal cancer progressing after standard first-line bevacizumab-based treatment. Methods In an open-label, phase 3 study in 220 centres in Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, the Netherlands, Norway, Portugal, Saudi Arabia, Spain, Sweden, and Switzerland, patients (aged ≥18 years) with unresectable, histologically confirmed metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy were randomly assigned in a 1:1 ratio to second-line chemotherapy with or without bevacizumab 2·5 mg/kg per week equivalent (either 5 mg/kg every 2 weeks or 7·5 mg/kg every 3 weeks, intravenously). The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). A combination of a permuted block design and the Pocock and Simon minimisation algorithm was used for the randomisation. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00700102. Findings Between Feb 1, 2006, and June 9, 2010, 409 (50%) patients were assigned to bevacizumab plus chemotherapy and 411 (50%) to chemotherapy alone. Median follow-up was 11·1 months (IQR 6·4–15·6) in the bevacizumab plus chemotherapy group and 9·6 months (5·4–13·9) in the chemotherapy alone group. Median overall survival was 11·2 months (95% CI 10·4–12·2) for bevacizumab plus chemotherapy and 9·8 months (8·9–10·7) for chemotherapy alone (hazard ratio 0·81, 95% CI 0·69–0·94; unstratified log-rank test p=0·0062). Grade 3–5 bleeding or haemorrhage (eight 2% vs one <1%), gastrointestinal perforation (seven 2% vs three <1%), and venous thromboembolisms (19 5% vs 12 3%) were more common in the bevacizumab plus chemotherapy group than in the chemotherapy alone group. The most frequently reported grade 3–5 adverse events were neutropenia (65 16% in the bevacizumab and chemotherapy group vs 52 13% in the chemotherapy alone group), diarrhoea (40 10% vs 34 8%, respectively), and asthenia (23 6% vs 17 4%, respectively). Treatment-related deaths were reported for four patients in the bevacizumab plus chemotherapy group and three in the chemotherapy alone group. Interpretation Maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy beyond disease progression has clinical benefits in patients with metastatic colorectal cancer. This approach is also being investigated in other tumour types, including metastatic breast and non-small cell lung cancers. Funding F Hoffmann-La Roche.
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