...all three EGFR-TKIs are considered to be current first-line standards of care for EGFR mutation-positive NSCLC. ...there is a rationale for the development of novel treatment combination regimens ...that target multiple aberrant pathways in patients with T790M-negative tumors. Sun JM, Park K. Can we define the optimal sequence of epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of epidermal growth factor receptor-mutant nonsmall cell lung cancer? Dual inhibition of the epidermal growth factor receptor with cetuximab, an IgG1 monoclonal antibody, and gefitinib, a tyrosine kinase inhibitor, in patients with refractory non-small cell lung cancer (NSCLC): a Phase I study.
First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course ...(two cycles) of chemotherapy to this combination would further enhance the clinical benefit.
This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0–1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov, number NCT03215706.
Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 50%) or four cycles of chemotherapy alone (n=358 50%). At the pre-planned interim analysis (median follow-up 9·7 months IQR 6·4–12·8), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months 95% CI 13·2–16·2 vs 10·7 months 9·5–12·4; hazard ratio HR 0·69 96·71% CI 0·55–0·87; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months IQR 6·4–17·0), median overall survival was 15·6 months (95% CI 13·9–20·0) in the experimental group versus 10·9 months (9·5–12·6) in the control group (HR 0·66 95% CI 0·55–0·80). The most common grade 3–4 treatment-related adverse events were neutropenia (in 24 7% patients in the experimental group vs 32 9% in the control group), anaemia (21 6% vs 50 14%), diarrhoea (14 4% vs two 1%), increased lipase (22 6% vs three 1%), and febrile neutropenia (14 4% vs ten 3%). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related.
Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk–benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC.
Bristol Myers Squibb.
For the Polish and Russian translations of the Article see Supplementary Materials section.
Patients with advanced esophageal cancer have a poor prognosis and limited treatment options after first-line chemotherapy.
In this open-label, phase III study, we randomly assigned (1:1) 628 ...patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus, that progressed after one prior therapy, to pembrolizumab 200 mg every 3 weeks for up to 2 years or chemotherapy (investigator's choice of paclitaxel, docetaxel, or irinotecan). Primary end points were overall survival (OS) in patients with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10, in patients with squamous cell carcinoma, and in all patients (one-sided α 0.9%, 0.8%, and 0.8%, respectively).
At final analysis, conducted 16 months after the last patient was randomly assigned, OS was prolonged with pembrolizumab versus chemotherapy for patients with CPS ≥ 10 (median, 9.3
6.7 months; hazard ratio HR, 0.69 95% CI, 0.52 to 0.93;
= .0074). Estimated 12-month OS rate was 43% (95% CI, 33.5% to 52.1%) with pembrolizumab versus 20% (95% CI, 13.5% to 28.3%) with chemotherapy. Median OS was 8.2 months versus 7.1 months (HR, 0.78 95% CI, 0.63 to 0.96;
= .0095) in patients with squamous cell carcinoma and 7.1 months versus 7.1 months (HR, 0.89 95% CI, 0.75 to 1.05;
= .0560) in all patients. Grade 3-5 treatment-related adverse events occurred in 18.2% of patients with pembrolizumab versus 40.9% in those who underwent chemotherapy.
Pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients with PD-L1 CPS ≥ 10, with fewer treatment-related adverse events.
The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth ...factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).
In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs).
A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio HR, 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain.
Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.
In recent years, advances in molecular diagnostics have transformed the management of advanced non-small-cell lung cancer (NSCLC), allowing for increasingly personalized approaches ....
Background
The correlation between immune cells and the Lauren classification subtypes and their prognostic impact in advanced gastric cancer (AGC) are unknown.
Methods
Circulating natural killer ...(NK) cells, CD4
+
and CD8
+
T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were quantified in peripheral blood mononuclear cells (PBMCs) from 67 patients with untreated AGC enrolled in the PRODIGE 17-ACCORD 20 trial. CD56
+
cells (NK), CD8
+
, and FoxP3
+
(Treg) tumor-infiltrating lymphocytes (TILs) were assessed in tumor samples.
Results
Circulating NK and Treg proportions were significantly lower in patients with diffuse/mixed-type AGC (
n
= 27) than those with intestinal type (
n
= 40; median 6.3% vs 11.5%;
p
= 0.02 and median 3.3% vs 5.2%;
p
= 0.03, respectively). Proportions of circulating MDSC, CD4
+
and CD8
+
T cells were not associated with one pathological type. Among tumor-infiltrating cells, CD8
+
T cells, but not NK or FoxP3
+
cells, were significantly lower in diffuse/mixed-type AGC (median 21 vs 59 cells/field;
p
= 0.009). Patients with high circulating NK cell counts (> 17%) had a better overall survival than those with < 17% (HR 0.40; 95% CI 0.15–1.06;
p
= 0.04). Patients with high CD8
+
TIL counts (> 31 cells/field) had significantly longer overall survival (HR 0.44; 95% CI 0.21–0.92;
p
= 0.02). The prognostic value of CD8
+
TILs was maintained after adjustment for confounding factors, including the Lauren classification (HR = 0.42; 95% CI 0.18–0.96;
p
= 0.039).
Conclusion
Diffuse/mixed-type AGC has lower rates of CD8
+
TILs and circulating NK cells and Tregs than the intestinal type. This “cold tumor” phenotype may be associated with a worse outcome.
Summary Background We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, ...randomised, phase 3 trials. Methods Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin LUX-Lung 3 or gemcitabine-cisplatin LUX-Lung 6), stratified by EGFR mutation (exon 19 deletion del19, Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov , numbers NCT00949650 and NCT01121393. Findings Median follow-up in LUX-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In LUX-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in LUX-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in LUX-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 16% of 229 patients in LUX-Lung 3 and 35 15% of 239 patients in LUX-Lung 6), diarrhoea (33 14% and 13 5%), paronychia (26 11% in LUX-Lung 3 only), and stomatitis or mucositis (13 5% in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 18% of 111 patients), fatigue (14 13%) and leucopenia (nine 8%) were the most common chemotherapy-related grade 3–4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 27% of 113 patients), vomiting (22 19%), and leucopenia (17 15%). Interpretation Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials. Funding Boehringer Ingelheim.
Treatment options for patients with advanced esophageal or esophagogastric junction (EGJ) cancer are limited. Current guidelines for first-line treatment of advanced esophageal or EGJ cancer ...recommend chemotherapy containing a platinum and a fluoropyrimidine agent. Pembrolizumab demonstrated antitumor activity in previously treated patients with advanced esophageal cancer and in patients with gastroesophageal junction cancer.
To describe the design and rationale for the randomized, double-blind, placebo-controlled Phase III KEYNOTE-590 study, which will be conducted to investigate pembrolizumab in combination with chemotherapy as first-line treatment in patients with advanced esophageal or EGJ cancer.
: NCT03189719.
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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