Immune checkpoint inhibitors plus chemotherapy versus chemotherapy or immunotherapy for first?line treatment of advanced non?small cell lung cancer: a generic protocol
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SUBMITTER: Syn N
PROVIDER: S-EPMC6494557 | biostudies-literature | 2018 Apr
REPOSITORIES: biostudies-literature
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Project description:BackgroundImmune-checkpoint inhibitors plus chemotherapy are emerging as effective first-line treatment in advanced non-small-cell lung carcinoma (NSCLC), but little is known about the magnitude of benefits and potential clinical predictors.MethodsWe performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy in first line of treatment for advanced NSCLC. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity.ResultsSix trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS. In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).ConclusionsPD-1/PD-L1 inhibitor plus chemotherapy, compared with chemotherapy, is associated with significantly improved PFS, ORR, and OS in first-line therapy in NSCLC, at the expense of increased treatment-related AEs.
| S-EPMC6303974 | biostudies-literature
Project description:In BRAF wild type advanced melanoma, immune checkpoint blockers such as anti-PD1 (anti-programmed cell death 1) are usually continued beyond progression for a hypothetical rare further response. Chemotherapy as a second-line option is considered ineffective by many practitioners based on historical data. Continuing anti-PD1 beyond progression has a high health-economic impact and is not recommended by the FDA. This study aimed to describe the efficacy and survival of advanced melanoma patients who received second-line (or more) chemotherapy after immunotherapy failure.This was a retrospective single center study conducted in a French University Hospital during an 11-month period. All advanced melanoma patients treated with chemotherapy after immunotherapy failure were included.Eighteen patients were analyzed. Therapeutic response to chemotherapy was evaluable in 16 patients: partial response was achieved in 3/16 (19%), stable disease in 1/16 (6%) and progressive disease in 12/16 (75%). Median overall survival from chemotherapy start was 12 months. Median progression-free survival was 5.4 months. The 6-month overall survival rate was 81% and the 6-month progression-free survival rate was 40%.Although the disease control rate with chemotherapy was low (25%), survival data in our study are far superior to those previously published. This could be linked to a high proportion of patients treated with anti-PD1 just prior to chemotherapy, which may suggest a potential synergy between immunotherapy and chemotherapy.
| S-EPMC7373626 | biostudies-literature
Project description:IntroductionPlatin-based chemotherapy (CT) has long been the first-line standard-of-care for patients with extensive-stage small-cell lung cancer (ES-SCLC). Adding immune-checkpoint inhibitor(s) to CT (ICI+CT) in this setting is an option of interest, although its benefit is apparently modest.MethodsThis meta-analysis was conducted on randomized trials comparing first-line ICI+CT versus CT alone for ES-SCLC. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), response at 12?months and adverse events (AEs). Subgroup analyses were computed according to the immunotherapy used, performance status (PS), age, platinum salt, liver metastases and brain metastases at diagnosis.ResultsThe literature search identified one randomized phase II (ECOG-ACRIN-5161) and four phase III trials (CASPIAN, IMPOWER-133, KEYNOTE-604 and Reck et al. 2016) that included 2775 patients (66% males, 95% smokers, median age: 64?years, PS?=?0 or 1). ICI+CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS [0.82 (0.75-0.89); p?<??0.00001] and PFS [0.81 (0.75-0.87); p?<??0.00001], with OS benefits for anti-PD-L1 [0.73 (0.63-0.85); p?<?0.0001] or anti-PD-1 [0.76 (0.63-0.93); p?<?0.006] but not for anti-CTLA-4 [0.90 (0.80-1.01), p?=?0.07]. ORRs for ICI+CT or CT alone were comparable [odds ratio 1.12 (0.97-1.00); p?=?0.12], but responses at 12?months favored ICI+CT [4.16 (2.81-6.17), p?<?0.00001]. Serious grade-3/4 AEs were more frequent with ICI+CT [odds ratio 1.18 (1.02-1.37); p?=?0.03]. Compared with CT, no ICI+CT benefit was found for ES-SCLC with brain metastases at diagnosis [HR 1.14 (0.87-1.50); p?=?0.34].ConclusionsFirst-line ICI+CT appears to be superior to CT alone for ES-SCLC except for patients with brain metastases at diagnosis.
| S-EPMC7731693 | biostudies-literature
Project description:ObjectivesUse of immune checkpoint inhibitors as first-line treatment for advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) remains controversial. Clinical trials comparing single-drug immunotherapy (IO) with immunotherapy plus chemotherapy (IC) are lacking. We aimed to compare the efficacy of IO alone with that of IC as first-line treatment for advanced NSCLC.DesignSystematic review.Data sourcesPubMed, the Cochrane Library and Embase for related studies on NSCLC; ClinicalTrials.gov, American Society of Clinical Oncology Meeting Library and World Conference on Lung Cancer for relevant conference abstracts (to July 2019).Eligibility criteriaArticles meeting the following criteria were selected: (1) randomised controlled trials on NSCLC treatment, (2) all individuals in the studies had not received treatment previously and (3) research on IO monotherapy using programmed death-1/programmed death ligand-1 (PD-L1) inhibitors or IC.Data extraction and synthesisAfter reading the original literature, two reviewers independently extracted the relevant information. The primary outcomes were progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). We also extracted data on treatment-related adverse events and immune-related adverse events (irAEs).ResultsOverall, 10 randomised controlled clinical trials (n=5765) were included. As first-line treatment for advanced NSCLC, IC tended to yield better PFS, OS and ORR than did IO. Furthermore, IC yielded significantly better PFS than IO when tumour PD-L1 expression was at least 50% (HR: 1.81, 95% CI: 1.18 to 2.78) and yielded a better OS and PFS when tumour PD-L1 expression was at least 1%; IO resulted in fewer adverse events than did IC. However, the incidence of irAEs was higher for IO than for IC.ConclusionsThe findings of the indirect comparison indicate that IC as first-line treatment for advanced NSCLC is significantly more effective than IO in patients with PD-L1 expression in at least 50% of tumour cells.Trial registration numberCRD 42018116589.
| S-EPMC7682470 | biostudies-literature
Project description:ObjectiveTo compare the relative efficacy of immune checkpoint inhibitors (ICIs) or chemotherapy (CT) alone, or their combination modality in the first-line treatment of advanced nonsmall cell lung cancer (NSCLC).MethodsThis meta-analysis was performed on the eligible randomized controlled trials (RCTs) after searching web databases and meeting abstracts. The main research endpoints were the comparisons of median overall survival (mOS), the OS rate of 6 months (OSR6m), 1 year (OSR1y) and 2 years (OSR2y), median progression-free survival (mPFS), the PFS rate of 6 months (PFSR6m) and 1-year (PFSR1y), objective response rates (ORR), and treatment-related adverse events (TRAEs).ResultsEleven RCTs comprising 6278 cases were included. In the subgroup of programmed death-ligand 1 (PD-L1) ?50%, compared with chemotherapy, the ICIs showed similar OSR6m (P > 0.05), but significantly improved efficacy in mOS, OSR1y, OSR2y, and ORR (all P < 0.05), also had less grade ? 3 TRAEs. Compared with pembrolizumab alone, pembrolizumab plus CT in the subgroup of PD-L1 ? 50% had similar mOS, OSR6m, OSR1y, and PFSR1y (all P > 0.05), but significantly improved mPFS, PFSR6m, and ORR (all P < 0.05 for interaction). Compared with the CT group, ICIs plus CT group with PD-L1 ? 50% or <1% showed significant benefit in OS, PFS, and ORR (all P < 0.05). However, in the ICIs plus CT group with 1% ? PD-L1 ? 49%, only PFS and ORR showed significant benefit compared with CT group (all P < 0.05), but not for results of OS.ConclusionsThe findings support the rationale for using pembrolizumab alone in the first-line treatment of PD-L1 ? 50% advanced NSCLC due to the similar OS and lower grade ? 3 TRAEs. However, the combination of ICIs and chemotherapy is strongly recommended in patients with PD-L1 ? 49% for significant survival benefit.
| S-EPMC6718602 | biostudies-literature
Project description:BACKGROUND:Lung cancer is the leading cause of cancer-related deaths worldwide and the prognosis remains poor. The recent introduction of the immune checkpoint inhibitor (ICI), or plus chemotherapy, both resulted in the survival benefit for patients with advanced non-small-cell lung cancer (NSCLC), but it remains unanswered which is superior. The current study aimed to estimate the comparative efficacy and safety of ICI-chemotherapy versus ICI-monotherapy in advanced NSCLC. METHODS:Studies were identified by searching PubMed, Embase, and Cochrane library. The randomized controlled trials (RCTs) that ICI monotherapy or ICI plus chemotherapy compared with chemotherapy in NSCLC were included with available primary endpoints of progression-free survival (PFS), overall survival (OS), objective response rate, or treatment-related adverse events. A fixed-effect or random-effects model was adopted depending on between-study heterogeneity. RESULTS:A total of 20 RCTs involving 12,025 patients with NSCLC were included. Both ICI-monotherapy and ICI-chemotherapy resulted in significantly prolonged survival compared to chemotherapy and the former led to significantly longer PFS. The magnitude of survival benefits appeared to be greatest among those treated with pembrolizumab plus platinum-based chemotherapy (OS, 0.56; PFS, 0.54). Additionally, OS and PFS advantages of ICI therapies were observed in patients with NSCLC with low or high programmed cell death 1 ligand 1 (PD-L1) expression level, but not in intermediate PD-L1 TPS. CONCLUSIONS:Pembrolizumab plus platinum-based chemotherapy was recommended as the optimal first-line therapy for advanced patients with NSCLC. Additionally, PD-L1 alone is not recommended as an adequate molecular biomarker to identify eligible patients for routine clinical practice in immunotherapy.
| S-EPMC7028135 | biostudies-literature
Project description:New ways of exploiting the immune system for cancer treatment have been tested for decades with moderate outcomes. Based on previous immunotherapy knowledge, agents targeting immune checkpoints seem to be remarkably effective in a wide range of tumors. Immune checkpoint inhibitors in metastatic non-small cell lung cancer (NSCLC) provide longlasting responses in specific patients. Nevertheless, with overall response rates ? 20%, combinational protocols for various patient subgroups are needed. A good partner treatment to immunotherapy could be chemotherapy, as it successfully modulates the immune response either by controlling or enhancing the antitumor immune activity. Primary research provides promising results in metastatic NSCLC patients using this approach, but further large-scale trials are needed. The implementation of immunotherapy in nonmetastatic cases is also appealing. We review the potential clinical benefits of immunotherapy alone or in concert with chemotherapy in NSCLC.
| S-EPMC6217867 | biostudies-literature
Project description:BackgroundGemcitabine plus platinum as the first-line chemotherapy for cholangiocarcinoma (CCA) has limited efficacy. The aim of this study was to evaluate the effectiveness of modified FOLFIRINOX (mFOLFIRINOX) compared to that of gemcitabine plus oxaliplatin (Gemox) for patients with locally advanced or metastatic CCA.MethodsFrom January 2016 to December 2019, consecutive patients who were diagnosed with locally advanced or metastatic CCA were treated with either mFOLFIRINOX or Gemox as a first-line chemotherapy. The main endpoint was Progression free survival (PFS). The second endpoints were Overall survival (OS), Disease control rate (DCR) and incidence of severe toxicity (grade 3-4). Tumors were evaluated at baseline and thence every 4-6 weeks. The study was designed and carried out in accordance with the principles of the declaration of Helsinki, approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine (XHEC-D-2020-154) and registered with ClinicalTrials.gov , number NCT04305288 (registration date: 12/03/2020).ResultsOf 49 patients in this study, 27 were in the FOLFIRINOX regimen group and 22 in the Gemox regimen group. There were no significant differences between groups in baseline characteristics. The DCR was 77.8% in the mFOLFIRINOX group and 63.5% in the Gemox group. The corresponding median PFS was 9.9 months (95% confidence interval [CI], 7.3-12.4) in the mFOLFIRINOX group versus 6.4 months (95% CI,3.6-9.2, p = 0.040) in the Gemox group. The corresponding median OS was 15.7 months (95% CI, 12.5-19.0) versus 12.0 months (95% CI, 9.3-14.8, p = 0.099). Significantly more grade 3-4 vomiting occurred in the mFOLFIRINOX than the Gemox groups (7 (25.9%) vs 1 (4.5%), p = 0.044).ConclusionsFirst-line mFOLFIRINOX offered more promising results in patients with advanced or metastatic CCA.
| S-EPMC8283916 | biostudies-literature
Project description:BackgroundLimited data compare first-line carboplatin-based chemotherapy and immune checkpoint blockade in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. The primary evidence guiding treatment decisions was a recent Food and Drug Administration/European Medicines Agency safety alert based on emerging data from two ongoing phase III trials, reporting shorter survival in programmed death-ligand 1 (PD-L1)-negative patients receiving immunotherapy. Final results from these trials are unknown.ObjectiveTo compare survival in cisplatin-ineligible mUC patients receiving first-line immunotherapy versus those receiving carboplatin-based chemotherapy.Design, setting, and participantsWe conducted a retrospective cohort study of 2017 mUC patients receiving first-line carboplatin-based chemotherapy (n = 1530) or immunotherapy (n = 487) from January 1, 2011 to May 18, 2018 using the Flatiron Health electronic health record-derived database.Outcome measurements and statistical analysisThe primary outcomes were overall survival (OS), comparing 12- and 36-mo OS, and hazard ratios before and after 12 mo. Propensity score-based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression model estimates of comparative effectiveness.Results and limitationsIPTW-adjusted OS rates in the immunotherapy group were lower at 12 mo (39.6% [95% confidence interval {CI} 34.0-45.3%] vs 46.1% [95% CI 43.4-48.8%]) but higher at 36 mo (28.3% [95% CI 21.8-34.7%] vs 13.3% [95% CI 11.1-15.5%]) relative to the chemotherapy group. Immunotherapy treatment demonstrated inferior OS during the first 12 mo relative to carboplatin-based chemotherapy (IPTW-adjusted hazard ratio [HR] 1.37, 95% CI 1.15-1.62), but superior OS beyond 12 mo (IPTW-adjusted HR 0.50, 95% CI 0.30-0.85). Limitations include retrospective design and potential unmeasured confounding.ConclusionsIn the setting of mUC, clinicians and patients should carefully consider how to balance the short-term benefit of chemotherapy against the long-term benefit of immunotherapy.Patient summaryTo determine the optimal first-line therapy for metastatic bladder cancer patients who are unfit for cisplatin, we compared carboplatin-based chemotherapy versus immunotherapy using real-world data. Survival in the 1st year of treatment was lower with immunotherapy relative to chemotherapy, but for patients surviving beyond the 1st year, immunotherapy was superior.
| S-EPMC6822167 | biostudies-literature
Project description:BackgroundFirst-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.MethodsIn this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116.FindingsFrom March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.InterpretationNivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.FundingBristol Myers Squibb, in collaboration with Ono Pharmaceutical.
| S-EPMC8436782 | biostudies-literature