Efficacy and safety of PD-1 inhibitors as first- and second- line treatments for advanced gastroesophageal cancers: A network meta-analysis of phase III clinical trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16032-e16032
Author(s):  
Laercio Lopes Da Silva ◽  
Robin Park ◽  
Pedro Nazareth Aguiar ◽  
Eduardo Edleman Saul ◽  
Benjamin Haaland ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Treatment Options ◽  
Single Agent ◽  
Phase Iii ◽  
Bibliographic Databases ◽  
Second Line ◽  
First Line ◽  
Esophageal Cancers

e16032 Background: Advanced gastroesophageal tumors are among the most prevalent and burdensome cancers worldwide. They have a poor prognosis and limited treatment options. Recent studies show that PD-1/PD-L1 inhibitors can improve outcomes, but the results are inconsistent across trials. Herein, we compare the effectiveness and safety of PD-1/PD-L1 inhibitors with chemotherapy in patients with ERBB2 negative advanced/metastatic gastric and esophageal cancers. Methods: We searched bibliographic databases (PubMed, Embase, Cochrane Central, Web of Science, Medline, Scopus) and ClinicalTrials.gov from January 1, 2010, to November 23, 2020. We included phase III randomized clinical trials comparing anti-PD-1/PD-L1 single-agent or in combination with chemotherapy (chemoimmunotherapy) for advanced gastric or esophageal cancers in the first- or second-line settings. We performed a network meta-analysis with a frequentist approach and a random-effects model using the package ‘netmeta’ for R statistical software. A prospective protocol was uploaded to PROSPERO (CRD42020221822). Results: The final analysis included a total of 8 trials that compared different anti-PD-1 agents; none of them involved anti-PD-L1 agents. The four first-line studies involved 3817 patients. Chemoimmunotherapy improved OS and PFS with no significant safety difference: Nivolumab + chemotherapy, OS (HR, 0.83; 95% CI, 0.75-0.92), PFS (HR, 0.68; 95% CI, 0.57-0.81), SAE (OR 0.54; 0;95% CI, 0.1-2.92); Pembrolizumab + chemotherapy: OS (HR, 0.77; 95% CI, 0.67-0.88), PFS (HR, 0.72; 95% CI, 0.60-0.85), SAE (OR, 1.31; 0;95% CI, 0.23-7.35). Pembrolizumab monotherapy was the safest first-line treatment, SAE (OR, 0.02; 95% CI, 0.00-0.2), but did not improve survival, OS (HR, 0.91; 95% CI, 0.71-1.16), PFS (HR, 1.62; 95% CI, 1.23-2.14). The four second-line studies totalized 2087 individuals. Anti-PD-1 drugs were significantly safer but did not significantly improve survival: camrelizumab, OS (HR 0.71; 95% CI, 0.54-0.93), PFS (HR 0.69; 95% CI, 0.45-1.06), SAE (OR, 0.37; 95% CI, 0.24-0.56); nivolumab, OS (HR 0.77; 95% CI, 0.58-1.02), PFS (HR 1.08; 95% CI, 0.77-1.66), SAE (OR, 0.13; 95% CI, 0.08-0.2) pembrolizumab, OS (HR 0.86; 95% CI, 0.72-1.04), PFS (HR 1.28; 95% CI, 0.96-1.71), SAE (OR, 0.4; 95% CI, 0.30-0.53). Conclusions: the combination of PD-1 inhibitors with chemotherapy improves OS and PFS in previously untreated gastroesophageal cancers. Single-agent anti-PD-1 drugs improve safety in refractory disease, with no significant change in OS and PFS.

scholarly journals Recent Advances in Systemic Therapy for Hepatocellular Carcinoma in an Aging Society: 2020 Update

Liver Cancer ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 640-662
Author(s):  
Masatoshi Kudo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Systemic Therapy ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
New Drugs ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Recent Advances

Systemic therapy for hepatocellular carcinoma (HCC) has changed markedly since the introduction of the molecular targeted agent sorafenib in 2007. Sorafenib increased the available treatment options for patients with extrahepatic spread and vascular invasion and improved survival in patients with advanced HCC; however, various shortcomings such as low response rates and relatively high toxicity (e.g., hand-foot skin reaction) prompted concerted efforts aimed at developing new molecular targeted agents to provide more treatment options and second-line agents for patients with disease progression or intolerance to sorafenib. Despite many attempts to develop new drugs between 2007 and 2016, all first-line and second-line clinical trials conducted during this period failed. However, between 2017 and 2019, 4 drugs (lenvatinib as a first-line agent and regorafenib, cabozantinib, and ramucirumab as second-line agents) emerged in quick succession from clinical trials and became available for clinical use. In addition, nivolumab and pembrolizumab were approved as second-line agents after sorafenib. A recent phase III trial (IMbrave150) showed that combination immunotherapy with atezolizumab plus bevacizumab increases overall survival compared with sorafenib therapy; Food and Drug Agency already approved this combination therapy, and worldwide approval is expected soon. This review describes the recent advances in systemic therapy and the use of tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib, and cabozantinib), monoclonal antibodies (ramucirumab and bevacizumab), and immune checkpoint inhibitors (nivolumab, pembrolizumab, and atezolizumab) in elderly patients and the similarity of their efficacy and safety profiles to those in the general population.

Oxaliplatin Plus Irinotecan Compared With Irinotecan Alone as Second-Line Treatment After Single-Agent Fluoropyrimidine Therapy for Metastatic Colorectal Carcinoma

2008 ◽  
Vol 26 (28) ◽  
pp. 4544-4550 ◽  
Author(s):  
Daniel G. Haller ◽  
Mace L. Rothenberg ◽  
Alfred O. Wong ◽  
Piotr M. Koralewski ◽  
Wilson H. Miller ◽  
...  
Keyword(s):  
Median Overall Survival ◽  
Single Agent ◽  
Phase Iii ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Open Label ◽  
Sensory Disturbances ◽  
Previously Treated ◽  
Grade 3

Purpose To determine whether irinotecan plus oxaliplatin (IROX) is superior to irinotecan alone in patients with metastatic colorectal cancer (CRC) previously treated with single-agent fluoropyrimidines. Patients and Methods A phase III, randomized, open-label, multicenter study of patients with metastatic or recurrent CRC that had progressed or recurred during or after adjuvant or first-line fluoropyrimidines (fluorouracil/leucovorin or capecitabine, the latter only for metastatic CRC). Patients received IROX (irinotecan 200 mg/m2 plus oxaliplatin 85 mg/m2) or irinotecan alone (350 mg/m2) every 3 weeks. Results At the data cutoff (when 447 of 628 randomly assigned patients had died), median overall survival was 13.4 months (95% CI, 12.4 to 14.7 months) and 11.1 month (95% CI, 10.0 to 12.7 months) in the IROX and irinotecan groups, respectively (hazard ratio = 0.78; 95% CI, 0.65 to 0.94; P = .0072). Overall response rate (22% v 7%, respectively; P < .0001), median time to progression (5.3 v 2.8 months, respectively; P < .0001), and improvement in tumor-related symptoms (32% v 19%, respectively; P = .0072) were also improved with IROX as compared with irinotecan. With the exception of granulocytopenia (25% v 13%), diarrhea (28% v 23%), and sensory disturbances (5% v 0%), grade 3 to 4 toxicities were comparable between the IROX and irinotecan groups, respectively. Conclusion IROX is an effective treatment for metastatic CRC that has progressed after first-line fluoropyrimidine therapy. IROX improves efficacy compared with irinotecan alone, providing an additional option in the postadjuvant or second-line treatment setting for patients who experience treatment failure with single-agent fluoropyrimidine therapy.

Comparative Effectiveness of Rituximab-Based Immunochemotherapy in Waldenstrom's Macroglobulinemia (WM)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2986-2986 ◽  
Author(s):  
Adam J Olszewski ◽  
Steven P Treon ◽  
Jorge J Castillo
Keyword(s):  
Clinical Trials ◽  
Comparative Effectiveness ◽  
Research Funding ◽  
Randomized Clinical Trials ◽  
Single Agent ◽  
The United States ◽  
Population Based ◽  
First Line ◽  
Prophylactic Measures ◽  
Significant Difference

Abstract Background: Waldenström macroglobulinemia (WM) is difficult to study in randomized clinical trials because of its rarity, and higher incidence among older patients (pts). The most recent published trial focusing on WM (Leblond et al., J Clin Oncol 2013) compared chlorambucil with fludarabine-treatments no longer in common use. Recent data (Olszewski et al., Oncologist 2016) show that over 80% of WM pts in the United States are now treated with rituximab (R) alone or in combination with chemotherapy, although the effect of R on overall survival (OS) in WM has not been shown in clinical trials (Buske et al., Leukemia, 2009). Our objective was to provide comparative evidence of therapeutic efficacy for R-based immunochemotherapy in WM by applying causal inference methods to population-based, observational data. Methods: Using Medicare claims from 1999-2013, linked to the Surveillance, Epidemiology and End Results registry data, we identified WM patients (pts) >65 years old, who initiated first-line chemotherapy with or without R, with purine analogues (PUR, fludarabine or cladribine) and/or classic alkylating agents (ALK, chlorambucil or cyclophosphamide). Pts receiving both fludarabine and cyclophosphamide were grouped as PUR. Factors associated with treatment selection were studied in multivariable mixed-effects logistic models. We then conducted 3 separate comparative analyses: 1) regimens with R versus without R, 2) R monotherapy versus combination immunochemotherapy, and 3) PUR- versus ALK-based regimens. In each case, we balanced baseline characteristics (age, sex, race, socioeconomic status, comorbidities, performance status, time from diagnosis), and indicators of WM severity previously validated to correlate with OS (anemia, transfusions, plasmapheresis) using propensity score analysis, to minimize indication bias and simulate a randomized experiment. We then compared OS and select adverse events within 90 days of treatment (hospitalization, transfusion, or plasmapheresis) using survival or log-binomial models weighted by inverse probability of treatment (IPT), reporting hazard ratio (HR) or relative risk (RR) with 95% confidence intervals (CI). Results: Among 1,310 pts (median age 78 years, 43% women), 54% received first-line R monotherapy, 12% R+PUR, 12% R+ALK, 14% PUR-(without R)- and 8% ALK-(without R)-based regimen. Receipt of R was more likely among pts with metropolitan residence, diagnosis after 2003, and baseline neuropathy, and significantly varied by treating physician (intra-class correlation, 45%, CI 25-66%, P<.0001). Unadjusted 5-year OS was 42.0% (CI, 36.1-47.8) for chemotherapy without R, 51.9% (CI, 46.0-57.6) for chemotherapy with R, and 50.6% (CI, 46.4-54.7) for R alone. In each comparative analysis, we achieved adequate balance of confounding variables using propensity scores. In the IPT-weighted outcome models, OS was significantly better for pts who received R as part of their therapy compared with those who did not (HR, 0.77; CI, 0.64-0.93; P=.0058; Fig. A), without difference in the studied toxicities. Within 3 months of starting therapy, there was an overall 20.4% frequency of transfusion, 9.6% of hospitalization, and 4.4% of plasmapheresis. The RR for plasmapheresis after R-based regimen was 1.09 (CI, 0.63-1.90, P=.76). There was no significant difference in OS between pts receiving R alone or in combination with chemotherapy (HR, 0.90, CI, 0.74-1.08, P=.25, Fig. B), but the risk of transfusions (RR, 0.71; CI, 0.56-0.88; P=.002) and hospitalizations (RR, 0.52; CI, 0.34-0.79; P=.002) was lower after single-agent R. Furthermore, there was no evident difference between PUR- or ALK-based regimens in OS (HR, 1.13, CI, 0.90-1.42, P=.30, Fig. C), or in the studied toxicities. Conclusions: This population-based, comparative effectiveness study provides evidence of OS benefit of R (as monotherapy or combination immunochemotherapy) for Medicare beneficiaries (>65 years old) with WM. Toxicity of single-agent R was lower compared with combination regimens, without a difference in survival, thus confirming its utility as a treatment option for older pts who do not have a strong indication for cytotoxic therapy. Acknowledging likely pre-selection on the basis of (unrecorded) IgM levels, and possible uncaptured prophylactic measures, R-based therapy did not appear to result in a higher risk of plasmapheresis or hospitalization. Figure Figure. Disclosures Olszewski: TG Therapeutics: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy. Treon:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy. Castillo:Janssen: Honoraria; Millennium: Research Funding; Pharmacyclics: Honoraria; Abbvie: Research Funding; Otsuka: Consultancy; Biogen: Consultancy.

A phase II trial of pemetrexed (P) in patients (pts) with performance status (PS) 2 and 3 as first- and second-line treatment for advanced non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18149-18149 ◽  
Author(s):  
R. Zinner ◽  
F. V. Fossella ◽  
M. S. Kies ◽  
R. S. Herbst ◽  
C. Lu ◽  
...  
Keyword(s):  
Performance Status ◽  
Single Agent ◽  
Stage Iiib ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Minor Response ◽  
Men 2 ◽  
Line Of Therapy ◽  
Few Data

18149 P (Alimta) is approved as second-line therapy in pts with advanced NSCLC. In a phase III trial comparing P with docetaxel (D), median survival was 8.3 mos (P) vs 7.9 mos (D); P had a more favorable safety profile than D (Hanna, 2004). There are few data on pts with PS 3, and ASCO 2003 guidelines recommend that chemotherapy be reserved for pts with PS 0, 1 and possibly 2. Since P is well tolerated, PS3 pts may tolerate and benefit from it. In this trial, we treated 20 pts with stage IIIb/IV NSCLC and PS 2–3 who were chemo-naive or had received 1 prior regimen. Pts received P 500 mg/m2 IV D1 Q 3 wks. All pts received folic acid, vitamin B12 and dexamethasone prophylaxis. Serial blood samples were obtained to monitor inflammatory cytokines, and symptoms were monitored using the validated MDASI instrument. All pts were assessable for toxicity-symptoms, and 17 pts were evaluable for response (assessed after first cycle). Pt characteristics: 8 pts were PS 3 (4/8 first line) and 12 pts were PS 2 (6/12 first line). Median age was 69 for PS3 and 68 for PS2. 5/8 PS3 pts and 6/12 PS2 pts were men. 2/8 PS3 pts and 4/12 PS2 pts had stage IIIb. 4/8 PS3 pts and 6/12 PS2 pts were chemo-naive. Grade 3–4 toxicities for PS3/PS2 cohorts were: neutropenia 0/1 pt, anemia 1/2, fatigue 2/0, pneumonia 1/1, hypotension 1/1, neutropenic fever 0/1, atrial fibrillation 1/1. Response rates (RR) in PS3 pts were minor response (MR) 1/8, stable disease (SD) 5/8, progressive disease (PD) 2/8; RR in PS2 pts were partial response (PR) 1/12, MR 2/12, SD 3/12, PD 3/12, inevaluable 3/12. RR by line of therapy: first-line 6/10 SD, 2/10 PD, 2/10 inevaluable, and second-line, 1/10 PR, 2/10 MR, 3/10 SD, 3/10 PD, and 1/10 inevaluable. Reasons for PS3 pts coming off study were progression (4/8), constitutional toxicity (3/8), fatal pulmonary emboli (1/8); PS2 pts came off study due to progression (5/12), constitutional toxicity (2/12), and pneumonia (1/12). 4/12 PS2 pts are still on study. These preliminary data suggest that single-agent P is well-tolerated and has a promising RR in poor PS pts. Total planned accrual is 30 PS3 and 45 PS2 pts. Survival, symptom, cytokine data will be presented. [Table: see text]

A review of the patterns of docetaxel use for hormone refractory prostate cancer (HRPC) at the Princess Margaret Hospital

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16161-e16161
Author(s):  
S. N. Chin ◽  
L. Wang ◽  
A. Lau ◽  
M. Moore ◽  
S. S. Sridhar
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Practice ◽  
Median Duration ◽  
Response Rates ◽  
Routine Clinical Practice ◽  
Phase Iii ◽  
Line Treatment ◽  
Second Line ◽  
First Line

e16161 Background: Docetaxel is standard of care for the treatment of HRPC, based on two large randomized clinical trials. The aim of this study was to determine if docetaxel use and effectiveness in routine clinical practice was similar to that seen in the TAX 327 randomized phase III clinical trial. Methods: A retrospective chart review was undertaken to assess patterns of docetaxel use for HRPC at our institution for the 2-year period since its approval for the first-line treatment of HRPC in 2005. Results: Eighty-eight patients, median age 71 and baseline PSA 107, received docetaxel in the first line setting. Main reasons for initiating docetaxel were rising PSA (90%) and progressive symptoms (71%). Eighteen percent of patients received docetaxel for rising PSA alone. A median of 7 cycles was administered. PSA response rates were 61%, time to response 1.5 months, and response duration 6.8 months. Disease progression was the most common reason for treatment discontinuation (36%). Main toxicities were fatigue (32%) and neuropathy (22%). Kaplan Meier survival analysis showed median duration of survival was 15.9 months (95% CI 12.4–20.5) from first drug use. 1-year survival was 0.63 (95% CI 0.52–0.72). Post-docetaxel, 36 patients received second-line treatment, mostly with mitoxantrone (89%). Second-line response rates were 22%, and median duration of response was 4 months. Conclusions: In routine clinical practice, docetaxel is a well-tolerated regimen for the treatment of HRPC. Response rates and toxicity profiles were comparable to the randomized trials. However, compared with the TAX 327 clinical trial, survival was slightly shorter than expected (15.9 vs. 18.9 months), possibly due to inclusion of patients with poorer performance status and comorbidities, who may be excluded from clinical trials. Second-line response rates were also comparable with previous reports. No significant financial relationships to disclose.

scholarly journals Role of immunotherapy in the management of hepatocellular carcinoma: current standards and future directions

2020 ◽  
Vol 27 (S3) ◽  
Author(s):  
A. Weinmann ◽  
P.R. Galle
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Clinical Trials ◽  
Statistical Significance ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Promising Therapeutic Approach

 The multikinase inhibitor sorafenib was the only approved systemic therapy in advanced hepatocellular carcinoma (hcc) for about a decade. In recent years, the number of approved agents has increased significantly as a result of a number of positive phase iii clinical trials. Lenvatinib as a first-line treatment, and regorafenib, cabozantinib, and ramucirumab in the second-line setting are now approved by the U.S. Food and Drug Administration (fda) and the European Medicines Agency. In phase ii studies, immunotherapy with nivolumab and monotherapy using pembrolizumab yielded impressive results for overall survival in therapy-naïve and pretreated patients, leading to the accelerated approval by the fda of nivolumab and pembrolizumab for second-line treatment. However, phase iii trials of nivolumab in the first line and pembrolizumab in the second line as single agents failed to reach statistical significance, although clinical benefit for a subset of patients with long durations of response could be demonstrated. Despite that setback, immunotherapy for hcc is a promising therapeutic approach, and the combination of immunotherapy with other treatment modal­ities such as monoclonal antibodies, tyrosine kinase inhibitors, or local therapies has the potential to increase the overall response rate and survival. Recently, the results of a phase iii trial of combination atezolizumab–bevacizumab compared with sorafenib showed a highly significant survival benefit and median overall survival that was not reached in the immunotherapy arm, making the combination the preferred standard of care in first-line therapy. Despite the impressive results and generally good toxicity profile of immunotherapy, patients who respond to therapy constitute only a subset of the overall population, and response rates are still limited. This review focuses on the currently reported results and ongoing clinical trials of checkpoint inhibitor–based immunotherapy in hcc.

Magnitude of benefit of the addition of bevacizumab (BEVA) to first-line chemotherapy (CT) for advanced/metastatic colorectal cancer (MCRC): Meta-analysis of randomized clinical trials

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15021-e15021
Author(s):  
V. Vaccaro ◽  
F. Cuppone ◽  
F. Loupakis ◽  
M. Milella ◽  
P. Carlini ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Clinical Trials ◽  
Regression Analysis ◽  
Phase Ii ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Meta Regression ◽  
Meta Regression Analysis

e15021 Background: The monoclonal antibody against vascular endothelial growth factor BEVA has recently demonstrated to improve survival for MRC patients (pts). Nevertheless, the magnitude of the provided benefit in the daily practice is still controversial. In order to quantify the benefit of adding BEVA to CT for MCRC, a literature-based meta-analysis was conducted. Methods: Survival Hazard Ratios (HR) were extracted from prospective, randomized clinical trials (RCTs, either phase II/III) reports. HR and event-based relative risks (RR) with 95% confidence intervals (CI) were derived through a random-effect model. Differences in primary (progression-free- and overall-survival, PFS/OS) and secondary outcomes (overall, partial and complete response rates, ORR/PR/CR) were explored. Absolute differences (AD) and the number of patients needed to treat (NNT) were calculated. Heterogeneity test and a meta-regression analysis with clinical predictors for outcomes were conducted as well. A sensitivity analysis according to the trial phase-design was accomplished. Results: Five trials (2,728 pts), 2 phase II (313 pts) and 3 phase III (2,415 pts), were gathered. No significant interaction was found in the sensitivity analysis between phase II and III, although a trend showed a better PFS results for BEVA in phase II trials (p=0.057). At the meta-regression analysis female gender and rectal primary site were significant predictors for PFS (p=0.003, p=0.005). Toxicity analysis is ongoing. Conclusions: Although concerns regarding costs and toxicities still exist, BEVA significantly improves the outcome of untreated MCRC pts. The absolute benefit provided into an unselected population for molecular features should be considered of paramount importance for advanced disease. [Table: see text] No significant financial relationships to disclose.

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