-
Nature Communications Oct 2022We previously identified a chemotherapy-induced paracrine inflammatory loop that paradoxically mitigates the anti-tumor effect of chemotherapy and triggers metastatic...
We previously identified a chemotherapy-induced paracrine inflammatory loop that paradoxically mitigates the anti-tumor effect of chemotherapy and triggers metastatic propagation in breast and lung cancer models. Therefore, we sought to further validate and translate these findings into patient care by coupling the anti-TNF-α drug certolizumab pegol with standard cisplatin doublet chemotherapy. Here we first validate the anti-metastatic effect of certolizumab in a liver-metastatic Lewis Lung Carcinoma model. We then evaluate the safety, efficacy, and pharmacodynamic effects of certolizumab with cisplatin and pemetrexed in an open label Phase 1 clinical trial (NCT02120807) of eighteen adult patients with stage IV lung adenocarcinomas. The primary outcome is maximum tolerated dose. Secondary outcomes are response rate and progression-free survival (PFS); pharmacodynamic changes in blood and tumor are evaluated as a correlative outcome. There were nine partial responses among 16 patients evaluable (56%, 95% CI 30 to 80%). The median duration of response was 9.0 months (range 5.9 to 42.6 months) and median PFS was 7.1 months (95% CI 6.3 to NR). The standard 400 mg dose of certolizumab, added to cisplatin and pemetrexed, is well-tolerated and, as a correlative endpoint, demonstrates potent pharmacodynamic inhibition of peripheral cytokines associated with the paracrine inflammatory loop.
Topics: Adult; Humans; Adenocarcinoma of Lung; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Certolizumab Pegol; Cisplatin; Lung Neoplasms; Pemetrexed; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha
PubMed: 36241629
DOI: 10.1038/s41467-022-33719-6 -
Journal For Immunotherapy of Cancer Sep 2023ONCOS-102, an oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor, can alter the tumor microenvironment to an immunostimulatory state.... (Randomized Controlled Trial)
Randomized Controlled Trial
ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: a randomized phase 2 study investigating clinical outcomes and the tumor microenvironment.
BACKGROUND
ONCOS-102, an oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor, can alter the tumor microenvironment to an immunostimulatory state. Combining ONCOS-102 with standard-of-care chemotherapy for malignant pleural mesothelioma (MPM) may improve treatment outcomes.
METHODS
In this open-label, randomized study, patients with unresectable MPM received intratumoral ONCOS-102 (3×10 virus particles on days 1, 4, 8, 36, 78, and 120) and pemetrexed plus cisplatin/carboplatin (from day 22), or pemetrexed plus cisplatin/carboplatin alone. The primary endpoint was safety. Overall survival (OS), progression-free survival, objective response rate, and tumor immunologic activation (baseline and day 36 biopsies) were also assessed.
RESULTS
In total, 31 patients (safety lead-in: n=6, randomized: n=25) were enrolled. Anemia (15.0% and 27.3%) and neutropenia (40.0% and 45.5%) were the most frequent grade ≥3 adverse events (AEs) in the ONCOS-102 (n=20) and chemotherapy-alone (n=11) cohorts. No patients discontinued ONCOS-102 due to AEs. No statistically significant difference in efficacy endpoints was observed. There was a numerical improvement in OS (30-month OS rate 34.1% vs 0; median OS 20.3 vs 13.5 months) with ONCOS-102 versus chemotherapy alone in chemotherapy-naïve patients (n=17). By day 36, ONCOS-102 was associated with increased T-cell infiltration and immune-related gene expression that was not observed in the control cohort. Substantial immune activation in the tumor microenvironment was associated with survival at month 18 in the ONCOS-102 cohort.
CONCLUSIONS
ONCOS-102 plus pemetrexed and cisplatin/carboplatin was well tolerated by patients with MPM. In injected tumors, ONCOS-102 promoted a proinflammatory environment, including T-cell infiltration, which showed association with survival at month 18.
Topics: Humans; Pemetrexed; Platinum; Mesothelioma, Malignant; Cisplatin; Tumor Microenvironment; Carboplatin
PubMed: 37661097
DOI: 10.1136/jitc-2023-007552 -
Journal of Cellular and Molecular... Jul 2023Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are strongly recommended for non-small-cell lung cancer (NSCLC) patients harbouring active EGFR...
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are strongly recommended for non-small-cell lung cancer (NSCLC) patients harbouring active EGFR mutations, while drug resistance makes exploring resistance mechanisms and seeking effective therapeutic strategies urgent endeavours. Thymidylate synthetase (TYMS or TS) is a dominant enzyme in thymidylate nucleotide metabolism. In this study, we found a positive correlation between TS expression and overall survival (OS) and disease-free survival (DFS) in lung adenocarcinoma. The examination of gene sets from 140 NSCLC patients received EGFR-TKI therapy demonstrated a negative correlation between high TS expression and the efficacy of EGFR-TKI therapy. 24 tissue specimens from NSCLC patients exhibited upregulated TS mRNA expression in NSCLC patients resistant to gefitinib. The NSCLC cell PC9 and HCC827 sensitive to gefitinib and relatively resistant PC9/GR and HCC827/GR cells were used to demonstrate the knockdown of TS restored the sensitivity of resistant cells to gefitinib. Furthermore, pemetrexed effectively suppressed TS-mediated thymidylate metabolism and induced ROS generation, DNA damage and cellular senescence, thereby hampering cancer progression and restoring sensitivity to gefitinib. Our findings illuminate the potential mechanism of TS-triggered gefitinib resistance and indicate inhibition of TS by pemetrexed can potentiate the effect of gefitinib in NSCLC. Pemetrexed combined with gefitinib has potent anti-progression potential in gefitinib-resistant NSCLC. This study suggests that NSCLC patients with both high TS expression and EGFR-driving mutations might benefit more from a combination strategy of EGFR-TKI and pemetrexed-based chemotherapy than EGFR-TKI monotherapy, which has profound clinical implications and therapeutic value.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Gefitinib; Pemetrexed; Reactive Oxygen Species; Lung Neoplasms; ErbB Receptors; Quinazolines; Drug Resistance, Neoplasm; Cell Line, Tumor; Cellular Senescence; Mutation; Protein Kinase Inhibitors
PubMed: 37278440
DOI: 10.1111/jcmm.17799 -
Journal of Thoracic Oncology : Official... Dec 2021Sintilimab plus chemotherapy significantly prolonged progression-free survival (PFS) compared with chemotherapy alone in nonsquamous NSCLC in the ORIENT-11 study....
Updated Overall Survival Data and Predictive Biomarkers of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC in the Phase 3 ORIENT-11 Study.
INTRODUCTION
Sintilimab plus chemotherapy significantly prolonged progression-free survival (PFS) compared with chemotherapy alone in nonsquamous NSCLC in the ORIENT-11 study. Updated overall survival (OS) and PFS data and corresponding biomarker analyses are reported here.
METHODS
In this study, a total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC were assigned to sintilimab plus chemotherapy combination treatment (combo) group or placebo plus chemotherapy treatment group. The patients were stratified by programmed death-ligand 1 (PD-L1) expression levels. Immune signature profiles from tumor RNA sequencing and PD-L1 immunohistochemistry were correlated with clinical outcome to identify predictive biomarkers.
RESULTS
As of January 2021, with median follow-up of 22.9 months, median OS was significantly improved in the combo group compared with the placebo plus chemotherapy treatment group (not reached versus 16.8 mo; hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.45-0.79, p = 0.0003). High or medium immune cell infiltration was strongly associated with improved PFS in the combo group, in contrast to absent or low immune cell infiltration, which suggests that chemotherapy could not prime "immune deserts" to obtain benefit from programmed cell death protein-1 inhibition. In particular, high major histocompatibility complex (MHC) class II presentation pathway expression was significantly correlated with prolonged PFS (HR = 0.32, 95% CI: 0.19-0.54, p < 0.0001) and OS (HR = 0.36, 95% CI: 0.20-0.64, p = 0.0005) in the combo group. Importantly, patients with low or absent PD-L1 but high MHC class II expression could still benefit from the combo treatment. In contrast, MHC class I antigen presentation pathway was less relevant in this combination setting.
CONCLUSIONS
The addition of sintilimab to chemotherapy resulted to significantly longer OS in nonsquamous NSCLC. Expression of MHC class II antigen presentation pathway could identify patients benefiting most from this combination.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Humans; Lung Neoplasms; Pemetrexed; Platinum
PubMed: 34358724
DOI: 10.1016/j.jtho.2021.07.015 -
Journal of Thoracic Oncology : Official... Jan 2020
Topics: Biomarkers; ErbB Receptors; Gefitinib; Humans; Lung Neoplasms; Mutation; Pemetrexed
PubMed: 31864546
DOI: 10.1016/j.jtho.2019.10.017 -
Clinical Lung Cancer May 2022Before immune checkpoint blockade therapy, chemotherapy with pemetrexed maintenance was the standard of care for patients with advanced nonsquamous non-small-cell lung... (Meta-Analysis)
Meta-Analysis
Overall Survival and Safety With Pemetrexed/Platinum ± Anti-VEGF Followed by Pemetrexed ± Anti-VEGF Maintenance in Advanced Nonsquamous Non-Small-Cell Lung Cancer: A Pooled Analysis of 4 Randomized Studies.
BACKGROUND
Before immune checkpoint blockade therapy, chemotherapy with pemetrexed maintenance was the standard of care for patients with advanced nonsquamous non-small-cell lung cancer (NSQ-NSCLC) and remains such where immunotherapy is not applicable. This pooled analysis aimed to characterize overall survival (OS) and safety of pemetrexed ± anti-VEGF maintenance, by treatment duration.
PATIENTS AND METHODS
Data from 4 randomized clinical trials (PARAMOUNT, PRONOUNCE, PointBreak, JVBL) of patients with NSQ-NSCLC receiving pemetrexed ± anti-VEGF maintenance therapy were pooled as 2 groups (Group A: pemetrexed-only maintenance, n = 486; and Group B: pemetrexed + anti-VEGF maintenance, n = 329). OS and treatment-emergent adverse events (TEAEs) were analyzed in both groups by treatment duration.
RESULTS
Baseline characteristics were well balanced between both groups. Median OS did not significantly differ between Group A (16.1 months) and Group B (18.4 months; hazard ratio: 1.17, P= .1417). A correlation between median OS and treatment duration was numerically stronger in Group A (r = 0.72) versus B (r = 0.62). Across treatment groups, TEAEs were largely grade 1 to 2 and, with few exceptions, did not increase with increased treatment duration.
CONCLUSION
There was no significant OS difference between pemetrexed-only and pemetrexed ± anti-VEGF maintenance in patients with NSQ-NSCLC. Patients receiving pemetrexed + anti-VEGF experienced a slightly less favorable safety profile with more reported TEAEs compared to pemetrexed monotherapy. Pemetrexed ± anti-VEGF maintenance therapy may be considered in NSQ-NSCLC, based on an individualized patient approach, particularly where immunotherapy is not clinically indicated.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pemetrexed; Platinum
PubMed: 34852947
DOI: 10.1016/j.cllc.2021.10.010 -
PloS One 2016Gemcitabine and pemetrexed have been used as maintenance therapy. However, few systematic reviews and meta-analyses have assessed their effects in the newest studies.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Gemcitabine and pemetrexed have been used as maintenance therapy. However, few systematic reviews and meta-analyses have assessed their effects in the newest studies. This systematic review and meta-analysis were conducted to assess the role of gemcitabine and pemetrexed in the maintenance treatment of non-small-cell lung carcinoma (NSCLC).
METHODS
We performed a literature search using PubMed, EMBASE and Cochrane library databases from their inceptions to September 16, 2015. We also searched the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) databases from 2008 to 2015. Two authors independently extracted the data. The Cochrane Collaboration's risk of bias graph was used to assess the risk of bias. The GRADE system was used to assess the grading of evidence, and a meta-analysis was conducted using Stata 11.0 software.
RESULTS
Eleven randomized controlled trial (RCT) studies were collected. Ten studies were included in the meta-analysis and divided into the following 4 groups: gemcitabine vs. best supportive care (BSC)/observation, pemetrexed vs. BSC/placebo, pemetrexed + bevacizumab vs. bevacizumab and pemetrexed vs. bevacizumab. Gemcitabine exhibited significantly improved progression-free survival (PFS) compared with BSC (hazard ratio (HR) = 0.62, p = 0.000). Pemetrexed exhibited significantly improved PFS (HR = 0.54, p = 0.000) and OS (HR = 0.75, p = 0.000) compared with BSC. Pemetrexed + bevacizumab almost exhibited significantly improved PFS (HR = 0.71, p = 0.051) compared with bevacizumab. Pemetrexed exhibited no improvement in PFS or overall survival (OS) compared with bevacizumab. Regarding the grade, the GRADE system indicated that the gemcitabine group was "MODERATE", the pemetrexed group was "HIGH", and both the pemetrexed + bevacizumab vs. bevacizumab groups and pemetrexed vs. B groups were "LOW".
CONCLUSIONS
Gemcitabine or pemetrexed compared with BSC/observation/placebo significantly improved PFS or OS. Whether pemetrexed + bevacizumab compared with bevacizumab alone significantly improves PFS requires further investigation.
Topics: Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Disease-Free Survival; Female; Humans; Lung Neoplasms; Male; Pemetrexed; Randomized Controlled Trials as Topic; Survival Rate; Gemcitabine
PubMed: 26954503
DOI: 10.1371/journal.pone.0149247 -
Cancer Medicine Jul 2023Cisplatin plus pemetrexed followed by pemetrexed is an efficacious platinum combination regimen for advanced non-squamous, non-small cell lung cancer (NSCLC). Data... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized, Phase II study of pemetrexed plus bevacizumab versus pemetrexed alone after treatment with cisplatin, pemetrexed, and bevacizumab in advanced non-squamous, non-small cell lung cancer: TORG (thoracic oncology research group) 1321.
INTRODUCTION
Cisplatin plus pemetrexed followed by pemetrexed is an efficacious platinum combination regimen for advanced non-squamous, non-small cell lung cancer (NSCLC). Data regarding the addition of bevacizumab, especially in maintenance treatment, are insufficient.
METHODS
Eligibility criteria included: no prior chemotherapy; advanced, non-squamous, NSCLC; performance status ≤1; and epidermal growth factor receptor mutation-negative. Patients (N = 108) received induction chemotherapy with cisplatin, pemetrexed, and bevacizumab every 3 weeks for four cycles, and tumor response was needed to confirm four-week response duration. Patients with at least stable disease were randomized to pemetrexed/bevacizumab or pemetrexed alone. The primary endpoint was progression-free survival (PFS) after induction chemotherapy. Myeloid-derived suppressor cell (MDSC) counts of peripheral blood samples were also analyzed.
RESULTS
Thirty-five patients each were randomized to the pemetrexed/bevacizumab group and the pemetrexed alone group. PFS was significantly better in the pemetrexed/bevacizumab group than in the pemetrexed alone group (7.0 vs. 5.4 months, hazard ratio: 0.56 [0.34-0.93], log-rank p = 0.023). In patients with partial response to induction therapy, median overall survival was 23.3 months in the pemetrexed alone group and 29.6 months in the pemetrexed/bevacizumab group (log-rank p = 0.077). Pretreatment monocytic (M)-MDSC counts tended to be greater in the pemetrexed/bevacizumab group with poor PFS than in those with good PFS (p = 0.0724).
CONCLUSIONS
Addition of bevacizumab to pemetrexed as maintenance therapy prolonged PFS in patients with untreated, advanced, non-squamous NSCLC. Furthermore, an early response to induction therapy and pretreatment M-MDSC counts may be related to the survival benefit of the addition of bevacizumab to the combination of cisplatin and pemetrexed.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Cisplatin; Lung Neoplasms; Pemetrexed; Treatment Outcome
PubMed: 37226421
DOI: 10.1002/cam4.6135 -
Journal of Clinical Oncology : Official... Mar 2024We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor ()-mutated advanced... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor ()-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status.
METHODS
Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR).
RESULTS
On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR.
CONCLUSION
Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with -mutated advanced NSCLC, including those with CNS metastases.
Topics: Humans; Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; ErbB Receptors; Indoles; Lung Neoplasms; Mutation; Pemetrexed; Platinum; Protein Kinase Inhibitors; Pyrimidines
PubMed: 38042525
DOI: 10.1200/JCO.23.02219 -
Journal of Thoracic Oncology : Official... Jun 2023Systemic treatment options for NSCLC with brain metastases (BMs) are scarce. We evaluated the activity and safety of camrelizumab plus chemotherapy as first-line therapy...
Efficacy, Safety, and Health-Related Quality of Life With Camrelizumab Plus Pemetrexed and Carboplatin as First-Line Treatment for Advanced Nonsquamous NSCLC With Brain Metastases (CAP-BRAIN): A Multicenter, Open-Label, Single-Arm, Phase 2 Study.
INTRODUCTION
Systemic treatment options for NSCLC with brain metastases (BMs) are scarce. We evaluated the activity and safety of camrelizumab plus chemotherapy as first-line therapy in patients with advanced nonsquamous NSCLC with BMs.
METHODS
This was a multicenter, single-arm, phase 2 trial (NCT04211090) conducted at seven hospitals in China. Eligible patients had treatment-naive metastatic nonsquamous NSCLC and BMs that were asymptomatic or symptoms controlled with dehydration therapy and no previous systemic treatment or local therapy for the target brain lesion. Patients received camrelizumab (200 mg) plus pemetrexed (500 mg/m) and carboplatin (area under the curve 5) intravenously on day 1 of each 21-day cycle for four cycles, followed by maintenance with camrelizumab (200 mg) and pemetrexed (500 mg/m) every 21 days until disease progression, unacceptable toxicity, or death. The primary end point was confirmed intracranial objective response rate according to modified Response Evaluation Criteria in Solid Tumors version 1.1, which was primarily analyzed in the efficacy analysis set (EAS).
RESULTS
A total of 45 patients were enrolled and treated (full analysis set), with 40 patients having at least one post-baseline tumor assessment (EAS). As of August 30, 2022, median follow-up duration was 12.5 months (95% confidence interval [CI]: 9.2-17.3). The confirmed intracranial objective response rate was 52.5% (95% CI: 36.1-68.5) in EAS and 46.7% (95% CI: 31.7-62.1) in full analysis set. The extracranial objective response rate was 47.5% (95% CI: 31.5-63.9) and 42.2% (95% CI: 27.7-57.8), respectively. Median intracranial progression-free survival was 7.6 months (95% CI: 4.6-not reached [NR]), median overall progression-free survival was 7.4 months (95% CI: 4.4-NR), and median overall survival was 21.0 months (95% CI: 15.9-NR). The most common treatment-related adverse events of grade 3 or higher were neutrophil count decrease (six [13.3%]) and anemia (four [8.9%]). One treatment-related death occurred owing to immune-related pneumonia. Linear mixed-effects model displayed that a positive trend for improvement in cognitive function and quality of life was observed based on Montreal Cognitive Assessment and Functional Assessment of Cancer Therapy-Lung scores (p = 0.025, p < 0.001).
CONCLUSIONS
Camrelizumab plus pemetrexed and carboplatin was found to have an activity with manageable toxicity and to improve cognitive function and quality of life for patients with nonsquamous NSCLC with BMs in the first-line setting.
Topics: Humans; Pemetrexed; Carboplatin; Lung Neoplasms; Quality of Life; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36738928
DOI: 10.1016/j.jtho.2023.01.083