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Cancer Jun 2022The current standard treatment for patients with inoperable, locally advanced esophageal squamous cell carcinoma (ESCC) is definitive concurrent chemoradiotherapy (CCRT).
BACKGROUND
The current standard treatment for patients with inoperable, locally advanced esophageal squamous cell carcinoma (ESCC) is definitive concurrent chemoradiotherapy (CCRT).
METHODS
Patients with locally advanced ESCC received 2 cycles of 5-fluorouracil, cisplatin, durvalumab, and tremelimumab every 3 weeks with concurrent radiation therapy (60.2 or 64.5 grays). After completing CCRT plus immunotherapy, patients received 2 cycles of consolidative durvalumab and tremelimumab followed by durvalumab monotherapy every 4 weeks for 2 years after enrollment. Their survival outcomes were compared with those from a propensity score-matched historical control group that had received CCRT alone.
RESULTS
In total, 40 patients were enrolled and analyzed. The 24-month progression-free survival (PFS) and overall survival rates were 57.5% and 75%, respectively. Compared with the historical control group (n = 75), the study population had significantly longer PFS (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.28-0.97; P = .040) and overall survival (HR, 0.49; 95% CI, 0.25-0.98; P = .043). In the study population, patients who had PD-L1-positive tumors (n = 28) had significantly longer PFS (HR, 0.20; 95% CI, 0.07-0.54; P < .001) and overall survival (HR, 0.16; 95% CI, 0.05-0.56; P = .001) compared with those who had PD-L1-negative tumors (n = 11). However, there was no difference in survival outcomes according to PD-L1 status in the historical control group, indicating a strong interaction between PD-L1-positive status and survival outcomes in the treatment groups (PFS, P for interaction = .003; overall survival, P for interaction = .002).
CONCLUSIONS
Durvalumab and tremelimumab with definitive CCRT had promising efficacy in patients with locally advanced ESCC. In addition, PD-L1 expression had strong predictive value in the study population.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Chemoradiotherapy; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Humans
PubMed: 35319779
DOI: 10.1002/cncr.34176 -
Cancers Sep 2020Small-cell lung cancer (SCLC) is an aggressive tumor type with limited therapeutic options and poor prognosis. Chemotherapy regimens containing platinum represent the... (Review)
Review
Small-cell lung cancer (SCLC) is an aggressive tumor type with limited therapeutic options and poor prognosis. Chemotherapy regimens containing platinum represent the cornerstone of treatment for patients with extensive disease, but there has been no real progress for 30 years. The evidence that SCLC is characterized by a high mutational burden led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy. Randomized phase III trials demonstrated that the combination of atezolizumab (IMpower-133) or durvalumab (CASPIAN) with platinum-etoposide chemotherapy improved overall survival of patients with extensive disease. Instead, the KEYNOTE-604 study demonstrated that the addition of pembrolizumab to chemotherapy failed to significantly improve overall survival, but it prolonged progression-free survival. The safety profile of these combinations was similar with the known safety profiles of all single agents and no new adverse events were observed. Nivolumab and pembrolizumab single agents showed anti-tumor activity and acceptable safety profile in Checkmate 032 and KEYNOTE 028/158 trials, respectively, in patients with SCLC after platinum-based therapy and at least one prior line of therapy. Future challenges are the identification predictive biomarkers of response to immunotherapy in SCLC and the definition of the role of immunotherapy in patients with limited stage SCLC, in combination with radiotherapy or with other biological agents.
PubMed: 32899891
DOI: 10.3390/cancers12092522 -
Cancer Oct 2019The position of immunotherapy as a pillar of systemic cancer treatment has been firmly established over the past decade. Immune checkpoint inhibitors are a welcome... (Review)
Review
The position of immunotherapy as a pillar of systemic cancer treatment has been firmly established over the past decade. Immune checkpoint inhibitors are a welcome option for patients with different malignancies. This is in part because they offer the possibility of durable benefit, even for patients who have failed other treatment modalities. The recent demonstration that immunotherapy is effective for patients with hepatocellular carcinoma (HCC) is a milestone in the history of this recalcitrant disease. The treatment of HCC has been a challenge, and for many years was limited to the tyrosine kinase inhibitor sorafenib and to several novel tyrosine kinase inhibitors that have shown efficacy and have been approved. The current role of immune checkpoint inhibitors in the management of HCC, and how this role is likely to evolve in the years ahead, are key. Other than efforts evaluating single checkpoint inhibitors, potential combination strategies, including combinations with existing local and systemic approaches, including novel therapies are evolving. This is understandably of special interest considering the potential unique immune system of the liver, which may impact the use of immunotherapy in patients with HCC going forward, and how can it be enhanced further.
Topics: Adaptive Immunity; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; CTLA-4 Antigen; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Clinical Trials as Topic; Combined Modality Therapy; Humans; Liver; Liver Neoplasms; Programmed Cell Death 1 Receptor; Treatment Outcome; Tumor Escape; Tumor Microenvironment
PubMed: 31290997
DOI: 10.1002/cncr.32076 -
Journal of Thoracic Oncology : Official... Jan 2023
Topics: Animals; Humans; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms
PubMed: 36543434
DOI: 10.1016/j.jtho.2022.11.004 -
Hepatic Oncology Oct 2014Newer immunotherapy agents may break the barrier that tumors create to evade the attack from the immune system. Dendritic cell vaccination has shown encouraging clinical... (Review)
Review
Newer immunotherapy agents may break the barrier that tumors create to evade the attack from the immune system. Dendritic cell vaccination has shown encouraging clinical activity and a favorable safety profile in advanced tumor stages. However, optimal cell maturation status, choice of tumor antigens and route of administration have not been established. Single or multiple peptides derived from tumor-associated antigens may also be used for cancer vaccination. Intratumoral delivery of oncolytic viruses expressing immunostimulating cytokines like GM-CSF have produced stimulating clinical results that need further verification. But it is probably T-cell checkpoint modulation with monoclonal antibodies that has attracted the highest expectations. Promising activity has been reported for tremelimumab, a CTLA-4 inhibitor, and a clinical trial testing the PD-1 antibody nivolumab is underway. Future progress will probably come from a better understanding of the mechanisms of cancer-related immunosuppression, improvement in agents and strategies and combination of the available therapeutic tools.
PubMed: 30190978
DOI: 10.2217/hep.14.16 -
Biomedicines Feb 2022In advanced bladder cancer (BCa), platinum-based chemotherapy represents the first-choice treatment. In the last ten years, immune checkpoint inhibitors (ICIs) have... (Review)
Review
BACKGROUND
In advanced bladder cancer (BCa), platinum-based chemotherapy represents the first-choice treatment. In the last ten years, immune checkpoint inhibitors (ICIs) have changed the therapeutic landscape of many solid tumors. Our review aims to summarize the main findings regarding the clinical use of ICIs in advanced BCa.
METHODS
We searched PubMed, Embase, and Cochrane databases, and conference abstracts from international congresses (ASCO, ESMO, ASCO GU) for clinical trials, focusing on ICIs as monotherapy and combinations in metastatic BCa.
RESULTS
18 studies were identified. ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, atezolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab) were used. Survival outcomes have been improved by second-line ICIs, whereas first-line results are dismal. Avelumab maintenance in patients obtaining disease control with chemotherapy has achieved the highest survival rates.
CONCLUSIONS
ICIs improve survival after platinum-based chemotherapy. Avelumab maintenance represents a new practice-changing treatment. The combinations of ICIs and other compounds, such as FGFR-inhibitors, antibody-drug conjugates, and anti-angiogenic drugs, represent promising therapeutic approaches. Biomarkers with predictive roles and sequencing strategies are warranted for best patient selection.
PubMed: 35203620
DOI: 10.3390/biomedicines10020411 -
Journal For Immunotherapy of Cancer Oct 2023This study assessed the antitumor activity and safety of durvalumab plus tremelimumab combined with neoadjuvant chemotherapy (NAC) in patients newly diagnosed with...
Phase II study of durvalumab and tremelimumab with front-line neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer: primary analysis in the original cohort of KGOG3046/TRU-D.
BACKGROUND
This study assessed the antitumor activity and safety of durvalumab plus tremelimumab combined with neoadjuvant chemotherapy (NAC) in patients newly diagnosed with advanced ovarian cancer. Here, we report the primary endpoint of the original cohort of the KGOG 3046/TRU-D study.
METHODS
In this investigator-initiated single-arm, phase II trial, patients with stage IIIC-IVB ovarian cancer were administered three cycles of durvalumab (1500 mg) and tremelimumab (75 mg) with NAC, followed by interval debulking surgery (IDS). After surgery, three cycles of durvalumab (1120 mg) and adjuvant chemotherapy followed by durvalumab maintenance (1120 mg [total 12 cycles]) were administered. The primary endpoint of the study was 12-month progression-free survival (PFS) rate.
RESULTS
Twenty-three patients were enrolled. The median patient age was 60 years (range 44-77 years), and most patients presented with high-grade serous carcinoma (87.0%) and stage IV disease (87.0%). At the time of data cut-off on January 17, 2023, the median follow-up duration was 29.2 months (range 12.0-42.2). The 12-month, 24-month, and 30 month PFS rates were 63.6%, 45.0%, and 40.0%, respectively. All patients underwent IDS, with an R0 resection rate of 73.9%, and 17.4% achieved pathological complete response. Skin rashes were the most common treatment-related adverse events (TRAEs, 69.6%). However, all TRAEs completely resolved after steroid use.
CONCLUSION
This study showed promising activity with a durable clinical response, supporting the potential of NAC with dual immune checkpoint blockade in advanced-stage ovarian cancer.
TRIAL REGISTRATION NUMBER
NCT03899610.
Topics: Humans; Female; Adult; Middle Aged; Aged; Neoadjuvant Therapy; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Staging; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms
PubMed: 37865397
DOI: 10.1136/jitc-2023-007444 -
Oncology 2017Clinical trials are currently ongoing to evaluate the utility of antibodies against programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic... (Review)
Review
Clinical trials are currently ongoing to evaluate the utility of antibodies against programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) as monotherapy or combination therapy in patients with hepatocellular carcinoma (HCC). Results of combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab in HCC were presented at the 2017 annual meeting of the ASCO (American Society of Clinical Oncology). Response rates were 25% in all 40 patients and 40% in the 20 uninfected patients, both of which are encouraging. Transcatheter arterial chemoembolization and radiofrequency ablation can activate tumor immunogenicity by releasing tumor-associated antigen and by inducing the migration of cytotoxic T lymphocytes to small intrahepatic metastatic nodules. Subsequent administration of anti-PD-1 antibody could control these small intrahepatic metastatic nodules. In a nonclinical study, the combination of pembrolizumab and lenvatinib inhibited the cancer immunosuppressive environments induced by tumor-associated macrophages and regulatory T cells. This, in turn, decreased the levels of TGF-β and IL-10, the expression of PD-1, and the inhibition of Tim-3, triggering anticancer immunity mediated by immunostimulatory cytokines such as IL-12. Studies such as these may provide insight into the appropriate molecular targeted agents to be used with immune checkpoint inhibitors.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; CTLA-4 Antigen; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Programmed Cell Death 1 Receptor
PubMed: 29258079
DOI: 10.1159/000481245 -
Clinical Cancer Research : An Official... Feb 2020This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer.
PATIENTS AND METHODS
Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months.
RESULTS
A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively.
CONCLUSIONS
Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; CTLA-4 Antigen; Circulating Tumor DNA; Esophagogastric Junction; Female; Humans; Interferon-gamma; Male; Middle Aged; Prospective Studies; Stomach Neoplasms; Transcriptome; Young Adult
PubMed: 31676670
DOI: 10.1158/1078-0432.CCR-19-2443 -
Frontiers in Oncology 2022Lung cancer is one of the deadliest types of cancer responsible for thousands of cancer-related deaths. Its treatment has remained a challenge for researchers, but an... (Review)
Review
Lung cancer is one of the deadliest types of cancer responsible for thousands of cancer-related deaths. Its treatment has remained a challenge for researchers, but an increase in the knowledge of molecular pathways and biology of lung cancer has dramatically changed its management in recent decades. Immunotherapies and immunomodulation of lung cancer have previously failed for a long time but thanks to continuous research work and enthusiasm, now, this field is emerging as a novel effective therapy. Now, it is hope with potential benefits and promising results in the treatment of lung cancer. This review article focuses on immune checkpoints inhibitors: CTLA-4 inhibitors (ipilimumab and tremelimumab) and PDL-1 inhibitors (durvalumab and atezolizumab) that can be blocked to treat lung carcinoma. It is also focused on critically analyzing different studies and clinical trials to determine the potential benefits, risks, and adverse events associated with immunotherapeutic treatment.
PubMed: 36237320
DOI: 10.3389/fonc.2022.1014156