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The Lancet. Oncology Dec 2020The Lung Cancer Master Protocol (Lung-MAP; S1400) is a completed biomarker-driven master protocol designed to address an unmet need for better therapies for squamous... (Clinical Trial)
Clinical Trial
BACKGROUND
The Lung Cancer Master Protocol (Lung-MAP; S1400) is a completed biomarker-driven master protocol designed to address an unmet need for better therapies for squamous non-small-cell lung cancer. Lung-MAP (S1400) was created to establish an infrastructure for biomarker screening and rapid regulatory intent evaluation of targeted therapies and was the first biomarker-driven master protocol initiated with the US National Cancer Institute (NCI).
METHODS
Lung-MAP (S1400) was done within the National Clinical Trials Network of the NCI using a public-private partnership. Eligible patients were aged 18 years or older, had stage IV or recurrent squamous non-small-cell lung cancer, had previously been treated with platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The study included a screening component using the FoundationOne assay (Foundation Medicine, Cambridge, MA, USA) for next-generation sequencing, and a clinical trial component with biomarker-driven substudies and non-match substudies for patients who were ineligible for biomarker-driven substudies. Patients were pre-screened and received their substudy assignment upon progression, or they were screened at progression and received their substudy assignment upon completion of testing. Patients could enrol onto additional substudies after progression on a substudy. The study is registered with ClinicalTrials.gov, NCT02154490, and all research related to Lung-MAP (S1400) is completed.
FINDINGS
Between June 16, 2014, and Jan 28, 2019, 1864 patients enrolled and 1841 (98·9%) submitted tissue. 1674 (90·9%) of 1841 patients had biomarker results, and 1404 (83·9%) of 1674 patients received a substudy assignment. Of the assigned patients, 655 (46·7%) registered to a substudy. The biomarker-driven substudies evaluated taselisib (targeting PIK3CA alterations), palbociclib (cell cycle gene alterations), AZD4547 (FGFR alteration), rilotumumab plus erlotinib (MET), talazoparib (homologous recombination repair deficiency), and telisotuzumab vedotin (MET). The non-match substudies evaluated durvalumab, and nivolumab plus ipilimumab for anti-PD-1 or anti-PD-L1-naive disease, and durvalumab plus tremelimumab for anti-PD-1 or anti-PD-L1 relapsed disease. Combining data from the substudies, ten (7·0%) of 143 patients responded to targeted therapy, 53 (16·8%) of 315 patients responded to anti-PD-1 or anti-PD-L1 therapy for immunotherapy-naive disease, and three (5·4%) of 56 responded to docetaxel in the second line of therapy. Median overall survival was 5·9 months (95% CI 4·8-7·8) for the targeted therapy groups, 7·7 months (6·7-9·2) for the docetaxel groups, and 10·8 months (9·4-12·3) for the anti-PD-1 or anti-PD-L1-containing groups. Median progression-free survival was 2·5 months (95% CI 1·7-2·8) for the targeted therapy groups, 2·7 months (1·9-2·9) for the docetaxel groups, and 3·0 months (2·7-3·9) for the anti-PD-1 or anti-PD-L1-containing groups.
INTERPRETATION
Lung-MAP (S1400) met its goal to quickly address biomarker-driven therapy questions in squamous non-small-cell lung cancer. In early 2019, a new screening protocol was implemented expanding to all histological types of non-small-cell lung cancer and to add focus on immunotherapy combinations for anti-PD-1 and anti-PD-L1 therapy-relapsed disease. With these changes, Lung-MAP continues to meet its goal to focus on unmet needs in the treatment of advanced lung cancers.
FUNDING
US National Institutes of Health, and AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Clinical Decision-Making; Disease Progression; Female; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Precision Medicine; Predictive Value of Tests; Progression-Free Survival; Time Factors; Young Adult
PubMed: 33125909
DOI: 10.1016/S1470-2045(20)30475-7 -
Drugs in R&D 2010Tremelimumab (CP 675206; CP-675; CP-675,206; CP-675206; Ticilimumab) is a fully human IgG2 anitbody, which is directed against human cytotoxic T lymphocyte-associated... (Review)
Review
Tremelimumab (CP 675206; CP-675; CP-675,206; CP-675206; Ticilimumab) is a fully human IgG2 anitbody, which is directed against human cytotoxic T lymphocyte-associated antigen 4 (CTLA4). It is being developed by Pfizer for the treatment of various cancers. It is currently in worldwide phase III development for malignant melanoma, phase II development for colorectal cancer, gastrointestinal cancer, gynecological cancer, and non-small cell lung cancer in the US and other countries, and is also being investigated for prostate, breast, and pancreatic cancer in various countries. This review discusses the key development milestones and therapeutic trials of this drug.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD; CTLA-4 Antigen; Drug Design; Humans; Neoplasms
PubMed: 20698721
DOI: 10.2165/11584530-000000000-00000 -
Cancers Sep 2022Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating... (Review)
Review
Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as "adjuvants" to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner.
PubMed: 36139683
DOI: 10.3390/cancers14184523 -
OncoTargets and Therapy 2016The immune checkpoint therapy is a relatively recent strategy that aims to tweak the immune system to effectively attack cancer cells. The understanding of the immune... (Review)
Review
The immune checkpoint therapy is a relatively recent strategy that aims to tweak the immune system to effectively attack cancer cells. The understanding of the immune responses and their regulation at the intracellular level and the development of fully humanized monoclonal antibodies are the pillars of an approach that could elicit durable clinical responses and even remission in some patients with cancer. Most of the immune checkpoints that regulate the T-cell responses (activation and inhibition) operate through proteins present on the cytoplasmic membrane of the immune cells. Therefore, specific antibodies capable of blocking the inhibitory signals should lead to unrestrained immune responses that supersede the inhibitory mechanisms, which are naturally present in the tumor microenviroment. The best-known and most successful targets for immune checkpoint therapy are the cytotoxic T-lymphocyte antigen-4 and programmed cell death-1 coreceptors. Tremelimumab (CP-675,206) is a fully humanized monoclonal antibody specific for cytotoxic T-lymphocyte antigen-4, which has been successfully used to treat patients with metastatic melanoma and some other cancers. Although still a work in progress, the use of tremelimumab as an immune checkpoint therapeutic agent is a promising approach alone or in combination with other anticancer drugs. Here, we review the use of this antibody in a number of clinical trials against solid tumors.
PubMed: 27042127
DOI: 10.2147/OTT.S65802 -
Cancer Medicine Aug 2023Advanced or metastatic esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis; new first-line systemic treatment options are needed. Combining...
BACKGROUND
Advanced or metastatic esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis; new first-line systemic treatment options are needed. Combining immuno-oncology therapies with standard chemotherapy may represent a promising approach for the treatment of solid tumors. Results from a Phase Ib study evaluating durvalumab with tremelimumab and chemotherapy in patients with advanced or metastatic ESCC are reported.
METHODS
Adults with advanced or metastatic ESCC who were candidates for first-line platinum-based chemotherapy received durvalumab 1500 mg (Day 1), tremelimumab 75 mg (Day 1), cisplatin 80 mg/m (Day 1) and 5-fluorouracil (5-FU) 800 mg/m (Days 1-5) in 28-day cycles until disease progression or discontinuation due to toxicity. The study consisted of safety run-in (Part A) and expansion (Part B) periods. The primary endpoint was safety. Antitumor activity was an exploratory endpoint.
RESULTS
Sixteen patients were enrolled, 6 in Part A and 10 in Part B, and received a median of 4.0 treatment cycles. All patients were Asian; median age was 65.0 years. All patients experienced adverse events (AEs) related to cisplatin and 5-FU, and 8 (50.0%) patients experienced AEs related to durvalumab and tremelimumab. Grade ≥3 treatment-related AEs occurred in 7 (43.8%) patients. There were no deaths associated with AEs. Six (37.5%) patients achieved an objective response. Median progression-free survival was 3.75 months, and median overall survival was 9.69 months.
CONCLUSIONS
Durvalumab with tremelimumab and chemotherapy demonstrated manageable safety and antitumor activity in patients with advanced or metastatic ESCC, warranting further investigation in randomized trials. Registered with ClinicalTrials.gov: NCT02658214.
Topics: Adult; Humans; Aged; Esophageal Squamous Cell Carcinoma; Cisplatin; Esophageal Neoplasms; Fluorouracil; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37489066
DOI: 10.1002/cam4.6260 -
Cancers Dec 2019With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as... (Review)
Review
With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as yet unresolved dilemma for clinicians, pharmaceutical companies and researchers. Drugs which inhibit cytotoxic T-lymphocyte associated protein-4 (CTLA-4), such as ipilimumab and tremelimumab, programmed cell death protein-1 (PD-1), such as nivolumab and pembrolizumab, and programmed cell death ligand-1 (PD-L1), such as atezolizumab, durvalumab and avelumab, each appear to have varying pharmacokinetics and clinical activity in different cancer types. Each drug differs in terms of dosing, which becomes an issue when drug comparisons are attempted. Here, we examine the various checkpoint inhibitors currently used and in development. We discuss the antibodies and their protein targets, their pharmacokinetics as measured in various tumor types, and their binding affinities to their respective antigens. We also examine the various dosing regimens for these drugs and how they differ. Finally, we examine new developments and methods to optimize delivery and efficacy in the field of checkpoint inhibitors, including non-fucosylation, prodrug formations, bispecific antibodies, and newer small molecule and peptide checkpoint inhibitors.
PubMed: 31877721
DOI: 10.3390/cancers12010038 -
Current Opinion in Pulmonary Medicine Sep 2022Immune checkpoint inhibitors (ICIs) have rapidly become a mainstay of cancer treatment. However, immune modulation resulting from checkpoint inhibition can cause... (Review)
Review
PURPOSE OF REVIEW
Immune checkpoint inhibitors (ICIs) have rapidly become a mainstay of cancer treatment. However, immune modulation resulting from checkpoint inhibition can cause inflammation in any organ system, with pneumonitis being one of the most severe immune-related adverse events (irAEs). Here, we review the most recent literature on pulmonary adverse events following ICIs.
RECENT FINDINGS
Several systematic reviews and meta-analyses of data from trials of antiprogrammed death-1 (PD-1; nivolumab, pembrolizumab), anti-PD-ligand-1 (PD-L1; atezolizumab, avelumab, durvalumab) and anticytotoxic T lymphocyte antigen-4 (CTLA-4; ipilimumab or tremelimumab) in patients with advanced cancer have explored the relative risk and incidence of lung toxicity among different tumor types and therapeutic regimens. They have showed that the incidence of all-grade (1-4) and high-grade (3-4) pneumonitis is significantly higher in nonsmall cell lung cancer (NSCLC) compared with other tumor types. In addition, they have demonstrated that immunotherapy, especially monoimmunotherapy, has a significantly lower risk of irAEs compared to immune-chemotherapy. Treatment for lung cancer, preexisting interstitial lung disease, smoking history and male sex appear to increase the risk for ICI-related pneumonitis.
SUMMARY
Lung toxicity is an uncommon but potentially severe and even fatal complication of ICIs. Timely recognition is critically important but challenging, particularly in patients with lung cancer wherein drug toxicity can mimic disease progression or recurrence.
Topics: Antineoplastic Agents, Immunological; Carcinoma, Non-Small-Cell Lung; Drug-Related Side Effects and Adverse Reactions; Humans; Immune Checkpoint Inhibitors; Lung; Lung Neoplasms; Male; Pneumonia
PubMed: 35838354
DOI: 10.1097/MCP.0000000000000895 -
The Eurasian Journal of Medicine Feb 2019Immune checkpoint inhibitors (ICI) are monoclonal antibodies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1), or PD-1 ligand... (Review)
Review
Immune checkpoint inhibitors (ICI) are monoclonal antibodies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1), or PD-1 ligand (PD-L1). ICI are approved for the treatment of malign melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, head and neck squamous cell carcinoma, urothelial carcinoma, and renal cell carcinoma. They can lead to long-term anti-tumor responses by deactivating the brake mechanism in the immune system. Ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab are examples of ICI. CTLA-4 is a brake mechanism in immune response. Ipilimumab and tremelimumab are antibodies against CTLA-4. PD-1 is another important immune checkpoint co-inhibitor receptor that is expressed by activated T cells in the peripheral tissue. As a result of blockage of the PD-1/PD-L1 pathway, local tumor-specific immune response augments, and long-term tumor control can be achieved. In recent years, ICI are approved for the treatment of various malignities. They may be responsible for specific toxicities called immune-related adverse events (irAEs). irAEs are a consequence infiltration of normal tissues by activated T lymphocytes that are responsible for autoimmunity. Corticosteroids and anti-tumor necrosis factor agents, such as infliximab and mycophenolate mofetil, are effective in the treatment of irAEs. Immune checkpoint inhibition with monoclonal antibodies against CTLA-4 and/or PD-1/PD-L1 by single agent or combination treatments became a new option in various solid tumors. However, ICI have unique adverse events, and these adverse events should be considered in any new onset clinical situation and should be managed properly. Future prospective randomized clinical trials will clarify recent questions.
PubMed: 30911265
DOI: 10.5152/eurasianjmed.2018.18194 -
Oncoimmunology 2023The use of immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 and CTLA-4 has transformed the oncology practice of hepatocellular carcinoma. However, only 25-30% of... (Review)
Review
The use of immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 and CTLA-4 has transformed the oncology practice of hepatocellular carcinoma. However, only 25-30% of the patients with advanced HCC treated with atezolizumab-bevacizumab or tremelimumab-durvalumab (STRIDE) respond initially, and mechanistic biomarkers and novel treatment strategies are urgently needed for patients who present with or acquire resistance to first-line ICI-based therapies. The recent approval of the STRIDE regimen has also engendered new questions, such as patient selection factors (e.g. portal hypertension and history of variceal bleed) and biomarkers, and the optimal combination and sequencing of ICI-based regimens. Triumphs in the setting of advanced HCC have also galvanized considerable interest in the broader application of ICIs to early- and intermediate-stage diseases, including clinical combination of ICIs with locoregional therapies. Among these clinical contexts, the role of ICIs in liver transplantation - which is a potentially curative strategy unique to HCC management - as a bridge to liver transplant in potential candidates or in the setting of post-transplant recurrence, warrants investigation in view of the notable theoretical risk of allograft rejection. In this review, we summarize and chart the landscape of seminal immuno-oncology trials in HCC and envision future clinical developments.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Immune Checkpoint Inhibitors; Immunotherapy
PubMed: 37284696
DOI: 10.1080/2162402X.2023.2214478 -
American Society of Clinical Oncology... Jan 2024This review explores the dynamic landscape of hepatocellular carcinoma (HCC) treatment, emphasizing on recent developments across various stages and therapeutic... (Review)
Review
This review explores the dynamic landscape of hepatocellular carcinoma (HCC) treatment, emphasizing on recent developments across various stages and therapeutic approaches. Although curative strategies such as hepatectomy and thermal ablation are standard for early-stage cases, high relapse rates drive investigations into adjuvant and perioperative treatment. Adjuvant therapies face hurdles, but noteworthy advances include IMbrave050 setting a new standard with atezolizumab/bevacizumab. Locoregional treatments gain significance, especially for multifocal HCC, with the integration of innovative combinations with systemic therapies, showing improved outcomes. In the advanced setting, the evolution from sorafenib as the primary first-line option to new standards, such as atezolizumab/bevacizumab and tremelimumab/durvalumab, to other emerging therapies such as tislelizumab and pembrolizumab with lenvatinib, is explored. Additionally, second-line treatments and insights into the interplay between immunotherapies and antiangiogenic agents, as well as novel combination strategies that add complexity to treatment decisions, are discussed.
Topics: Humans; Carcinoma, Hepatocellular; Bevacizumab; Liver Neoplasms; Immunotherapy; Combined Modality Therapy
PubMed: 38175973
DOI: 10.1200/EDBK_430028