Neoadjuvant combination PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable urothelial carcinoma
ABSTRACT: Immune checkpoint therapy (ICT) is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma (UC), with one study reporting data in cisplatin-ineligible patients who received anti PD-L1 monotherapy. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathologic complete response (pCR) rate of 17%. Here, we report on the first pilot combination neoadjuvant trial (NCT02812420) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high risk features (N=28). Primary endpoint was safety and we observed 6 of 28 patients (21%) with
grade Ã¢Â‰Â¥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (N=4), hepatitis and colitis (N=2). We also observed pCR of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (N=24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized UC, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment.
Project description:Background:Recently, a series of clinical trials showed that combination of anti-programmed cell death-1 (?-PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (?-CTLA-4) could effectively eliminate tumor. However, in comparison with widely adopted mono-immune checkpoint inhibitors, chemotherapy, and targeted therapy, the advantage of combination therapy of ?-PD-1 and ?-CTLA-4 in response rate and prognosis is controversial especially considering probably increased treatment related adverse event. Thus, we conducted this meta-analysis to explore the efficacy and safety of combination treatment of ?-PD-1 and ?-CTLA-4. Methods:This meta-analysis involved 8 clinical trials. In most trials, the primary endpoint was objective response rate (ORR). Thus we calculated risk ratio (RR) and 95% confidence interval (CI) to compare ORR of patients undergoing different treatment strategies. Moreover, the co-primary endpoints in few trials included progression-free survival and overall survival. Hazard ratio (HR) with 95% CI were employed to weigh the influence of different treatments on prognosis of patients. Subgroup analysis was conducted in patients with high and low expression of PD-L1. Lastly, the safety of combination therapy was evaluated by comparing treatment related adverse events among various treatment groups. Results:Our results showed that ORR was significantly higher in patients receiving ?-PD-1 plus ?-CTLA-4 compared with ?-PD-1 (RR 1.31, 95% CI 1.16-1.48) or ?-CTLA-4 monotherapy (RR 2.11, 95% CI 1.84-2.43), chemotherapy and targeted therapy (RR 1.41, 95% CI 1.26-1.58). ?-PD-1 plus ?-CTLA-4 treated patients had a great advantage on monotherapy, chemotherapy and targeted therapy treated patients in PFS. Notably, no significant alteration in total adverse event rate was observed in ?-PD-1 plus ?-CTLA-4 treated patients. Results of subgroup analysis showed that combination therapy could enhance anti-tumor response in comparison with other treatments, especially for low PD-L1 expression patients undergoing nivolumab treatment (ORR: RR 1.35, 95% CI 1.11-1.65). Conclusion:Combination treatment of ?-PD-1 and ?-CTLA-4 is a feasible strategy with enhanced efficacy and acceptable adverse event. Moreover, for some low PD-L1 expression patients, ?-CTLA-4 might decrease the risk of resistance to ?-PD-1 and demonstrate the synergistic anti-tumor effect.
Project description:The goal of this article is to provide recommendations about the management of muscle-invasive (MIBC) and metastatic bladder cancer. New molecular subtypes of MIBC are associated with specific clinical-pathological characteristics. Radical cystectomy and lymph node dissection are the gold standard for treatment and neoadjuvant chemotherapy with a cisplatin-based combination should be recommended in fit patients. The role of adjuvant chemotherapy in MIBC remains controversial; its use must be considered in patients with high-risk who are able to tolerate a cisplatin-based regimen, and have not received neoadjuvant chemotherapy. Bladder-preserving approaches are reasonable alternatives to cystectomy in selected patients for whom cystectomy is not contemplated either for clinical or personal reasons. Cisplatin-based combination chemotherapy is the standard first-line protocol for metastatic disease. In the case of unfit patients, carboplatin-gemcitabine should be considered the preferred first-line chemotherapy treatment option, while pembrolizumab and atezolizumab can be contemplated for individuals with high PD-L1 expression. In cases of progression after platinum-based therapy, PD-1/PD-L1 inhibitors are standard alternatives. Vinflunine is another option when anti-PD-1/PD-L1 therapy is not possible. There are no data from randomized clinical trials regarding moving on to immuno-oncology agents.
Project description:The treatment of metastatic renal cell carcinoma (RCC) and urothelial carcinoma (UC) remains a major challenge. Past research has implicated the immune system in tumor surveillance of both malignancies, leading to the application of immunotherapy agents for both cancers. Among them, the most promising agents are the checkpoint blockade drugs, such as antibodies targeting the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death receptor 1 (PD-1), and PD-1 ligand (PD-L1). In normal physiology, these immune checkpoints act as inhibitory signals to fine-tune the duration and strength of immune reactions, which is pivotal for maintaining self-tolerance. However, tumor cells also utilize immune checkpoint pathways to evade anti-tumor immune response, leading to disease progression and metastasis. Thus, there has been intense preclinical and clinical effort focused on the application of checkpoint inhibitors in metastatic RCC and UC. To date, nivolumab (anti-PD-1) and atezolizumab (anti-PD-L1) have been approved for the treatment of metastatic RCC and UC, respectively. Despite these successes, challenges remain in how to further improve response rates to immunotherapy and how to select patients that will benefit from this approach. In this report, we review existing data and research on immunotherapy in metastatic RCC and UC.
Project description:Advancements in the understanding of tumor immunology in urothelial carcinoma (UC) have led to U.S Food and Drug Administration (FDA) approval of five novel anti-programmed cell death protein-1/ligand 1 (PD-1/L1) checkpoint inhibitors. In 2017, the anti-PD-L1 antibody atezolizumab and the anti-PD-1 antibody pembrolizumab gained approval for use in cisplatin-ineligible patients with locally advanced and metastatic UC. These approvals were based on single-arm trials, IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). Since then, additional checkpoint inhibitors, including avelumab, durvalumab, and nivolumab, have gained approval. Preliminary results suggest additional benefits with combinations of these agents in both first- and subsequent-line therapies, inferring a paradigm shift in the future treatment approach in advanced UC. Ongoing clinical trials will investigate how to utilize predictive biomarkers for optimal patient selection and to incorporate immunotherapy into earlier lines of multimodal treatment. In this comprehensive review, we summarize the evidence supporting the use of checkpoint inhibitors for patients with UC, and highlight ongoing clinical trials that are investigating novel combinations of immunotherapy in various disease settings.
Project description:Recently, checkpoint inhibition of the PD-1/PD-L1 axis has been shown to be therapeutically relevant in urothelial carcinoma (UC). To evaluate the predictive and prognostic value of PD-L1 on response and survival in UC patients after cystectomy, chemotherapy, or anti-PD-1/PD-L1 therapy, a systematic review of PubMed, Embase, Web of Science, and the Cochrane Library was performed. A total of 2154 patients from 14 published studies were included. In all UC patients after cystectomy, tumour cell (TC) PD-L1 expression was not associated with the OS or PFS. For the subset of patients with organ-confined disease, TC PD-L1 expression significantly predicted OS after cystectomy (P = 0.0004). There was no significant evidence of an association between TC PD-L1 status and ORR or OS for UC patients treated with platinum-based chemotherapy. For UC patients treated with anti-PD-1/PD-L1 therapy, TC PD-L1 expression ? 5% could predict the response (P = 0.005), but not for the 1% cut-off (P ? 0.05). As for PD-L1 expression in tumour-inflating immune cells (TIICs), both subsets with IC2/3 vs. IC0/1 and IC1/2/3 vs. IC0 were associated with ORR to anti-PD-1/PD-L1 therapy. In the TIIC subset, IC2/3 vs. IC0/1 of PD-L1 was associated with higher CR (P = 0.002), PR (P = 0.04), and PD (P = 0.007). Further, higher TIIC PD-L1 status benefited from longer PFS (P < 0.001), but was not associated with OS in UC patients with anti-PD-1/PD-L1 therapy. Our study suggested that TIIC PD-L1 expression with 5% cut-off was valuable as a predictive and prognostic biomarker for ORR and PFS in UC patients with anti-PD-1/PD-L1 therapy.
Project description:Targeting checkpoints of immune cell activation has been demonstrated to be the most effective approach for activation of anti-tumor immune responses. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), both inhibitory checkpoints commonly seen on activated T-cells have been found to be the most reliable targets for the treatment of cancer. Six drugs targeting PD-1 or its ligand PD-L1 and one drug targeting CTLA-4 have been approved for treatment of different types of cancers and several others are in advanced stages of development. The drugs when administered as monotherapy had dramatic increase in durable response rates and had manageable safety profile, but more than 50% of patients failed to respond to treatment. Combination of CTLA-4 and PD-1 blockers was then evaluated to increase the response rates in patients, and ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) combination was shown to significantly enhance efficacy in metastatic melanoma patients. Subsequently, ipilimumab plus nivolumab was approved for treatment of metastatic melanoma, advanced renal cell carcinoma and metastatic colorectal cancer with MMR/MSI-H aberrations. The success of combination encouraged multiple clinical studies in other cancer types. Efficacy of the combination has been shown in a number of published studies and is under evaluation in multiple ongoing studies. This review aims to support future research in combination immunotherapy by discussing the basic details of CTLA-4 and PD-1 pathways and the results from clinical studies that evaluated combination of CTLA-4 and PD-1/PD-L1 blockers.
Project description:Combined immunotherapy targeting the immune checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1), or CTLA-4 and the PD-1 ligand (PD-L1) exhibits superior anti-tumor responses compared with single-agent therapy. Here, we examined the molecular basis for this synergy. Using reconstitution assays with fluorescence readouts, we found that PD-L1 and the CTLA-4 ligand CD80 heterodimerize in cis but not trans. Quantitative biochemistry and cell biology assays revealed that PD-L1:CD80 cis-heterodimerization inhibited both PD-L1:PD-1 and CD80:CTLA-4 interactions through distinct mechanisms but preserved the ability of CD80 to activate the T cell co-stimulatory receptor CD28. Furthermore, PD-L1 expression on antigen-presenting cells (APCs) prevented CTLA-4-mediated trans-endocytosis of CD80. Atezolizumab (anti-PD-L1), but not anti-PD-1, reduced cell surface expression of CD80 on APCs, and this effect was negated by co-blockade of CTLA-4 with ipilimumab (anti-CTLA-4). Thus, PD-L1 exerts an immunostimulatory effect by repressing the CTLA-4 axis; this has implications to the synergy of anti-PD-L1 and anti-CTLA-4 combination therapy.
Project description:The prognosis of patients with unresectable or metastatic urothelial carcinoma (UC) is poor. Platinum-based chemotherapy has been the standard first-line treatment in these patients for the past decade; however, the 5-year overall survival (OS) rate is only 13-22%. Recent advances in cancer immunology research have highlighted the pivotal role of the immune system in cancer development and progression, and new immune checkpoint inhibitors (ICIs) have demonstrated efficacy in a large variety of tumors including UC. Currently, five ICIs, including two anti-PD-1 antibodies (pembrolizumab and nivolumab) and three anti-PD-L1 antibodies (atezolizumab, avelumab, and durvalumab), have been granted approval by the US Food and Drug Administration (FDA) for patients with unresectable or metastatic UC who recurred or progressed after platinum-based chemotherapy. Among these agents, only pembrolizumab is supported by strong evidence from a large randomized Phase III trial (KEYNOTE-045). This trial demonstrated statistically significant improvements in OS for patients assigned to the pembrolizumab arm compared with the chemotherapy arm, both in the total population (HR 0.73; P=0.002) and in the population with high PD-L1 expression (HR 0.57; P=0.005). For patients with cisplatin-ineligible UC, pembrolizumab and atezolizumab were approved based on Phase II studies, with limitations on the use of these agents in patients with high tumor PD-L1 expression later imposed by the FDA. In conclusion, pembrolizumab may be a potential first-choice second-line therapy for unresectable or metastatic UC patients following platinum-based chemotherapy. Several Phase III trials are ongoing to evaluate the efficacy and toxicity of combination therapies of ICIs with chemotherapy, and ICIs with other ICIs with or without chemotherapy as first-line therapy. The results of these trials might redirect treatment strategies for patients with unresectable or metastatic UC.
Project description:Immunotherapy with programmed cell death 1/ligand 1 (PD-1/PD-L1) checkpoint inhibitors has expanded a previously limited pool of effective treatment options for patients with metastatic urothelial carcinoma, particularly those with recurring or refractory disease and those who are ineligible for cisplatin. This review reports key findings from completed and ongoing clinical trials that highlight the potential of PD-1/PD-L1 blockade in urothelial carcinoma. A literature search was performed of PubMed, Embase, ClinicalTrials.gov, and selected annual congress abstracts. Prospective studies, reviews, editorials, and descriptions of ongoing anti-PD-1/PD-L1 studies in bladder cancer were included. Anti-PD-1/PD-L1 monoclonal antibodies have shown efficacy and safety across patient subgroups with urothelial carcinoma, including those with poor prognostic factors. Efficacy was similar across different anti-PD-1/PD-L1 agents. Although these antibodies have demonstrated durable responses in a subset of patients with urothelial carcinoma, clinicians are currently unable to predict which patients may derive benefit from immune checkpoint blockade. Anti-PD-1/PD-L1 antibodies have shown favorable clinical activity and tolerability in patients with metastatic urothelial carcinoma refractory to platinum-based therapy or who are ineligible for cisplatin. The activity of PD-1/PD-L1 inhibitors is now also being studied as first-line monotherapy in cisplatin-eligible patients in combination with chemotherapy as maintenance therapy after first-line chemotherapy, and in earlier disease states, such as muscle-invasive and non-muscle-invasive bladder cancer. Better predictive tools to define target patient populations are needed, as are further investigations to define optimal combinations or sequencing of treatments.
Project description:Objective: Immune checkpoint inhibitors, especially the programmed cell death receptor-1/ligand 1 (PD-1/L1) inhibitors, displayed promising efficacy in non-small cell lung cancer (NSCLC) patients. Incorporation of anti-PD-1/L1 antibodies into other therapeutic regimens (including CTLA-4 inhibitors, chemotherapy, EGFR-TKIs and IDO inhibitors) is currently in active clinical research. This meta-analysis summarized recent developments in four combination regimens of PD-1/L1 inhibitors. Methods: We searched PubMed, the Cochrane Library and the Embase database up to July 2018, on the combination therapy of PD-1/L1 inhibitors in NSCLC patients. Results: Seventeen trials were finally included in the current meta-analysis. The combined objective response rate s (ORR) for PD-1/L1 inhibitors in combination with CTLA-4 inhibitors, chemotherapy, EGFR-TKIs, and IDO inhibitors were 32% (19%-44%), 49% (46%-53%), 55% (28%-83%) and 35% (20%-50%) respectively. The combined ORR for first line PD-1/L1 inhibitors combination with CTLA-4 inhibitors, chemotherapy, and EGFR-TKIs were 35% (17%-53%), 51% (46%-56%) and 43% (-7%-93%) respectively, and the combined ORR in the second or more line setting were 36% (8%-65%), 17% (-13%-46%), 39% (19%-59%) and 35% (20%-50%) respectively. The pooled 6-month progression-free survival rate (6m PFSr) and 1-year overall survival rate (1y OSr) for combination therapy of PD-1/L1 inhibitors with CTLA-4 inhibitors or chemotherapy were 35% or 65% (6m PFSr) and 31% or 70% (1y OSr) respectively. Anti-PD-1/L1 drugs combined with anti-CTLA-4 drugs exhibited a more potent efficacy on PD-L1 positive patients (OR=0.33, 95%CI: 0.12-0.88). This trend was not observed in patients receiving combination therapy of PD-1/L1 inhibitors with chemotherapy (OR=0.96, 95%CI: 0.51-1.78). Conclusion: The included four combination regimens were potential treatment strategies and well tolerated for NSCLC patients. Further, the therapy lines and PD-L1 expression status were correlated with treatment efficacy.