Unequal Access to Novel Systemic Therapies for Bladder Cancer: A Global Analysis of Clinical Trials of Immune Checkpoint Inhibitors and Antibody-Drug Conjugates.

IMPORTANCE Immune Checkpoint Inhibitors (ICIs), frequently combined with other therapies, have become the standard of care for the treatment of several cancers, and hundreds of clinical trials evaluate the efficacy of novel combinations with ICI. However, it is unclear whether combination therapies truly enhance ICI activity or simply provide multiple “shots on target” for a response to occur. OBJECTIVE To assess whether ICIs in combination with other therapies result in ‘additive' or ‘synergistic' anti-tumor activity. The null hypothesis is independent drug action, where each patient's response to a combination of therapies is equal to that patient's best single-agent response. DATA SOURCES We analyzed twelve randomized-controlled clinical trials testing combinations of ICIs with other drug classes in patients with advanced cancers, including melanoma and lung, breast, gastric, kidney, and head and neck cancers. For each analysis, the clinical activity of each constituent therapy of the combination was available in the respective study population. METHODS We digitized Progression Free Survival curves for combination therapies and their constituents, and computed PFS expected for the null hypothesis of independent action by randomly sampling single-agent PFS durations (with correlation ρ=0.3±0.2 to account for cross-resistance), and assigning each simulated patient the longer of the two sampled PFS values. For each combination therapy, simulated and clinically observed PFS distributions were compared. RESULTS None of the analyzed clinical trials of ICIs in combination therapies exhibited PFS surpassing the null hypothesis of independent drug action. This suggest that there is no additive or synergistic effect in patients receiving combination therapies with ICIs. Rather, these combinations provided benefits that are largely predictable from the response probabilities of each constituent therapy. CONCLUSIONS Combining ICIs with other cancer therapies provides predictable and clinically meaningful benefit by bet-hedging: providing patients with more chances of a response to any one therapy. This implies that similar benefits may in principle result from sequential treatments or biomarker-stratified choice of treatment. This insight may be most valuable in cases where toxicity prevents full-dose combinations. Citation Format: Adam C. Palmer, Peter K. Sorger, Benjamin Izar. Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1047.

Commentary: Why does neoadjuvant therapy suddenly make sense for early stage non–small cell lung cancer?

Progression-free survival (PFS) rate at 6 months has been proposed as a potential surrogate for overall survival (OS) rate at 12 months for immune checkpoint inhibitor (ICI) trials but requires further assessment for validation. To validate 6-month PFS and objective response rate (ORR) as estimators of 12-month OS in the ICI arms of randomized clinical trials (RCTs). Electronic databases (Medline, EMBASE, and the Cochrane Central Register of Controlled Trials) were searched for ICI RCTs published between January 2000 and June 2019. Eligible studies were phase 2 and phase 3 ICI RCTs in advanced solid cancers that reported ORR, PFS, and OS. A total of 99 articles (from 60 studies) of 2502 articles were selected by consensus. Data were screened and extracted independently. Estimation models for 12-month OS and to assess correlation coefficient between end points were developed using linear regression. Data were extracted in July 2019, and analyses were conducted in September 2019. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Validation of previously reported 6-month PFS and ORR estimation models for 12-month OS using contemporary RCTs. Calibration of 6-month PFS and ORR model-estimated vs observed 12-month OS in ICI arms were assessed by correlation coefficient (r) and weighted Brier scores. Secondary analyses were performed for subgroups (ie, ICI-only, ICI-combination, line of therapy, programmed cell death 1 ligand 1 selected, and unselected). Data from 60 RCTs with 74 experimental ICI arms were used. The development data set included 25 arms from studies published January 2000 to January 2017. The estimation model for 12-month OS using 6-month PFS was: (1.06 × PFS6) + 0.16 + (0.04 × melanoma) - (0.03 × NSCLC) + (0 × other tumors), in which PFS6 indicates 6-month PFS and NSCLC indicates non-small cell lung cancer. The estimation model for 12-month OS using ORR was (0.15 × ORR) + 0.52 + (0 × melanoma) - (0.02 × NSCLC) - (0.01 × other tumors). A total of 49 arms from studies published after January 2017 to June 2019 formed the validation data set. When the models were applied on the validation data set, calibration between the 6-month PFS model estimated vs observed 12-month OS was good (r = 0.89; Brier score, 0.008), but poor for the ORR model (r = 0.47; Brier score, 0.03). Findings were similar across all subgroups. The findings of this study suggest that the estimation model using 6-month PFS could reliably estimate 12-month OS in ICI trials. This study could assist in better selection and prioritization of ICI agents for testing in RCTs based on phase 2 single-arm RCT results.

Background on the Scientific Group on Methodologies for the Safety Evaluation of Chemicals and Workshop 16: Gender differences

Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis

Purpose of ReviewTo discuss recent advances in the treatment of advanced urothelial carcinoma (UC) and how best to incorporate new therapies into clinical practice.Recent FindingsThere have been several recent practice-changing phase 2 and 3 trials of immune checkpoint inhibitors (ICIs), antibody–drug conjugates (ADCs), and targeted agents in advanced UC. Based on data from these trials, ICIs can be used as first-line maintenance therapy in patients who do not progress on platinum-based chemotherapy, second-line therapy for those with progression, and first-line therapy in cisplatin-ineligible patients with PD-L1 expression; ADCs and targeted agents provide later-line treatment options.SummaryDespite substantial progress in the treatment of advanced UC, there are still many uncertainties, including the optimal treatment sequence for novel agents, and reliable predictive biomarkers to aid in treatment selection. There is also an unmet need for effective treatment options in patients unfit for any platinum-based chemotherapy.

Simple SummaryImmunotherapy has a rapidly expanding role for the treatment of several cancers due to durable clinical activity and favorable tolerability. However, the unique biology of thymic epithelial tumors (TETs) increases the risk of immune-mediated toxicity. In this paper we review the biology of thymic cancers and its impact on the potential benefits and risks of immunotherapy. We describe the results of completed clinical trials of immune checkpoint inhibitors for advanced TETs and provide an overview of potential biomarkers of response or toxicity of immunotherapy that might influence future development of immunotherapeutic modalities for the treatment of advanced thymoma and thymic carcinoma.Thymic epithelial tumors (TETs) are rare thoracic cancers that are broadly classified as thymomas and thymic carcinomas. Surgery is the cornerstone of management for early-stage disease. There are a limited number of effective treatment options for patients with advanced or recurrent disease. The occurrence of paraneoplastic autoimmune disorders in patients with TETs, especially thymomas, creates significant challenges for the development of immunotherapy, including immune checkpoint inhibitors, as a feasible treatment option. In addition, patients with TETs are at increased risk for the development of immune-mediated toxicity with a predilection for musculoskeletal and neuromuscular adverse events upon treatment with immunotherapy. The identification of biomarkers of response and toxicity is expected to play a key role in harnessing the benefits of immunotherapy for patients with TETs. In this paper we review the biology of TETs and the potential effects on the tolerability of immunotherapy. The results of clinical trials of immune checkpoint inhibitors for the treatment of advanced TETs are described to understand the potential risks and benefits of immunotherapy. We also provide an overview of future avenues for treatment with novel immunotherapeutic modalities and opportunities to develop biomarkers to improve the safety and tolerability of immunomodulatory treatments in patients with TETs.

Exploring novel therapeutic targets in vulvar squamous cell carcinoma.

e18817 Background: Recent clinical trials testing use of immune-checkpoint inhibitors in esophageal and gastric carcinomas have shown both positive and negative results. Given these mixed signals, we aimed to assess outcomes and tolerability of key subgroups using the ASCO Net Health Benefit Score (NHBS) and ESMO Magnitude of Clinical Benefit Scale (MCBS). Methods: A detailed search for phase III trials investigating use of FDA-approved anti PD-1 or anti PD-L1 drugs in esophageal and gastric cancer trials was completed using www.clinicaltrials.gov followed by primary literature identification on PubMed. These studies were then independently selected, reviewed, and scored using the ASCO NHBS and ESMO MCBS by two investigators, and any discrepancy was mutually resolved. The ASCO NGBS scores were compared by primary site of cancer (esophageal vs gastric) and PD-L1 expression using the Mann-Whitney test. The ESMO-MCBS grading were compared using Fisher's Exact test. Results: Of the 45 records identified, 15 clinical trials were included. Of them, six were primarily esophageal cancer trials, and nine were primarily gastric cancer trials. Of all 15, 10 stratified their analysis based on PD-L1 expression. The ASCO NHBS score was significantly higher for esophageal cancer than gastric cancer (mean 40, range 20 – 56.6 vs. mean 12, range -1.1 – 18.4, p < .01). No difference, however, was observed in survival and response rate outcome endpoints between the two groups. Similarly, the ESMO MCBS was also higher for esophageal cancer group than gastric cancer (p < .05). Additionally, the median scores were higher in the patients with high PD-L1 expression vs low PD-L1 expression (mean 37, range 11.2 – 66.6 vs. mean 14, range -19.5 – 43.6, p < .05). Conclusions: In this cohort of drug registration trials of immune checkpoint inhibitors for upper GI cancers, we showed the ASCO NHB scores and ESMO scores were consistently higher among esophageal cancer trials than gastric cancer trials and in those with high PD-L1 expression than those with low PD-L1 expression. Oncologists should carefully discuss overall clinical value and expectations of immunotherapy benefit with their patients per cancer histology and PDL1 expression, exercising caution in cases of gastric adenocarcinoma with low PD-L1 expression.[Table: see text]

although MMR-D may be surrogate of immune checkpoint inhibitors in most of the solid tumors, this response is not independent of disease biology, which appears to lead to distinct outcomes across different types of cancers.

1065P Adverse events reporting in phase III oncology clinical trials of checkpoint inhibitors: A systematic review

Thyroid cancer incidence has risen in recent years, with high mortality rates in aggressive subtypes. Clinical trials of immune checkpoint inhibitors (ICIs), indicate efficacy against a range of solid tumours. However, their role in the thyroid remains to be established. This systematic review (PROSPERO: CRD420250634944) assesses the effectiveness and safety of ICIs in thyroid cancer, reported following PRISMA guidelines. Searches were performed in 6 databases (EMBASE, PubMed, CENTRAL, Scopus, Web of Science and Clinicaltrials.gov) from inception to 10th January 2025. All studies reporting efficacy outcomes for ICIs in thyroid cancer were included. Clinical trials databases were searched for the most recent results and ongoing trials. Study quality was assessed using the CASP checklist. Of 1,207 studies retrieved, 33 met the inclusion criteria. Of these trials, 14 investigated ICI plus tyrosine kinase inhibitors, and 5 studies each evaluated dual ICI combinations, ICI monotherapy, or ICIs plus chemotherapy or radiotherapy. Included studies reported variable efficacy and safety. Studies in anaplastic thyroid cancer (ATC) using biomarker-stratified ICI combinations demonstrated the greatest effectiveness. The safety profiles were generally manageable, with common adverse events including fatigue, anorexia, and increased lipase levels. ICIs show promising responses in thyroid cancer, particularly in ATC. However, the current evidence is limited to non-randomised phase I-II studies, and no phase III trials have been conducted to date. Further investigation in larger, placebo-controlled trials is required to assess efficacy in clinical practice. Predictive biomarkers can help identify patients who may experience the greatest clinical benefit, maximising cost-effectiveness.

Checkpoint inhibitors have a unique mechanism of action that differs from chemotherapy or targeted therapies. The validity of objective response rate (ORR) as a surrogate for progression-free survival (PFS) and overall survival (OS) in checkpoint-inhibitor trials is uncertain. To determine the types of primary end points used in phase 2 checkpoint-inhibitor trials, and to assess the strength of associations for ORR with PFS and OS. Trials listed in electronic databases from 2000 to 2017 (PREMEDLINE, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials). Advanced solid cancers in phase 2 and phase 3 trials. Correlations between ORR odds ratios and hazard ratios (HRs) for PFS and OS were examined for randomized comparisons. Within checkpoint-inhibitor treatment arms, correlations for ORR with 6-month PFS and 12-month OS rates were examined. All analyses were weighted by trial size. Multivariable models to predict 6-month PFS and 12-month OS rates from ORR were developed and their performance validated in an independent sample of trials. Correlation coefficient (r) of ORR with PFS and OS. Of 87 phase 2 trials identified, ORR was the most common (52 [60%]) primary end point. Twenty randomized clinical trials with 25 treatment comparisons were identified. Checkpoint-inhibitor therapy was associated with pooled ORR of 24% (95% CI, 18%-31%). For randomized comparisons, r between ORR odds ratio and PFS HR was 0.63 (95% CI, 0.35-0.89), ORR odds ratio and OS HR was 0.57 (95% CI, 0.23-0.89), and between PFS HR and OS HR was 0.42 (95% CI, 0.04-0.81). Within the checkpoint-inhibitor arms, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% CI, -0.06 to 0.95), 0.08 (95% CI, -0.17 to 0.70), and 0.74 (95% CI, 0.57-0.92), respectively. In validation, when 6-month PFS was used to predict 12-month OS, there was a good calibration between actual and predicted 12-month OS. When ORR was used to predict 6-month PFS and 12-month OS rates, respectively, the actual vs predicted rates calibrated poorly. In checkpoint-inhibitor trials, ORR correlated poorly with OS. For future phase 2 studies, 6-month PFS rate is recommended as an end point.

Breast cancer is a common malignancy among women, with a reported incidence rate of 7-10% among all types of malignant tumors. Heredity frequently contributes to its incidence, and the prevalence typically increases with age, peaking in women between the ages of 40 and 60. Immune checkpoint inhibitors are a type of molecule that can activate the immune cells to enhance the host immune system to fight cancer. With these inhibitors, immune checkpoint inhibitor therapy (ICIT) aims to block the inhibitory signal of immune cell activation by antibodies or chemicals to promote an anti-tumor immune response, which lets immune cells recognize and kill cancer cells more effectively. This article offers crucial insights into immune checkpoint inhibitor therapy, outlining its principles and diverse applications.Moreover, it delves into the findings derived from pre­vious clinical trials of immune checkpoint inhibitors, analyzing the collected data. Specifically, the article will extensively examine the role of immune checkpoint in­hibitor therapy in the context of breast cancer treatment. By summarizing existing examples of immune checkpoint inhibitor therapy and their outcomes, the article aims to evaluate the feasibility of employing this therapeutic ap­proach in breast cancer treatment.

Gastric and esophageal adenocarcinomas are aggressive malignancies. Systemic therapy for these tumors relies primarily on cytotoxic chemotherapy but outcomes remain poor. In recent years, immunotherapy has emerged as a new, promising therapeutic approach for a variety of solid tumors. Characterization of gastroesophageal cancers has revealed genomic and immune features of these tumors that may predict response to immunotherapy. Indeed, preliminary results from the initial trials of immune checkpoint inhibitors have been encouraging, with objective response rates of 20% in heavily pretreated patient populations. Based on these results, additional trials of single-agent checkpoint inhibitors as well as combinations with chemotherapy and targeted therapies are currently ongoing. Further work to identify predictive biomarkers will be crucial for the successful implementation of immunotherapy.