Bavencio (avelumab)

Importantly, plate-coated or beads-coupled PD-L1-pHLIP enable robust activation and expression of cytotoxic mediators of NK cells via engaging avelumab. Overall, this work provides proof of concept that recombinant PD-L1 protein decorated on the cellular membrane driven by pHLIP in combination with appropriate monoclonal antibody has potentials to elicit NK cytotoxicity, which may represent a novel and promising therapeutic avenue in cancer.

P=N/A, N=300, Recruiting, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

P1/2, N=90, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P2, N=24, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jan 2031 --> Sep 2031 | Trial primary completion date: Dec 2024 --> Sep 2025

P2, N=130, Active, not recruiting, University College, London | Trial completion date: Oct 2023 --> Oct 2024

The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced endometrial cancer.

Maintenance therapy with avelumab revealed improved overall (OS) and progression-free survival (PFS) compared with best supportive care alone in patients with platinum-responsive mUC...In the former, the combination of enfortumab vedotin and pembrolizumab showed significant improvements in OS, PFS and overall response rate compared with chemotherapy alone; the combination of nivolumab with gemcitabine-cisplatin chemotherapy demonstrated a significant extension in median OS, PFS and overall response rate compared with chemotherapy alone. In addition, erdafitinib therapy resulted in significantly longer OS than chemotherapy among patients with mUC and FGFR alterations after previous treatment with immune checkpoint inhibitors. This comprehensive summary of the current treatment landscape for mUC incorporates clinical trial evidence and discussion of agents that are currently under investigation to provide support for clinical decision making and understanding of future therapeutic approaches.

Six targeted and immunotherapeutic agents have been approved for patients with advanced urothelial bladder cancer. They all have demonstrated activity in patients for whom disease has progressed during or after platinum-based therapy. Pembrolizumab, with and without enfortumab, has demonstrated first-line activity, and avelumab is a key maintenance therapy after first-line treatment. The results of additional clinical trials should provide evidence to establish the exact role in therapy of each agent in patients with advanced disease.

P2, N=19, Completed, 4SC AG | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Feb 2024

P1, N=32, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Phase classification: P1b --> P1 | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

Clinical Trial Registration Number: NCT02603432

P1/2, N=24, Active, not recruiting, Georgetown University | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Dec 2024

P=N/A, N=150, Terminated, Pfizer | Trial completion date: Oct 2023 --> Jun 2023 | Not yet recruiting --> Terminated | Trial primary completion date: Oct 2023 --> Jun 2023; The trial was terminated for strategic reasons. The decision was not based on any safety and/or efficacy concerns.

Starting in 2017, four programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors-avelumab, pembrolizumab, nivolumab (utilized in both neoadjuvant and adjuvant settings), and retifanlimab-have demonstrated efficacy in treating patients with disseminated MCC on the basis of prospective clinical trials. Nevertheless, while randomized studies directly comparing immune checkpoint inhibitors and chemotherapy in MCC are lacking, immunotherapy shows response rates comparable to those previously reported with chemotherapy but with more enduring responses. Notably, adjuvant nivolumab has proven superiority to the standard-of-care therapy (observation) in the adjuvant setting.

P2, N=132, Recruiting, Melanoma and Skin Cancer Trials Limited | Trial completion date: Dec 2028 --> Apr 2028 | Trial primary completion date: Dec 2025 --> Apr 2027

When the tumors have metastasized, systemic therapy with protein-tyrosine kinase antagonists including sorafenib, sunitinib, pazopanib, and tivozanib that target vascular endothelial, platelet-derived, fibroblast, hepatocyte, and stem cell factor growth factor receptors (VEGFR, PDGFR, FGFR, MET, and Kit) were prescribed after 2005. The monoclonal antibody immune checkpoint inhibitor nivolumab (targeting PD1) was approved for the treatment of RCCs in 2015. It is usually used now in combination with ipilimumab (targeting CTLA-4) or cabozantinib (a multikinase blocker). Other combination therapies include pembrolizumab (targeting programed cell death protein 1) and axitinib (a VEGFR and PDGFR blocker) or lenvatinib (a multikinase inhibitor). Since the KEYNOTE-426 clinical trial, the use of immune checkpoint inhibitors in combination with protein-tyrosine kinase inhibitors is now the standard of care for most patients with metastatic renal cell carcinomas and monotherapies are used only in those individuals who cannot receive or tolerate immune checkpoint inhibitors.

Patients received anti-EGFR rechallenge therapy, including cetuximab plus avelumab, trifluridine-tipiracil plus panitumumab, irinotecan plus cetuximab, or panitumumab monotherapy. Within the limitation of a subgroup analysis, the absence of liver metastases was associated with significant improved survival. ClinicalTrials.gov Identifiers: NCT02296203; NCT04561336; NCT03227926; NCT05468892.

PFS was superior in patients treated with EV after avelumab to EV after pembrolizumab. However, OS showed no significant difference between the two groups. Because the prognosis of patients with cachexia is extremely poor, the initiation of EV should be discussed in these patients.

Currently, seven ICIs, namely ipilimumab (anti-cytotoxic T lymphocyte-associated protein 4 [CTLA4]), pembrolizumab, nivolumab (anti-programmed cell death protein 1 [PD-1]), atezolizumab, avelumab, durvalumab, and cemiplimab (anti-PD-L1), have been approved for various cancer types. Consequently, ongoing studies are evaluating the next generation of ICIs, such as lymphocyte activation gene-3 (LAG3), T cell immunoglobulin and mucin-domain containing 3 (TIM3), and T cell immunoglobulin and ITIM domain (TIGIT). Our review provides a summary of clinical trials evaluating these novel immune checkpoints in cancer treatment.

P2, N=35, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P3, N=61, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=262 --> 61 | Trial completion date: May 2025 --> Sep 2026 | Trial primary completion date: May 2025 --> Sep 2026

P1/2, N=150, Active, not recruiting, Transgene | Recruiting --> Active, not recruiting | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies.

P1, N=34, Completed, Gilead Sciences | Phase classification: P1b --> P1

P1, N=16, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=33, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Jul 2024

P1/2, N=29, Not yet recruiting, VA Office of Research and Development | Phase classification: P2 --> P1/2 | Trial completion date: Jun 2028 --> Dec 2028 | Trial primary completion date: Dec 2027 --> Jun 2028

P1/2, N=7, Active, not recruiting, Fred Hutchinson Cancer Center | Recruiting --> Active, not recruiting | N=16 --> 7 | Trial completion date: Apr 2025 --> Jan 2025 | Trial primary completion date: Apr 2024 --> Jan 2024

Cytotoxicity was investigated in primary cardiomyocytes and splenocytes, incubated with ipilimumab, Pem and avelumab. We established for the first time an in vivo model of Pem-induced cardiotoxicity. Coronary endothelial dysfunction precedes Pem-induced cardiotoxicity, whereas atorvastatin emerges as a novel prophylactic therapy.

P3, N=654, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=92, Terminated, G1 Therapeutics, Inc. | Active, not recruiting --> Terminated; Sponsor no longer pursuing trila for the indication.

The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.

P2, N=30, Recruiting, Massachusetts General Hospital | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P3, N=1214, Completed, EMD Serono Research & Development Institute, Inc. | Active, not recruiting --> Completed

P3, N=101, Active, not recruiting, University of Washington | Recruiting --> Active, not recruiting | Trial completion date: Jul 2025 --> Feb 2029 | Trial primary completion date: Jul 2025 --> Apr 2026

P1, N=72, Recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Dec 2023 --> May 2026 | Trial primary completion date: Dec 2023 --> Mar 2026

Pts with unresectable locally advanced or metastatic UC without progression after 4-6 cycles of 1L cisplatin or carboplatin + gemcitabine were enrolled (N=700). Long-term outcomes from JAVELIN Bladder 100 confirm that avelumab 1L maintenance provides similar OS and PFS benefits with acceptable safety in pts with advanced UC without progression after 1L cisplatin- or carboplatin-based chemotherapy. The median OS measured from start of chemotherapy further supports the use of avelumab 1L maintenance as standard of care in this setting and provides a benchmark for future clinical trials.

P1, N=50, Not yet recruiting, Inimmune Corporation

No abstract available

P2, N=30, Active, not recruiting, Johannes Gutenberg University Mainz | Recruiting --> Active, not recruiting

AVM is associated with moderate AE rates. Despite similarities in baseline characteristics compared to trial-selected JAVELIN Bladder 100 mUC patients, AVM resulted in longer/similar PFS but significantly shorter OS in in real-world setting.

The PACE study (NCT03147287) enrolled patients (pts) with hormone receptor-positive (HR+)/ human epidermal growth factor receptor 2-negative (HER2-) MBC after progression on CDK4/6 inhibitor (CDK4/6i) and endocrine therapy, and randomized pts to fulvestrant (ful) alone; ful with palbociclib; or ful, palbociclib, and avelumab [Mayer et al., SABCS 2022]. Future analyses are needed to investigate the correlation between ER expression levels on CTCs with survival and treatment response. This, together with information about the mutational status of ESR1 by ctDNA sequencing, might provide a new perspective on the development of resistance to ful and CDK4/6i in HR+/HER2- MBC.