Brentuximab vedotin and the PD-1 inhibitors have improved outcomes for classic Hodgkin lymphoma (cHL), but better therapies are needed for patients who relapse after these agents...Rational combinations with existing agents and next generation antibody and CAR-T constructs may improve response rates and durability. Identifying biomarkers of response to these immunotherapies and using more sensitive tools to assess response, such as circulating tumor DNA, may further inform treatment decisions and enable a precision medicine approach in the future.

The following biomarkers were associated with better outcomes for patients treated with T-DM1 + neratinib: (1) ctHER2-amp (C1D1) or in TP1; (2) Molecular Response scores; (3) loss of detectable ctDNA; (4) RNA levels of HER2; and (5) on-treatment loss of detectable ctHER2-amp. HER2 transcriptional and IHC/FISH status identify HER2-low cases (IHC 1+ or IHC 2+ and FISH negative) in these heavily anti-HER2 treated patients. Due to the small number of patients and samples in this study, the associations we have shown are for hypothesis generation only and remain to be validated in future studies. Clinical Trials registration NCT02236000.

Since the FDA's approval of Enfortumab Vedotin and Sacituzumab Govitecan, the therapeutic landscape has expanded, heralding a shift towards antibody-drug conjugates as potential first-line therapies. These findings affirm the increasing significance of antibody-drug conjugates in urothelial carcinoma treatment, transitioning them from posterior-line to frontline therapies. Future research is poised to focus on new therapeutic targets, combination therapy optimization, treatment personalization, exploration of double antibody-coupled drugs, and strategies to overcome drug resistance.

P1/2, N=68, Active, not recruiting, Australasian Myeloma Research Consortium | Recruiting --> Active, not recruiting

Research and development on Nectin-4 antibody-drug conjugates (ADC) have been greatly accelerated since the approval of enfortumab vedotin to treat uroepithelial cancer...Importantly, inhibiting autophagy by LY294002 and chloroquine significantly enhances the cytotoxicity effects of Nectin-4-MMAE in bladder cancer cells...The combination group exhibited a notable rise in apoptosis and necrosis, as indicated by H&E staining and immunohistochemistry (cleaved caspase-3, ki67). These findings demonstrated the cytoprotective role of autophagy during Nectin-4-MMAE treatment and highlighted the potential of combining Nectin-4-MMAE with autophagy inhibitors for bladder cancer treatment.

The significant differences in pCR rates observed in both treatment arms did not significantly impact long-term outcomes for patients treated with cabazitaxel versus paclitaxel in the GENEVIEVE trial.

Lu-PSMA demonstrated a substantial PSA decline but limited rPFS after cabazitaxel in a real-life setting. Adverse baseline characteristics, baseline positron-emission tomography parameters, and quality of PSA response may help identify patients less likely to benefit from Lu-PSMA.

NLC-MBZ decreased tumor size, suppressed tumor lung metastases, and lowered the expression of CDC25A, SKP2, RbX1 and Cullin1 while boosting the Rb proteins. NLC-MBZ displayed antiangiogenic potential and resulted in a reduced rate of lung metastasis in vivo.

P1, N=50, Suspended, University of Washington | Recruiting --> Suspended

P2, N=28, Recruiting, Zhejiang Cancer Hospital

NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

In the context of early-stage HER2+ breast cancer in Spain, a notable diversity in therapeutic approaches was observed. The majority of interviewed medical oncologists acknowledged HER2DX as a clinically valuable test for specific patients, in line with the 2022 SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer. To facilitate the full integration of HER2DX into clinical guidelines, conducting prospective studies to further validate its efficacy and utility was recommended.

ADCs have advanced from hematologic to solid tumours, notably in breast cancer, and are now pivotal in metastatic urological cancers as both monotherapies and in combination regimens, underscored by the FDA's approval of enfortumab vedotin and sacituzumab govitecan for metastatic urothelial cancer. There is a continual search for agents in the metastatic, relapsed testicular cancer landscape. ADCs have emerged as a pivotal innovation in oncology, blending targeted antibody therapy with potent cytotoxic drugs, significantly advancing treatment options for urological malignancies.

P2, N=14, Completed, Imagine Institute | Active, not recruiting --> Completed | N=25 --> 14 | Trial completion date: Feb 2024 --> Sep 2023

P1/2, N=24, Not yet recruiting, RemeGen Co., Ltd.

P2, N=33, Not yet recruiting, Cristiana Costa Chase, DO | Initiation date: Mar 2024 --> Jun 2024

P2/3, N=260, Recruiting, Merck Sharp & Dohme LLC | N=420 --> 260 | Trial completion date: Dec 2025 --> Jun 2027 | Trial primary completion date: Dec 2025 --> Jun 2027

P2, N=71, Recruiting, Memorial Sloan Kettering Cancer Center

This study suggests that concurrent ADC and radiotherapy are associated with a higher risk of SRN in HER2-positive breast cancer patients.

These findings suggest that the expression of these platelet surface proteins may be correlated with the prognosis of T-DM1 treatment. These indicators offer valuable insights for predicting the therapeutic response to T-DM1 and may become important references in future clinical practice, contributing to a better understanding of the impact of ADC therapies and optimizing personalized cancer treatment strategies.

INA03 administration in hCD71/hTf mice did not reveal, even at high doses, any improper toxicities. Hence, these data demonstrate promising pre-clinical efficacy and safety of INA03 and support its development as a novel acute leukemia treatment.

P1/2, N=300, Recruiting, BioAtla, Inc. | N=120 --> 300

P1, N=95, Recruiting, Eisai Co., Ltd. | Trial completion date: Apr 2027 --> Jun 2025 | Trial primary completion date: Apr 2027 --> Jun 2025

P3, N=995, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2032 --> Apr 2025 | Trial primary completion date: Jun 2023 --> Mar 2024

Studies to date have shown that patients with high levels of the protein NECTIN4 on their cancer cells respond well to EV. This information has the potential to guide future treatment strategies for mUC.

P1/2, N=206, Active, not recruiting, LaNova Medicines Zhejiang Co., Ltd. | Recruiting --> Active, not recruiting

P1/2, N=34, Completed, The Thai Lymphoma Study Group | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Apr 2024 | Trial primary completion date: Dec 2023 --> Apr 2024

P1, N=70, Recruiting, TORL Biotherapeutics, LLC | Not yet recruiting --> Recruiting

P4, N=51, Active, not recruiting, Zhongnan Hospital | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P1, N=17, Completed, Turning Point Therapeutics, Inc. | Active, not recruiting --> Completed | N=42 --> 17

P2/3, N=600, Recruiting, Sutro Biopharma, Inc. | Phase classification: P2 --> P2/3 | N=140 --> 600

The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse large B-cell lymphoma (DLBCL). An increase of <50% in acMMAE/unconjugated MMAE exposure did not lead to a clinically meaningful increase in adverse events of special interest. ER data and the benefit-risk profile support the use of polatuzumab vedotin 1.8 mg/kg once every 3 weeks with R-CHP for six cycles in patients with previously untreated DLBCL.

P2, N=9, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting | N=70 --> 9 | Trial completion date: Oct 2027 --> Mar 2026 | Trial primary completion date: Oct 2026 --> Mar 2025

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.

HER2-targeting agents, such as the tyrosine kinase inhibitor lapatinib, the antibody drug conjugate (ADC) trastuzumab-emtansine or dual HER2 inhibition (pertuzumab and trastuzumab), have been investigated in the second-line setting but led to negative study results. More recently, the ADC trastuzumab-deruxtecan was authorized after the failure of trastuzumab-based treatment. However, further improvements in HER2-directed therapy are required as resistance mechanisms and HER2 heterogeneity limit the existing treatment options. This review aims to give an overview of the current standard-of-care HER2-directed therapy in gastric cancer, as well as its challenges and future developments.

These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity.

In 2019, the Food and Drug Administration approved enfortumab vedotin, the first antibody-drug conjugate targeting Nectin-4, for the treatment of urothelial carcinoma...However, the exact mechanisms by which Nectin-4 affects tumorigenesis and progression are still unclear, and the emergence of drug resistance and treatment-related adverse reactions poses challenges. This article reviews the diagnostic potential, prognostic significance, and molecular role of Nectin-4 in tumors, with a focus on clinical trials in the field of Nectin-4-related tumor treatment and the development of new drugs targeting Nectin-4.

P=N/A, N=0, Available, Seagen Inc.

P1, N=56, Terminated, Sanofi | Trial completion date: Aug 2024 --> Mar 2024 | Active, not recruiting --> Terminated; Tusamitamab ravtansine clinical development program is discontinued as CARMEN-LC03 trial did not meet dual primary endpoint of improving progression-free survival. The decision is not related to any safety concern.

P2, N=32, Not yet recruiting, University of Michigan Rogel Cancer Center

P2, N=54, Not yet recruiting, Swiss Group for Clinical Cancer Research

These findings provide an epigenetic mechanism of action of eribulin, supporting its use early in the disease process for MET induction to prevent metastatic progression and chemoresistance. These findings warrant prospective clinical evaluation of the chemosensitizing effects of eribulin in the treatment-naive setting.