FOLFIRI (5-FU, leucovorin, irinotecan) is the first-line chemotherapy for metastatic colorectal cancer (mCRC), but response rates are under 50%...In conclusion, the REO-based signature effectively identifies mCRC patients likely to benefit from FOLFIRI. Furthermore, these signature genes may play a crucial role in the chemotherapy.

This narrative review explores key predictive factors influencing the efficacy of ADCs, focusing on HER2-targeted therapies, such as trastuzumab emtansine and trastuzumab deruxtecan, as well as sacituzumab govitecan for triple-negative breast cancer. Finally, future perspectives on the sequential use of ADCs and potential combination therapies are highlighted, along with emerging agents targeting alternative antigens like HER3 and LIV-1. Overall, identifying predictive biomarkers and overcoming resistance mechanisms are essential for optimizing the use of ADCs in metastatic breast cancer, thereby improving patient outcomes.

Furthermore, this treatment may modulate TME immune profiles. Further validation using a larger sample size is warranted.

Employing a humanized TROP2 syngeneic TNBC model, we show that TROP2 targeting via hRS7, the antibody component of Sacituzumab govitecan (SG), enhances the anti-PD1 response associated with improved T cell accessibility and effector function...This study defines a new mechanism of barrier-mediated immune exclusion in cancer controlled by TROP2-dependent tight junctions. This mechanism drives tumor progression but can be targeted via TROP2-directed antibody drug conjugates to activate anti-tumor immunity and enhance immunotherapy response.

CA19-9 response to NAT alone is not enough to identify long-term post-resection PDAC survivors. The co-existence of CA19-9 and major pathologic response was predictive of the most optimal survival outcome.

We searched the FAERS database for reports of cardiovascular adverse events in patients with HER2-positive breast cancer receiving trastuzumab, ado-trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (T-Dxd). Proportionate analysis showed age and weight were the two key factors contributing to the occurrence of T-DCs induced MACE. HER2-positive breast cancer patients receiving T-DCs require additional cardiac monitoring, particularly for stroke in younger patients.

P1/2, N=65, Recruiting, AstraZeneca | Trial completion date: Aug 2026 --> Apr 2027 | Trial primary completion date: Aug 2026 --> Apr 2027

P1, N=66, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2025

First, topotecan hydrochloride (TPT) and vascular endothelial growth factor antisense oligonucleotide (ASOVEGF) were coself-assembled in water through electrostatic interaction to produce chemotherapeutic drug-gene nanoparticles (TPT-ASOVEGF NPs)...In MBC mouse models, the in vivo inhibition rate of TPT-ASOVEGF@MM NPs for lung metastasis was 89.5%, with minor toxic side effects and the least number of metastatic nodules in the lungs. In summary, TPT-ASOVEGF@MM NPs would be a promising biomimetic nanodrug for chemo-gene combination therapy of MBC with high efficacy and safety in clinics.

P2, N=23, Not yet recruiting, Guangzhou Women and Children's Medical Center

P2, N=80, Active, not recruiting, Gilead Sciences | Trial completion date: Dec 2024 --> Dec 2025

P2, N=270, Recruiting, Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd. | N=190 --> 270

P1, N=26, Completed, The Hospital for Sick Children | Recruiting --> Completed | Trial completion date: Oct 2030 --> Oct 2024 | Trial primary completion date: Oct 2025 --> Oct 2024

P3, N=504, Not yet recruiting, Shanghai Escugen Biotechnology Co., Ltd

P2, N=10, Completed, Liverpool Hospital | Active, not recruiting --> Completed

These data demonstrate the clinical potential of Trop-2-directed therapy in managing heavily pretreated patients with advanced HNSCC.

The introduction of antibody-drug conjugates, in specific trastuzumab deruxtecan, has resulted in the best progression-free survival among patients with this subtype of breast cancer...Tucatinib, capecitabine, and trastuzumab combination represent one such promising strategy. With the increasing longevity of these patients, important clinical questions include optimal treatment sequencing, the role of de-escalation of treatment in excellent responders, and the associated financial toxicity. Despite the aggressive nature of this subtype of breast cancer, the outcomes continue to improve for these patients with the evolving treatments.

P3, N=726, Not yet recruiting, Daiichi Sankyo

We report a case of a 61-year-old female with HR+HER2- metastatic breast cancer (MBC) who developed resistance to fulvestrant and subsequent chemotherapy but achieved a durable partial response (PR) lasting more than 22.5 months following ESG401 treatment. Furthermore, the patient's exceptionally long clinical benefit distinguishes her from other patients receiving ESG401 treatment. Further exploration of the use of ESG401 in HR+HER2- MBC patients, as well as a deeper understanding of the characteristics of patients that may impact sustained efficacy, in expanded clinical trials is warranted.

P3, N=254, Active, not recruiting, Sichuan Kelun Pharmaceutical Research Institute Co., Ltd. | Trial completion date: Dec 2024 --> Mar 2025

P2, N=35, Not yet recruiting, National Cancer Institute (NCI)

P1/2, N=36, Not yet recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

In this large French observational study, T-DXd users were older, had more comorbidities, and had more brain metastases than patients included in registration trials. The rapid expansion of clinical indications of T-DXd calls for proactive surveillance and timely management of potentially life-threatening T-DXd-related toxicity.

P2, N=14, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Dec 2025

P=N/A, N=135, Not yet recruiting, AstraZeneca

P1, N=20, Recruiting, Henry Ford Health System | Not yet recruiting --> Recruiting

P1, N=124, Not yet recruiting, MacroGenics

P1/2, N=340, Recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Jun 2026 | Trial primary completion date: Dec 2025 --> Jun 2026

To date, the clinical benefit and utility of implementing a DPYD/UGT1A1 pharmacogenetic-informed therapy with fluoropyrimidines and/or irinotecan have not been prospectively investigated...Clinical benefit did not appear to be affected. ClinicalTrials.gov Identifier: NCT03093818.

Although current first- and second-line therapies stratify for KRAS/NRAS/BRAF mutations, microsatellite instability, tumour location and co-morbidities, the therapeutic mainstay for the first- and second-line treatment of the majority of patients consists of 5-fluorouracil (5-FU)-based chemo-immunotherapy. By exchanging the chemotherapeutic combination partner from oxaliplatin to irinotecan or vice versa, plus the additive anti-epidermal growth factor receptor/anti-vascular endothelial growth factor antibody, the negative factor of non-response to first-line therapy could not be overcome by second-line treatment in this study population. These findings must be confirmed in larger studies, but indicate the need for novel treatment options, especially for patients not responding to first-line 5-FU-based chemo-immunotherapy.

With the approval of trastuzumab deruxtecan for the treatment of unresectable/metastatic HER2-low breast cancer, human epidermal growth factor receptor 2 (HER2)-low has emerged as a clinically actionable biomarker...Patients with discordant HER2 status had better responses to platinum-based chemotherapy. Therefore, for patients with HER2-0 primary lesions, re-evaluation of HER2 status in metastatic lesions through biopsy may offer new treatment opportunities.

Regarding responses, 5 patients had partial response (including 2 patients that were pretreated with trastuzumab), 1 patient had stable disease at 12 weeks and 4 patients had disease progression at initial assessment. All patients but one that derived clinical benefit had HER2 3 + expression.DiscussionIn the real-world setting, T-DXd showed activity in a cohort of heavily pre-treated patients with HER2-expressing gynecological malignancies.

P1/2, N=74, Not yet recruiting, Fudan University

P3, N=110, Not yet recruiting, Children's Oncology Group | Initiation date: Dec 2024 --> Mar 2025

Additionally, inhibition of translesion DNA synthesis enhances SG and PARP inhibitor (PARPi) sensitivity in PARPi-resistant OC cells. These findings provide mechanistic insights for clinical development of SG in drug-resistant OC.

P2, N=72, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Feb 2025 --> Nov 2024

P=N/A, N=800, Recruiting, Sun Yat-sen University | Trial completion date: Sep 2024 --> Jan 2025 | Trial primary completion date: Sep 2024 --> Jan 2025

The current in vitro study provides molecular evidence that taurine plays a beneficial role in protecting against irinotecan-induced muscle dysfunction by modulating oxidative stress and endoplasmic reticulum stress.

P=N/A, N=110, Active, not recruiting, GERCOR - Multidisciplinary Oncology Cooperative Group | Unknown status --> Active, not recruiting | Trial completion date: Oct 2020 --> Jan 2025

P2, N=30, Recruiting, Samsung Medical Center | Not yet recruiting --> Recruiting

P1, N=890, Active, not recruiting, Daiichi Sankyo Co., Ltd. | Recruiting --> Active, not recruiting

P1, N=120, Not yet recruiting, SystImmune Inc.