BACKGROUND: Until recently, treatment options for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) and resistance to endocrine therapy were limited to chemotherapy. This real-world study describes treatment patterns and outcomes in patients treated with chemotherapy in the United States before approval of antibody-drug conjugates.
METHODS: This retrospective, observational study included adults with HR+/HER2- mBC from the ConcertAI Patient360™ Breast Cancer dataset who initiated their first chemotherapy in the metastatic setting between January 2011 and June 2021. Treatment patterns were described; real-world overall survival, time to next treatment or death, and real-world progression-free survival were evaluated for all eligible patients and patients treated with subsequent chemotherapy. Index dates were the start date of each chemotherapy treatment.
RESULTS: Among 1545 eligible patients, 76% were white, 12% had Eastern Cooperative Oncology Group performance status ≥2, 38% had de novo mBC, and median age was 61 years (range, 52-69 years). Within the index period, capecitabine was used the most as the first chemotherapy agent and decreased in later treatments, while the use of eribulin increased between first and fourth chemotherapies. Median (95% confidence interval) real-world overall survival was 23.3 months (21.3-25.4 months) from start of first chemotherapy, time to next treatment or death was 6.5 months (5.9-7.1 months), and real-world progression-free survival was 6.9 months (6.4-7.6 months); median times from second, third, and fourth chemotherapies decreased with each additional chemotherapy treatment.
CONCLUSIONS: This real-world study demonstrates that for patients with HR+/HER2- mBC, chemotherapy provides relatively limited survival benefit which decreases with each additional chemotherapy line, and highlights the need for improved treatment options.

This review highlights significant advancements in antibody-drug conjugates (ADCs) equipped with metal-based and nature-inspired payloads, focusing on synthetic strategies for antibody conjugation. Traditional methods such us maleimide and succinimide conjugation and classical condensation reactions are prevalent for metallodrugs and natural compounds. However, emerging non-conventional strategies such as photoconjugation are gaining traction due to their milder conditions and, in an aspect which minimizes side reactions, selective formation of ADC. The review also summarizes the therapeutic and diagnostic properties of these ADCs, highlighting their enhanced selectivity and reduced side effects in cancer treatment compared to non-conjugated payloads. ADCs combine the specificity of monoclonal antibodies with the cytotoxicity of chemotherapy drugs, offering a targeted approach to the elimination of cancer cells while sparing healthy tissues. This targeted mechanism has demonstrated impressive clinical efficacy in various malignancies. Key future advancements include improved linker technology for enhanced stability and controlled release of cytotoxic agents, incorporation of novel, more potent, cytotoxic agents, and the identification of new cancer-specific antigens through genomic and proteomic technologies. ADCs are also expected to play a crucial role in combination therapies with immune checkpoint inhibitors, CAR-T cells, and small molecule inhibitors, leading to more durable and potentially curative outcomes. Ongoing research and clinical trials are expanding their capabilities, paving the way for more effective, safer, and personalized treatments, positioning ADCs as a cornerstone of modern medicine and offering new hope to patients.

Lung cancer continues to contribute to the highest percentage of cancer-related deaths worldwide. Advancements in the treatment of non-small cell lung cancer like immune checkpoint inhibitors have dramatically improved survival and long-term disease response, even in curative and perioperative settings. Unfortunately, resistance develops either as an initial response to treatment or more commonly as a progression after the initial response. Several modalities have been utilized to combat this. This review will focus on the various combination treatments with immune checkpoint inhibitors including the addition of chemotherapy, various immunotherapies, radiation, antibody-drug conjugates, bispecific antibodies, neoantigen vaccines, and tumor-infiltrating lymphocytes. We discuss the status of these agents when used in combination with immune checkpoint inhibitors with an emphasis on lung cancer. The early toxicity signals, tolerability, and feasibility of implementation are also reviewed. We conclude with a discussion of the next steps in treatment.

Multiple classes of therapies targeting claudin-18 isoform 2 (CLDN18.2) are under development for the treatment of advanced gastroesophageal adenocarcinoma and other solid tumors. At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the final results of the phase 3 SPOTLIGHT trial were presented, demonstrating a significant survival benefit from the addition of the CLDN18.2-specific antibody zolbetuximab to chemotherapy in the first-line treatment of advanced gastroesophageal adenocarcinomas with ≥ 75% CLDN18.2 expression. Early-phase trial results presented at ASCO 2024 showed promising efficacy and safety of the afucosylated CLDN18.2-specific antibody FG-M108 in combination with chemotherapy in the first-line treatment of CLDN18.2-positive advanced gastroesophageal and pancreatic cancers. In addition, several early-phase trials presented at ASCO 2024 investigate other CLDN18.2-targeting approaches in CLDN18.2-positive refractory advanced solid tumors, including the CLDN18.2-targeting antibody-drug conjugates LM-302 and IBI343, the bispecific anti-CLDN18.2/CD3 antibody IBI38, and the chimeric antigen receptor T cell therapy satricabtagene autoleucel. These novel approaches could potentially expand the benefit of CLDN18.2-targeting therapies to a broader range of tumor types and to tumors expressing lower levels of CLDN18.2.

The last few years have seen a rise in the identification and development of bio-therapeutics through the use of cutting-edge delivery methods or bio-formulations, which has created bio-analytical difficulties. Every year, new bio-pharmaceutical product innovations come out, but the analytical development of these products is challenging. Quantifying the products and components of conjugated molecular structures is essential for preclinical and clinical research in order to guide therapeutic development, given their intrinsic complexity. Furthermore, a significant amount of information is needed for the measurement of these unique modalities by LC-MS techniques. Numerous LC-MS based methods have been developed, including AEX-HPLC-MS, RP-IP-LCMS, HILIC-MS, LCHRMS, Microflow-LC-MS, ASMS, Hybrid LBA/LC-MS, and more. However, these methods continue to face problems, prompting the development of alternative approaches. Therefore, developing bio-molecules that are this complicated and, low in concentration requires a skilled LC-MS based approach and knowledgeable personnel. This review covers general novel modalities classifications, sample preparation techniques, current status and bio-analytical strategies for analyzing various novel modalities, including gene bio-therapeutics, oligonucleotides, antibody-drug conjugates, monoclonal antibodies and PROTACs. It also covers how these strategies have been used in the past and how they are being used now to address challenges in the development of LC-MS based methods, as well as improvement strategies, current advancements and recent developed methods. We additionally covered on the benefits and drawbacks of different LC-MS based techniques for the examination of bio-pharmaceutical products and the future perspectives.

Antibody-drug conjugates (ADCs), which combine the precise targeting capabilities of antibodies with the powerful cytotoxicity of small-molecule drugs, have evolved into a promising approach for tumor treatment. However, the traditional covalent coupling method requires the design of a specific linker tailored to the properties of the small-molecule drugs, which greatly limits the development of ADCs and the range of drugs that can be used. Herein, a novel type of antibody-calixarene drug conjugates (ACDCs) that function similarly to ADCs by delivering drugs to their targets using antibodies but without the requirement of covalent conjugation of the drugs with antibodies is presented. By replacement of conventional linkers with supramolecular linkers, the ACDCs can load various chemotherapeutic drugs through host-guest interactions. Furthermore, ACDCs are readily reduced upon reaching the hypoxic microenvironment, resulting in rapid release of the drugs. With this precise drug encapsulation and controlled release mechanism, ACDCs deliver drugs to tumor tissues effectively and achieve a significantly enhanced antitumor effect. Considering that the ACDCs can be easily prepared by combining antibody-calixarene conjugates derived from tumor-targeting antibodies with various small-molecule drugs, ACDCs may provide a promising platform technology to accelerate ADC development and thus improve the therapeutic efficacy of chemotherapy.

Antibody-drug conjugates (ADCs) consist of monoclonal antibodies that target tumor cells and cytotoxic drugs linked through linkers. By leveraging antibodies\' targeting properties, ADCs deliver cytotoxic drugs into tumor cells via endocytosis after identifying the tumor antigen. This precise method aims to kill tumor cells selectively while minimizing harm to normal cells, offering safe and effective therapeutic benefits. Recent years have seen significant progress in antitumor treatment with ADC development, providing patients with new and potent treatment options. With over 300 ADCs explored for various tumor indications and some already approved for clinical use, challenges such as resistance due to factors like antigen expression, ADC processing, and payload have emerged. This review aims to outline the history of ADC development, their structure, mechanism of action, recent composition advancements, target selection, completed and ongoing clinical trials, resistance mechanisms, and intervention strategies. Additionally, it will delve into the potential of ADCs with novel markers, linkers, payloads, and innovative action mechanisms to enhance cancer treatment options. The evolution of ADCs has also led to the emergence of combination therapy as a new therapeutic approach to improve drug efficacy.

Current therapies targeting the human epidermal growth factor receptor (HER) family, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are limited by drug resistance and systemic toxicities. Antibody-drug conjugates (ADCs) are one of the most rapidly expanding classes of anti-cancer therapeutics with 13 presently approved by the FDA. Importantly, ADCs represent a promising therapeutic option with the potential to overcome traditional HER-targeted therapy resistance by delivering highly potent cytotoxins specifically to HER-overexpressing cancer cells and exerting both mAb- and payload-mediated antitumor efficacy. The clinical utility of HER-targeted ADCs is exemplified by the immense success of HER2-targeted ADCs including trastuzumab emtansine and trastuzumab deruxtecan. Still, strategies to improve upon existing HER2-targeted ADCs as well as the development of ADCs against other HER family members, particularly EGFR and HER3, are of great interest. To date, no HER4-targeting ADCs have been reported. In this review, we extensively detail clinical-stage EGFR-, HER2-, and HER3-targeting monospecific ADCs as well as novel clinical and pre-clinical bispecific ADCs (bsADCs) directed against this receptor family. We close by discussing nascent trends in the development of HER-targeting ADCs, including novel ADC payloads and HER ligand-targeted ADCs.

BACKGROUND: Triple-negative breast cancer (TNBC) remains a clinically challenging subtype due to its aggressive nature and limited treatment options post-neoadjuvant failure. Historically, capecitabine has been the cornerstone of adjuvant therapy for TNBC patients not achieving a pathological complete response (pCR). However, the integration of new modalities such as immunotherapy and PARP inhibitors has prompted a re-evaluation of traditional post-neoadjuvant approaches.
METHODS: This review synthesizes data from pivotal clinical trials and meta-analyses to evaluate the efficacy of emerging therapies in the post-neoadjuvant setting. We focus on the role of immune checkpoint inhibitors (ICIs), PARP inhibitors (PARPis), and antibody-drug conjugates (ADCs) alongside or in place of capecitabine in TNBC treatment paradigms.
RESULTS: The addition of ICIs like pembrolizumab to neoadjuvant regimens has shown increased pCR rates and improved event-free survival, posing new questions about optimal post-neoadjuvant therapies. Similarly, PARPis have demonstrated efficacy in BRCA-mutated TNBC populations, with significant improvements in disease-free survival (DFS) and overall survival (OS). Emerging studies on ADCs further complicate the adjuvant landscape, offering potentially efficacious alternatives to capecitabine, especially in patients with residual disease after neoadjuvant therapy.
CONCLUSIONS: The challenge remains to integrate these new treatments into clinical practice effectively, considering factors such as drug resistance, patient-specific characteristics, and socio-economic barriers. This review discusses the implications of these therapies and suggests a future direction focused on personalized medicine approaches in TNBC.
CONCLUSIONS: As the treatment landscape for TNBC evolves, the role of capecitabine is being critically examined. While it remains a viable option for certain patient groups, the introduction of ICIs, PARPis, and ADCs offers promising alternatives that could redefine adjuvant therapy standards. Ongoing and future trials will be pivotal in determining the optimal therapeutic strategies for TNBC patients with residual disease post-neoadjuvant therapy.

Platinum-based chemotherapy has been the cornerstone of first-line treatment for advanced urothelial carcinoma for decades, based on its proven efficacy and well-characterized safety profile. Although enfortumab vedotin (EV) plus pembrolizumab showed superior efficacy versus platinum-based chemotherapy in the EV-302 phase 3 trial, common and potentially cumulative toxicities associated with EV plus pembrolizumab may make this combination less suitable for some patients, such as those with pre-existing neuropathy, hyperglycemia, or hepatic impairment, or patients likely to have favorable outcomes with platinum-based chemotherapy. The availability of EV plus pembrolizumab in various countries may also be limited by financial considerations. Thus, platinum-based chemotherapy is likely to remain a valuable option for advanced urothelial carcinoma. Eligibility for cisplatin- or carboplatin-based regimens can be determined by assessing renal function, performance status, and specific comorbidities. In cisplatin-eligible and -ineligible patients without disease progression following platinum-based chemotherapy, avelumab first-line maintenance is standard of care based on findings from the JAVELIN Bladder 100 phase 3 trial, which showed that avelumab first-line maintenance plus best supportive care prolonged overall survival and progression-free survival compared with best supportive care alone across clinically relevant subgroups. Adverse events associated with avelumab were generally consistent with those observed with other immune checkpoint inhibitors, and long-term follow-up showed no new safety concerns with prolonged treatment. Efficacy benefits and safety profiles were similar in patients who received avelumab first-line maintenance after cisplatin- or carboplatin-based chemotherapy. The effectiveness and safety of avelumab first-line maintenance have been confirmed in several real-world studies. Overall, these data support the use of avelumab first-line maintenance for all platinum-treated patients without disease progression. In this podcast, we discuss the evolving role of platinum-based chemotherapy in this disease setting in the context of EV-302 trial results and describe practical considerations in patients receiving first-line cisplatin- or carboplatin-based chemotherapy followed by avelumab maintenance therapy.