Antibody-Drug Conjugates in Oncology: Breakthroughs, Clinical Updates, and Pipeline Innovation

Revolutionizing Cancer Therapy: The Rise of Antibody‑Drug Conjugates (ADCs)

Antibody-drug conjugates (ADCs) are transforming the landscape of cancer treatment by combining the targeting precision of monoclonal antibodies with the potent cell-killing ability of cytotoxic drugs. This innovative approach enables selective delivery of chemotherapy directly to tumor cells, minimizing damage to healthy tissues and reducing systemic toxicity. With over a dozen ADCs already approved and dozens more in clinical development, this class of therapeutics is reshaping treatment paradigms across various malignancies.

The appeal of ADCs lies in their unique structure: an antibody directed against a tumor-specific antigen, a cytotoxic payload, and a specialized linker that ensures controlled drug release. Early-generation ADCs struggled with stability and safety, but newer platforms such as those incorporating cleavable linkers and highly potent payloads have demonstrated improved efficacy and manageable toxicity profiles.

Recent ADC breakthroughs in breast cancer (e.g., trastuzumab deruxtecan), lymphomas (e.g., polatuzumab vedotin), and urothelial carcinoma (e.g., enfortumab vedotin) exemplify their clinical impact. As research advances, ADCs are being explored in combination regimens, bispecific antibody strategies, and novel indications like prostate and lung cancer. The rise of ADCs represents a powerful step forward in precision oncology, offering patients more effective and tailored treatment options with the potential for better outcomes.

Recent Advances in ADC Therapies for Breast Cancer

Antibody-drug conjugates (ADCs) are significantly reshaping the treatment landscape in breast cancer, particularly through breakthroughs in HER2-targeted and HER2-low subtypes. One of the most notable advancements is trastuzumab deruxtecan, which has demonstrated impressive results across multiple trials. Initially approved for HER2-positive breast cancer, this ADC has now shown substantial benefits in patients with HER2-low expression, marking a new classification and treatment option in metastatic breast cancer. Clinical trials have shown superior progression-free and overall survival compared to traditional chemotherapy and earlier ADCs.

In hormone receptor–positive, HER2-negative metastatic breast cancer, datopotamab deruxtecan represents another major step forward. This ADC targets TROP2 and has recently demonstrated significantly improved progression-free survival in patients previously treated with endocrine therapy and chemotherapy. Its favorable response rates and manageable toxicity profile make it a compelling option in heavily pretreated populations.

These developments are redefining breast cancer subtypes and opening new avenues for treatment personalization. The ability of ADCs to target previously untreatable or refractory tumors with precision while minimizing systemic toxicity is shifting therapeutic strategies. As more data emerge, especially in earlier lines of therapy, ADCs are poised to become central pillars in the management of both HER2-positive and HER2-low breast cancers.

Trastuzumab Deruxtecan (Enhertu): A HER2-Targeted Game Changer in Breast Cancer

Trastuzumab deruxtecan, marketed as Enhertu, has emerged as a groundbreaking antibody-drug conjugate (ADC) in the treatment of HER2-expressing breast cancers. Designed to target the HER2 receptor with high precision, Enhertu combines a humanized anti-HER2 monoclonal antibody with a topoisomerase I inhibitor payload, linked by a cleavable, stable linker. This allows for potent cytotoxic activity directly within cancer cells while minimizing damage to surrounding healthy tissue.

Its clinical performance has exceeded expectations, particularly in patients with HER2-positive metastatic breast cancer who have progressed after prior HER2-directed therapies. Enhertu has demonstrated significantly longer progression-free and overall survival compared to trastuzumab emtansine (T-DM1), positioning it as the new standard of care in this setting. Remarkably, it has also shown efficacy in patients with low HER2 expression, redefining traditional HER2 classifications and expanding treatment access to a broader patient population.

The success of Enhertu lies in its high drug-to-antibody ratio, efficient internalization, and the ability to induce a bystander killing effect. While interstitial lung disease remains a notable toxicity concern, careful monitoring and prompt management have allowed for continued safe use. Enhertu represents a transformative shift in HER2-targeted therapy and underscores the potential of next-generation ADCs in breast oncology.

Polatuzumab Vedotin in DLBCL: A Critical Resource for Physicians

Polatuzumab vedotin is a CD79b-targeted antibody-drug conjugate (ADC) that has become a pivotal therapeutic option for patients with diffuse large B-cell lymphoma (DLBCL), particularly those with relapsed or refractory disease. It combines a monoclonal antibody targeting CD79b, a B-cell–specific surface protein with the microtubule-disrupting agent monomethyl auristatin E (MMAE), delivered via a cleavable linker that facilitates targeted intracellular cytotoxicity.

Polatuzumab vedotin has shown significant efficacy in combination with bendamustine and rituximab (Pola-BR), demonstrating improved response rates and prolonged survival compared to standard treatments in heavily pretreated DLBCL patients. In newly diagnosed DLBCL, its integration into frontline therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) has yielded promising results, offering an alternative to traditional R-CHOP regimens.

The manageable safety profile, with common adverse effects including peripheral neuropathy, cytopenias, and gastrointestinal symptoms, allows for its use in older or frail patients who are not candidates for intensive chemotherapy or stem cell transplant.

For physicians, polatuzumab vedotin provides a targeted, effective, and increasingly versatile tool in DLBCL management. As ongoing studies continue to refine its optimal combinations and sequencing, it is becoming a cornerstone in the evolving therapeutic landscape of aggressive B-cell lymphomas.

Datopotamab Deruxtecan for HR+ HER2‑ Breast Cancer: New Hope for a Difficult Subtype

Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate that offers renewed hope for patients with hormone receptor–positive (HR+), HER2-negative breast cancer, a subtype that becomes increasingly difficult to treat after resistance to endocrine therapies and chemotherapy develops. This ADC targets TROP2, a transmembrane glycoprotein commonly overexpressed in breast cancer cells, and delivers a potent topoisomerase I inhibitor via a tumor-cleavable linker.

In clinical trials, datopotamab deruxtecan has demonstrated significantly improved progression-free survival compared to standard chemotherapy in patients with previously treated HR+ HER2‑ breast cancer. Importantly, it offers a targeted alternative with higher response rates and fewer treatment-related toxicities than conventional cytotoxic agents. The ADC's favorable pharmacokinetics and potent bystander killing effect enhance its activity even in tumors with heterogeneous TROP2 expression.

While side effects such as stomatitis, nausea, fatigue, and neutropenia are observed, they are generally manageable with supportive care and dose adjustments. Interstitial lung disease remains a known risk and requires vigilant monitoring.

Datopotamab deruxtecan’s approval marks a pivotal milestone in ADC therapy for breast cancer, addressing a significant treatment gap in HR+ HER2‑ disease. Its success highlights the expanding potential of ADCs in solid tumors and supports further exploration across additional breast cancer subtypes.

Targeting c-Met in NSCLC: The Promise of Telisotuzumab Vedotin

Telisotuzumab vedotin is an investigational antibody-drug conjugate (ADC) designed to target c-Met, a receptor tyrosine kinase that is frequently overexpressed in non-small cell lung cancer (NSCLC) and associated with tumor growth, invasion, and poor prognosis. This ADC consists of a c-Met-targeting monoclonal antibody linked to the potent cytotoxic agent monomethyl auristatin E (MMAE) via a cleavable linker, allowing for selective delivery of chemotherapy to c-Met–expressing tumor cells.

Telisotuzumab vedotin has shown promising activity in patients with advanced NSCLC, particularly those with high c-Met expression and no targetable EGFR or ALK mutations. Early-phase clinical trials have demonstrated encouraging response rates, even in heavily pretreated patients. Its mechanism of action is especially valuable in cases where MET amplification or overexpression contributes to resistance to standard therapies.

Adverse events are generally consistent with other MMAE-based ADCs, including peripheral neuropathy, fatigue, and gastrointestinal symptoms. However, the toxicity profile is manageable with appropriate dose modifications and monitoring.

As research advances, telisotuzumab vedotin holds potential as a precision therapy for a biomarker-defined NSCLC subgroup. If ongoing trials confirm its efficacy and safety, it could become an important addition to the targeted treatment landscape for lung cancer.

177Lu‑PSMA Radioligand vs ADCs in Prostate Cancer: A Comparative Outlook

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) is rapidly evolving, with two novel targeted strategies gaining traction: 177Lu-PSMA radioligand therapy and antibody-drug conjugates (ADCs). Both modalities aim to deliver cytotoxic agents directly to cancer cells while sparing healthy tissue, but their mechanisms and clinical profiles differ significantly.

177Lu-PSMA is a radioligand therapy that targets the prostate-specific membrane antigen (PSMA), highly expressed on prostate cancer cells. Upon binding, the attached radioactive isotope, lutetium-177, emits beta particles that induce DNA damage and cell death. This approach has shown substantial efficacy in mCRPC patients who have progressed after androgen receptor–targeted therapies and chemotherapy, improving both progression-free and overall survival.

In contrast, ADCs in prostate cancer though still largely investigational use monoclonal antibodies to deliver potent chemotherapy drugs directly to surface antigens like PSMA, STEAP1, or Trop-2. While ADCs have shown promising early-phase results, including antitumor activity and manageable toxicity, none are yet approved for prostate cancer.

Comparatively, 177Lu-PSMA offers a validated, systemically delivered radiotherapeutic option with established benefits, whereas ADCs present an exciting future avenue for highly specific, cytotoxic delivery. Both represent precision medicine strategies, but radioligands currently lead the way in late-stage prostate cancer treatment.

Trends in the Oncology ADC Development Pipeline: What’s Next?

The oncology antibody-drug conjugate (ADC) development pipeline is expanding rapidly, reflecting a growing recognition of ADCs as a cornerstone in targeted cancer therapy. Current trends point toward greater refinement in antibody engineering, payload selection, and linker stability enhancements that aim to improve efficacy while minimizing toxicity.

One major shift is the movement beyond traditional targets like HER2 and CD30, toward novel antigens such as TROP2, c-Met, HER3, and B7-H3. This diversification is broadening the utility of ADCs across hard-to-treat solid tumors, including triple-negative breast cancer, lung cancer, and prostate cancer. Additionally, there’s a growing focus on tumor-selective targets and biomarker-driven development, ensuring better patient selection and treatment response.

New payload classes are also being explored beyond microtubule inhibitors such as DNA-damaging agents and immune-stimulating compounds, offering alternative mechanisms of action. Improved linker technologies are enabling site-specific conjugation and controlled drug release, which enhances stability and reduces off-target effects.

Another key trend is combining ADCs with immune checkpoint inhibitors or bispecific antibodies, aiming to leverage synergistic anti-tumor effects. As clinical trial results continue to validate these strategies, ADCs are poised to become not only salvage therapies but also frontline options in various cancers. The pipeline’s future is one of precision, potency, and expanded indications.

Next-Generation Cytotoxic Payloads and Linkers: Driving ADC Performance Forward

Advancements in cytotoxic payloads and linker technologies are central to the evolution of next-generation antibody-drug conjugates (ADCs). These components determine not only the potency of the therapeutic payload but also its precision, safety, and therapeutic index key factors that influence clinical success.

Next-generation payloads are moving beyond traditional microtubule inhibitors like monomethyl auristatin E (MMAE) and maytansinoids. New classes include DNA alkylating agents, topoisomerase I inhibitors, and pyrrolobenzodiazepine (PBD) dimers. These agents are ultra-potent and designed to overcome resistance mechanisms, enhance tumor cell kill, and induce immunogenic cell death. Importantly, some of these payloads also exhibit a bystander killing effect, allowing the destruction of neighboring tumor cells with low or heterogeneous target expression.

Equally transformative are advances in linker technology. Modern linkers are more stable in circulation but release their payload efficiently in the tumor microenvironment or within target cells upon internalization. Cleavable linkers sensitive to enzymatic activity, pH changes, or redox conditions are being fine-tuned for optimal performance. Site-specific conjugation techniques are also improving drug-to-antibody ratio consistency and reducing off-target effects.

Together, these innovations in payloads and linkers are propelling ADCs toward greater efficacy, safety, and versatility across a growing range of solid and hematologic malignancies.

Combining ADCs with Bispecific Antibodies: Synergistic Strategies in Clinical Trials

The combination of antibody-drug conjugates (ADCs) with bispecific antibodies is an emerging strategy in oncology aimed at enhancing tumor cell kill through complementary mechanisms. While ADCs deliver potent cytotoxic agents directly to tumor cells, bispecific antibodies simultaneously engage immune cells particularly T cells with cancer-associated antigens, promoting targeted immune-mediated destruction.

This dual-targeted approach is gaining traction in clinical trials, particularly in hematologic malignancies and solid tumors that exhibit resistance to monotherapy. For example, in B-cell malignancies, ADCs targeting CD79b or CD22 are being evaluated in combination with bispecific T-cell engagers directed at CD3 and CD20. The rationale is to use the ADC for direct tumor debulking while the bispecific antibody recruits the immune system for sustained surveillance and elimination of residual disease.

In solid tumors, clinical studies are exploring the pairing of HER2-targeted ADCs with bispecific antibodies that activate immune checkpoints or redirect T cells to HER2-positive cells. This synergistic approach may not only enhance efficacy but also overcome tumor heterogeneity and immune evasion.

Challenges remain, including potential overlapping toxicities and immunogenicity, but preliminary results are promising. This combination strategy represents a novel frontier in cancer therapy, with the potential to redefine treatment paradigms for refractory and high-risk malignancies.

Roche’s Latest ADC Clinical Trials: Key Insights for Oncologists

Roche continues to strengthen its oncology ADC portfolio through strategic partnerships and innovative trials, offering fresh hope across multiple cancer types.

1. Collaborations expanding novel ADC targets

• In early 2025, Roche secured exclusive global rights to Innovent Biologics' DLL3‑targeting ADC IBI3009, now in Phase I studies for small cell lung cancer (SCLC) and neuroendocrine tumors. Roche invested $80 million upfront, with potential milestones up to $1 billion.
• Roche also partnered with MediLink Therapeutics to develop YL211 (also known as RG6648), a c‑Met‑targeting ADC entering Phase I trials for solid tumors.

2. Combination trials enhancing lymphoma outcomes
Data from Roche’s Phase III SUNMO trial show that combining its bispecific antibody mosunetuzumab (Lunsumio) with its ADC polatuzumab vedotin (Polivy) resulted in a progression‑free survival of 11.5 months compared with 3.8 months via standard R‑GemOx chemotherapy in second‑line large B‑cell lymphoma. That reflects a 59% reduction in risk of progression or death, with fewer treatment‑related fatalities.

3. Diagnostic innovation meets precision therapy
Roche’s PATHWAY HER2 (4B5) companion diagnostic has recently gained FDA approval to identify patients with HER2-ultralow metastatic breast cancer who may benefit from treatment with trastuzumab deruxtecan (Enhertu). This marks an important expansion of its HER2-low diagnostic platform in recognition of evolving biomarker definitions.

In summary, Roche’s ongoing ADC trial programs highlight a multipronged strategy: acquiring assets targeting novel tumor antigens, combining ADCs with immune-engaging bispecific antibodies to boost response rates, and leveraging companion diagnostics to perfect patient selection.

AstraZeneca’s Push in Breast Oncology: ADC Milestones and News

AstraZeneca, in collaboration with Daiichi Sankyo, continues to lead the antibody-drug conjugate (ADC) space in breast oncology, primarily through the success of trastuzumab deruxtecan (Enhertu). Enhertu has achieved multiple milestones, solidifying its role in HER2-targeted therapy and expanding its reach to HER2-low and HER2-ultralow breast cancer.

A major advancement came with Enhertu’s FDA label expansion to include hormone receptor–positive, HER2-low and HER2-ultralow metastatic breast cancer patients who progressed on endocrine therapy. Clinical data demonstrated superior progression-free survival and higher objective response rates compared to chemotherapy, offering a much-needed option for a previously underserved group.

Additionally, in the first-line setting for HER2-positive metastatic disease, Enhertu combined with pertuzumab showed significantly improved outcomes compared to standard THP therapy. This may lead to regulatory filings for front-line use, further expanding its clinical footprint.

On the commercial front, Enhertu’s global sales continue to grow, driven by increased recognition and updated clinical guidelines. Meanwhile, AstraZeneca is also advancing datopotamab deruxtecan, a TROP2-targeting ADC, for HR-positive, HER2-negative breast cancer. Although overall survival results are still maturing, early data are encouraging.

Together, these developments underscore AstraZeneca’s strategic focus on redefining ADC use across the breast cancer continuum.

Daiichi Sankyo’s Expanding ADC Portfolio: Data-Driven Development

Daiichi Sankyo, in close partnership with AstraZeneca, has rapidly expanded its antibody‑drug conjugate (ADC) pipeline, leveraging deep biological insights and robust clinical data to drive innovation in oncology.

Core Asset: Trastuzumab Deruxtecan (Enhertu)
Enhertu is the flagship ADC co-developed by Daiichi Sankyo and AstraZeneca. Initially approved for HER2-positive metastatic breast cancer, it has since been shown to benefit patients with HER2-low and HER2-ultralow expression, significantly improving progression‑free and overall survival over chemotherapy. Its high drug‑to‑antibody ratio and powerful topoisomerase‑I payload underpin consistent clinical success.

Leading Variant: Datopotamab Deruxtecan (Dato‑DxD)
Datopotamab Deruxtecan targets TROP‑2 and is positioned for patients with hormone receptor–positive, HER2-negative breast cancer who have exhausted endocrine therapy. Clinical trial data demonstrate notable improvements in progression-free survival and response rates in heavily pretreated populations. While overall survival results await maturation, its response and tolerability profile make it a strong contender.

Emerging ADCs and Novel Targets
Daiichi Sankyo is broadening its ADC portfolio with emerging programs against targets such as Trop‑2, HER3, and others across solid tumors including lung and gastric cancers. These experimental ADCs employ next‑generation payloads such as DNA alkylators and immune‑stimulating agents and highly stable, tumor‑responsive linkers to balance potency with safety.

Data-Driven Strategy and Development
The company’s approach integrates biomarker-based patient selection, adaptive Phase II/III designs, and companion diagnostics to optimize clinical outcomes. This calibrated strategy rooted in pharmacology and translational science, is establishing Daiichi Sankyo as an ADC innovator poised to address treatment gaps across diverse cancer subtypes.

Daiichi Sankyo’s pipeline exemplifies a transition from single‑target ADCs to a diversified, precision‑driven portfolio grounded in deep data and cutting‑edge biology.

Managing ADC Toxicities: A Practical Guide for Physicians on Prevention and Response

Antibody-drug conjugates (ADCs) have transformed oncology care by selectively delivering cytotoxic agents to tumor cells. However, their complex structure and potent payloads also present unique toxicity profiles that require proactive management by clinicians.

Common ADC-Related Toxicities
The most frequent adverse effects include hematologic toxicities (neutropenia, thrombocytopenia), gastrointestinal issues (nausea, diarrhea), and fatigue. Certain ADCs such as those with topoisomerase I inhibitors are associated with interstitial lung disease (ILD) or pneumonitis, requiring high clinical vigilance. Skin rash and ocular toxicity are more common with TROP2- and nectin-4-targeting ADCs.

Prevention Strategies
Pre-treatment assessments should include baseline organ function tests, pulmonary evaluations, and detailed medication histories to identify potential risk factors. Dose modifications, scheduled monitoring, and supportive care (e.g., growth factor support, antiemetics) are essential to mitigate anticipated toxicities.

Early Recognition and Intervention
Timely identification of symptoms such as new-onset cough, dyspnea, or vision changes is critical. Early-grade toxicities may respond to corticosteroids, dose holds, or reductions, while severe reactions often necessitate permanent discontinuation.

By combining vigilant monitoring with patient education and multidisciplinary care, physicians can effectively manage ADC toxicities ensuring treatment continuity while minimizing harm in an increasingly ADC-driven oncology landscape.
Read more such content on @ Hidoc Dr | Medical Learning App for Doctors