HER2-targeting Antibody-drug Conjugate Research Articles

Incidence of HER2-targeted antibody-drug conjugates-related cardiac events: a meta-analysis.

Background: Human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) has emerged as a hotspot for research and brought breakthroughs in the treatment of breast cancer and other solid tumors. While the occurrence of cardiac events (CEs) has yet not been systematically reported. Methods: The prospective clinical trials of marketed HER2-targeted ADCs were systematically searched in PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception to May 2023. Two investigators independently extracted data with priority given to ClinicalTrials.gov, followed by peer-reviewed articles. Stata 15.0 software was used to perform the meta-analysis. The effect statistics were estimated as pooled incidence with 95% confidence intervals (CI). The primary objectives were to assess the incidence of all-grade and ≥3 /serious grades CEs related to HER2-targeted ADC. Our study strictly adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and has been registered on PROSPERO (NO. CRD42023440448). Results: After conducting a comprehensive literature search, initially 7000 relevant studies were identified, and eventually a total of 47 trials involving 10594 patients were included for analysis. The pooled incidence of all-grade and ≥3/serious grades CEs respectively were 4.7% [95% CI, 3.7-5.8%] and 0.6% (95% CI, 0.5-0.8%). The pooled incidence of CEs leading to dosage discontinuation was 0.8% (95% CI, 0.4-1.3%). Subgroup analysis revealed a significantly higher incidence of all-grade CEs in T-DXd treatment compared to T-DM1 treatment (7.7% versus 3.6%; p=0.017), as well as in phase I/II trials compared to phase III trials (6.9% versus 3.2%; p=0.002) and combination therapy compared to monotherapy (7.6% versus 3.9%; p=0.013). The electrocardiogram QT corrected interval prolonged was identified as the CE with the highest pooled incidence, occurring at a rate of 5.9% (95% CI, 3.3-8.5%). Conclusions: The incidence of CEs associated with HER2-targeted ADC is relatively low. However, it is crucial to enhance surveillance measures, particularly for T-DXd treatment and combination therapy.

Generation and Characterization of SORT1-Targeted Antibody-Drug Conjugate for the Treatment of SORT1-Positive Breast Tumor.

Antibody-drug conjugates (ADCs) have greatly improved the outcomes of advanced breast tumors. However, the treatment of breast tumors with existing ADCs is still hindered by many issues, such as tumor antigen heterogeneity and drug resistance. Therefore, ADCs against new targets would provide options for the treatment of these challenges. Sortilin-1 (SORT1) may be a promising target for ADC as it is upregulated in breast cancer. To evaluate the possibility of SORT1 as an ADC target, a humanized antibody_8D302 with high affinity against SORT1 was generated. Additionally, 8D302 was conjugated with MMAE and DXd to generate two ADCs_8D302-MMAE and 8D302-DXd, respectively. Both 8D302-MMAE and 8D302-DXd showed effective cytotoxicity against SORT1 positive breast tumor cell lines and induced bystander killing. Consequently, 8D302-MMAE showed relatively better anti-tumor activity than 8D302-DXd both in vitro and in vivo, but 8D302-DXd had superior safety profile and pharmacokinetics profile over 8D302-MMAE. Furthermore, SORT1 induced faster internalization and lysosomal trafficking of antibodies and had a higher turnover compared with HER2. Also, 8D302-DXd exhibited superior cell cytotoxicity and tumor suppression over trastuzumab-DXd, a HER2-targeted ADC. We hypothesize that the high turnover of SORT1 enables SORT1-targeted ADC to be a powerful agent for the treatment of SORT1-positive breast tumor.

Abstract B041: A phase 1 study of DS-8201a in combination with olaparib in HER2-expressing malignancies (CTEP #10355): Results of module 1 dose escalation

Abstract Background: DS-8201a is a HER2-targeting antibody drug conjugate with a topoisomerase 1 (top1) inhibitor payload. Preclinical evidence suggests that inhibiting PARP can potentiate top1 inhibitor-induced DNA damage and cytotoxicity. However, the clinical activity of combined top1-inhibiting chemotherapy and PARP inhibition has been limited by toxicity. We hypothesized that targeted delivery of a top1 inhibitor via DS-8201a may reduce systemic toxicity while maintaining synergistic cytotoxic activity in combination with olaparib. This combination is being investigated in the ongoing phase 1 trial CTEP #10355 (NCT04585958) in patients (pts) with advanced solid tumors expressing HER2. We present the safety analysis of pts enrolled to Module 1 (Mod 1) of dose escalation (continuous olaparib). Preliminary efficacy results are explored. Methods: Accrual was limited to pts ≥18 years old with advanced or recurrent solid tumors expressing HER2, defined as HER2 IHC ≥1+ (local testing allowed) or amplification of ERBB2 by NGS or ISH. In Mod 1, pts received DS-8201a IV once every 3 weeks and olaparib twice daily (BID) continuously in a 3+3 dose escalation design. Dose Level 1 (DL1) of Mod 1 evaluated DS-8201a dosed at 4.4mg/kg with olaparib 100mg BID Days 1-21. Dose Level 2 (DL2) of Mod 1 evaluated DS-8201a dosed at 5.4mg/kg with olaparib 100mg BID Days 1-21. The primary objective was to evaluate the safety and tolerability of combined DS-8201a + olaparib as graded by CTCAE v5. Secondary objectives include assessment of clinical activity as measured by objective response rate (ORR), clinical benefit rate (CBR; partial response [PR] + complete response [CR] + stable disease [SD] ≥6 months [mo]), median progression-free survival (PFS), and duration of response (DOR). Results: As of 30-Nov-2022, 10 pts were treated in Mod 1, with median age of 62.5 years. 10% were Asian, 10% were African American, and 80% were white. 40% had endometrial cancer and 60% had ovarian cancer. 6 of 7 pts treated on DL1 were DLT-evaluable, of which 1 patient experienced a DLT of Grade (G) 4 neutropenia. All 3 pts in DL2 were DLT-evaluable, and each experienced a DLT (2 pts with G4 febrile neutropenia, 1 pt with G4 neutropenia). Most common TRAEs in Mod 1 included: ANC decrease (60% G4, 20% G3, 20% G1/2), platelet count decrease (20% G4, 20% G3, 40% G1/2), and anemia (70% G3, 20% G1/2). All Mod 1 pts required dose holds, dose reductions, and/or discontinuation of olaparib. Of the 10 pts in Mod 1, 40% achieved a RECIST response (1 CR, 3 PR). 40% had SD lasting ≥6 mo, for a CBR of 80%. Median PFS is estimated at 7.4 mo (95% CI 4.7mo-not reached), with 7 patients alive and progression-free at 6 mo. Conclusion: Continuous dosing of olaparib in combination with DS-8201a yielded an unacceptable safety profile and dose escalation in Mod 1 was not continued. An alternative dosing schedule was initiated in Module 2 (Mod 2) evaluating DS-8201a IV every 3 weeks and olaparib BID Days 8-14; accrual to Mod 2 is ongoing. There is preliminary evidence of clinical activity of this combination. Citation Format: Elizabeth K. Lee, Andrea E. Wahner Hendrickson, Gerardo Colon-Otero, Cheryl A. Pickett, Niya Xiong, Su-Chun Cheng, Madeline Polak, Hannah Sawyer, Martin Hayes, Ursula A. Matulonis, Geoffrey I. Shapiro, Panagiotis A. Konstantinopoulos. A phase 1 study of DS-8201a in combination with olaparib in HER2-expressing malignancies (CTEP #10355): Results of module 1 dose escalation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B041.

Abstract LB_A22: Advancing personalized therapies for small cell lung cancer: Exploring HER2-targeting antibody-drug conjugates (ADCs) and SLFN11 biomarker insights

Abstract Background: Small-cell lung cancer (SCLC) is a highly aggressive malignancy constituting 15% of all lung cancers, with a 5-year survival rate of less than 7%. Our group has established four transcriptionally defined subtypes of SCLC, each with distinct cell surface targets (Gay et al, Cancer Cell 2021). Further, we identified SLFN11 (a putative DNA/RNA helicase) as a candidate biomarker of sensitivity to DNA-damaging agents, including topoisomerase I inhibitors. Despite these advances, SCLC is still treated clinically with a “one-size-fits-all” approach. Human epidermal growth factor receptor 2 (HER2/ERBB2) has been previously described in a subset of SCLCs and has been linked to poor prognosis. Notably, HER2-targeting antibody-drug conjugates (ADCs) like Trastuzumab Deruxtecan (T-DXd) (where the payload is a topoisomerase I inhibitor) have received FDA approval for various solid tumors, highlighting their therapeutic potential. Methods: We analyzed ERBB2 mRNA expression in publicly available patient datasets and profiled HER2 protein expression in cell lines and patient-derived xenograft models by flow cytometry and IHC. We then assessed the cytotoxicity of Trastuzumab Deruxtecan in a panel of cell lines representative of the heterogeneity of SCLC to test whether levels of HER2 and/or SLFN11 predicted response. Results: Analyses of HER2/ERBB2 in SCLC cell lines and patient-derived xenograft (PDX) models revealed an enrichment in the SCLC-POU2F3 (SCLC-P) subtype. HER2 expression was validated by IHC and flow cytometry in a subset of SCLC cell lines and PDX models. ERBB2 mRNA expression data was analyzed using publicly available SCLC patient datasets, where we uncovered high expression of ERBB2 in a subset of patient tumors. Consistent with this, single-cell RNA-Seq data revealed ERBB2 expression in POU2F3+ cells in tumors from patients with relapsed SCLC. As predicted, we found a strong correlation between the in vitro cytotoxicity of Trastuzumab Deruxtecan and both the level of surface HER2 expression and SLFN11 level. Importantly, the SCLC cell lines with the highest HER2 surface expression exhibited the lowest IC50 of Trastuzumab Deruxtecan, and the response was predicted by the presence of SLFN11. Conclusion: We demonstrate HER2/ERBB2 mRNA and protein expression in a subset of SCLC, with enrichment in the SCLC-P subtype. Further, the FDA-approved HER2-targeting ADC Trastuzumab Deruxtecan had significant cytotoxicity, correlating with expression of the surface target (HER2) as well as with SLFN11 (a candidate predictive biomarker for the topoisomerase inhibitor payload). These findings suggest the potential of tailoring HER2-targeting strategies based on HER2 and SLFN11 expression in SCLC as an effective and personalized approach for tackling SCLC. Citation Format: Ali H. Ibrahim, Bingnan Zhang, C. Allison Stewart, Alejandra Serrano, Luisa M. Solis, Wei-Lien Wang, Kavya Ramkumar, Robert J. Cardnell, Runsheng Wang, Alberto Duarte Jr, Lixia Diao, Yuanxin Xi, Jing Wang, Lauren A. Byers, Carl M. Gay. Advancing personalized therapies for small cell lung cancer: Exploring HER2-targeting antibody-drug conjugates (ADCs) and SLFN11 biomarker insights [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A22.

Macrolide and Ketolide Antibiotics Inhibit the Cytotoxic Effect of Trastuzumab Emtansine in HER2-Positive Breast Cancer Cells: Implication of a Potential Drug-ADC Interaction in Cancer Chemotherapy.

Macrolides are widely used for the long-term treatment of infections and chronic inflammatory diseases. The pharmacokinetic features of macrolides include extensive tissue distribution because of favorable membrane permeability and accumulation within lysosomes. Trastuzumab emtansine (T-DM1), a HER2-targeting antibody-drug conjugate (ADC), is catabolized in the lysosomes, where Lys-SMCC-DM1, a potent cytotoxic agent, is processed by proteinase degradation and subsequently released from the lysosomes to the cytoplasm through the lysosomal membrane transporter SLC46A3, resulting in an antitumor effect. We recently demonstrated that erythromycin and clarithromycin inhibit SLC46A3 and attenuate the cytotoxicity of T-DM1; however, the effect of other macrolides and ketolides has not been determined. In this study, we evaluated the effect of macrolide and ketolide antibiotics on T-DM1 cytotoxicity in a human breast cancer cell line, KPL-4. Macrolides used in the clinic, such as roxithromycin, azithromycin, and josamycin, as well as solithromycin, a ketolide under clinical development, significantly attenuated T-DM1 cytotoxicity in addition to erythromycin and clarithromycin. Of these, azithromycin was the most potent inhibitor of T-DM1 efficacy. These antibiotics significantly inhibited the transport function of SLC46A3 in a concentration-dependent manner. Moreover, these compounds extensively accumulated in the lysosomes at the levels estimated to be 0.41-13.6 mM when cells were incubated with them at a 2 μM concentration. The immunofluorescence staining of trastuzumab revealed that azithromycin and solithromycin inhibit the degradation of T-DM1 in the lysosomes. These results suggest that the attenuation of T-DM1 cytotoxicity by macrolide and ketolide antibiotics involves their lysosomal accumulation and results in their greater lysosomal concentrations to inhibit the SLC46A3 function and T-DM1 degradation. This suggests a potential drug-ADC interaction during cancer chemotherapy.

Generation of a Novel SORT1×HER2 Bispecific Antibody-Drug Conjugate Targeting HER2-Low-Expression Tumor.

Human epidermal growth factor receptor 2 (HER2) is considered an ideal antibody-drug conjugate (ADC) target because the gene is overexpressed in many tumors compared to normal tissues. Multiple anti-HER2 ADCs conjugated with different toxic payloads bring benefits to patients with high HER2 expression. However, HER2-targeted ADC technology needs further optimization to improve its effect for the treatment of patients with low HER2 expression. We hypothesized that bispecific antibody-drug conjugate (bsADC) targeting HER2 and Sortilin-1 (SORT1) would overcome this limitation. SORT1 is a suitable target for pairing with HER2 to generate a bispecific antibody (BsAb) since the gene is co-expressed with HER2 in tumors and possesses rapid internalization. We developed a BsAb (bsSORT1×HER2) that exhibited strong binding and internalization activity on HER2-low-expression tumor cells and facilitated higher HER2 degradation. The bsSORT1×HER2 was further conjugated with DXd to generate a bsADC (bsSORT1×HER2-DXd) that showed strong cytotoxicity on HER2-low-expression tumor cells and antitumor efficacy in an MDA-MB-231 xenograft mice model. These results demonstrated that employment of a SORT1×HER2-targeted bsADC may be promising to improve the antitumor efficacy of HER2-targeted ADC for the treatment of tumors with low HER2 expression.

Antibody-Drug Conjugates (ADC) in HER2/neu-Positive Gynecologic Tumors.

Antibody-drug conjugates (ADCs) are a new class of targeted anti-cancer therapies that combine a monoclonal tumor-surface-receptor-targeting antibody with a highly cytotoxic molecule payload bonded through specifically designed cleavable or non-cleavable chemical linkers. One such tumor surface receptor is human epidermal growth factor 2 (HER2), which is of interest for the treatment of many gynecologic tumors. ADCs enable the targeted delivery of a variety of cytotoxic therapies to tumor cells while minimizing delivery to healthy tissues. This review summarizes the existing literature about HER2-targeting ADC therapies approved for use in gynecologic malignancies, relevant preclinical studies, strategies to address ADC resistance, and ongoing clinical trials.

HER2-targeted antibody-drug conjugates: no increase in risk of fatal AEs

HER2-targeted antibody-drug conjugates: no increase in risk of fatal AEs

Analytical and clinical validation of PATHWAY Anti-HER-2/neu (4B5) antibody to assess HER2-low status for trastuzumab deruxtecan treatment in breast cancer

In DESTINY-Breast04 (DB-04), safety and efficacy of HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in previously treated HER2-low unresectable/metastatic breast cancer were established. This manuscript describes the analytical validation of PATHWAY Anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (PATHWAY HER2 (4B5)) to assess HER2-low status and its clinical performance in DB-04. Preanalytical processing and tissue staining parameters were evaluated to determine their impact on HER2 scoring. The recommended antibody staining procedure provided the optimal tumor staining, and deviations in cell conditioning and/or antibody incubation times resulted in unacceptable negative control staining and/or HER2-low status changes. Comparisons between antibody lots, kit lots, instruments, and day-to-day runs showed overall percent agreements (OPAs) exceeding 97.9%. Inter-laboratory reproducibility showed OPAs of ≥97.4% for all study endpoints. PATHWAY HER2 (4B5) was utilized in DB-04 for patient selection using 1340 tumor samples (59.0% metastatic, 40.7% primary, (0.3% missing data); 74.3% biopsy, 25.7% resection/excisions). Overall, 77.6% (823/1060) of samples were HER2-low by both central and local testing, with the level of concordance differing by sample region of origin and collection date. In DB-04, the efficacy of T-DXd over chemotherapy of physician’s choice was consistent, regardless of the characteristics of the sample used (primary or metastatic, archival, or newly collected, biopsy or excision/resection). These results demonstrate that PATHWAY HER2 (4B5) is precise and reproducible for scoring HER2-low status and can be used with multiple breast cancer sample types for reliably identifying patients whose tumors have HER2-low expression and are likely to derive clinical benefit from T-DXd.

A HER2-targeted Antibody-Drug Conjugate, RC48-ADC, Exerted Promising Antitumor Efficacy and Safety with Intravesical Instillation in Preclinical Models of Bladder Cancer.

More than half of non-muscle-invasive bladder cancer (NMIBC) patients eventually relapse even if treated with surgery and BCG without optional bladder-preserving therapy. This study aims to investigate the antitumor activity and safety of a HER2-targeted antibody-drug conjugate, RC48-ADC, intravesical instillation for NMIBC treatment. In this preclinical study, itis revealed that human epidermal growth factor receptor 2 (HER2) expression scores of 1+, 2+, and 3+ are recorded for 16.7%, 56.2%, and 14.6% of NMIBC cases. The antitumor effect of RC48-ADC is positively correlated with HER2 expression in bladder cancer (BCa) cell lines and organoid models. Furthermore, RC48-ADC is revealed to exert its antitumor effect by inducing G2/M arrest and caspase-dependent apoptosis. In an orthotopic BCa model, tumor growth is significantly inhibited by intravesical instillation of RC48-ADC versus disitamab, monomethyl auristatin E, epirubicin, or phosphate-buffered saline control. The potential toxicity of intravesical RC48-ADC is also assessed by dose escalation in normal nude mice and revealed that administration of RC48-ADC by intravesical instillation is safe within the range of effective therapeutic doses. Taken together, RC48-ADC demonstrates promising antitumor effects and safety with intravesical administration in multiple preclinical models. These findings provide a rational for clinical trials of intravesical RC48-ADC in NMIBC patients.

Incidence and risk of fatal adverse events in cancer patients treated with HER2-targeted antibody-drug conjugates: a systematic review and meta-analysis of randomized controlled trials

ObjectiveAntibody-drug conjugates (ADCs) that target human epidermal growth factor receptor 2 (HER2) are leading a new era of targeted cancer therapy. These drugs have also been associated with several fatal adverse events, such as pneumonia, interstitial lung disease, and infection. We performed a meta-analysis of randomized controlled trials (RCTs) to estimate the incidence and risk of fatal adverse events in cancer patients treated with HER2-targeted ADCs.MethodsWe performed a systematic search in Embase, PubMed, Web of Science, and Scopus databases from inception to February 1, 2022, and the last search was updated to July 1, 2023. The eligible studies for inclusion in our analysis were limited to RCTs of HER2-targeted ADCs that were approved by the US Food and Drug Administration and examined on cancer patients with available data on fatal adverse events. The protocol for this study was registered in PROSPERO (No. CRD42022331627).ResultsFifteen studies (13 RCTs) involving 7,277 patients were finally included for meta-analysis. Of these patients, 4,246 received HER2-targeted ADCs and 3,481 received the control treatment. The data were combined using Bayesian hierarchical modeling, which allowed for the estimation of the mean incidence of fatal adverse events to be 0.78% (95% CrI: 0.28-1.37%, τ = 0.006) for the patients treated with HER2-targeted ADCs. The relative risk was 0.80 (95% CrI, 0.5–1.26, τ = 0.17) compared to control patients. Among 43 reported deaths caused by HER2-targeted ADCs, the most common fatal adverse event was respiratory toxicity, including pneumonia, pneumonitis, and interstitial lung disease. On subgroup analysis, no difference in the risk of fatal adverse events was found between different HER2-targeted ADCs or cancer types.ConclusionOur findings suggest that the risk of fatal adverse events with HER2-targeted ADCs may be lower compared to standard control therapies in cancer patients, and there is no significant difference in risk observed between different HER2-targeted ADCs or cancer types. However, the most common fatal adverse event was respiratory toxicity, suggesting that cancer patients who use the above drugs should strengthen respiratory system monitoring and take preventive measures in some severe cases.

Leveraging TROP2 Antibody-Drug Conjugates in Solid Tumors.

Antibody-drug conjugates (ADCs) have become the cornerstone of effective therapeutics in solid and hematological malignancies by harnessing potent cytotoxic payloads with targeted tumoricidal delivery. Since the monumental shift occurred with HER2-targeted ADCs, the discovery of the TROP2 antigen has revolutionized the landscape of ADC development. Moving beyond the traditional ADC design, multiple novel ADCs have successfully shaped and improved survival outcomes in patients with various tumor histologies. Here we review and contrast the clinical impact of the well-known TROP2 ADCs currently in clinical use. We also shed light on upcoming investigational TROP2 ADCs showing promise with novel ADC platforms.

Her-2 promoting tumor progression and cisplatin resistance as a novel therapeutic target in penile squamous cell carcinoma.

67 Background: Cisplatin-based chemotherapy has been the first choice for advanced penile squamous cell carcinoma (PSCC) in the last decade, but remains challenging owing the unsatisfied response rates, frustrating systemic toxicity and chemoresistance leading to poor prognosis. There is no standard second-line therapy for advanced PSCC. Antibody-drug conjugates (ADC) were novel targeted and low-toxicity agents, of which Her-2 targeted ADCs widely used and have greatly improved clinical outcomes in breast, gastric and bladder cancers. We aimed to explore the expression pattern, clinical significance, oncogenic roles of Her-2 and the therapeutic potentiality of Her-2 target ADCs in PSCC. Methods: The immunohistochemical expression of Her-2 was detected in the largest single center cohort of 367 PSCC patients up to date. PSCC cell lines, cisplatin-resistant cell lines and animal models were established to investigated the biological roles of Her-2 in PSCC progression and cisplatin chemoresistance. Disitamab vedotin (RC48), an Her-2 targeted ADC drug, was used to evaluate the efficiency in PSCC. Results: Her-2 was an unfavourable prognostic indicator with around 47.7% immunohistochemical expression rate (1+, 23.2%; 2+, 18.0%; 3+, 6.5%) in PSCC. Her-2 positive immunohistochemical expression (2+/3+) was associated with advanced pT, pN stages, metastasis and poor overall survival (positive vs. negative, HR (95%Cl): 3.133 (2.120-4.631), p=0.000). Cellular and animal experiments confirmed that Her-2 promoted tumor progression, inhibited cisplatin-induced cell apoptosis via Akt pathways and increased cisplatin resistance in PSCC. Meanwhile, cisplatin-resistant PSCC cells up-regulated Her-2 expression. More importantly, Her-2 targeted ADCs Disitamab Vedotin displayed remarkable anti-tumor activities both in Her2-positive and cisplatin-resistant PSCC tumors. Conclusions: Our study suggested that Her-2 was an available therapeutic biomarker in PSCC. Targeting Her-2 ADCs might be a prospective option to improve clinical outcomes in high-risk Her-2 positive advanced PSCC patients and provided precious opportunity for cisplatin-based chemoresistance patients.

Antibody-Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence.

Antibody-drug conjugates (ADCs) are an innovative family of agents assembled through linking cytotoxic drugs (payloads) covalently to monoclonal antibodies (mAbs) to be delivered to tumor tissue that express their particular antigen, with the theoretical advantage of an augmented therapeutic ratio. As of June 2023, eleven ADCs have been approved by the Food and Drug Administration (FDA) and are on the market. These drugs have been added to the therapeutic armamentarium of acute myeloblastic and lymphoblastic leukemias, various types of lymphoma, breast, gastric or gastroesophageal junction, lung, urothelial, cervical, and ovarian cancers. They have proven to deliver more potent and effective anti-tumor activities than standard practice in a wide variety of indications. In addition to targeting antigen-expressing tumor cells, bystander effects have been engineered to extend cytotoxic killing to low-antigen-expressing or negative tumor cells in the heterogenous tumor milieu. Inevitably, myelosuppression is a common side effect with most of the ADCs due to the effects of the cytotoxic payload. Also, other unique side effects are specific to the tissue antigen that is targeted for, such as the cardiac toxicity with Her-2 targeting ADCs, and the hemorrhagic side effects with the tissue factor (TF) targeting Tisotumab vedotin. Further exciting developments are centered in the strategies to improve the tolerability and efficacy of the ADCs to improve the therapeutic window; as well as the development of novel payloads including (1) peptide-drug conjugates (PDCs), with the peptide replacing the monoclonal antibody, rendering greater tumor penetration; (2) immune-stimulating antibody conjugates (ISACs), which upon conjugation of the antigen, cause an influx of pro-inflammatory cytokines to activate dendritic cells and harness an anti-tumor T-cell response; and (3) the use of radioactive isotopes as a payload to enhance cytotoxic activity.

Thrombopoietin Receptor Agonists for Thrombocytopenia Secondary to HER2-Targeted Antibody Drug Conjugates.

Trastuzumab emtansine and trastuzumab deruxtecan are widely used in breast cancer and other solid tumor malignancies. Thrombocytopenia is a common adverse event associated with the use of these agents that can lead to a treatment delay, reduction in dose intensity, and discontinuation. The role of thrombopoietin receptor agonists (TPO-RA) remains unknown in this setting. We report a case series of 6 individuals with breast cancer that experienced dose-reductions and therapy delays due to thrombocytopenia secondary to trastuzumab emtansine or trastuzumab deruxtecan therapy and received intervention with TPO-RA. All 6 were able to resume therapy with TPO-RA support.

HER2-targeted antibody–drug conjugates for breast cancer: ancestry and dose adjustment for thrombocytopenia

BackgroundThrombocytopenia is a common adverse event on HER2-targeted therapies, fam-trastuzumab deruxtecan (T-DXd) and ado-trastuzumab emtansine (T-DM1). A reported association of Asian ancestry with this event merits investigation to rule out potential confounding.MethodsSubjects in this retrospective cohort were female patients with HER2 positive breast cancer, of Asian or non-Hispanic White ancestry, who initiated T-DM1 or T-DXd from January 2017 through October 2021. Follow-up closed in January 2022. Primary endpoint was dose adjustment for thrombocytopenia. Competing endpoints were discontinuation of drug for other toxicity, disease progression, or for completion of prescribed cycles. The association between Asian ancestry and thrombocytopenia-related dose adjustment was tested at p < 0.01 in a proportional hazards model for the sub-distributions of 4 (primary and competing) endpoints. Covariates examined as potential confounders were age, metastatic disease, specific HER2-targeted drug, and prior drug switching for toxicity.ResultsAmong 181 subjects, 48 reported Asian ancestry. Incidence of dose adjustment for thrombocytopenia was higher in patients with Asian ancestry and among patients switched to T-DXd after experiencing thrombocytopenia on T-DM1. Independent of specific drug and prior drug switching, Asian ancestry was associated with dose adjustment for thrombocytopenia (hazards ratio 2.95, 95% confidence interval 1.41–6.18) but not with competing endpoints. Among participants of Asian ancestry, the ancestral origin was usually China or the Philippines (where Chinese ancestry is common).ConclusionsThe association between Asian ancestry and thrombocytopenia on HER2-targeted therapy is independent of age, metastatic disease, drug, and history of similar toxicity. This association may have a genetic basis linked to Chinese ancestry.

Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study

Approximately 15-20% of advanced gastric and gastro-oesophageal junction cancers overexpress HER2. In DESTINY-Gastric01, the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan improved response and overall survival versus chemotherapy in patients from Japan and South Korea with locally advanced or metastatic HER2-positive gastric or gastro-oesophageal junction cancer whose disease progressed after two lines of previous therapy including trastuzumab. Here, we report primary and updated analyses of the single-arm, phase 2 DESTINY-Gastric02 trial, which aimed to examine trastuzumab deruxtecan in patients living in the USA and Europe. DESTINY-Gastric02 is a single-arm, phase 2 study in adult patients from 24 study sites in the USA and Europe (Belgium, Spain, Italy, and the UK). Eligible patients were aged at least 18 years and had an Eastern Cooperative Oncology Group performance status of 0 or 1, pathologically documented unresectable or metastatic gastric or gastro-oesophageal junction cancer, progressive disease on or after first-line therapy with a trastuzumab-containing regimen, with at least one measurable lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and centrally confirmed HER2-positive disease on a postprogression biopsy. Patients were given 6·4 mg/kg of trastuzumab deruxtecan intravenously every 3 weeks until disease progression, withdrawal by patient, physician decision, or death. The primary endpoint was confirmed objective response rate by independent central review. The primary endpoint and safety were assessed in the full analysis set (ie, participants who received at least one dose of study drug). Here, we report the primary analysis of this study, with a data cutoff of April 9, 2021, and an updated analysis, with a data cutoff of Nov 8, 2021. This trial is registered with ClinicalTrials.gov, NCT04014075, and is ongoing. Between Nov 26, 2019, and Dec 2, 2020, 89 patients were screened and 79 were enrolled and subsequently treated with trastuzumab deruxtecan (median age 60·7 years [IQR 52·0-68·3], 57 [72%] of 79 were male, 22 [28%] were female, 69 [87%] were White, four [5%] were Asian, one [1%] was Black or African American, one [1%] was Native Hawaiian or Pacific Islander, one had missing race, and three [4%] were other races). At the primary analysis (median follow-up 5·9 months [IQR 4·6-8·6 months]), confirmed objective response was reported in 30 (38% [95% CI 27·3-49·6]) of 79 patients, including three (4%) complete responses and 27 (34%) partial responses, as assessed by independent central review. As of data cutoff for the updated analysis (median follow-up 10·2 months [IQR 5·6-12·9]), a confirmed objective response was reported in 33 (42% [95% CI 30·8-53·4]) of 79 patients, including four (5%) complete responses and 29 (37%) partial responses, as assessed by independent central review. The most common grade 3 or worse treatment-emergent adverse events were anaemia (11 [14%]), nausea (six [8%]), decreased neutrophil count (six [8%]), and decreased white blood cell count (five [6%]). Drug-related serious treatment-emergent adverse events occurred in ten patients (13%). Deaths determined to be associated with study treatment occurred in two patients (3%) and were due to interstitial lung disease or pneumonitis. These clinically meaningful results support the use of trastuzumab deruxtecan as second-line therapy in patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. Daiichi Sankyo and AstraZeneca.

AMT-562, a Novel HER3-targeting Antibody-Drug Conjugate, Demonstrates a Potential to Broaden Therapeutic Opportunities for HER3-expressing Tumors.

HER3 is a unique member of the EGFR family of tyrosine kinases, which is broadly expressed in several cancers, including breast, lung, pancreatic, colorectal, gastric, prostate, and bladder cancers and is often associated with poor patient outcomes and therapeutic resistance. U3-1402/Patritumab-GGFG-DXd is the first successful HER3-targeting antibody-drug conjugate (ADC) with clinical efficacy in non-small cell lung cancer. However, over 60% of patients are nonresponsive to U3-1402 due to low target expression levels and responses tend to be in patients with higher target expression levels. U3-1402 is also ineffective in more challenging tumor types such as colorectal cancer. AMT-562 was generated by a novel anti-HER3 antibody Ab562 and a modified self-immolative PABC spacer (T800) to conjugate exatecan. Exatecan showed higher cytotoxic potency than its derivative DXd. Ab562 was selected because of its moderate affinity for minimizing potential toxicity and improving tumor penetration purposes. Both alone or in combination therapies, AMT-562 showed potent and durable antitumor response in low HER3 expression xenograft and heterogeneous patient-derived xenograft/organoid models, including digestive system and lung tumors representing of unmet needs. Combination therapies pairing AMT-562 with therapeutic antibodies, inhibitors of CHEK1, KRAS, and tyrosine kinase inhibitor showed higher synergistic efficacy than Patritumab-GGFG-DXd. Pharmacokinetic and safety profiles of AMT-562 were favorable and the highest dose lacking severe toxicity was 30 mg/kg in cynomolgus monkeys. AMT-562 has potential to be a superior HER3-targeting ADC with a higher therapeutic window that can overcome resistance to generate higher percentage and more durable responses in U3-1402-insensitive tumors.

AI-based HER2-low IHC scoring in breast cancer across multiple sites, clones, and scanners.

516 Background: Assessment of immunohistochemical (IHC) HER2 expression plays a pivotal role in breast cancer diagnostics. In the era of HER2-low and HER2-targeted antibody drug conjugates, accurate discrimination of defined HER2 IHC scores is essential. At the same time, HER2 IHC scoring suffers from poor interobserver concordance. Artificial intelligence (AI) may optimize this scoring in regard to standardization, accuracy and efficiency, but previous approaches fail to show the required consistency across samples from different sites, clones and scanning hardware. Methods: We have investigated the use of an AI-based HER2 IHC quantifier software to support pathologists in standardized HER2 IHC assessment in breast cancer. Validation specimens were derived from four institutions and five scanners. Using the “region of interest” (ROI) software version (part I), pathologists choose the ROI to be assessed within the whole slide image (WSI). In contrast, the fully automatic version (part II) analyzes the complete WSI. Part I: Three pathologists selected one ROI per slide from a cohort of n = 150 specimens. They scored HER2 expression in these ROIs (path-only) according to ASCO/CAP 2018 guidelines (each pathologist n = 50). After a 2-week washout period, the same pathologists were presented with the same ROIs and corresponding AI-suggested results (AI-only), and then decided on final HER2 scores (AI-assisted). Scoring times were recorded. Part II: Fully automatic AI accuracy without human intervention was analyzed using the WSI cohort of part I and an additional cohort of n = 94 WSIs. For both parts, IHC scores were compared to the clinical workflow derived ground truth defined as the manually assessed HER2 IHC score. Results: Part I: In discriminating HER2-neg from HER2-low/pos cases, AI-assisted and AI-only ROI scoring showed agreement rates of 91.3% and 86.7%, respectively, with path-only decisions across all institutions and scanners. In discriminating the four HER2 scores (0, 1+, 2+, 3+) individually, interrater-agreement of AI-assisted vs. path-only ROI HER2 scoring was 78.7%, exceeding literature rates of &lt; 70%, with the mean scoring time per ROI being 29 sec vs. 50 sec, respectively; interrater-agreement of AI-only vs. AI-assisted was 85.3%. Part II: In discriminating HER2-neg from HER2-low/pos cases, fully automatic AI WSI scoring showed 89.1%/86.2% agreement for both cohorts, respectively. Conclusions: Across challenging validation data from four institutions and five scanners, scoring with the support of an AI HER2 IHC quantifier software showed very high agreement when discriminating HER2-neg from HER2-low/pos cases and high accuracy for general HER2 scoring. When using AI-assistance, scoring time was reduced by almost 50%. Altogether, these results demonstrate the potential of AI solutions to increase consistency and efficiency of HER2 scoring and ultimately to improve patient outcome.

HER2 persistence after treatment with T-DXd in breast and gastrointestinal cancers.

1052 Background: T-DXd is a HER2-targeted antibody drug conjugate approved for treatment of advanced HER2-positive breast and gastroesophageal cancers and HER2-low breast cancers. The prevalence of HER2 loss after exposure to T-DXd is unknown and has implications for treatment strategies in refractory patients. Methods: We investigated clinically reported HER2 immunohistochemistry (IHC) scoring on post-treatment tissue biopsies from patients who received at least 2 cycles of T-DXd as of 2/2023. IHC was performed using mAB clone 4B5 (Ventana) and scored by ASCO/CAP guidelines on a scale of 0 to 3+. MSK-IMPACT next generation sequencing (NGS) was performed on paired pre- and post-treatment samples when available. Statistics are descriptive. Results: A total of 62 patients with breast, gastroesophageal, or colon cancer had available post-treatment biopsies. The majority (n = 51) had breast cancer, including 32 with HER2-positive and 19 with HER2-low disease. Median time on therapy was 30 weeks in HER2-positive and 21 weeks in HER2-low breast cancer. All 32 patients with HER2-positive breast cancer had detectable HER2 expression by IHC on post-treatment biopsies (median IHC score 2+; range 1+ to 3+). Of those with HER2-low breast cancer, 12 (63.1%) patients had detectible IHC after treatment. Of the 7 with IHC scores of zero, 3 also had scores of zero on the most proximal pre-treatment biopsies. Seven patients with gastroesophageal and 3 with colorectal cancer were included, with a median time on therapy of 12 and 9 weeks respectively, of which 1 (9%) exhibited HER2-loss after treatment. Among all patients with HER2-positive cancers, the rate of complete HER2-loss by IHC after exposure to T-DXd was 2.3%. Thirty-two patients had paired genomic analysis, including 25 breast and 7 gastrointestinal cancers. No change was observed in the fraction of genome altered (p = 0.0736, q = .327) or tumor mutational burden (p = 0.139, q = .487) with T-DXd exposure. Changes in ERBB2 copy number did not show clear directionality, with 15 patients (46.7%) exhibiting ERBB2 amplification pre-treatment and 12 (37.5%) post-treatment, the sum of 3 temporal gains and 6 losses of ERBB2 amplification across the threshold of 1.8. Conclusions: HER2 remained detectable by IHC in the majority of patients treated with T-DXd in this cohort, especially those with HER2-positive cancers. These findings suggest that resistance to T-DXd may occur via target-independent factors, and that HER2 could still be exploited therapeutically in these populations. Further prospective studies using quantitative assays are needed to confirm these hypotheses. [Table: see text]