anti-HER2 Monoclonal Antibody Research Articles

Supramolecular antibody-drug conjugates for combined antibody therapy and photothermal therapy targeting HER2-positive cancers

Antibody therapy of anti-HER2 monoclonal antibody (mAb) has been an important strategy in treating HER2-positive cancers. However, the efficacy is restricted by many factors, including the level of HER2 expressed by tumor cells and antibody resistance. To overcome these and boost the efficacy, a novel nanoparticle (NP) was constructed in this study for combined antibody therapy of antibody and photothermal therapy (PTT). This novel NP was assembled from 1-pyrenecarboxylic acid (PCA) functionalized anti-HER2 mAb and indocyanine green (ICG), a photothermal transduction agents (PTA), by non-covalent interactions, which was named as Anti-HER2 mAb-pyrene-indocyanine green (H-P-I). Notably, the constructed H-P-I NP not only maintained the affinity and cytotoxicity of anti-HER2 mAb, but also exhibited high photothermal conversion efficiency mediated by ICG. Both in vitro and in vivo assessments confirmed that compared with monotherapy of antibody or ICG, H-P-I demonstrated preferable efficacy in treating HER2-positive cancers. Further biochemistry analysis and pathological analysis ensured the biosafety of H-P-I administration. Taked together, this study proposes a feasible method for constructing tumor-targeted nano PTA based on anti-HER2 mAb through supramolecular self-assembly strategy, achieving synergistic antibody photothermal anticancer treatment, which has the potential to be a promising candidate for combination therapy of HER2-positive cancers.

Neoadjuvant inetetamab and pertuzumab with taxanes and carboplatin (TCbIP) In locally advanced HER2-positive breast cancer: a prospective cohort study with propensity-matched analysis

BackgroundInetetamab is the first domestically developed innovative anti-HER2 monoclonal antibody in China, proven effective and safe in HER2-positive advanced breast cancer. However, its efficacy and safety in neoadjuvant treatment of HER2-positive locally advanced breast cancer (LABC) remain to be validated.MethodsThis prospective cohort study aimed to evaluate the efficacy and safety of inetetamab combined with pertuzumab, taxanes, and carboplatin (TCbIP) in neoadjuvant therapy for HER2-positive LABC, comparing it to data from patients treated with the TCbHP regimen (trastuzumab combined with pertuzumab, taxanes, and carboplatin) using propensity score matching (PSM). The primary endpoint was total pathological complete response (tpCR). Adverse events (AEs), objective response rate (ORR), and near-pCR were key secondary endpoints.ResultsForty-four patients with clinical stage IIA-IIIC HER2-positive LABC were prospectively enrolled and treated with the TCbIP regimen. The tpCR rate among 28 patients who completed surgery was 60.7%, comparable to and slightly higher than the TCbHP group in PSM (60.7% vs. 53.6%, P = 0.510). The ORR was 96.4%, and the DCR reached 100.0%. The most common ≥ grade 3 AE was neutropenia (21.4% vs. 11.9%, P = 0.350). No significant reduction in left ventricular ejection fraction was observed, and no patient withdrew from treatment due to AEs.ConclusionNeoadjuvant therapy with TCbIP showed good efficacy and safety in patients with HER2-positive LABC and might be another promising option for neoadjuvant treatment.Trial registrationNCT05749016 (registration date: Nov 01, 2021).

Antibody Recognition of Human Epidermal Growth Factor Receptor-2 (HER2) Juxtamembrane Domain Enhances Anti-Tumor Response of Chimeric Antigen Receptor (CAR)-T Cells.

Chimeric antigen receptor (CAR) T cell therapy shows promise in treating malignant tumors. However, the use of human epidermal growth factor receptor-2 (HER2) CAR-T cells carries the risk of severe toxicity, including cytokine release syndrome, due to their "on-target off-tumor" recognition of HER2. Enhancing the quality and functionality of HER2 CARs could greatly improve the therapeutic potential of CAR-T cells. In this study, we developed a novel anti-HER2 monoclonal antibody, Ab8, which targets domain III of HER2, distinct from the domain IV recognition of trastuzumab. Although two anti-HER2 mAbs induced similar levels of antibody-dependent cellular cytotoxicity, trastuzumab-based CAR-T cells exhibited potent antitumor activity against HER2-positive cancer cells. In conclusion, our findings provide scientific evidence that antibody recognition of the membrane-proximal domain promotes the anti-tumor response of HER2-specific CAR-T cells.

YL202/BNT326, a HER3-targeted ADC, in patients with locally advanced or metastatic non-small cell lung cancer and breast cancer: Preliminary results from a first-in-human phase I trial.

3034 Background: YL202/BNT326 is a novel ADC consisting of an anti-HER3 IgG1 monoclonal antibody linked to 8 molecules of YL0010014, a novel topoisomerase I inhibitor, via a tripeptide linker. We report preliminary safety and efficacy results from a phase I trial of YL202/BNT326. Methods: This multinational trial is recruiting patients (pts) with locally advanced/metastatic non-small cell lung cancer (NSCLC) with an EGFR-activating mutation who were previously treated with 3rd generation TKI and platinum-based chemotherapy, and pts with unresectable, locally advanced or metastatic, HR-positive and HER2-negative (IHC 0,1+,2+/ISH-) breast cancer (BC) who were previously treated with CDK4/6 inhibitor and at least one line of chemotherapy. YL202/BNT326 was given at 6 dose levels (DLs, Q3W, iv) in a BOIN dose escalation (D-ESC) scheme, followed by cohort backfill(BF) at selected doses. Primary endpoints are safety and tolerability (dose-limiting toxicities [DLTs] and adverse events [AEs]). Secondary endpoints include pharmacokinetics [PK] and efficacy per RECIST v1.1(ORR, DCR, BOR). Results: At data cutoff (4 Feb 2024), 52 pts were enrolled in D-ESC and BF (39 NSCLC, 13 BC). One DLT (grade 3 febrile neutropenia) occurred during D-ESC at the highest dose. Most common TRAEs (>20%, all grade / ≥ G3) were anemia (71%/20%), white blood cell count decreased (67%/31%), neutrophil count decreased (63%/29%), nausea (52%/0%), decreased appetite (42%/4%), lymphocyte count decreased (37%/23%), platelet count decreased (37%/10%), vomiting (37%/0%), dry mouth (25%/0%), fatigue (25%/0%), stomatitis (23%/2%), alopecia (21%/0%). Interstitial pneumonia occurred in 1 (2%) pt after COVID-19 infection. PK exposure was increased through dose escalation, with low systemic exposure of payload and no accumulation of YL202/BTN326 upon repeated administration. In 46 pts with at least 1 tumor assessment were evaluable for efficacy. Of the non-evaluable pts, 5 are on treatment pending first tumor assessment and 1 discontinued treatment prior to first assessment. In DL3 to DL5 dose range, ORR was 41.0% (95%CI, 25.6, 57.9), DCR was 94.9% (95%CI, 82.7, 99.4) across all tumor types; and the ORR in BC pts was 54.5% (95%CI, 23.4, 83.3), DCR was 100% (95%CI, 71.5, 100.0). Conclusions: YL202/BNT326 demonstrated encouraging efficacy in heavily pretreated locally advanced/ metastatic NSCLC and BC. The safety profile showed adequate safety and tolerability. Clinical trial information: NCT05653752 . [Table: see text]

HERTHENA-PanTumor01: A global, multicohort, phase 2 trial of HER3-DXd in relapsed/refractory metastatic solid tumors.

TPS3164 Background: Human epidermal growth factor receptor 3 (HER3) is a member of the HER/EGFR family of receptor tyrosine kinases. HER3 is expressed in numerous solid tumors, including melanoma, head and neck squamous cell cancer (HNSCC), and gastric cancer, and high levels of HER3 expression in multiple tumor types are associated with poor clinical outcomes. HER3-DXd is a potential first-in-class HER3-directed antibody-drug conjugate (ADC) composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a potent topoisomerase I inhibitor payload via a tumor-selective cleavable linker. HER3-DXd has shown antitumor activity and a manageable safety profile in previously treated EGFR-mutated metastatic NSCLC and metastatic breast cancer. Based on clinical data and exposure-response analyses, HER3-DXd 5.6 mg/kg IV every 3 weeks (Q3W) was selected as the monotherapy dose for investigation in new indications. HERTHENA-PanTumor01 (NCT06172478) is a global, multicohort, open-label, single-arm, phase 2 trial evaluating the efficacy and safety of HER3-DXd in previously treated patients (pts) with cutaneous melanoma, HER2-negative gastric cancer, or HNSCC. Methods: Each cohort of HERTHENA-PanTumor01 will enroll 40 pts. Study sites are in Australia, Belgium, France, Japan, South Korea, Spain, Taiwan, the UK, and the US. Key inclusion criteria for melanoma include cutaneous or acral subtype, BRAF–wild-type or -mutant status, and progression on or after ≥1 anti–PD-(L)1 therapy. Key inclusion criteria for HNSCC include HPV+ or negative status and progression after platinum-based chemotherapy (PBC) ± anti–PD-(L)1 therapy; pts with nasopharyngeal cancer are excluded. Key inclusion criteria for gastric or gastroesophageal junction cancer include confirmed HER2-negative tumor status (immunohistochemistry [IHC] 0/1+ or IHC 2+/in situ hybridization negative) and progression after PBC ± anti–PD-(L)1 therapy; pts with HER2+ cancer are excluded. Other key exclusion criteria for all cohorts include any history of, suspected, or current interstitial lung disease; active brain metastases (treated/asymptomatic brain metastases are allowed); or prior treatment with an anti-HER3 antibody and/or ADC containing an exatecan derivative. A fresh biopsy or pretreatment archival biopsy performed since progression on or after treatment with the most recent cancer therapy is required for all cohorts. Pts will be treated with HER3-DXd 5.6 mg/kg IV Q3W; tumor assessments will occur every 6 wks for the first 48 wks, then every 12 wks until disease progression, adverse events, or other discontinuation criteria are met. The primary endpoint for each cohort is ORR by investigator per RECIST version 1.1. Secondary endpoints include safety and tolerability, DOR, DCR, PFS, overall survival, pharmacokinetics, and the correlation between HER3 IHC protein expression and efficacy. Clinical trial information: NCT06172478 .

Efficacy and safety of recombinant humanized anti-HER2 antibody-MMAE conjugate (RC48) in neoadjuvant for HER2-positive breast cancer: A single-arm phase II study.

e12636 Background: Breast cancer patients who achieve pCR after neoadjuvant therapy have a relatively good prognosis. Whether antibody‐drug conjugates (ADCs) can replace traditional chemotherapy combined with dual-target therapy in neoadjuvant therapy still needs to be explored. RC48 is a novel recombinant human anti-HER2 monoclonal antibody conjugated with a microtubule inhibitor (MMAE) via a cleavable linker, which can effectively kill HER2-positive tumors as well as tumors with low or heterogeneous HER2 expression through the bystander effect. The purpose of this study was to evaluate the efficacy and safety of RC48 in neoadjuvant treatment of HER2-positive breast cancer. Methods: Patients with HER2-positive breast cancer (size>20mm) or confirmed axillary lymph node metastasis were eligible and received RC48 at a dose of 2.5mg/kg alone every 2 weeks for 6 cycles followed by surgery. EC was administered postoperatively every 21 days for 4 cycles. Trastuzumab combined with pertuzumab was administered for 1 year in the adjuvant setting. The primary endpoints were ORR and pCR rates. Results: 23 patients had been enrolled, and all of them had completed surgical treatment. The median age was 45(38-70) years. The current results showed that 13.0% (3/23) achieved pCR, 78.3% (18/23) achieved PR, and 8.7% (2/23) experienced PD. The ORR was 91.3%. 42% (5/12) of patients with initially positive axillary lymph nodes turned negative after surgery. 11.8% (2/17) HR-/HER2+ patients achieved pCR. According to the proportion of target lesion reduction, patients were divided into mild response (0-50%) and moderate-to-severe response (51%-100%). In the HR-/HER2+ subtype group, 23.5% (4/17) had a mild response, and 76.5% (13/17) had a moderate-to-severe response. 6 patients with HR+ have been enrolled, and 16.7% (1/6) of them achieved pCR. All of HR+ subtypes had a moderate-to-severe response. No relevant serious (grade 3/4) toxicity has been reported. Conclusions: The present data showed an acceptable pCR rate with RC48 in HER2-positive breast cancer. Although the pCR rate was lower than the traditional chemotherapy combined with targeted therapy, the effect of rapid reduction of tumor volume was better (the moderate-severe remission rate was 82.6%). For HR+/HER2+ breast cancer, the ORR in this study reached 100%, indicating that the novel ADC had a significant inhibitory effect on the crosstalk between ER and HER2. And it was expected that the Destiny Breast 11 study would show similar results. This scheme had a good negative conversion rate for patients with positive axillary lymph nodes. Finally, RC48 provided a neoadjuvant treatment option with low toxicity and high patient compliance for HER2-positive breast cancer. Clinical trial information: NCT05134519 .

A propensity-matched analysis of the efficacy and safety of neoadjuvant inetetamab and pertuzumab with paclitaxel and carboplatin (TCbIP) on locally advanced HER2-positive breast cancer.

e12609 Background: Inetetamab is an Fc segment-modified innovative anti-HER2 monoclonal antibody. It has been proven to be effective and safe in HER2-positive advanced breast cancer. However, its efficacy and safety in the neoadjuvant treatment of HER2-positive locally advanced breast cancer (LABC) remains to be validated. This study aimed to evaluate the efficacy and safety of Inetetamab-based neoadjuvant therapy (TCbIP). Methods: In this prospective cohort study, we investigated the efficacy and safety of TCbIP in neoadjuvant therapy for HER2-positive LABC, and compared with TCbHP regimen (trastuzumab combined with pertuzumab, paclitaxel, and carboplatin) with propensity score matching (PSM). Thirty-four patients (clinical stage IIA-IIIC, HER2-positive LABC) were prospectively enrolled in this study and treated with the TCbIP regimen. The primary endpoint was total pathological complete response (tpCR). Adverse events (AEs), objective response rate (ORR), and near-pCR were key secondary endpoints. Results: The pCR rate of 28 patients who finished surgery was 60.7%, and was comparable and slightly higher (60.7% vs. 53.6%, P = 0.510) than the TCbHP group in PSM. The ORR was 96.4% and DCR reached 100.0%. The most common ≥grade 3 AE was neutropenia (21.4% vs. 11.9%, P = 0.350). No significant reduction in left ventricular ejection fraction was observed, and no patient withdrew from treatment due to AEs. Conclusions: Neoadjuvant therapy with TCbIP resulted in good efficacy and safety in patients with HER2-positive LABC, and might be another promising option for neoadjuvant treatment. Clinical trial information: NCT05749016 .

Combined transcriptome and proteome analysis reveals MSN and ARFIP2 as biomarkers for trastuzumab resistance of breast cancer.

HER2-positive breast cancer (BC) accounts for 20-30% of all BC subtypes and is linked to poor prognosis. Trastuzumab (Tz), a humanized anti-HER2 monoclonal antibody, is a first-line treatment for HER2-positive breast cancer which faces resistance challenges. This study aimed to identify the biomarkers driving trastuzumab resistance. Differential expression analysis of genes and proteins between trastuzumab-sensitive (TS) and trastuzumab-resistant (TR) cells was conducted using RNA-seq and iTRAQ. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were used to study their functions. The prognostic significance and protein levels of ARFIP2 and MSN were evaluated using online tools and immunohistochemistry. Sensitivity of MSN and ARFIP2 to other therapies was assessed using public pharmacogenomics databases and the R language. Five genes were up-regulated, and nine genes were down-regulated in TR cells at both transcriptional and protein levels. Low ARFIP2 and high MSN expression linked to poor BC prognosis. MSN increased and ARFIP2 decreased in TR patients, correlating with shorter OS. MSN negatively impacted fulvestrant and immunotherapy sensitivity, while ARFIP2 had a positive impact. Our findings suggest that MSN and ARFIP2 could serve as promising biomarkers for predicting response to Tz, offering valuable insights for future research in the identification of diagnostic and therapeutic targets for BC patients with Tz resistance.

Abstract PO2-01-04: Efficacy and safety of anti-HER2 therapy in neoadjuvant therapy for HER2-positive breast cancer: a network meta-analysis

Abstract Background: Human epidermal growth factor receptor-2 overexpression or gene amplification (HER2+) breast cancer is considered to be a highly aggressive, dangerous and even fatal subtype..In recent years, with the application of large molecule anti-HER2 monoclonal antibody and its biosimilar in neoadjuvant therapy of HER2-positive breast cancer, small molecule tyrosine kinase inhibitors (TKIs) have also performed strong advantages of antineoplastic activity in breast cancer. At present, there is no direct evidence to demonstrate the differences in neoadjuvant efficacy of anti-HER2 monoclonal antibody and tyrosine kinase inhibitors (TKIs) in this subtype of breast cancer.We conducted a preliminary network meta-analysis to explore the difference of efficacy and safety between anti-HER2 monoclonal antibody and TKIs for neoadjuvant therapy in patients with HER2-positive early or locally advanced breast cancer. Method: A systematic literature search in the Cochrane Central Register of Controlled Trials, PubMed, Embase and Web of Science was performed.Randomized or non-randomized controlled studies of neoadjuvant therapy for HER2-positive breast cancer including large molecules trastuzumab, pertuzumab and small molecules TKIs (pyrotinib, lapatinib, nenatinib, etc.) were screened.Studies had to satisfy the following criteria: i) randomized or non-randomized controlled trials, ii) at least one treatment group received an anti-HER2 agent, iii) available information of any efficacy end-point. A network meta-analysis with a frequentist framework using random-effects model was used to pool direct and indirect evidence. Pathologic complete response (pCR) were the efficacy end-points of interest, and selected safety end-points were also analysed. Results: A total of 5885 published manuscripts were identified,and 19 studies including 6517 patients were finally included in our analysis. and 19 different regimens were evaluated. Dual anti-HER2-therapy,trastuzumab with pertuzumab or tyrosine kinase inhibitors, combined with chemotherapy was significantly superior to trastuzumab or TKIs and chemotherapy in terms of pCR(OR=2.20, 95%CI=1.92-2.52).In the comparison of dual-target treatment regiments, the efficacy of pyrotinib plus trastuzumab combined chemotherapy was superior to that of pertuzumab plus trastuzumab combined chemotherapy (OR=1.20, 95%CI=0.85-1.70), but the difference was not statistically significant.In addition, compared with pertuzumab combined with trastuzumab and chemotherapy,there was no significant difference in the efficacy aspect of TKIs combined with trastuzumab and chemotherapy (OR=1.15, 95%CI=0.88-1.51). Conclusion:For the selection of neoadjuvant treatment for HER2-positive early or locally advanced breast cancer, trastuzumab plus pertuzumab combined with chemotherapy is still the preferred strategy at present.As our study showed that pyrotinib combined with trastuzumab and chemotherapy maybe could provide another option for neoadjuvant target therapy for HER2-positive breast cancer. Keywords: breast cancer, HER2-positive, neoadjuvant, network meta-analysis, target therapy. Characteristics of eligible studies. NAC=Neoadjuvant chemotherapy;T=nab-paclitaxel,paclitaxel or Docetaxel;F= fluorouracil;E=epirubicin;A=doxorubicin;C=cyclophosphamide; Cb=carboplatin;tzmb=trastuzumb;pzmb=pertuzumab;Py=pyrotinib;lpnb=lapatinib;Ne=neratinib. Cross-comparison odds ratios (ORs) and their respective 95% CIs for pCR among different experimental arms. CT=chemotherapy;tzmb=trastuzumb;pzmb=pertuzumab;TKI=tyrosine kinase inhibitors;Py=pyrotinib;lpnb=lapatinib;Ne=neratinib. Cross-comparison odds ratios (ORs) and their respective 95% confidence intervals (CIs) for pathologic complete response (pCR) in HR-positive and HR-negative subgroups. CT=chemotherapy;tzmb=trastuzumb;pzmb=pertuzumab;TKI=tyrosine kinase inhibitors;Py=pyrotinib;lpnb=lapatinib;Ne=neratinib. Citation Format: Lu Gan, Fangxuan Li, Jialin Su. Efficacy and safety of anti-HER2 therapy in neoadjuvant therapy for HER2-positive breast cancer: a network meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-04.

Abstract PO5-04-02: Combination of trastuzumab competing and non-competing fully human internalizing anti-Her2 monoclonal antibodies drug conjugates increases their inhibitory effect on the growth of HER2 positive metastatic breast cancer cells

Abstract The human epidermal growth factor receptor (HER) family of receptors plays a key role in proliferation stimulator for several human cancers. In particular, HER2 is overexpressed in 15-30% of breast cancers with or without gene amplification with prognostic and predictive implications. HER2 overexpression is associated with shorter disease-free and overall survivals, resistance to hormonal agents and increased risk of brain metastasis. Trastuzumab is a humanized anti-HER2 monoclonal antibody that binds to domain IV of HER2 extracellular domain and blocks its signaling. More recently, two antibody drug conjugates using trastuzumab have been approved: Ado-Trastuzumab-Emtansine (Kadcyla) consisting of trastuzumab conjugated to the drug mertansine DM1 and fam-trastuzumab-deruxtecan-nhki (Enhertu to deliver the topoisomerase inhibitor deruxtecan. We are reporting here the development of fully human internalizing anti-HER2 antibodies with distinct epitopes on the HER2protein which compete or not with trastuzumab for binding to HER2. These monoclonal antibodies have been developed by immunizing fully human (TC-Mab mouse) mice with recombinant HER2 protein. After production of hybridoma secreting fully human immunoglobulins, the screening process included competition with trastuzumab for binding to Her2 by enzyme linked immunoassay and Octet epitope binning and affinity determination as well as internalization assay. Several internalizing antibodies able to compete or not with trastuzumab and with high affinity (Kd ranging from 10−9 M to 10−12 M) were selected. Their ability to deliver a cytotoxic payload in HER2 overexpressing breast cancer cells such as SKBR3, BT474 and AU565 was next investigated. Two groups of antibodies: one competing with trastuzumab and the other one non-competing were further characterized. Data related to these antibodies’ biochemical characteristics as well as their ability to inhibit proliferation in vitro and in vivo in mouse xenografts studies will be presented here. In conclusion, the use of fully human mice to develop monoclonal antibodies provides a powerful and attractive approach to develop fully human monoclonal antibodies against cancer targets by-passing the need for humanization and affinity maturation of antibodies. This work is supported by 5R44CA224718 SBIR grant from the National Cancer Institute. Citation Format: Ginette Serrero, Binbin Yue, Jianping Dong, Jun Hayashi. Combination of trastuzumab competing and non-competing fully human internalizing anti-Her2 monoclonal antibodies drug conjugates increases their inhibitory effect on the growth of HER2 positive metastatic breast cancer cells [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-04-02.

Abstract PO4-26-07: HER2-low prevalence in early breast cancer (BC) across reference laboratories in Brazil: potential impact of immunohistochemistry (IHC) antibody assay sensitivity

Abstract Background: Current definition of HER2-positive and HER2-low BC follows ASCO/CAP guidelines using IHC and/or in situ hybridization (ISH)-based techniques. Although there is no recommendation for a specific antibody assay, the companion diagnostic test for trastuzumab deruxtecan in the USA is Ventana PATHWAY anti-HER2 monoclonal antibody (4B5) run on Benchmark Ultra instrument. In this study, we assessed the prevalence of HER2-low BC in samples stained with Dako anti-HER2 polyclonal antibody (A0485) and analyzed with Autostainer Link 48 Agilent/Dako, commonly used in different large-volume laboratories in Brazil. Methods: Retrospective study of all early-stage BC samples without exposure to neoadjuvant therapy tested for HR plus HER2 status in Oncoclínicas Precision Medicine (Locus Lab) from 2021 to 2023 and analyzed following ASCO/CAP guidelines. Tumors with HER2 IHC score 0 were classified as HER2-zero, whereas tumors with HER2 score 1+ and those with HER2 score 2+ with ISH-negative were classified as HER2-low. To assess the impact of preanalytical factors on HER2-low positivity, we stratified samples as in-house (part of Oncoclínicas network) or external (other institutions’ FFPE preparation conditions not controlled). Results were also validated in independent IRA Lab using the same Dako anti-HER2 polyclonal antibody (A0485) on Autostainer Link 48 Agilent/Dako. Results: Out of 1,638 eligible samples from Locus Lab, 84% were classified as HR-positive/HER2 negative, 12% HER2-positive, and 4% triple-negative. In 1,386 HR-positive/HER2 negative samples, 83% were HER2-zero, and 17% (CI95% 15%-19%) were HER2-low (1+ in 79% and 2+ with ISH negative in 21%). In 70 triple-negative samples, 62% were HER2-zero and 38% (CI95% 27%-51%) were HER2-low (1+ in 44% and 2+ with ISH negative in 56%). HER2-low positivity was 17% in the subset of in-house samples (N=1.090) and 16% in external referrals (P=0.41). In the independent cohort, out of 441 samples from IRA Lab, 80% were HR-positive/HER2 negative, 12% HER2-positive and 8% triple negative. In 352 HR positive/HER2 negative samples, 80% were HER2-zero and 20% (CI95% 16%-25%) were HER2-low. In 36 triple-negative samples, 72% were HER2-zero and 28% (CI95% 14%-45%) were HER2-low. Conclusions: Different from another Brazilian cohort where the prevalence of HER2-low was 50% with monoclonal anti-HER2 antibodies (Reinert et al., SABCS 2020), our data suggests that the reduced proportion of samples with HER2-low status may be related to antibody clone sensitivity and not linked to preanalytical factors or local ancestry/cancer biology. Indeed, a recent Italian cohort also had lower than expected prevalence of HER2-low in surgical specimens using anti-HER2 Dako A0485 assay on Omnis instrument (Rossi et al., Breast Cancer Res Treat 2023). Prior studies have found differential analytical sensitivity of antibodies for HER2-low status, while HER2 score 3+ detection is equivalent (Ruschoff et al., Virchows Archiv 2022). We recommend prospective evaluation of the HER2-low status with companion-diagnostic Ventana 4B5 assay and alternative antibodies and instruments. Citation Format: Leonard M da Silva, Fernanda Orpinelli Rego, Matheus Costa e Silva, Tomas Reinert, Fernanda Koyama, Daniel Bueno da Cunha, Vagner Duarte, Emílio Pereira, Bruno Ferrari, Rodrigo Dienstmann. HER2-low prevalence in early breast cancer (BC) across reference laboratories in Brazil: potential impact of immunohistochemistry (IHC) antibody assay sensitivity [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-26-07.

Abstract PO1-24-08: Targeting of HER3 potentiates the antitumor activity of paclitaxel against triple negative breast cancer

Abstract Background: Triple negative breast cancer (TNBC) is characterized by the absence of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) overexpression. This aggressive form of breast cancer carries a higher risk of recurrence compared to other subtypes, presenting a significant clinical challenge. Although chemotherapy is commonly used as the primary treatment for a substantial number of TNBC patients, it is often accompanied by drug resistance and frequent tumor recurrence. Urgent efforts are needed to identify novel molecular targets specific to TNBC and develop effective therapies to combat this aggressive disease. The ultimate objective is to discover treatments capable of overcoming drug resistance and improving the overall survival of patients with TNBC. Methods: Immunohistochemistry was performed to examine the expression of HER3 in TNBC samples. Western blots were used to assess protein expression and activation. Cell proliferation and viability were determined by cell growth (MTS) assays. TCGA databases were analyzed to correlate HER3 mRNA expression with the clinical outcomes of TNBC patients. Specific shRNA was used to knockdown HER3 expression. LIVE/DEAD Cell Imaging was to detect live and dead cells. Orthotopic tumor models were established in nude mice to determine the capability of TNBC cells forming tumors and to test if our newly developed anti-HER3 monoclonal antibody (mAb) 4A7 could potentiate the antitumor activity of paclitaxel in vivo. Results: The chemo-resistant subline HCC1806-TR was obtained by subjecting TNBC HCC1806 cells to prolonged treatment with paclitaxel. In comparison to the parental cell line HCC1806-P, HCC1806-TR exhibited enhanced HER3 expression and activation. It is noteworthy that approximately half of the tested TNBC specimens and cell lines displayed elevated expression of HER3. Analyzing TCGA databases revealed that TNBC patients with high levels of HER3 mRNA expression in their tumors had significantly poorer overall survival (OS) and relapse-free survival (RFS) compared to those with low HER3 expression. Specifically knockdown of HER3 markedly inhibited TNBC cell proliferation and mammosphere formation in vitro and tumor growth in vivo. Blockade of HER3 signaling with our mAb (4A7) in combination with paclitaxel exerted significant antitumor activity against TNBC in vitro and in vivo. Conclusions: Our data demonstrate that increased HER3 is an effective therapeutic target for TNBC and our anti-HER3 mAb (4A7) may enhance the efficacy of paclitaxel in TNBC. Keywords: HER3, Anbibody, Chemotherapy, Triple Negative Breast Cancer Citation Format: Hui Lyu, Sanbao Ruan, Congcong Tan, Ann Thor, Bolin Liu. Targeting of HER3 potentiates the antitumor activity of paclitaxel against triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-24-08.

Abstract PO1-04-07: Disitamab vedotin, a clinical stage HER2-directed antibody-drug conjugate, shows potent antitumor activity as a monotherapy and in combination with tucatinib in preclinical breast cancer models

Abstract Disitamab vedotin (DV, RC48-ADC) is an antibody-drug conjugate (ADC) that targets cancers expressing HER2. DV consists of an anti-HER2 monoclonal antibody, disitamab, conjugated with the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a cleavable vedotin linker. DV has multimodal antitumor mechanisms of action that include direct cytotoxicity of HER2-expressing cancer cells and bystander effect-based cytotoxicity of neighboring cells, both of which are mediated by the intracellular release of MMAE. Released MMAE can also induce immunogenic cell death, which promotes immune cell recruitment to the tumor. In addition, DV stimulates Fc-gamma receptor mediated antibody-dependent cellular cytotoxicity, which can lead to target cell death. DV also inhibits HER2-activated downstream signaling pathways, further blocking cell growth, survival, and proliferation. Previously, we showed the cytotoxic activity of DV against a panel of breast cancer cell lines with varying levels of HER2 expression, including the HER2-low range. Here, we sought to further characterize the preclinical antitumor activity of DV in patient-derived 3D models and patient-derived xenographs (PDX). In cultured breast cancer cells, DV was more potent and internalized to a greater magnitude than the HER2-directed ADCs trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). In patient-derived 3D models, DV had superior activity compared to T-DXd. We further explored whether dual HER2 targeting with DV in combination with the HER2-selective oral TKI tucatinib improved the antitumor outcomes. In PDX models with varying HER2 IHC levels and models refractory to T-DXd, DV as a monotherapy and in combination with tucatinib showed significant tumor growth inhibition. This result is consistent with previous in vitro results that showed increased cytotoxicity of the combination of DV and tucatinib in cell lines with a wide range of HER2 expression, which may be mechanistically attributed to elevated HER2 cell surface levels upon treatment with tucatinib. Overall, these findings provide scientific rationale to explore DV in HER2-positive and HER2-low breast cancer patients as a monotherapy or in combination with tucatinib. Citation Format: Kelsi Willis, Renee Hein, Katie Snead, Robert Thurman, Anita Kulukian. Disitamab vedotin, a clinical stage HER2-directed antibody-drug conjugate, shows potent antitumor activity as a monotherapy and in combination with tucatinib in preclinical breast cancer models [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-07.

Abstract PO3-04-01: Population Pharmacokinetics of trastuzumab deruxtecan (T-DXd) in HER2-positive breast cancer subjects: analyses across 12 Phase 1-3 studies

Abstract Background: T-DXd, an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody and a topoisomerase I inhibitor payload, is approved for adult patients with unresectable or metastatic HER2-positive (HER2+) BC administered T-DXd 5.4 mg/kg Q3W with a prior anti-HER2–based therapy either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. The objective of this analysis was to present pharmacokinetic (PK) characterization of T-DXd and DXd in patients with advanced/metastatic HER2-positive breast cancer from a pooled data source of 12 phase 1 to 3 clinical trials. Methods: Data from subjects with HER2-positive breast cancer and other solid tumors enrolled in studies DS8201-A-J101, DS8201-A-J102, DS8201-A-A103, DS8201-A-A104, DS8201-A-U201, DS8201-AJ202, DS8201-A-U205, DS8201-A-U204, DS8201-A-U206, DS8201-A-U301, DS8201-A-U302, and DS8201-A-U303 were used for this analysis. A population PK (PopPK) analysis was performed using nonlinear mixed effects modeling approach using NONMEM® (version 7.4.3). The effect of significant covariates was evaluated by univariate and multivariate analyses on steady-state exposure of T-DXd and DXd. Results: Data across T-DXd doses 0.8 to 8 mg/kg with 2216 subjects were included. The PK of T-DXd and DXd were adequately described by PopPK analysis based on standard model diagnostic techniques. T-DXd elimination clearance and volume of distribution of central and peripheral compartments were estimated at 0.402 L/day, 2.68 L and 5.91 L, respectively. DXd elimination clearance was estimated at 18.4 L/hour. Covariates previously detected to be statistically significant (cancer type, tumor size, albumin, race-country, body weight and sex for T-DXd; age, cancer type, AST, total bilirubin, ritonavir or itraconazole use, race-country, formulation and body weight for DXd) were retained in the PopPK model. No new covariates were identified as statistically significant in the PopPK analysis. All covariates were contained within the 0.8 to 1.25 exposure ratio interval in T-DXd and DXd steady-state area under the concentration-time curve (AUC), indicating no clinically meaningful effect, except for subjects with high body weight (90 kg; 95th percentile) showing a 28% and 26% higher T-DXd and DXd AUC, respectively, relative to a BC subject with median body weight of 60 kg. None of these changes were clinically meaningful based on exposure-response analyses of efficacy and safety endpoints. T-DXd and DXd post hoc exposure estimates in all BC subjects (HER2-positive and HER2-low) as well as BC subjects with HER2- positive were comparable across hepatic function, renal function, region, race-country and line of therapy. Conclusions: Similar T-DXd and DXd exposures were obtained for the recommended dosing of 5.4 mg/kg Q3W T-DXd in BC subjects across categories of hepatic function, renal function, region, race-country, HER2 status, and line of therapy. Citation Format: Claire Li, Stefanie henning, Kashyap Patel, Katrina Hui, Gerly van der Vleuten, malaz Abutarif, Tushar Garimella, Amit Khatri. Population Pharmacokinetics of trastuzumab deruxtecan (T-DXd) in HER2-positive breast cancer subjects: analyses across 12 Phase 1-3 studies [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-04-01.

Abstract RF02-05: Report on Cohort Expansion of Phase I Study to Investigate the Safety, Tolerability, Pharmacokinetics and Antitumor Activity of BB-1701 in Patients with Locally Advanced/Metastatic HER2 Low Breast Cancer

Abstract Background: BB-1701 is an antibody-drug conjugate (ADC) consisting of a humanized IgG1κ monoclonal anti-HER2 antibody with the same sequence as trastuzumab and eribulin linked together by a cathepsin-cleavable valine-citrulline linker. Eribulin is an inhibitor of microtubule approved for the treatment of metastatic breast cancer and advanced liposarcoma, following prior therapies. When BB-1701 targets HER2 expressing cancer cells and it is internalized, free eribulin is cleaved from the ADC by cathepsin b and causes cytotoxicity to cancer cells. The neighboring cells were affected with bystander effects, like cytotoxicity on tumor cells and non-cytotoxic effects on microenvironment, by free eribulin released from dying cancer cells. Here, we report preliminary results from the ongoing cohort expansion of a phase I study of BB-1701 in patients with HER2 low breast cancer (ClinicalTrials.gov Identifier: NCT 04257110). Methods: Patients ≥ 18 years of age with confirmed locally advanced/metastatic HER2 low breast cancer (IHC 2+ and FISH negative or IHC 1+), that had progressed on at least two lines of prior standard therapies, with ECOG PS ≤ 2 and measurable disease (RECIST 1.1) were enrolled. HER2 expressions was determined by IHC and FISH before enrollment. Total of four dose levels of BB-1701 (1.0 mg/kg Q3W, 1.2 mg/kg Q3W, 1.4 mg/kg Q3W and 1.6 mg/kg Q3W) were administered during the cohort expansion. The safety, tolerability and preliminary anti-tumor activity of BB-1701 were assessed during study. Radiographic assessment was conducted every 6 weeks. Results: As of 30 June 2023, 40 patients with HER2 low breast cancer were enrolled in the four dose levels, 5 patients at 1.0 mg/kg Q3W, 20 patients at 1.2 mg/kg Q3W, 5 patients at 1.4 mg/kg Q3W and 10 patients at 1.6 mg/kg Q3W. Median age was 55 years (range 30-74), 97.5% were female, and 30.0%/70.0% patients were ECOG PS 0/1. The median prior lines of systemic therapy were 3 (range 2 – 9). All subjects experienced at least one treatment emergent adverse events and treatment-related adverse events (TRAEs) occurred in 30 subjects. The most common all grade TRAEs (≥20%) were peripheral neuropathy, aspartate aminotransferase increased, alanine aminotransferase increased, anemia, white blood cell count decreased. Grade 3 TRAEs were peripheral neuropathy (3 subjects), peripheral sensory neuropathy (2 subjects), neutrophil count decreased (2 subjects), platelet count decreased (1 subject), white blood cell count decreased (1 subject). There were no grade 4 or grade 5 events. The treatment related serious adverse events (SAEs) were peripheral sensory neuropathy (1 subject) and infusion related reaction (1 subject). There was no interstitial lung disease reported. No patients discontinued the study treatment due to AE. Of the 40 patients enrolled, 38 patients were evaluable for antitumor activity. At 1.0 mg/kg dose level, of 5 patients treated, 2 achieved partial response (PR), 2 had stable disease (SD), best overall response rate (BOR) was 40.0% (2/5) and disease control rate (DCR) was 80.0% (4/5). At 1.2 mg/kg dose level, of 18 patients treated, 5 achieved PR, 11 had SD with BOR of 27.8% (5/18) and DCR of 88.9% (16/18). At 1.4 mg/kg dose level, of 5 patients treated, 2 achieved PR, 2 had SD with BOR of 40.0% (2/5), and DCR was 80.0% (4/5). One patient who achieved PR was previously progressed on sacituzumab govitecan. At 1.6 mg/kg dose level, of 10 patients treated, 1 achieved CR, 3 achieved PR, 2 had SD with BOR of 40.0% (4/10), and DCR of 60.0% (6/10). Among these patients, the patient who achieved CR was previously treated by disitamab vedotin, and one patient who achieved PR was previously treated by trastuzumab deruxtecan. Conclusions: BB-1701 has demonstrated promising preliminary antitumor activity in HER2 low breast cancer including patients who received prior anti-HER2 ADCs, and a manageable safety profile. Citation Format: Fei Ma, Pamela Munster, Xiaoxiang Guan, Jingfen Wang, Herui Yao, Erika Hamilton, Xian Wang, Yehui Shi, Xinjun Liang, Nong Xu, Huoling Tang, Yuhong Zhou, Ziping Wei. Report on Cohort Expansion of Phase I Study to Investigate the Safety, Tolerability, Pharmacokinetics and Antitumor Activity of BB-1701 in Patients with Locally Advanced/Metastatic HER2 Low Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-05.

The Efficacy and Safety of Inetetamab and Pyrotinib in Combination with Vinorelbine for Second-line Therapy and Beyond in HER2-positive Metastatic Breast Cancer: A Single-institution Clinical Experience.

This study aimed to observe the efficacy and safety of inetetamab and pyrotinib in combination with vinorelbine in second-line therapy and beyond in HER2-positive metastatic breast cancer (MBC). Patients with HER2-positive MBC admitted to our hospital from January 2016 to December 2021 were selected. For patients who could not receive antibody‒drug conjugates (ADCs) during second-line (2nd-line) or third-line and beyond (≥ 3rd-line) anti-HER2 therapy, inetetamab + pyrotinib + vinorelbine was used for treatment until unacceptable adverse events occurred or the disease progressed, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 every 2 cycles. The progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), and adverse reactions were recorded. Multivariate Cox regression analysis was performed to explore the prognostic factors influencing the curative effect. Overall, 52 patients were included; 13 patients received 2nd-line treatment, and 39 patients received ≥ 3rd-line treatment. The median PFS (mPFS) for all patients treated with inetetamab + pyrotinib + vinorelbine was 7 months. The mPFS of the 2nd-line subgroup was significantly better than that of the ≥ 3rd-line subgroup (17 vs. 5 months, P = 0.001). The mPFS of the subgroups that received trastuzumab (H) or trastuzumab and pertuzumab (HP) only was significantly better than that of the H or HP and tyrosine kinase inhibitor (TKI) subgroups (8 vs. 5 months, P = 0.030). The mPFS of the HER2 resistance subgroup was better than that of the HER2 refractoriness subgroup (14 vs. 7 months, P = 0.025). Cox regression analysis showed that the treatment line (2nd-line more so than ≥ 3rd-line) was an independent prognostic factor for PFS. In addition, the ORR and CBR of 2nd-line patients were significantly higher than those of ≥ 3rd-line patients (69.2% vs. 30.8% and 92.3% vs. 64.1%, respectively). The most common hematological toxicities were leukopenia and neutropenia, and the most common nonhematological toxicity was diarrhea. Inetetamab and pyrotinib in combination with vinorelbine have good efficacy in ≥ 2nd-line treatment of HER2-positive MBC with controllable toxicity, and the combination is a new treatment option, especially for patients who cannot use ADCs in 2nd-line treatment.

DB-1310, an ADC comprised of a novel anti-HER3 antibody conjugated to a DNA topoisomerase I inhibitor, is highly effective for the treatment of HER3-positive solid tumors

BackgroundHER3 (ErbB3), a member of the human epidermal growth factor receptor family, is frequently overexpressed in various cancers. Multiple HER3-targeting antibodies and antibody–drug conjugates (ADCs) were developed for the solid tumor treatment, however none of HER3-targeting agent has been approved for tumor therapy yet. We developed DB-1310, a HER3 ADC composed of a novel humanized anti-HER3 monoclonal antibody covalently linked to a proprietary DNA topoisomerase I inhibitor payload (P1021), and evaluate the efficacy and safety of DB-1310 in preclinical models.MethodsThe binding of DB-1310 to Her3 and other HER families were measured by ELISA and SPR. The competition of binding epitope for DB-1310 and patritumab was tested by FACS. The sensitivity of breast, lung, prostate and colon cancer cell lines to DB-1310 was evaluated by in vitro cell killing assay. In vivo growth inhibition study evaluated the sensitivity of DB-1310 to Her3 + breast, lung, colon and prostate cancer xenograft models. The safety profile was also measured in cynomolgus monkey.ResultsDB-1310 binds HER3 via a novel epitope with high affinity and internalization capacity. In vitro, DB-1310 exhibited cytotoxicity in numerous HER3 + breast, lung, prostate and colon cancer cell lines. In vivo studies in HER3 + HCC1569 breast cancer, NCI-H441 lung cancer and Colo205 colon cancer xenograft models showed DB-1310 to have dose-dependent tumoricidal activity. Tumor suppression was also observed in HER3 + non-small cell lung cancer (NSCLC) and prostate cancer patient-derived xenograft (PDX) models. Moreover, DB-1310 showed stronger tumor growth-inhibitory activity than patritumab deruxtecan (HER3-DXd), which is another HER3 ADC in clinical development at the same dose. The tumor-suppressive activity of DB-1310 synergized with that of EGFR tyrosine kinase inhibitor, osimertinib, and exerted efficacy also in osimertinib-resistant PDX model. The preclinical assessment of safety in cynomolgus monkeys further revealed DB-1310 to have a good safety profile with a highest non severely toxic dose (HNSTD) of 45 mg/kg.ConclusionsThese finding demonstrated that DB-1310 exerted potent antitumor activities against HER3 + tumors in in vitro and in vivo models, and showed acceptable safety profiles in nonclinical species. Therefore, DB-1310 may be effective for the clinical treatment of HER3 + solid tumors.

Maitake Beta-Glucan Enhances the Therapeutic Effect of Trastuzumab via Antibody-Dependent Cellular Cytotoxicity and Complement-Dependent Cytotoxicity.

Trastuzumab, an anti-HER2 monoclonal antibody, is the mainstay treatment for of HER2-positive breast cancer. However, trastuzumab resistance is often observed during treatment. Therefore, new therapeutic strategies are needed to enhance the clinical benefits of trastuzumab. Maitake β-glucan MD-Fraction, isolated from Grifola frondosa, inhibits tumor growth by enhancing immune responses. In this study, we examined the effect of MD-Fraction on trastuzumab treatment of HER2-positive breast cancer. MD-Fraction did not directly inhibit the survival of HER2-positive breast cancer cells, alone or in the presence of trastuzumab in vitro. In HER2-positive xenograft models, the combination of MD-Fraction and trastuzumab was more effective than trastuzumab alone. Peripheral blood lymphocytes and splenic natural killer cells isolated from BALB/c nu/nu mice treated with MD-Fraction showed enhanced trastuzumab-induced antibody-dependent cellular cytotoxicity (ADCC) ex vivo. MD-Fraction-treated macrophages and neutrophils did not show enhanced trastuzumab cytotoxicity in the presence of heat-inactivated serum, but they showed enhanced cytotoxicity in the presence of native serum. These results suggest that MD-Fraction-treated macrophages and neutrophils enhance trastuzumab-induced complement-dependent cellular cytotoxicity (CDCC). Treatment of HER2-positive breast cancer cells with MD-Fraction in the presence of trastuzumab and native serum increased C3a release and tumor cell lysis in a dose-dependent manner, indicating that MD-Fraction enhanced trastuzumab-induced complement-dependent cytotoxicity (CDC) by activating the complement system. This study demonstrates that the combination of trastuzumab and MD-Fraction exerts a greater antitumor effect than trastuzumab alone by enhancing ADCC, CDCC, and CDC in HER2-positive breast cancer.

Abstract CT168: A phase 1/2a, multicenter, open-label, non-randomized first-in-human study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1310 (a HER3-targeting ADC) in patients with advanced/metastatic solid tumors

Abstract Background: Overexpression of epidermal growth factor receptor 3 (HER3 or ERBB3) has been reported in various cancers, including lung, prostate, head and neck, breast, and ovarian cancers, and is associated with disease progression and poor prognosis. DB-1310 is an antibody-drug conjugate (ADC) comprised of a humanized anti-HER3 IgG1 monoclonal antibody, covalently linked to a proprietary DNA topoisomerase I inhibitor (P1021) via a maleimide tetrapeptide-based cleavable linker, with a high drug-to-antibody ratio (~8). Preclinical studies of DB-1310 demonstrated promising antitumor activity in solid tumors and a tolerable safety profile, warranting further clinical development. Methods: This global, first-in-human, Phase 1/2a study includes dose escalation and expansion parts to assess the safety, tolerability, pharmacokinetics, and antitumor activity of DB-1310 in patients (pts) with pretreated advanced/metastatic solid tumors (NCT05785741). Eligible pts must have progressed on or after standard systemic anticancer treatments have ECOG PS ≤1, and evidence adequate organ function. Phase 1 part will evaluate 5 ascending dose levels of DB-1310 with a standard “3+3” design to identify the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) in pts with advanced/metastatic solid tumors. Phase 2a part will initiate after MTD and/or RP2D are determined and enroll pts with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutation, NSCLC without EGFR activating mutation, castration-resistant prostate cancer, head and neck squamous cell carcinoma, and HER2-positive (immunohistochemistry [IHC] 3+, or IHC 2+ and in situ hybridization-positive) breast cancer (BC). DB-1310 is administrated intravenously every 3 weeks as monotherapy, or plus trastuzumab in pts with HER2-positive BC only, until discontinuation criteria are met. The study plans to enroll approximately 95 pts in Phase 1 and 192 in Phase 2a from the United States and China. Citation Format: Aaron Lisberg, Shun Lu, Alexander Starodub, Harshad Amin, Julia Rotow, Lin Wu, Alexander Spira, Erika Hamilton, Weidi Shen, Liming Liu, Zhongyuan Zhu, Wei Gu, Yang Qiu, Rong Shi, Shengxue Liu. A phase 1/2a, multicenter, open-label, non-randomized first-in-human study to assess the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DB-1310 (a HER3-targeting ADC) in patients with advanced/metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT168.

A Phase I Clinical Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of GB221 Injection and Trastuzumab (Herceptin®) in Healthy Chinese Adults.

GB221 is a recombinant humanized anti-HER2 monoclonal antibody. The purpose of this study was to evaluate the pharmacokinetic, safety, and immunogenicity of GB221 in healthy Chinese adults in comparisontotrastuzumab (Herceptin®). In this randomized, double-blind, parallel-group phase I clinical trial, 88 subjects were randomized 1:1 to receive a single intravenous infusion (90-100 min) of GB221 or trastuzumab (6 mg/kg). The primary pharmacokinetic parameters-maximum observed serum concentration (Cmax), area under the serum concentration-time curve from zero to the last quantifiable concentration at time t (AUC0-t), and area under the serum concentration-time curve from time zero to infinity (AUC0-∞)-of GB221 and trastuzumab were compared to establish whether the 90% confidence interval (CI) attained the 80-125% bioequivalence standard. Safety and immunogenicity were also evaluated. The GB221 group (n=43) and the trastuzumab group (n=44) showed similar pharmacokinetic characteristics. The geometric mean ratios (90% CI) of Cmax, AUC0-t, and AUC0-∞ between the two groups were 107.53% (102.25-113.07%), 108.31% (103.57-113.26%), and 108.34% (103.57-113.33%), respectively. The incidence of treatment-emergent adverse events (TEAEs) was 83.7% (36/43) of the subjects in the GB221 group and 95.5% (42/44) of the subjects in the trastuzumab group. No subjects withdrew from the trial due to TEAEs, and there were no occurrences of serious adverse events. All subjects tested negative for antidrug antibodies (ADA). GB221 demonstrated similar pharmacokinetics to trastuzumab and comparable safety and immunogenicity in healthy Chinese adults.