HER2-positive Tumors Research Articles

STAR-221: A randomized, open-label, multicenter, phase 3 trial of domvanalimab, zimberelimab, and chemotherapy versus nivolumab and chemotherapy in previously untreated, locally advanced, unresectable or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma.

TPS4206 Background: The addition of programmed cell death/ligand protein 1 (PD-[L]1) inhibitors to standard chemotherapy has improved outcomes in patients with HER2-negative unresectable or metastatic esophago-gastric adenocarcinomas. Current first-line (1L) treatment for these patients comprises FOLFOX (oxaliplatin, leucovorin, and fluorouracil) and CAPOX (capecitabine and oxaliplatin) chemotherapy, with or without the addition of a PD-1 inhibitor. Domvanalimab (dom) is an Fc-silent humanized IgG1 monoclonal antibody (mAb) that blocks T cell Immunoglobulin and ITIM domains (TIGIT), reducing immunosuppression of T/natural killer (NK) cells and promoting antitumor activity. Zimberelimab (zim) and nivolumab are mAbs that bind to PD-1 on T/NK cells, preventing the immunosuppressive effects of PD-L1 and leading to enhanced immune-mediated tumor cell death. Prior studies (including ARC-7) have demonstrated that the combination of dom + zim is safe, tolerable, and has promising activity in patients with lung cancer and esophago-gastric cancers. This study will investigate whether adding anti-TIGIT therapy to the standard combination of anti-PD-1 therapy and chemotherapy in patients with locally advanced unresectable or metastatic gastric, GEJ, and esophageal adenocarcinoma provides additional clinical benefit. Methods: STAR-221 (NCT05568095) is a global, phase 3, randomized, open-label study. Eligible patients are adults with locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma treated in the 1L setting with ≥1 measurable lesion(s) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with known HER2-positive tumors are not eligible. Approximately 970 patients will be randomized 1:1 into 1 of 2 treatment arms. Patients randomized to Arm A will receive either dom 1600 mg + zim 480 mg every 4 weeks (Q4W) in addition to FOLFOX chemotherapy once every 2 weeks (Q2W) or dom 1200 mg + zim 360 mg once every 3 weeks (Q3W) in addition to CAPOX chemotherapy Q3W. Patients randomized to Arm B will receive either nivolumab 240 mg Q2W + FOLFOX Q2W or nivolumab 360 mg Q3W + CAPOX Q3W. Randomization will be stratified by PD-L1 expression (tumor area positivity [TAP] ≥ 5% vs TAP < 5%), ECOG performance status (0 vs 1), and region (USA, Canada, and EU5 countries vs Asia vs rest of world). The dual primary endpoints are overall survival (OS) in the intent-to-treat population and OS in patients with high PD-L1 expression (TAP ≥ 5%). Secondary endpoints include progression-free survival, objective response rate, duration of response, and safety and tolerability. STAR-221 is currently enrolling globally. Clinical trial information: NCT05568095 .

A novel anti-HER2 monoclonal antibody IAH0968 in HER2-positive, heavily pretreated solid tumors: Results from a phase Ⅰa/Ⅰb, first-in-human, open-label, single-center study.

e15098 Background: IAH0968 is an afucosylated anti-epidermal growth factor receptor 2 (HER2) monoclonal antibody which possessing the same binding properties to HER2 as trastuzumab and improving antibody-dependent cellular cytotoxicity (ADCC) activity and superior anti-tumor efficacy. We present results from patients with advanced HER2 positive malignant solid tumors including trastuzumab resistant and ineffective patients to establish the recommended dose of IAH0968 for phase II trials, as well as to investigate the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of the drug. Methods: This was a single institution investigator-initiated phaseⅠa/Ⅰb study, using 3+3 design. The primary endpoint was safety, tolerability and preliminary clinical activity. Secondary endpoints included PK, recommended phase II dose, and anti-drug antibody (ADA). PK detection used ELISA to quantitatively determine blood drug concentration of IAH0968. Results: Eighteen pts were evaluable for safety and fifteen pts were suitable for efficacy analysis. The primary cancer sites included breast (8/18), colon (3/18), stomach (2/18), rectum (2/18), biliary tract (2/18), and pancreas (1/18). Median age was 54.2±9.7, ECOG 1/2 = 17/1, and 72.2% received anti-HER2 therapy in prior lines. Doses escalation were 6mg/kg (N = 3), 10mg/kg (N = 6), 15mg/kg (N = 5), and tolerable up to 20mg/kg (N = 4). Only one DLT was found at dosage 10mg/kg, and no MTD was reached. No ADA against IAH0968 was detected. The main PK parameters included mean T1/2 for doses 6~20 mg/kg ranging from 105 to 118 hours. The volume of distribution (Vz-obs) ranged from 4110.16 mL to 5395.64 mL. EC50 of ADCC activity of IAH0968 was 17.75~63.25 ×10-3 µg/mL. All grade treatment-related adverse events (TRAEs) occurred in 100% of pts, including grade 3 in 16.7%, and grade 4 in 5.6% of pts. The most common grade 3 TRAEs were hypokalemia (5.6%), arrhythmia (5.6%), QTC interval extension (5.6%), and infusion reaction (5.6%). The grade 4 TRAE was arrhythmia (5.6%). No serious TRAE or G5 were reported. 22.2% of pts had a TRAE leading to dose adjustment and 16.7% leading to discontinuation of IAH0968. After a median follow-up of 56.5 days (range, 0-479), objective response rate (ORR) was 13.3% (2/15), disease control rate (DCR) was 53.3% (8/15), and median progression-free survival (PFS) was 57.5 days (range, 42-236), with 4/15 responses ongoing. Conclusions: In heavily pretreated metastatic pts with HER2 positive, IAH0968 demonstrated promising clinical activity and tolerable safety profiles. IAH0968 will be further assessed in Phase Ⅱ study in combination treatment. Clinical trial information: NCT04934514 .

Preclinical antitumor activity of an anti-HER2/Trop-2 bispecific antibody-drug conjugate with a new DNA topoisomerase I inhibitor.

e15013 Background: In recent years, antibody-drug conjugates (ADCs) have made significant progress in cancer therapy and show a promising future. Among the approved ADCs, Enhertu, the HER2 directed ADC and Trodelvy, the Trop-2 directed ADC, have shown considerable clinical benefits. Bispecific antibody-drug conjugate represents a fast-growing class of next generation ADC due to its potentials in enhancing specificity, improving efficacy, and reducing toxicity. Additionally, targeting more than one molecule can be useful to avoid resistance to treatment and broaden the patient population. Methods: We generated a novel bispecific ADC (BIO-201) co-targeting HER2 and Trop-2 which are the two clinically validated tumor-associated antigens that are expressed on a wide variety of tumors. BIO-201 is consisted of a novel bispecific anti-HER2/Trop-2 antibody conjugated with a potent DNA topoisomerase I inhibitor (TOPO Ii) via a cleavable linker. TOPO Ii is a proprietary payload platform developed in house that exhibits similar characteristics including in vitro and in vivo anti-tumor activities and safety profile to DXd. The bispecific antibody was fully characterized and in vitro and in vivo anti-tumor activity of BIO-201 was assessed using preclinical models. Results: The bispecific antibody showed comparable or increased cell binding and internalization compared with the parental antibodies in various tumor cells that express different surface levels of HER2 and Trop-2. In the in vitro cytotoxicity assay, the bispecific ADC BIO-201 effectively killed cancer cells with IC50 in the sub nM range with BIO-201 being most potent against cancer cells that co-express HER2 and Trop-2. The anti-tumor activity of BIO-201 was further demonstrated in vivo in several tumor xenograft models. Treatment of BIO-201 induced significant tumor regression in HER2 or Trop-2 positive tumors, suggesting broader coverage of tumor types than conventional HER2 and Trop-2 ADCs. BIO-201 also showed similar anti-tumor activity to Herceptin-DXd. Conclusions: Taken together, these findings suggest that anti-HER2/Trop-2 bispecific ADC has potential as an effective therapy for a variety of cancers that co-express HER2/Trop-2 or express either of the targets. BIO-201 may be expected to have a similar clinical activity to Enhertu or Trodelvy but treat more patient sub-populations and indications.

DNA aneuploidy identifies a subset of Luminal subtype breast carcinoma patients with worse clinical outcome.

In breast carcinoma (BC), the relationship between the ploidy pattern and molecular subtyping is still unknown. We aim to investigate the prognostic impact of DNA ploidy within molecular subtypes of a large cohort of BC patients. The series involved 520 BC patients with no neoadjuvant therapy and a median follow-up of 115.5 months. Immunohistochemical assessment of hormonal receptors, ERBB2 (HER2) status and Ki67 proliferative activity was the basis of the surrogate molecular subtyping. Ploidy was evaluated by DNA flow cytometry in fresh/frozen tumour samples. Kaplan-Meier (K-M) survival estimation was used for prognostic statistical analysis. Luminal A subtype had the lowest prevalence of disease recurrences (23.6%) and deaths from disease (18.3%), while Luminal B (42.2%/37.9%), Triple-negative (46.4%/40.6%), and HER2-positive (55.9%/50.0%) subtypes had the highest. The Triple-positive subtype shows an intermediate/low frequency of adverse events (29.4% of disease recurrences and 17.6% of deaths from disease). Luminal A tumours were mostly diploid (55.3%), while Triple-negative and HER2-positive tumours showed a high incidence of aneuploidy (82.6% and 88.2%, respectively). Luminal B and Triple-positive tumours had an intermediate percentage of aneuploidy (63.8% and 70.6%, respectively). K-M survival curves showed that DNA aneuploidy is significantly associated with shorter disease-free survival and overall survival in Luminal A and Luminal B molecular subtypes. DNA aneuploidy identifies a subset of Luminal BC patients with worse clinical outcome, potentially eligible for more aggressive adjuvant therapy.

Synchronous Bilateral Breast Cancer With Discordant Receptor Status: Treating One Patient but Two Diseases

The expression of hormone receptors (estrogen and progesterone) and human epidermal growth factor receptor-2 (HER2) has been used for both therapeutic and prognostic purposes in the management of breast cancer. The presence of a discordant receptor status complicates the approach to treatment in patients with synchronous bilateral breast cancer. We describe the case of a 45-year-old female with synchronous bilateral breast cancer with a triple-negative tumor and a contralateral HER2-positive tumor and discussed the impact of this on the approach to therapeutic management.

Pathological measurement and staging of residual breast cancer after neoadjuvant chemotherapy.

The 8th Edition of the American Joint Committee on Cancer Staging System (yAJCC) excludes treatment-related fibrosis from the measurement of residual tumour after neoadjuvant chemotherapy (NAC) for breast cancer. The impact of the 8th Ed. yAJCC on post-NAC pathologic staging was examined in 188 breast cancer specimens from 183 patients with measurable residual tumour. Tumour size, ypT, and ypN categories were reassessed with the current yACC criteria and compared to the original pathology reports. Histological patterns of response in the breast were categorised as concentric or scattered. The reassessed breast tumour size or ypT category differed from the original report in 101 (53.7%) cases. Changes in the ypT and/or ypN category resulted in downstaging of 45/185 (24.3%). A smaller reassessed tumour size or lower ypT category occurred more often in hormone receptor-positive/HER2-negative (HR+/HER2-) (68.3%) and HER2-positive (HER2+) tumours (74.0%) than triple-negative breast cancer (TNBC) (37.5%) (P < 0.001). A scattered pattern of response was more frequent in HR+/HER2- (54.9%) and HER2+ (66.0%) tumours than TNBC (35.7%) (P = 0.006). Changes in size, ypT, or multifocality based on the 8th Ed. yAJCC criteria were more frequent in tumours with a scattered pattern of response (P < 0.001). Strict adherence to yAJCC criteria for measurement of the residual breast tumour after NAC resulted in smaller tumour size, lower ypT category, lower yAJCC stage, and more frequent classification of residual tumour as multifocal. Downstaging based on 8th Ed. yAJCC criteria was associated with tumour subtype and histological pattern of response.

Development of a Novel HER2-Targeted Peptide Probe for Dual-Modal Imaging of Tumors.

Human epidermal growth factor receptor 2 (HER2) may serve as a valid target for diagnosis of cancer. The probes with capability for near-infrared window one region II (NIR-II) and positron emission tomography (PET) dual-modal imaging are highly desired for HER2-positive tumor detection. Herein, three HER2-targeted peptides were designed and further modified with indocyanine green (ICG) and 2,2',2″,2″-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA), which were used for NIR-II imaging and complexation with 68Ga for PET. Among the resulted probes (DOTA-ZC01-ICG, DOTA-KSP-ICG, and DOTA-ZC02-ICG), NIR-II imaging revealed that DOTA-ZC02-ICG had the best tumor imaging performance in SKOV3 tumor-bearing mice. The highest T/N ratio (5.4) was achieved at 4 h post-injection. Furthermore, DOTA-ZC02-ICG was radiolabeled with 68Ga to generate [68Ga]-DOTA-ZC02-ICG for PET, and it clearly delineated at 0.5, 1, and 2 h post-injection. The tumor uptake reached 1.9 %ID/g at 0.5 h, and the tumor uptakes were significantly inhibited in the blocking study (p < 0.05). Overall, it provides a promising technique for tumor dual-modal imaging and a new molecular scaffold for developing HER2-targeted theranostic agents.

Correlation of PKM2 Expression With HER2/neu and Additional Breast Cancer Biomarkers and its Prognostic Significance.

Pyruvate kinase M2 (PKM2) has a central role in both tumor development and metastasis, and it has increasingly become a valuable subject for many cancer studies due to its important prognostic value in various tumor types. In this study, we aimed to elucidate the impact of PKM2 expression level on breast cancer prognosis and survival rates and its association with various clinicopathologic characteristics and tumor markers in breast cancer patients. This retrospective study included sample tissues from patients with breast cancer who did not receive chemotherapy or radiotherapy before surgery. Expression levels of PKM2, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and Ki-67 were analyzed using tissue microarray and immunohistochemistry. A total of 164 patients were included with an age range from 28 to 82 years. High PKM2 was observed in 48.8% of cases (80/164). A significant association was found between PKM2 expression and breast cancer molecular subtype and HER2 status ( P <0.001). In HER2-negative tumors, there was a significant association between PKM2 expression and tumor grade, TNM stage, pN stage, lymphovascular invasion, and estrogen receptor/progesterone receptor status. Survival analysis revealed that high PKM2 expression levels were associated with decreased overall survival rate in HER2-positive cases with high Ki-67 index. Moreover, in the HER2-positive group, low PKM2 expression level impacted the survival outcome of metastasis ( P =0.002). PKM2 is a valuable prognostic and a potential diagnostic and predictive marker in breast cancer. Moreover, the combination of PKM2 with Ki-67 provides excellent prognostic accuracy in HER2-positive tumors.

Ado-tratuzumab emtansine beyond breast cancer: therapeutic role of targeting other HER2-positive cancers.

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved by the FDA in 2013 for advanced HER2-positive breast cancer treatment exhibiting promising clinical benefits. However, HER2 overexpression and gene amplification have also been reported in other cancers like gastric cancer, non-small cell lung cancer (NSCLC), and colorectal cancer. Numerous preclinical studies have also revealed the significant antitumor effect of T-DM1 on HER2-positive tumors. With the advancement in research, several clinical trials have been conducted to investigate the antitumor effect of T-DM1. In this review, we briefly introduced the pharmacological effects of T-DM1. We reviewed its preclinical and clinical studies, especially on other HER2-positive cancers, establishing what has been encountered between its preclinical and clinical studies. In clinical studies, we found that T-DM1 has a therapeutic value on other cancers. An insignificant effect was observed on gastric cancer and NSCLC, inconsistent with the preclinical studies.

Tucatinib promotes immune activation and synergizes with programmed cell death-1 and programmed cell death-ligand 1 inhibition in HER2-positive breast cancer.

Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy. We investigated the antitumor efficacy and contribution of the immune response of tucatinib using 2 immunocompetent, HER2-positive murine breast cancer models (trastuzumab-sensitive H2N113; trastuzumab-resistant Fo5) and the efficacy of tucatinib with trastuzumab and PD-1 or PD-L1 checkpoint inhibitors. In both models, tucatinib statistically significantly inhibited tumor growth and demonstrated dose-dependent efficacy. Ex vivo analysis by flow cytometry of tumor-infiltrating lymphocytes in mice treated with tucatinib showed increased frequency, higher proliferation, and enhanced effector function of CD8+ effector memory T cells. Tucatinib treatment also increased frequency of CD8+PD-1+ and CD8+TIM3+ T cells, CD49+ natural killer cells, monocytes, and major histocompatibility complex II expression on dendritic cells and macrophages and a decrease in myeloid-derived suppressor cells. Gene expression analysis revealed statistically significant enrichment in pathways associated with immune activation, type I and II interferon response, adaptive immune response, and antigen receptor signaling. In vivo, tucatinib and α-PD-L1 or α-PD-1 demonstrated statistically significantly increased efficacy and improved survival of mice compared with tucatinib alone. Tucatinib modulates the immune microenvironment favorably, and combination treatment with α-PD-L1 or α-PD-1 demonstrated increased efficacy in preclinical HER2-positive tumor models. These findings provide a rationale for investigation of tucatinib and immune checkpoint inhibition in the clinic.

History and Future of HER2-Targeted Therapy for Advanced Gastric Cancer.

Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that belongs to the human epidermal growth factor receptor family. It is overexpressed/amplified in approximately 20% of gastric or gastroesophageal junction cancers. HER2 is being developed as a therapeutic target in a variety of cancers, and several agents have been shown to be effective in breast cancer. The development of HER2-targeted therapy for gastric cancer successfully began with trastuzumab. However, while effective in breast cancer, the successive anti-HER2 agents lapatinib, T-DM1, and pertuzumab failed to demonstrate benefits regarding survival in gastric cancer compared with the existing standard therapies. Intrinsic differences lie between gastric and breast cancer in terms of HER2-positive tumor biology, which may make development difficult. Recently, a novel anti-HER2 agent, trastuzumab deruxtecan, was introduced, and the development of HER2-positive gastric cancer agents has been moving to the next stage. This review summarizes the current HER2-targeted therapy for gastric or gastroesophageal cancer in chronological order and describes the promising future of HER2-targeted therapy.

ESMO update: upper gastrointestinal cancer

SummaryAt the European Society for Medical Oncology (ESMO) 2022 annual meeting, several pertinent studies in the field of upper gastrointestinal cancer were presented. The most practice-changing study appeared to be the Destiny-Gastric02 study evaluating trastuzumab–deruxtecan as a second-line treatment option in patients with Her2-positive gastric and gastroesophageal junction cancer. The median overall survival was 12.1 months with a confirmed overall response rate of 41.8%. 55.7% of patients experienced grade ≥ 3 events with nausea, vomiting, and fatigue being the most frequently observed. This study led to the approval of trastuzumab–deruxtecan as second-line therapy in patients with Her2-positive gastric and gastroesophageal junction tumors who have experienced disease progression after first-line trastuzumab-containing therapy.

Simultaneous Detection of Multiple Tumor-targeted Gold Nanoparticles in HER2-Positive Breast Tumors Using Optoacoustic Imaging.

Purpose To develop optoacoustic, spectrally distinct, actively targeted gold nanoparticle-based near-infrared probes (trastuzumab [TRA], TRA-Aurelia-1, and TRA-Aurelia-2) that can be individually identifiable at multispectral optoacoustic tomography (MSOT) of human epidermal growth factor receptor 2 (HER2)-positive breast tumors. Materials and Methods Gold nanoparticle-based near-infrared probes (Aurelia-1 and 2) that are optoacoustically active and spectrally distinct for simultaneous MSOT imaging were synthesized and conjugated to TRA to produce TRA-Aurelia-1 and 2. Freshly resected human HER2-positive (n = 6) and HER2-negative (n = 6) triple-negative breast cancer tumors were treated with TRA-Aurelia-1 and TRA-Aurelia-2 for 2 hours and imaged with MSOT. HER2-expressing DY36T2Q cells and HER2-negative MDA-MB-231 cells were implanted orthotopically into mice (n = 5). MSOT imaging was performed 6 hours following the injection, and the Friedman test was used for analysis. Results TRA-Aurelia-1 (absorption peak, 780 nm) and TRA-Aurelia-2 (absorption peak, 720 nm) were spectrally distinct. HER2-positive human breast tumors exhibited a significant increase in optoacoustic signal following TRA-Aurelia-1 (28.8-fold) or 2 (29.5-fold) (P = .002) treatment relative to HER2-negative tumors. Treatment with TRA-Aurelia-1 and 2 increased optoacoustic signals in DY36T2Q tumors relative to those in MDA-MB-231 controls (14.8-fold, P < .001; 20.8-fold, P < .001, respectively). Conclusion The study demonstrates that TRA-Aurelia 1 and 2 nanoparticles operate as a spectrally distinct HER2 breast tumor-targeted in vivo optoacoustic agent. Keywords: Molecular Imaging, Nanoparticles, Photoacoustic Imaging, Breast Cancer Supplemental material is available for this article. © RSNA, 2023.

Comparison of renal clearance of [18F]AlF-RESCA-HER2-BCH and [18F]AlF-NOTA-HER2-BCH in mice and breast cancer patients.

A novel HER2 affibody-based molecular probe, [18F]AlF-RESCA-HER2-BCH, was developed for reducing renal uptake, evaluated, and compared with [18F]AlF-NOTA-HER2-BCH. In preclinical studies, micro-PET/CT was performed using HER2-positive gastric cancer patient-derived xenografts (PDX) model at 0.5-1 (dynamic), 2, 4, and 6h post-injection. For blocking experiment, 0.5mg cold affibody was co-injected with probes. Biodistribution were performed on HER2-positive PDX models at 2h post-injection. For clinical study, PET/CT images were acquired at 2h and 4h after injection of 231.29 ± 17.77MBq [18F]AlF-NOTA-HER2-BCH or [18F]AlF-RESCA-HER2-BCH in five breast cancer patients (4 HER2-positive and 1 HER2-low). Standardized uptake values (SUVs) were measured in tumors and source-organs for semi-quantitative analysis. The OLINDA/EXM software (version 1.2) was used to calculate the radiation doses. [18F]AlF-NOTA-HER2-BCH and [18F]AlF-RESCA-HER2-BCH were stably labeled with [18F]F, with high binding specificity and affinity to HER2. Micro-PET/CT of both tracers could clearly visualize HER2-positive PDX tumors with high uptake of 16.24 ± 1.74% ID/g and 14.39 ± 2.45% ID/g at 2h post-injection. The renal accumulation of [18F]AlF-RESCA-HER2-BCH was significantly lower than that of [18F]AlF-NOTA-HER2-BCH (5.16 ± 0.22% ID/g vs. 158.73 ± 5.44% ID/g at 2h, p < 0.0001). In the clinical study, both [18F]AlF-NOTA-HER2-BCH and [18F]AlF-RESCA-HER2-BCH demonstrated favorable tumor targeting and image contrast. [18F]AlF-RESCA-HER2-BCH showed a higher SUVmax in both primary tumor and metastases, and a significantly higher target-to-nontarget ratio in metastases than [18F]AlF-NOTA-HER2-BCH. Moreover, [18F]AlF-RESCA-HER2-BCH had lower renal accumulation (43.56 ± 7.88 vs. 79.81 ± 3.81 at 2h, p < 0.0001; 33.23 ± 6.89 vs. 78.63 ± 4.00 at 4h, p < 0.0001) as well as a significantly lower renal absorbed dose than [18F]AlF-NOTA-HER2-BCH (0.4450 ± 0.1117mGy/MBq vs. 0.8030 ± 0.1604mGy/MBq, p < 0.01). [18F]AlF-RESCA-HER2-BCH tended to provide better image contrast than [18F]AlF-NOTA-HER2-BCH with a higher target-to-nontarget ratio in detection of metastases. Notably, [18F]AlF-RESCA-HER2-BCH had lower renal accumulation than [18F]AlF-NOTA-HER2-BCH.

Abstract CT178: GQ1001: A next generation HER2-targeting ADC that exhibits promising early clinical efficacy with excellent tolerance in a multi-center, Phase Ia study

Abstract Background: GQ1001 is a novel HER2-targeted antibody-drug conjugate (ADC) that was developed using innovative conjugation technologies coined intelligent Ligase-Dependent Conjugation (iLDC), that can significantly improves homogeneity and biostability of ADC. In preclinical studies, GQ1001 showed a robust anti-tumor response in multiple HER2+ models alone or in combination with HER2 TKIs and chemotherapeutics, and excellent pharmacokinetics and safety profiles in rats and monkeys due to low level of payload release. Herein we report the initial results of the ongoing phase Ia study, which aims to investigate the safety, tolerability, pharmacokinetics and antitumor activity of GQ1001 in subjects with HER2+ advanced solid tumors. Methods: In phase Ia dose escalation, a modified 3+3 model was adopted to assess the safety, dose-limiting toxicity (DLT) and maximal tolerable dose (MTD) or dose recommended for dose expansion (DRDE) of GQ1001. GQ1001 was administered intravenously as a monotherapy on Day 1 of 21-day cycles. The starting dose was 1.2 mg/kg, followed by 2.4, 3.6, 4.8, 6.0, 7.2 and 8.4 mg/kg. Results: As of Dec. 28th, 2022, 32 subjects with HER2-positive advanced solid tumors, predominantly in breast (9), gastric or gastro-esophageal junction (9) and salivary gland (4), were enrolled and received GQ1001 treatment. Patients had a median 3 (range, 0-11) prior lines of therapies, and 37.5% of those previously received ≥2 lines of anti-HER2 therapies. Median exposure time of GQ1001 was 18.5 weeks. The longest treatment duration exceeded 370 days. No DLT was observed in all doses, MTD was not reached up to 8.4 mg/kg, the highest dose tested. Treatment-related adverse events (TRAEs) occurred in 24 subjects (75%). The most common TRAEs (&amp;gt;10.0%) were aspartate aminotransferase (AST) increased (37.5%), thrombocytopenia (28.1%), alanine aminotransferase (ALT) increased (25.0%), pyrexia (21.9%), anemia (18.8%), alkaline phosphatase increased (12.5%), vomiting (12.5%) and nausea (12.5%). Grade ≥3 TRAEs occurred in 9 subjects (28.1%), including 5 myelosuppression, 2 abnormal liver function, 1 hypertension and 1 vomiting. There were no drug-related deaths. The pharmacokinetics analysis showed the concentration of GQ1001 and TAb generally peaked rapidly and declined in a roughly biphasic manner. Among 15 evaluable subjects who received ≥ 7.2 mg/kg, 6 cases achieved confirmed partial response, and 3 had stable disease, the median progression-free survival was 4.8 months Conclusions: GQ1001 demonstrates an excellent tolerability and promising antitumor activity in heavily pretreated HER2-positive advanced solid tumors, supporting further evaluation of the safety and efficacy of GQ1001 at DRDE of 8.4 mg/kg in the following phase Ib trial. (NCT04450732; sponsored by GeneQuantum Healthcare (Suzhou) Co., Ltd.) Citation Format: Charlotte Lemech, Chenfei Zhou, Xianbao Zhan, Yan Shi, Jieqiong Liu, Sarina A Piha-Paul, Gary Richardson, Gang Qin, Paul H. Song, Lili Shi, Yajun Sun, Yi Xia. GQ1001: A next generation HER2-targeting ADC that exhibits promising early clinical efficacy with excellent tolerance in a multi-center, Phase Ia study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT178.

Clinicopathological features and prognoses of very young patients (≤35 years) with breast cancer: a retrospective population-based study in China.

Clinicopathological features and prognoses of very young patients (≤35 years) with breast cancer: a retrospective population-based study in China.

Abstract 1773: Preclinical characterization of allogeneic Vγ9Vδ2 HER2-TAC T cells for the treatment of HER2-positive solid tumors

Abstract Background: The T cell antigen coupler (TAC) is a novel, proprietary chimeric receptor that facilitates the redirection of T cells to tumor cells and activates T cells by co-opting the endogenous T cell receptor complex with the goal to elicit safe and durable anti-tumor responses. TAC01-HER2, a first-in-class, autologous TAC T cell product targeting HER2 (ERBB2), has entered a phase I/II clinical trial in patients with HER2-positive solid tumors. Here, we describe the development of an allogeneic HER2-TAC T cell product based on Vγ9Vδ2 (γδ) T cells which belong to a subset of T cells that recognize target cells in a human leukocyte antigen (HLA) independent manner. Thus, γδ T cells do not cause GvHD and have the potential for allogeneic cell therapy applications. Materials and Methods: A variety of in vitro and in vivo assays were used to evaluate the potency and safety of HER2-TAC γδ T cells generated from multiple donors. In vitro assays included flow cytometric analysis determining the γδ T cell phenotype, intracellular cytokines, CD69 upregulation, and T cell proliferation. Anti-tumor cytotoxicity was assessed via real-time microscopy-based co-culture assays. Mixed lymphocyte reactions (MLR) were performed to measure cytokine production and proliferation of HER2-TAC γδ T cells in response to HLA mismatches between unrelated donors. In vivo studies examined the anti-tumor effect of HER2-TAC γδ T cells against established solid HER2-expressing tumors. Results: HER2-TAC γδ T cells selectively reacted to HER2-expressing tumor cells in co-culture, as demonstrated by CD69 upregulation, intracellular cytokine production, increase in proliferation, and cytotoxicity. In contrast, HER2-TAC γδ T cells failed to show activity in MLR assays, potentially indicating that HER2-TAC γδ T cells are free of GvH reactivity. These MLR assays comprised dendritic cells that represent the major HLA subtypes found in North America. In addition, HER2-TAC γδ T cells showed strong anti-tumor efficacy in HER2-positive tumor xenograft models without signs of toxicity. Conclusions: The in vitro and in vivo data confirm strong and specific activity of HER2-targeted TAC γδ T cells against HER2-expressing tumor models and highlights the potential of the TAC platform in the development of an allogeneic product for therapeutic applications in solid tumors. Citation Format: Suzanna L. Prosser, Stacey X. Xu, Ling Wang, Ritu R. Randhawa, Sailaja Pirati, Laura Ravensbergen, Seungmi Yoo, Miyoung Jung, Laurentia Gheorghiu, Angel Gomez, Gurleen Sandhu, Chris Ayers, Donna Rill, Christopher W. Helsen, Andreas G. Bader. Preclinical characterization of allogeneic Vγ9Vδ2 HER2-TAC T cells for the treatment of HER2-positive solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1773.

Abstract 3188: Patient-derived TAC01-HER2 TAC T cells produced in Cocoon® Platform is highly functional in models of solid tumors

Abstract Background: The T cell antigen coupler (TAC) is a novel, proprietary chimeric receptor that facilitates the re-direction of T cells to tumor cells and activates T cells by co-opting the endogenous T cell receptor complex with the goal to elicit a safe and durable anti-tumor response. TAC01-HER2, a first-in-class TAC T product targeting HER2 (ERBB2), has entered a Phase I/II clinical trial in patients with HER2-positive solid tumors. Here, we characterized the TAC T cell phenotypes and anti-tumor activity of TAC01-HER2 manufactured using leukocytes from Phase I/II patients in nonclinical in vitro and in vivo assays. Materials and Methods: TAC T cell proliferation, activation, and phenotype of patient-derived TAC01-HER2 were assessed by flow cytometric analysis. In vitro anti-tumor cytotoxicity was assessed via a real-time microscopy-based co-culture assay, and in vivo anti-tumor activity of TAC01-HER2 was assessed in mice engrafted with established solid HER2-expressing human tumors. Results: Complex phenotype analysis showed that patient-derived TAC01-HER2 products consisted of a high percentage of memory T cells similar to products generated from healthy donors. Patient-derived products had significant proportions of CD4 and CD8 T cells, with CD4 being the predominant population in several of these. In a 5-day in vitro potency assay, patient-derived products showed effective tumor cell killing at low E:T rations (1:1 to 1:20) which was comparable to product generated from healthy donors. Similarly, intravenous administration of patient-derived TAC01-HER2 in mice carrying HER2-positive tumors xenografts led to a complete and sustained tumor clearance. Conclusion: The in vitro and in vivo data confirm the potency of patient-derived TAC01-HER2 against HER2-expressing solid tumor models. This work combined with other biomarkers may help correlate nonclinical potency with clinical outcomes. Citation Format: Ling Wang, Stacey X. Xu, Tania Benatar, Ritu R. Randhawa, Philbert Ip, Prabha Lal, Thanyashanthi Nitya-Nootan, Laura Ravensbergen, Heather MacGregor, Suzy Prosser, Sadhak Sengupta, Christopher W. Helsen, Andreas G. Bader. Patient-derived TAC01-HER2 TAC T cells produced in Cocoon® Platform is highly functional in models of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3188.

Abstract 1873: D3L-001, a novel bispecific antibody targeting HER2 and CD47, demonstrates potent preclinical efficacy in solid tumors

Abstract Background: HER2 is overexpressed in different solid tumors, including 10-20% breast and gastric cancers. Many HER2-targeted drugs, including trastuzumab, pertuzumab, lapatinib, trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (T-DXd), have been approved for treatment of HER2-positive early and metastatic breast cancer (BC). However, trials involving pertuzumab, lapatinib and T-DM1 have failed to provide significant clinical improvements in patients with HER2-positive gastric cancer (GC), suggesting differences in HER2 mediated disease biology between HER2-positive BC and GC. Recent studies have suggested efficacy of HER2 antibodies could be further enhanced by antibody-dependent cellular phagocytosis (ADCP) principally regulated by “don’t-eat-me” CD47 signals, which is overexpressed in many HER2-positive cancers and suppresses phagocytosis through binding to SIRPα. Methods: BC and GC cell lines were used. Monocytes were isolated from human PBMC and differentiated into macrophages, which were used for in vitro ADCP assays. In in vivo animal experiments, D3L-001 and comparator antibodies were examined for efficacy in solid tumor xenograft models. Results: D3L-001 was designed to have higher HER2 affinity (KD &amp;lt; 1 nM) than that of CD47 (KD &amp;gt;10 nM). With this unique design, D3L-001 showed preferential binding to HER2/CD47 double positive tumor cells as compared to CD47 single positive cells. D3L-001 showed better anti-tumor effect than trastuzumab in a panel of solid tumor models, including but not limited to BC and GC cell lines or patient derived xenografts. Immunohistochemistry (IHC) analysis was performed in tumor FFPE slides to evaluate expression of HER2 and CD47 in the efficacy tested models, and we observed that D3L-001 showed broad tumor growth inhibition in HER2 or CD47 high/low expression models. In both in vitro and in vivo studies using breast cancer HCC1954, JIMT-1 and gastric cancer N87 models, we observed a synergistic effect in the combination of Trastuzumab with Magrolimab. Moreover, D3L-001 showed a trend of better efficacy than the combination of Trastuzumab and Magrolimab. These results confirm the synergistic effect of dual-targeting HER2 and CD47 simultaneously and suggest advantage of using bispecific antibodies to confer such effect. D3L-001 also displayed potent and comparable in vivo efficacy as Enhertu in gastric N87 model, and it showed synergistic in vivo efficacy, when combining with Pertuzumab or Paclitaxel, in breast HCC1954, JIMT-1 and gastric cancer N87 models. Conclusion: D3L-001, a novel HER2×CD47 bsAb, demonstrated potent anti-tumor effect in a variety of solid tumor models via HER2 guided CD47 co-blocking. It also showed synergistic efficacy when combining with other anti-tumor agents. D3L-001 will be further evaluated in clinic for its potential as a novel treatment option in HER2-positive BC, GC and other solid tumors. Citation Format: Haopeng Rui, Xiaofeng Yang, Jiahao Chen, Jia Wang, Zhiqiang Zheng, Zhiqiang Chen, Jingtao Lu, Peggy Wu, Janet Chen, Allison Wang, George Chen. D3L-001, a novel bispecific antibody targeting HER2 and CD47, demonstrates potent preclinical efficacy in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1873.

Abstract 2702: GQ1001 is a next generation HER2-targeting ADC with excellent druggability, safety and potency

Abstract Background: GQ1001 was developed to overcome the current limitation of existing HER2 ADCs by using the next generation site-specific conjugation and a stable linker technology, coined the intelligent ligase-dependent conjugation (iLDC) technology. iLDC provides a robust platform for the generation of ADC with high homogeneity and excellent stability. Our data show that GQ1001 is highly homogeneous with strong anti-tumor potency, more importantly, markedly enhanced linker stability and reduced off-target toxicity, and points to a safer HER2 ADC with a larger therapeutic window in human. Methods: In vitro and in vivo anticancer efficacy and the mechanism of action (MOA) of GQ1001 were assessed using several HER2+ cancer cell lines and animal models. Ex vivo linker stability was assessed by incubating GQ1001 with the plasma from different species. Pharmacokinetics in cynomolgus monkeys and safety profiles in rats and monkeys were evaluated. Results: GQ1001 was generated by conjugating trastuzumab to DM1 via an unique open-ring containing linker and the enzyme-based site-specific conjugation technology that significantly increases the stability of GQ1001. Optimal physiochemical property of GQ1001was demonstrated from the long-term stability study in liquid formulation. GQ1001 demonstrated similar in vitro anti-cancer activities to T-DM1 in HER2+ tumor cells. However, T-DM1 showed significant non-specific cytotoxicity in HER2- cells while GQ1001 didn’t. In animal studies, GQ1001 induced a robust dose-dependent tumor growth inhibition in multiple HER2-positive CDX and PDX models. From the combo treatment studies, GQ1001 showed synergistic anti-tumor response when combined with HER2-targeting tyrosine kinase inhibitors TKIs and chemotherapeutic agents in multiple HER2-positive models, including those resistant to anti-HER2 TKIs and/or mAbs. In ex vivo plasma stability assay, the DM1-shedding ratio of GQ1001 in human plasma was ~1/100th of that of T-DM1. This supreme linker stability was confirmed by the favorable pharmacokinetics in monkey with extremely low free DM1 exposure in circulation at a significantly lower level than T-DM1. The highest non-severely toxic dose HNSTD of GQ1001 in monkey was 45 mg/kg without any signs of peripheral neuropathy and interstitial lung disease, suggesting GQ1001 will demonstrate excellent tolerance in human. Consistent with this preclinical data, GQ1001 demonstrated superior tolerability profile in heavily pretreated HER2-positive advanced solid tumors patients in a global, open labeled multicenter phase Ia trial. Conclusions: GQ1001 is a unique HER2-targeting ADC that exhibits markedly-enhanced linker stability and safety profiles. Judging from preclinical data, GQ1001 demonstrates the potential to treat HER2-positive cancer patients, alone or in combination, who have progressed on previous HER2-targeting therapeutics with reduced toxicity. Citation Format: Lei Huang, Lili Shi, Yajun Sun, Cao Lv, Chengcheng Gong, Chong Liu, Jun Yang, Lu Jiang, Jinduo Yuan, Xuesong Li, Mingyu Hu, Xinju Gao, Yu Si, Hui Yang, Yan Shi, Bo Yang, Paul H. Song, Gang Qin, Biyun Wang. GQ1001 is a next generation HER2-targeting ADC with excellent druggability, safety and potency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2702.