Background: The management of chemotherapy induced anemia (CIA) remains challenging. The potential risk and benefits in providing patient-centered care need to be balanced; the disease is multifactorial; and the major treatments including red blood cell (RBC) transfusions, erythropoiesis-stimulating agents (ESAs) and intravenous injection (i.v.)iron supplementation have a unique set of strengths and limitations. Also, most previous survey based on the patient data could not reveal the process of evaluation and decision-making for CIA treatment from a physician's perspective. As the comparison of China Society of Clinical Oncology (CSCO), National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO) guidelines, the standard of CIA treatment in China will vary from United States and Europe, for example, the initial hemoglobin (Hb) for RBC transfusions. In order to understand the diagnosis, treatment, and unmet medical needs of CIA patients, the China Medical Education Association (CMEA), in conjunction with Cancer Hope Medium, initiated the first national survey of Chinese physicians regarding the diagnosis and treatment of CIA. Methods: The CMEA sent an online, 12-item questionnaire (via wjx.cn) to physicians across China from September 1, 2022 to October 22, 2022. Two hundred and sixty-five samples were calculated usingsurveyplanet.com. The questionnaire evaluated the impact of anemia on chemotherapy interruption, initial treatment, the target Hb level of CIA in, and the current status of ESAs prescription in clinical practice. Respondents were asked to score their reasons for not using ESAs (including safety issues, drug access in practice or adherence) and the risk options of the current treatment including ESAs, RBC transfusion, and i.v.iron. Results: A total of 331 questionnaires among 5,000 web visits were gathered, covering 247 hospitals in 29 provinces across China, of which 130 (53%) were tier IIIA hospitals, 50 (20%) were tier III B hospitals, 59 (24%) were tier IIA hospitals, and 8 (3%) were tier II B hospitals. The frequency of chemotherapy dose delay/reduction due to anemia was 24% [standard deviation (SD) 49%]. Most responding physicians rated an initial Hb level for ESAs treatment to be 80 g/L, with a favorable Hb level for chemotherapy being 100 g/L (60%), which would not limit treatment availability. The majority (67.6%, n=221) of physicians who responded indicated that they had used ESAs for anemia correction, while the others (32.4%, n=106) reported never using them. Conclusions: This is the first study in conducting a large-scale survey on the diagnosis and treatment of CIA in China from a physicians' perspective. We found that in China, nearly one-quarter of patients undergoing chemotherapy with concurrent anemia may experience interruption of chemotherapy and that the initiation of anemia treatment is not adequately timed. In treating CIA, most physicians prioritize the completion of chemotherapy via Hb level over treating the symptoms of anemia.
1084 Background: The combination of poly (ADP-ribose) polymerase inhibitors and immune-checkpoint inhibitors demonstrated synergistic antitumor activity in preclinical studies. Here we report the efficacy, safety, and biomarker analyses of the combination of niraparib and PD-1 inhibitor HX008 in metastatic breast cancer (MBC) patients with germline DDR gene mutations in a phase II trial (CHANGEABLE). Methods: Eligible patients had histologically confirmed MBC with at least one measurable disease and germline pathogenic/suspected pathogenic mutations in DDR genes. Patients were enrolled into two cohorts: the main cohort (HER2-negative MBC patients with gBRCA1/2, gPALB2, gCHEK2) and the exploration cohort (MBC patients with gDDR gene mutations and brain metastases). Simon's Two-Stage design was used for recruiting patients in the main cohort. Patients with HER2-negative MBC received niraparib 200 mg qd combined with HX008 200 mg q3w, while HER2-positive patients received additional anti-HER2 TKI pyrotinib 400mg qd if having brain metastases, until disease progression. The primary endpoint was ORR. NGS of tissue and ctDNA were performed for exploratory biomarker analyses. Results: As of January 12, 2024, 37 patients were enrolled. In the main cohort with gBRCA1/2 mutations (n = 28), ORR was 78.6% (22/28), with 3 patients having complete response. DCR was 96.4% (27/28). Median PFS was 7.3 months (95%CI 4.2 to 10.4). According to Simon's Two-Stage design, since two patients with gCHEK2 mutations in the first stage had only stable disease, the recruitment was terminated. One patient with gPALB2 mutation had stable disease and the remaining one is in the screening process. In the patients having brain metastases (exploration cohort), ORR was 40% (2/5) and DCR was 80% (4/5). The most common treatment-related adverse events of grade 3 or higher were anemia (13 [35.1%]), thrombocytopenia (4 [10.8%]), and neutropenia (3 [8.1%]). No treatment-related deaths were reported. In the biomarker analysis, NGS of 700 genes was performed on 24 patients with gBRCA1/2 mutations in the main cohort. No significant difference was found in ORR or PFS between gBRCA1 and gBRCA2 mutations. Somatic mutations in XPO1 (16 patients (73%), 15/18 PR+CR, 1/4 SD+PD) showed significant correlation with response. Somatic TP53 mutations are significantly correlated with shorter PFS, while ASXL1 mutations are significantly correlated with longer PFS. Four somatic mutations (AR_c.1418_1420del, AR_c.231_239dup, 2 DUSP22 mutations) showed a consistent trend of decreasing in PD samples, while NF1_c.3198-4dup showed a consistent trend of increasing in PD samples. Conclusions: The combination of niraparib and HX008 demonstrated promising clinical benefits with a tolerable safety profile in MBC patients with germline BRCA1/2 mutations, even in patients with brain metastases. Clinical trial information: NCT04508803 .
1046 Background: In the front-line setting, our previous work demonstrated an impressive median progression-free survival (PFS) of 11.3 months with 66.7% response rate, and concluded a recommended phase 2 dose of pyrotinib 320mg/d, dalpiciclib (SHR6390, a novel CDK4/6i) 125mg/d, and letrozole 2.5mg/d for HR+/HER2+ MBC patients (pts) (Xichun Hu, FRONT ONCOL 2022). Results and biomarkers analysis from phase II dose expansion study are presented. Methods: ER+/HER2+ MBC Pts eligible for first- or second-line treatment were enrolled to receive dalpiciclib combined with pyrotinib and ET (letrozole or fulvestrant determined by physician’s choice). The primary endpoint was objective response rate (ORR). For biomarkers analysis, 68 Ga-HER2 affibody, pre-treatment tissue-derived DNA and circulating tumor DNA (ctDNA) were assessed by PET/CT, and next-generation sequencing (NGS), respectively. Results: As of January 19, 2023, 48 pts were enrolled. 17 pts (35.4%) were treatment naïve, and 31 pts (64.6%) had received prior trastuzumab. The ORR was 68.1% (32/47) and disease control rate was 100% (47/47). In trastuzumab-naïve and trastuzumab-pretreated patients, ORR was 81.3% (13/16) and 61.3% (19/31), respectively. PFS and OS data were not mature by cut-off date. No new safety signals were observed. The most frequent treatment-related adverse events were neutropenia (95.8%; G3:60.4%, G4:6.3%), leukopenia (91.7%; G3:45.8%), diarrhea (87.5%; G3:2.1%), anemia (79.2%; G3:4.2%), oral mucositis (68.8%, G3:2.1%) and platelet count decreased (41.7%; G3:2.1%, G4:2.1%). The heterogeneity of 68 Ga-HER2 affibody uptake was observed among patients, both at baseline (N=16，median SUV max 7.5, range, 2.3-34.9) and after 2 cycles of therapy (N=12，median SUV max 4.0, range, 0-14.9). All patients with a decline in 68 Ga-HER2 affibody uptake (N=8) achieved partial response, while the uptake in non-responders was elevated (N=2). NGS was conducted to detect somatic and germline mutations in baseline tissue (n=10) and ctDNA (n=10) samples. Two patients with BRCA mutation (one had somatic BRCA1/ 2 mutation and another with germline BRCA2 mutation) had no tumor response. Conclusions: The chemotherapy-sparing regimens showed significant anti-tumor activity for ER+/HER2+ MBC pts in the front-line setting. The 68 Ga-HER2 affibody PET/CT may be a potential predictive biomarker of therapy response. Additional analysis including correlation of biomarkers with long-term outcomes is underway. Clinical trial information: NCT03772353 .
Trastuzumab, an anti-HER2/ErbB2 humanized antibody, has shown great clinical benefits in ErbB2-positive breast cancer treatment. Despite of its effectiveness, response rate to trastuzumab is limited and resistance is common. Here, we developed a new anti-ErbB2 antibody, denoted as H2-18, which was isolated from a phage display human antibody library. Previous studies have demonstrated that trastuzumab recognizes the juxtamembrane region of domain IV, and pertuzumab, another humanized ErbB2-specific antibody, binds to ErbB2 near the center of domain II. Our crystallographic analysis showed that the epitope recognized by H2-18 is within domain I of the ErbB2 molecule. H2-18 potently induced programmed cell death (PCD) in both trastuzumab-sensitive and -resistant breast cancer cell lines, while trastuzumab and pertuzumab, either used alone or in combination, only exhibits very weak PCD-inducing activity. More importantly, H2-18 could inhibit the growth of trastuzumab-resistant breast cancer cells far more effectively than trastuzumab plus pertuzumab, both in vitro and in vivo. In conclusion, H2-18 shows a unique ability to overcome trastuzumab resistance, suggesting that it has the great potential to be translated to the clinic.
The clinical characteristics and efficacy of human epidermal growth factor receptor-2 (HER-2)-directed agents against HER2 mutations and HER2 fusions in breast cancer are obscure due to their low frequency.We conducted a retrospective study in patients with advanced breast cancer harboring HER2 mutations and/or HER2 fusions between January 1, 2017 and January 1, 2021.Among a total of 22 patients, 17 HER2 mutations were detected, including L755S, S310F, R100=, V777L, R897W, T862A, 440-17C > G, H878Y, V842I, 73 + 9G > C, T278fs, E1069K, L755P, 226-11C > T, 574 + 12C>T, L114V and P128L. The majority of patients had ductal carcinoma, which mostly coexisted with HER2 amplification/overexpression. The median progression-free survival (PFS) of the 22 patients was 6.9 months (95% CI: 4.7, 9.1) in the first-line setting. The median PFS of patients who received first-line trastuzumab-based regimens was significantly longer than that of patients who received a first-line tyrosine kinase inhibitor (TKI) (10.8 months [95% CI: 2.9, 18.7] vs. 1.9 months [95% CI: 0.8, 3.0], p < 0.005). A total of 14 patients were treated with anti-HER2 antibody-drug conjugate (ADC), among whom the median treatment line of first-time of administration of anti-HER2 ADC was 4.5 (range, 1-10). Anti-HER2 ADC reached an objective response rate (ORR) of 42.9%, a disease control rate (DCR) of 85.7% and a median PFS of 7.3 months (95% CI: 4.4-10.1) from the first-time of administration.Our data demonstrated the clinical benefit of anti-HER2 treatment in Chinese breast cancer patients harboring HER2 mutation and/or HER2 fusion. The value of immunotherapy and treatment selection among individual HER2 variants needs further study.
In this phase I study, the safety, pharmacokinetics, and antitumour activity of the HER2-targeted antibody-drug conjugate A166 were evaluated in patients with HER2-expressing advanced solid tumours. Patients with advanced solid tumours refractory to standard therapies received A166 at doses of 0.1, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8 or 6.0 mg/kg Q3W in a standard "3 + 3" design. Dose cohorts were expanded at 4.8 and 6.0 mg/kg Q3W. Primary endpoints were assessment of the safety and tolerability of A166 and identification of the maximum tolerated dose or recommended phase II dose. In total, 81 patients were enroled and received A166 (n = 1 for 0.1 mg/kg; n = 3 for each of 0.3, 0.6, 1.2, 2.4 and 3.6 mg/kg doses; n = 27 for 4.8 mg/kg; n = 38 for 6.0 mg/kg). No dose-limiting toxicity or drug-related deaths occurred. The most common treatment-related adverse events at grade 3 or higher were corneal epitheliopathy (30.9%), blurred vision (18.5%), dry eyes (7.4%), and peripheral sensory neuropathy (6.2%). The Cmax and area under the curve of Duo-5, its free payload, were approximately 0.1% and 0.2% of those of the ADC, respectively. For all assessable HER2-positive breast cancer patients enroled in the 4.8 mg/kg and 6.0 mg/kg cohorts, the corresponding ORRs were 73.9% (17/23) and 68.6% (24/35), respectively, and the median PFS was 12.3 and 9.4 months, respectively. A166 has a recommended phase II dose of 4.8 mg/kg Q3W, manageable toxicity, good stability in the circulation and promising antitumour activities in HER2-positive breast cancer patients.
Trastuzumab resistance is a severe problem in the treatment of ErbB2‑amplified cancer. Although trastuzumab plus pertuzumab is able to partly overcome trastuzumab resistance in ErbB2‑overexpressing cancer, its antitumor efficacy remains limited. The present study investigated the antitumor activity of the combination of trastuzumab with H2‑18, which is an antibody targetinsg ErbB2 domain I. Cell proliferation and inhibition experiments indicated that H2‑18 and trastuzumab synergistically inhibited the proliferation of both the trastuzumab‑sensitive gastric cancer cell line, NCI‑N87 and the trastuzumab‑resistant gastric cancer cell line, NCI‑N87‑TraRT. Furthermore, H2‑18 plus trastuzumab inhibited the growth of NCI‑N87‑TraRT cells more effectively than trastuzumab plus pertuzumab, both in vitro and in vivo. Compared with trastuzumab plus pertuzumab, H2‑18 plus trastuzumab had a potent ability to inhibit NCI‑N87‑TraRT cells to form colonies. Notably, H2‑18 plus trastuzumab was more effective in inducing cell death than trastuzumab plus pertuzumab. The in vivo studies demonstrated that H2‑18 plus trastuzumab effectively inhibited the growth of both NCI‑N87 and NCI‑N87‑TraRT xenograft tumors. Further experiments revealed that in NCI‑N87‑TraRT cells, H2‑18 plus trastuzumab was comparable to trastuzumab plus pertuzumab in the inhibition of phosphorylated (p‑)HER3, p‑AKT and p‑ERK. However, compared with trastuzumab plus pertuzumab, H2‑18 plus trastuzumab effectively activated ROS production and the phosphorylation of JNK and c‑jun in NCI‑N87‑TraRT cells. Therefore, the superior antitumor efficacy of H2‑18 plus trastuzumab over trastuzumab plus pertuzumab may be mainly attributable to the potent cell death‑inducing activity. In addition, the in vitro and in vivo antitumor effect of the combination of H2‑18, trastuzumab and pertuzumab were further investigated. The results revealed that H2‑18 plus trastuzumab plus pertuzumab exhibited a maximal antitumor effect among all the anti‑ErbB2 monoclonal antibody combinations tested. In summary, H2‑18 plus trastuzumab may have potential as an effective strategy to overcome the resistance to trastuzumab in ErbB2‑amplified gastric cancer cell lines.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)