Neutropenia Research Articles

Ciprofloxacin prophylaxis during haematopoietic cell transplantation: a role for use in patients with germ cell tumours?

Introduction. Fluoroquinolone prophylaxis during haematopoietic cell transplantation (HCT) can lead to antimicrobial resistance (AMR). Identifying the groups of patients that have the highest likelihood of benefiting from prophylactic antimicrobials is important for antimicrobial stewardship (AMS).Hypothesis. We aimed to identify groups of HCT recipients that have the highest likelihood of benefiting from prophylactic fluroquinolones.Methods. All admissions for HCT in a tertiary centre between January 2020 and December 2022 (N = 400) were retrospectively studied. Allogeneic HCT (allo-HCT) recipients had prophylaxis with ciprofloxacin during the chemotherapy-induced neutropenia, while autologous HCT (auto-HCT) recipients did not. Bacteraemias were recorded when non-contaminant bacterial pathogens were isolated in blood cultures.Results. Allo-HCT was performed for 43.3 % (173/400) of patients and auto-HCT was performed for 56.7 % (227/400). A bacteraemia was documented in 28.3 % (113/400) of cases. Allo-HCT recipients were more likely to have a Gram-positive bacteraemia (20.8%, 36/173, vs 10.1%, 23/227, P = 0.03), while a difference was not observed for Gram-negative bacteraemias (18.5%, 32/173 vs 18.1%, 41/227, P = 0.91). Among auto-HCT recipients not receiving ciprofloxacin prophylaxis, patients with germ cell tumours had the highest probability (P for trend 0.09) of recording any bacteraemia (43.5%, 10/23) followed by patients with lymphomas (32.5%, 13/40), other auto-HCT indications (22.2%, 2/9), multiple myeloma (22.1%, 29/131) and multiple sclerosis (12.5%, 3/24). The higher number of bacteraemias in patients with germ cell tumours was primarily driven by Gram-negative pathogens.Conclusions. Ciprofloxacin prophylaxis was associated with a reduced incidence of Gram-negative bacteraemias in allo-HCT recipients. Auto-HCT recipients due to germ cell tumours, not receiving ciprofloxacin prophylaxis, recorded the highest incidence of bacteraemias and represent a possible target group for this intervention.

QL1209 (pertuzumab biosimilar) versus reference pertuzumab plus trastuzumab and docetaxel in neoadjuvant treatment for HER2-positive, ER/PR-negative, early or locally advanced breast cancer: A multicenter, randomized, double-blinded, parallel-controlled, phase III equivalence trial

BackgroundThis randomized, parallel-controlled, double-blinded, phase III equivalence study evaluated the equivalence of a proposed pertuzumab biosimilar QL1209 to the pertuzumab (Perjeta®) each with trastuzumab and docetaxel in neoadjuvant treatment of early or locally advanced breast cancer patients with HER2-positive, ER/PR-negative.MethodsEligible patients were randomly (1:1) assigned to receive 4 cycles of neoadjuvant QL1209 or pertuzumab each with trastuzumab and docetaxel, and adjuvant treatment. The primary endpoint was total pathologic complete response (tpCR), with equivalence margins of 0.76 to 1.32.ResultsAmong the 585 patients enrolled, 257 and 259 patients were assigned to the QL1209 and pertuzumab groups, respectively. The tpCR rates were comparable in the QL1209 (109/255, 42.75%; 90% CI 37.65 to 47.84) and pertuzumab (117/259, 45.17%; 90% CI 40.09 to 50.26) groups. The tpCR risk ratio was 0.95 (90% CI, 0.80 to 1.11), and the 90% CI fell within the predefined equivalence margin. The most common grade ≥3 treatment-related adverse event was decreased neutrophil count (10. 9% vs. 12.7%) in the QL1209 and pertuzumab groups.ConclusionsQL1209 demonstrated equivalent efficacy and comparable safety profile to the reference pertuzumab in neoadjuvant treatment of HER2-positive, ER/PR-negative, early, or locally advanced breast cancer.Trial registrationChinadrugtrials.org CTR20201073; ClinicalTrials.gov NCT04629846.

Safety, Efficacy, and Pharmacokinetics of SHR-A1811, a Human Epidermal Growth Factor Receptor 2-Directed Antibody-Drug Conjugate, in Human Epidermal Growth Factor Receptor 2-Expressing or Mutated Advanced Solid Tumors: A Global Phase I Trial.

SHR-A1811 is an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. We assessed the safety, tolerability, antitumor activity, and pharmacokinetics of SHR-A1811 in heavily pretreated HER2-expressing or mutated advanced solid tumors. This global, multi-center, first-in-human, phase I trial was conducted at 33 centers. Patients who had HER2-expressing or mutated unresectable, advanced, or metastatic solid tumors and were refractory or intolerant to standard therapies were enrolled. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg once every 3 weeks. The primary end points were dose-limiting toxicity, safety, and the recommended phase II dose. From September 7, 2020, to February 27, 2023, 307 patients who had undergone a median of three (IQR, 2-5) previous treatment regimens in the metastatic setting received SHR-A1811 treatment. As of data cutoff (February 28, 2023), one patient from the 6.4 mg/kg group experienced dose-limiting toxicities (pancytopenia and colitis). The most common grade 3 or higher adverse events (AEs) included decreased neutrophil count (119 [38.8%]) and decreased WBC count (70 [22.8%]). Interstitial lung disease occurred in only eight (2.6%) patients. Serious AEs and deaths occurred in 70 (22.8%) and 13 (4.2%) patients, respectively. SHR-A1811 led to objective responses in 59.9% (184/307) of all patients, 76.3% (90/118) of HER2-positive breast cancer, 60.4% (55/91) of HER2 low-expressing breast cancer, and 45.9% (39/85 with evaluable tumor responses) of the 98 nonbreast tumors. SHR-A1811 exhibited acceptable tolerability, promising antitumor activity, and a favorable pharmacokinetic profile in heavily pretreated advanced solid tumors. The recommended phase II dose of 4.8 or 6.4 mg/kg was selected for various tumor types.

Neutropenia in Childhood-A Narrative Review and Practical Diagnostic Approach.

Neutropenia refers to a decrease in the absolute neutrophil count according to age and race norms and poses a common concern in pediatric practice. Neutrophils serve as host defenders and act crucially in acute inflammation procedures. In this narrative review, we systematically present causes of neutropenia in childhood, mainly adopting the pathophysiological classification of Frater, thereby studying (1) neutropenia with reduced bone marrow reserve, (2) secondary neutropenia with reduced bone marrow reserve, and (3) neutropenia with normal bone marrow reserve. Different conditions in each category are thoroughly discussed and practically approached from the clinician's point of view. Secondary mild to moderate neutropenia is usually benign due to childhood viral infections and is expected to resolve in 2-4 weeks. Bacterial and fungal agents are also associated with transient neutropenia, although fever with severe neutropenia constitutes a medical emergency. Drug-induced and immune neutropenias should be suspected following a careful history and a detailed clinical examination. Cytotoxic chemotherapies treating malignancies are responsible for severe neutropenia and neutropenic shock. Rare genetic neutropenias usually manifest with major infections early in life. Our review of taxonomies clinical findings and associates them to specific neutropenia disorders. We consequently propose a practical diagnostic algorithm for managing neutropenic children.

Cost-effectiveness analysis of granulocyte colony-stimulating factors for the prophylaxis of chemotherapy-induced febrile neutropenia in patients with breast cancer in Taiwan.

To examine the cost-effectiveness of using granulocyte colony-stimulating factor (G-CSF) for primary or secondary prophylaxis in patients with breast cancer from the perspective of Taiwan's National Health Insurance Administration. A Markov model was constructed to simulate the events that may occur during and after a high-risk chemotherapy treatment. Various G-CSF prophylaxis strategies and medications were compared in the model. Effectiveness data were derived from the literature and an analysis of the National Health Insurance Research Database (NHIRD). Cost data were obtained from a published NHIRD study, and health utility values were also obtained from the literature. Sensitivity analyses were performed to assess the uncertainty of the cost-effectiveness results. In the base-case analysis, primary prophylaxis with pegfilgrastim had an incremental cost-effectiveness ratio (ICER) of NT$269,683 per quality-adjusted life year (QALY) gained compared to primary prophylaxis with lenograstim. The ICER for primary prophylaxis with lenograstim versus no G-CSF prophylaxis was NT$61,995 per QALY gained. The results were most sensitive to variations in relative risk of febrile neutropenia (FN) for pegfilgrastim versus no G-CSF prophylaxis. Furthermore, in the probabilistic sensitivity analysis, at a willingness-to-pay threshold of one times Taiwan's gross domestic product per capita, the probability of being cost-effective was 88.1% for primary prophylaxis with pegfilgrastim. Our study suggests that primary prophylaxis with either short- or long-acting G-CSF could be considered cost-effective for FN prevention in breast cancer patients receiving high-risk regimens.

Comparison of prophylactic effects for chemotherapy-induced neutropenia between same-day vs next-day administration of pegteograstim in chemotherapy regimen composed of day 1 intensive myelosuppressive agent: A randomized phase III trial (CONCISE, KCSG PC22-11).

TPS12149 Background: Administration of peg-GCSF 24 to 72 hours after chemotherapy is usually recommended. Next-day administration (after 24 hours) resulted in fewer duration of Gr4 chemotherapy-induced neutropenia (CIN) and decreased severity of CIN than same-day (within 4 hours). However, patients sometimes receive same-day Peg-GCSF for the sake of convenience. In addition, a few prior studies showed that the same-day method is comparable or superior to the next-day in preventing CIN, especially in regimens that include day 1 myelosuppressive agents. Thus, we aim to test hypothesis that same-day administration of pegteograstim, a new formulation of peg-GCSF, is non-inferior to next-day administration in terms of Gr4 CIN duration. Methods: This study is a randomized, multicenter, open-label, investigator-initiated phase 3 study. Patients with adjuvant/neoadjuvant or 1st palliative chemotherapy comprising intensively myleosuppressive agents on day 1 (mFOLFIRINOX, ECb, EP, FOLFIRI, and FOLFOX) are enrolled. The patients are assigned to the same-day arm or the next-day arm in a 1:1 ratio. Randomizations are stratified according to number of CIN risk (1 vs ≥2), setting (perioperative vs palliative), and interval (2- vs 3-week). In the same-day, pegteograstim 6 mg is SC injected within 4 hrs after chemotherapy, while 24-36 hrs in the next-day. CBC test is performed daily from day 5 to 9 during the cycle 1. From cycle 2 to 4, treatments are performed in accordance with general practice, including checking for febrile neutropenia (FN), dose intensity, and safety. The primary endpoint is duration of Gr4 CIN (during cycle 1), and secondary endpoints include incidence of Gr 3-4 CIN (cycle 1), severity of CIN (cycle 1), time to recovery ANC 1000/㎕ (cycle 1), incidence of FN, CIN-related dose delay, and dose intensity. In order to verify non-inferiority of 0.6 days of Gr4 CIN duration, we estimated a significance level of 5%, power of 80%, and drop-out rate of 15%. This results in the need for a total of 160 patients, 80 in each arm. We are currently recruiting patients (since Nov 2022). Clinical trial information: KCT0007694 .

Safety and efficacy of PEG-rhG-CSF as primary prophylaxis against neutropenia induced by combination chemotherapy regimens involving oral chemotherapy agents in gastrointestinal cancer patients: A prospective, exploratory, non-randomized controlled study.

e24107 Background: The safety and efficacy of PEGylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for prevention of chemotherapy-induced neutropenia (CIN) in patients undergoing oral chemotherapy remain unclear. This study investigated the safety and efficacy of PEG-rhG-CSF as primary prophylaxis against CIN in gastrointestinal (GI) cancer patients receiving combination chemotherapy regimens involving oral chemotherapy agents. Methods: This is a prospective, single-center, open-label, exploratory, non-randomized controlled study. GI cancer patients receiving two consecutive cycles of IV oxaliplatin (150mg/m2 on day 1) combined with oral capecitabine 1000mg/m2 or tegafur gimeracil oteracil potassium capsule 40-60mg twice daily on days 1-14 every 3 weeks. PEG-rhG-CSF (6mg) was administered subcutaneously 24 hours post-oxaliplatin treatment in the PEG-rhG-CSF group, while the control group did not receive it. The primary endpoint was safety, and secondary endpoints included CIN incidence and neutropenic complications. The study was registered with the Chinese Clinical Trial Registry (registration number ChiCTR2100054854). Results: Between March 2022 and January 2023, a total of 49 patients was screened, and 43 patients completed the treatment (26 in PEG-rhG-CSF group and 17 in control group). The average age was 61.4 years, with 90.7% males and 83.7% having gastric cancer. Baseline characteristics were similar between the two groups. The overall adverse events (AE) did not differ statistically (88.5% vs. 88.2%, p = 1.000), with grade £2 fatigue and nausea being the most common AEs. Grade 3 platelet reduction showed no significant difference between the two groups (7.69% vs. 17.65%, p = 0.432). Four cases of bone pain (15.4%) and five cases of injection site reactions below grade 3 (19.2%) were observed in the PEG-rhG-CSF group. Grade ≥2 CIN was significantly lower in the PEG-rhG-CSF group (3.84% vs. 58.82%, p < 0.001). One case in the PEG-rhG-CSF group required antibiotic treatment due to febrile neutropenia. Regarding neutropenic complications, the PEG-rhG-CSF group exhibited lower proportion of chemotherapy delay (3.85% vs. 35.29%, p < 0.001) and dose reduction (1.92% vs. 23.53%, p = 0.002). Rescue treatment with rhG-CSF for grade 3/4 CIN was significantly less frequent in the PEG-rhG-CSF group (1.92% vs. 23.53%, p = 0.002). Conclusions: Primary prophylaxis with PEG-rhG-CSF in GI cancer patients undergoing oral capecitabine/tegafur gimeracil oteracil potassium may be safe, without an increased chemotherapy-related AEs, and is associated with a reduced grade ≥2 CIN. Clinical trial information: ChiCTR2100054854.

A phase 1 study of SHR-A1912, a CD79b targeted antibody-drug conjugate (ADC), in patients (pts) with B-cell non-Hodgkin lymphoma (B-NHL).

7064 Background: CD79b is an attractive therapeutic target for B-NHL. SHR-A1912 is a novel ADC containing an anti-CD79b monoclonal antibody conjugated to the DNA topoisomerase I inhibitor. Here, we present results of the dose-escalation (D-ESC) and dose-expansion (D-EXP) parts of a first-in-human phase 1 study of SHR-A1912 in B-NHL. Methods: Pts with histologically confirmed B-NHL that had failed to respond to or had progressed after ≥1 prior anti-cancer therapy were enrolled. The D-ESC part commenced with accelerated titration at 0.1 and 0.3 mg/kg and then switched to an i3+3 scheme at escalated doses starting from 0.6 mg/kg (Q3W, IV). In the D-EXP part, additional pts were enrolled to selected doses (approximately 10–12 pts in total per dose level). Primary objectives were to assess the safety and tolerability of SHR-A1912 and determine the RP2D. Results: As of Nov 7, 2023, 49 pts were enrolled (n=1, 1, 7, 3, 13, 13, and 11 in the 0.1, 0.3, 0.6, 1.2, 1.8, 2.7, and 3.6 mg/kg dose cohorts), including 33 pts with diffuse large B-cell lymphoma (DLBCL), 12 with follicular lymphoma (FL), and 4 with marginal zone lymphoma (MZL). Pts had received a median of 2 lines of prior treatment (range, 1–9). DLTs occurred in 3 pts during D-ESC (grade 4 decreased neutrophil count lasting ≥3 days in 0.6 and 3.6 mg/kg cohorts, 1 pt for each; grade 3 pneumonia in 2.7 mg/kg cohort, 1 pt). The 1.8, 2.7, and 3.6 mg/kg cohorts were expanded. Overall, grade ≥3 treatment-related adverse events occurred in 20 (40.8%) pts, with the most common (≥20%) being decreased neutrophil count. 41 pts with baseline target lesions had at least one post-baseline assessment; ORR was 56.1% (95% CI, 39.8–71.5), and 6-mo DoR rate was 62.7% (95% CI, 26.7–84.8). As for subtypes, ORR was 51.9% in pts with DLBCL (57.1% and 77.8% in the 2.7 and 3.6 mg/kg cohorts, respectively), 63.6% in pts with FL, and 66.7% in pts with MZL (Table). The mean half-life of conjugated antibody ranged from 4.7 to 5.3 days for pts in the 1.8–3.6 mg/kg cohorts, with volume of distribution close to human plasma volume. The plasma exposure of free toxin was low, with the molar ratio of toxin/conjugated-antibody <1%, and no accumulation was observed. Conclusions: SHR-A1912 was tolerable up to 3.6 mg/kg and had promising anti-tumor activity in pts with previously treated B-NHL, supporting further investigations of SHR-A1912. Clinical trial information: NCT05113069 . [Table: see text]

Clinical and translational results from REVOLUTION cohorts A (nivolumab + ipilimumab + chemotherapy) and B (hydroxychloroquine + ipilimumab + chemotherapy) in patients with previously untreated metastatic pancreatic adenocarcinoma.

4137 Background: Metastatic pancreatic adenocarcinoma (mPDAC) is largely refractory to treatment, including immunotherapy. However, recent developments in chemoimmunotherapy combinations show promise. Herein, we report results from the first 2 cohorts of REVOLUTION, an ongoing, adaptive platform study designed to assess the safety and antitumor activity of novel chemoimmunotherapy combinations in patients (pts) with untreated mPDAC. Methods: REVOLUTION (NCT04787991) is an open-label, non-randomized, exploratory platform trial. Pts were assigned by investigator choice to one of the enrolling cohorts. All pts in Cohorts A and B received 1000 mg/m2 gemcitabine, 125 mg/m2 nab-paclitaxel, and 2 doses of 1 mg/kg ipilimumab. In addition, pts received 360 mg nivolumab Q3W in Cohort A or 600 mg hydroxychloroquine BID in Cohort B. Primary endpoint: safety. Secondary endpoints: ORR, DCR, DOR, PFS, and OS. Exploratory endpoints: pharmacodynamics and association of tumor and blood biomarkers with clinical activity. Each cohort utilized a Simon two-stage design: n=15 in Stage 1 with expansion to Stage 2 (an additional n=15) based on the totality of safety, efficacy and biomarker analyses. Results: Both cohorts enrolled 15 pts each. Median treatment duration was 6.5 and 5.6 months (mo), and median study duration was 19.1 and 12.7 mo for A and B, respectively. All pts experienced a treatment-related adverse event (TRAE). Grade 3-4 TRAEs occurred in 60% of A (most common: decreased neutrophil count [n=4]) and 53% of B (most common: anemia [n=5], decreased neutrophil count [n=4]). In B, 2 pts discontinued due to AEs, with none occurring in A. One grade 5 TRAE (multiple organ dysfunction syndrome, deemed related to chemotherapy) occurred in B; none in A. Table shows efficacy results. Cohort A revealed increased activated/proliferating CD4 T cells, CD8 T cells, Tregs, and soluble PD-1 in circulation. Cohort B showed increases in activated/proliferating CD4 T cells and signs of autophagy inhibition. Preliminary multi-omic analyses that aim to associate biomarkers with clinical response will be presented. Conclusions: REVOLUTION cohorts A and B demonstrated antitumor activity in pts with mPDAC. Cohort B treatment, which included hydroxychloroquine, incurred more early discontinuations. As designed, neither cohort will advance to Stage 2, highlighting the need for further tailored therapeutic approaches in mPDAC. Clinical trial information: NCT04787991 . [Table: see text]

Phase I safety and preliminary efficacy of PM1009, a bispecific antibody targeting TIGIT and PVRIG, in patients with advanced solid tumors.

e14695 Background: PM1009 is an anti-TIGIT x PVRIG bispecific antibody containing a fully human anti-TIGIT IgG1 fused with a fully human anti-PVRIG scFv at the C terminus. PM1009 can potently block the TIGIT/CD155/CD112 and PVRIG/CD112 signaling pathways, and supports the depletion of TIGIT-positive Treg cells in the tumor microenvironment through FcγR engagement. This leads to the enhancement of T cell and NK cell activity towards the killing of tumor cells. PM1009 showed robust in vitro and in vivo efficacy with good safety in preclinical studies. Methods: This is the first-in-human study of PM1009, which includes a dose escalation stage (accelerated titration & 3+3 design) followed by dose expansion. In the dose escalation stage, PM1009 was administered as flat doses of 120, 300, 600 and 1200 mg for DLT evaluation after 3 weeks followed by administration Q2W. Primary endpoints were safety and tolerability, and the secondary endpoints were PK, ORR and DCR (per RECIST 1.1). Results: As of February 1, 2024, a total of 12 patients were enrolled for dose escalation and received at least one dose of PM1009, with 3 patients in each of the 120, 300, 600 and 1200 mg dose-levels. Median number of prior therapies was 5 lines (range 1- 9). No DLTs were observed up to 1200 mg. Any-grade TRAEs occurred in 11 patients (91.7%), and ≥ Grade 3 TRAEs occurred in 2 patients (16.7%). Any-Grade irAEs occurred in 7 patients (58.3%), and ≥ Grade 3 irAEs occurred in 1 patient (8.3%). Treatment interruption due to TRAE occurred in 2 patients (16.7%), with infusion related reaction (the main symptom was nausea, and the single infusion was eventually completed), and neutrophil count decrease respectively. Treatment discontinuation due to TRAE occurred in 2 patients (16.7%), with acute myocardial infarction, and neutrophil count decrease respectively. The most common TRAEs were ALP elevation (33.3%) and AST elevation (25.0%). 12 patients completed at least one tumor evaluation. The DCR per RECIST 1.1 by investigator was 33.3% (4/12; 95% CI: 9.92 - 65.11), best overall response was SD. Pharmacokinetics were dose-proportional with a terminal half-life of 5.2-7.4 days across the dose range of 120-1200 mg. Conclusions: PM1009 was well-tolerated up to 1200 mg with signs of anti-tumor activity. These findings support further clinical investigation of PM1009 especially for the combination with chemotherapy or PD-1/L1-based checkpoint inhibitors. Clinical trial information: NCT05607563 .

Trastuzumab, pertuzumab and nab-paclitaxel plus pyrotinib or not in neoadjuvant treatment of HER2-positive breast cancer: A multi-center, randomized, open-label, phase II study.

e12634 Background: Trastuzumab plus pertuzumab (TP) combined with chemotherapy is the standard neoadjuvant treatment regimen for HER2+ breast cancer. Anti-HER2 tyrosine kinase inhibitor, pyrotinib, shows great efficacy in HER2+ metastatic breast cancer, but lacking efficacy data on the basis of TP and chemotherapy in the neoadjuvant setting. This study aims to evaluate the efficacy and safety of TP plus nab-paclitaxel with or without pyrotinib as neoadjuvant treatment in HER2+ breast cancer. Methods: Stage II-III HER2+ breast cancer patients, stratified by disease stage (II vs. III) and hormone receptor (HR) status (positive vs. negative), were randomized 1:1 into the pyrotinib group or the control group. Both groups received a combination of 3-weekly TP and weekly nab-paclitaxel for 12 weeks. The pyrotinib group was concurrent given 320mg pyrotinib once daily. Primary endpoint was the total pathological complete remission (tpCR), defined as no invasive cancer in the breast and axillary lymph node. Results: From Nov 2020 to Apr 2023, a total of 109 patients were enrolled, with 108 receiving treatment: 55 in the pyrotinib group and 53 in the control group.The tpCR rate was 65.5% (95% CI: 51.4%, 77.8%) in the pyrotinib group, which shows no significant difference with the control group [60.4% (95% CI: 46.0%,73.5), P = 0.585). The breast pathological complete response (bpCR) rates were 70.9% (95% CI: 57.1%,82.4%) and 64.2%(95% CI: 49.8%,76.9%) in the pyrotinib and control group, respectively (P = 0.453). In the pyrotinib group, 52 (94.5%), 31 (56.4%), and 23 (41.8%) patients experienced dose-interruption, dose-reduction, and discontinuation of pyrotinib, respectively. The most common grade ≥3 adverse events in the pyrotinib and control groups were diarrhea (58.1% vs. 0%), decreased neutrophil count (23.6% vs. 15.1%), and decreased white blood cell count (16.4% vs. 7.5%). Conclusions: Our study showed pyrotinib didn’t significantly improve tpCR rate with pyrotinib on the basis of TP and nab-paclitaxel neoadjuvant therapy of HER2+ breast cancer. Concurrent pyrotinib treatment with TP was associated with a high rate of severe diarrhea. Further biomarker analyses are needed to identify which population would receive great benefit with neoadjuvant pyrotinib therapy in HER2+ breast cancer. Clinical trial information: NCT04398914 .

Efficacy and safety of neoadjuvant trastuzumab, pyrotinib, and dalpiciclib without chemotherapy in early-stage HR-negative/HER2-positive breast cancer: An open-label, single-arm phase II trial.

e12613 Background: The chemotherapy-free neoadjuvant regimens of dual HER2 blockade has showed encouraging rates of pathological complete response (pCR) in patients with HER2-positive breast cancer. Additionally, combining cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors with anti-HER2 therapy has shown synergistic effects in hormone receptor (HR)-positive and HER2-positive breast cancer. However, there is limited data regarding this combination strategy in HR-negative/HER2-positive settings. The objective of this study was to evaluate the efficacy and safety of a chemotherapy-free regimen consisting of the CDK4/6 inhibitor dalpiciclib, and dual anti-HER2 components of pyrotinib and trastuzumab in patients with HR-negative/HER2-positive early breast cancer (EBC). Methods: This open-label, single-arm, phase II study was designed using the Simon two-stage method (Registration number: Chi-CTR-2200060748). Patients with HR-negative/HER2-positive operable EBC (tumor stage T1-3 and nodal stage N0-2) were enrolled. Eligible patients received trastuzumab (HLX02, 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks intravenously) for 15 weeks, plus pyrotinib (240 mg daily orally) and dalpiciclib (125 mg daily orally for 3 weeks, followed by 1 week off) for 16 weeks. Surgery was performed 3-6 weeks after the completion of the last cycle of study treatment. The primary endpoint was pCR (ypT0/Tis ypN0) at surgery, and secondary endpoints included objective response rate (ORR), change of Ki-67 labeling index, biomarker analysis, survival and safety. Results: Between Jun 24, 2022, and Sept 14, 2023, a total of 30 patients with a median age of 54.5 years (range: 35-66) were enrolled and treated in this ongoing trial. As of the data cutoff date on Jan 20, 2024, 26 patients underwent surgery, and pCR was achieved in 18 (69.2%) cases. Out of the 29 patients with evaluable response, 26 achieved partial response and 3 achieved stable disease, resulting in an ORR of 89.7%. The most common grade 3 or more treatment-related adverse events (AEs) were diarrhea (66.7%), decreased neutrophil count (33.3%), and decreased white blood cell count (20.8%). Most AEs were tolerable, and no treatment-related deaths occur. Conclusions: In patients with HR-negative/HER2-positive EBC, a dual HER2-targeted combination of pyrotinib and trastuzumab, along with dalpiciclib in the absence of chemotherapy showed promising efficacy with encouraging pCR and ORR rates, as well as a favorable safety profile in the neoadjuvant setting. Clinical trial information: Chi-CTR-2200060748.

Updated results from a phase 1/2 study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T-cell engager in patients (pts) with small cell lung cancer (SCLC) and other neuroendocrine cancers (NEC).

8090 Background: Delta-like canonical Notch ligand 3 (DLL3) is highly expressed on the cell surface of neuroendocrine carcinomas, which have few approved treatment options in the refractory, metastatic setting. HPN328 is DLL3-targeting T-cell engager. HPN328 has 3 binding domains including anti-DLL3 for target engagement, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. Methods: Pts with relapsed/refractory, metastatic SCLC, neuroendocrine prostate cancer (NEPC) and other NEC associated with DLL3 expression are eligible. Primary objectives are safety, maximum tolerated dose (MTD) and pharmacokinetics (PK). Secondary objectives are immunogenicity and efficacy. Overall response rate (ORR) is determined using modified RECIST v1.1 to include extracranial response assessment for pts treated with radiotherapy for brain metastases while on treatment. HPN328 is administered IV QW or Q2W with priming dose preceding target dose in higher dose cohorts. Results: As of January 5, 2024, 86 pts received HPN328 doses of 0.015-24 mg across 14 cohorts (SCLC [n = 54;63%]; other NEC [n = 32;37%]). The median (range) number of prior regimens was 3 (1-7); 83% previously received a PD-1/PD-L1 blocker. Treatment is ongoing in 24 of 46 (52%) pts in the dose optimization cohorts (1 mg priming dose with 12 or 24 mg target doses QW or Q2W). Treatment-related AEs in ≥ 10% of pts included CRS (59% [30% G1, 26% G2, 3% G3+]), dysgeusia (36%), fatigue (34%), diarrhea (19%), nausea (17%), vomiting (14%), decreased appetite and decreased neutrophil count (13% each), and weight decreased (11%). No G3-4 CRS was seen at target doses. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 9% of pts, all G1-2. The maximum tolerated priming dose was 1 mg; dose escalation of target dose continued up to 24 mg QW without reaching a maximum tolerated target dose. Among efficacy evaluable pts treated in dose optimization cohorts, the confirmed ORR in SCLC was 50% (12/24), with one complete response (CR). In NEC (other than NEPC) the confirmed ORR was 44% (4/9), with one CR. Four of eleven pts with NEPC had unconfirmed PRs in 1 mg priming dose cohorts, with 5 NEPC pts remaining on treatment > 20 weeks. HPN328 exhibited linear PK with dose-proportional increases in exposure and a median T1/2 of 71 hrs. Transient increases in cytokines up to 24 hrs post-dose and T-cell activation were observed. Conclusions: HPN328 is well tolerated and clinically active in SCLC, NEC, and NEPC. Current dose optimization cohorts have completed enrollment and data continue to mature; selection of a recommended phase 2 dose will be made based upon complete mature data. Updated safety and efficacy results will be presented. Clinical trial information: NCT04471727 .

Exploring the safety and efficacy of GT201 as a first-in-class autologous tumor-infiltrating lymphocyte monotherapy in advanced solid tumors.

2547 Background: GT201, featuring a membrane bound IL-15 stably expressed on tumor-infiltrating lymphocytes (TIL), aims to augment TIL persistence and function as well as ameliorate immune suppression within the tumor microenvironment, offering potential for durable responses in advanced solid tumor patients. We present data from 7 patients enrolled in an open-label, single-arm, multicenter clinical study (NCT05729399), investigating the safety profile and efficiency trend of GT201 therapy. Methods: The GT201 phase 1 trial is designed with the primary endpoint of DLT evaluation and the secondary endpoint of measuring preliminary efficacy parameters including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR, and overall survival (OS) following the RECIST v1.1. Results: As of January 22, 2024, a cohort of 7 pts has been enrolled in the study, with a median age of 48 and a median of 3 prior lines of therapy. Among these patients, 1 pt has a history of bone metastases, 2 pts have a history of liver metastases, and 1 pt has a history of brain metastases. Following the standard FC lymphodepletion, pts underwent infusion with GT201 at doses ≥ 5x109 total viable cells. Five pts subsequently received IL-2 as part of the treatment protocol. Treatment-related AEs were observed in ≥ 50% of pts with no grade≥3 AEs. Grade ≥ 3 AEs related to FC lymphodepleting chemotherapy and IL-2 included decreased lymphocyte count, decreased neutrophil count, and decreased white blood cell count, pyrexia and increased heart rate. Notably, all grade ≥3 AEs were either recovered or downgraded to grade ≤ 2 within 14 days. Among the 7 response-evaluable patients across various indications, including Non-Small-Cell-Lung Cancer (NSCLC), melanoma malignant, cervical cancer, and ovarian cancer, 3 patients (42.9%) achieved a confirmed partial response (PR), and 2 patients (28.6%) demonstrated stable disease (SD) as their best response. Notably, among the NSCLC subgroup, disease control (SD ≥ 24 weeks or any PR) was observed in all 3 pts (3/3, 100 %). GT201 cells can be detected in all patients receiving treatment, indicated by both staining IL15RA protein on peripheral T cells and measuring the transgene copy number in peripheral white blood cells. GT201 cells expanded robustly in patients and persist in peripheral blood beyond at least 6 months post cell infusion. Conclusions: In patients with heavily pretreated advanced or metastatic solid tumor, GT201, when infused after FC lymphodepletion and followed by high dose IL-2, exhibits a manageable safety profile. Notably, GT201 has demonstrated a favorable clinical profile in NSCLC, with an encouraging objective response rate, response durability, and no GT201-treatment related grade≥3 AEs. Clinical trial information: NCT05729399 .

Safety and efficacy of iparomlimab and tuvonralimab in combination with gemcitabine and cisplatin as first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma: A multicenter, single-arm, phase 2 trial (DUBHE-N-302).

6026 Background: Programmed cell death 1 (PD-1) inhibitor plus chemotherapy has been the standard first-line (1L) treatment for patients with recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). Iparomlimab and tuvoralimab (QL1706), a novel bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen 4, indicated promising anti-tumor activity for advanced solid tumors including NPC in phase 1/1b trial. This study aimed to evaluate the safety and efficacy of QL1706 combined with chemotherapy as 1L treatment in R/M NPC. Methods: This multicenter, single-arm, phase 2 study (NCT05576272) recruited patients with NPC who had no prior systemic therapy in the R/M setting. Intravenous injection of QL1706 5 mg/kg (day 1) combined with gemcitabine 1000 mg/m² (days 1 and 8) and cisplatin 80 mg/m² (day 1) was administered for four to six cycles (21 days per cycle), followed by maintenance treatment of QL1706. The primary endpoint was safety and tolerability. Key secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). Results: From May 19 2022 to Dec 9 2022, 29 patients were included. The median age was 50 years (range, 25-65), with 24 (83%) being male. Seven patients (24%) had an Eastern Cooperative Oncology Group Performance Status of 1. Nineteen (66%) had recurrent disease. As of the data cut-off on Dec 31 2023, the median follow-up was 15.5 months. Treatment-related adverse events (TRAEs) occurred in 29 patients (100%). TRAEs of grade 3 or 4 occurred in 18 patients (62%), with the most common being decreased neutrophil count (41%), decreased white blood cell count (35%), anemia (21%), and decreased platelet count (21%). Twenty patients (69%) experienced immune-related adverse events, with the most common being grade 1-2 hypothyroidism (38%). Serious TRAEs occurred in five patients (17%). Three patients (10%) discontinued treatment due to adverse events. No treatment-related deaths occurred. Among the 28 evaluable patients, the ORR was 82.1% (95% confidence interval [CI], 63.1% to 93.9%), including one achieving complete response. The DCR was 96.4% (95% CI, 81.7% to 99.9%). The median PFS was 12.5 months (95% CI, 5.7 to not evaluable [NE]), and the median DoR was 14.1 months (95% CI, 7.6 to NE). In 14 patients with high expression level of programmed cell death ligand 1 (combined positive score≥50), the median PFS was 16.2 months (95% CI, 9.9 to NE). The median OS was not reached. Conclusions: Iparomlimab and tuvoralimab combined with chemotherapy showed tolerable safety and promising efficacy as 1L treatment for patients with R/M NPC. Clinical trial information: NCT05576272 .

Phase 1 study of GT101 as an autologous tumor infiltrating lymphocyte (TIL) therapy in advanced solid tumors.

2548 Background: Adoptive cell therapy utilizing autologous TIL has demonstrated efficacy and durable long-term responses in patients with certain advanced solid tumors progressed after conventional therapies. We present data from 14 patients enrolled in the study of GT101, a Phase 1, open-label, single-arm, multicenter trial (NCT05430373) of autologous TIL therapy, aiming to investigate the safety profile, efficiency trend and the duration of response. Methods: The trial was designed with the primary endpoint on evaluating DLT and characterizing the safety profile of GT101 in solid tumor patients measured by the incidence of Grade ≥ 3 treatment-emergent adverse events (TEAEs). The secondary endpoints were to assess efficacy parameters including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS) according to RECIST v1.1. Results: As of November 10, 2023, a cohort of 14 patients received treatment with a median age of 46.9 and a median of 2.6 lines of prior therapies. Following a standard FC-based lymphodepletion, patients underwent GT101 infusion at doses ≥ 5x109 cells with median dose of 3.7x1010 cells, followed by high-dose IL-2 administration. Most of observed Grade ≥ 3 AEs were related to the FC conditioning regimen and IL-2, including decreased lymphocyte count, decreased white blood cell count, decreased neutrophil count, anemia, pyrexia and decreased platelet count. The majority of these AEs were recovered within 14 days, while a few were downgraded to ≤ Grade 2 within 4 weeks. Among 14 enrolled patients across various indications (small-cell-lung cancer, melanoma, cervical cancer), the ORR was 35.7%. Specifically, 4 pts (28.6%) had a confirmed partial response (PR), 1 pt (7.1 %) achieved complete response (CR), and 8 pts (57.1 %) had stable disease (SD) as their best response. One pt had unconfirmed disease progression (PD). Notably, among 11/14 patients with cervical cancer, the ORR was 45.5% (5/11) with 4 pts (36.4%) achieving PR and 1 pt (9.1 %) achieving CR. Disease control was observed in 10/11 pts (90.9%), and the median PFS was 4.2 months for this cohort. The CR patient underwent a long-term follow-up and the duration of CR and PFS (estimated by Kaplan-Meier) was 24 weeks and 36 weeks, respectively. Post GT101 infusion, T cell expanded robustly in the peripheral blood of all patients with median Tmax 6.83 days and average 15.9 days. Conclusions: In the GT101 Phase 1 study, no treatment-related SAEs and DLT were observed. In patients with heavily pretreated advanced or metastatic solid tumors, GT101 exhibited a manageable safety profile under the treatment protocol of lymphodepletion and high-dose IL-2 and a favorable clinical profile, particularly in cervical cancer, with an encouraging ORR and sustained response duration. Clinical trial information: NCT05430373 .

A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors.

3152 Background: Paclitaxel resistance in patients is a clinical challenge that limits the durability of clinical benefit in patients with taxane-responsive advanced solid tumors. One proposed mechanism for this resistance is overexpression of spleen tyrosine kinase (SYK); which can be inhibited with new molecules including TAK-659. In this phase I study, we have investigated the combination of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors; hypothesizing that use of TAK-659 would help to overcome resistance to prior taxane-based therapy. Methods: We included patients with advanced solid tumors who received and progressed on prior taxane-based therapy. Patients received treatment with intravenous paclitaxel on day 1,8, and 15 in addition of daily TAK-659 in 28-day cycles. Six cohorts were treated during dose escalation at different dose levels followed by a dose expansion phase in patients with advanced ovarian cancer. We used the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for evaluation of toxicity and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for assessment of preliminary efficacy. Results: We included 49 patients with advanced solid tumors. The maximum tolerated dose was not reached in this study; and no patients experienced treatment-related deaths. Most adverse events were either grade 1 or 2. Grade 3 or more adverse events were reported in 47% of patients (n=23). The most common grade ≥3 adverse events were decreased neutrophil count (n=7; 14%), elevated lipase (n=6; 12%), anemia (n=5; 10%), increased amylase (n=4; 8%), and decreased white blood cell counts (n=4; 8%). In 44 patients with taxane-refractory tumors who were evaluable for efficacy, 9% (n=4) had RECIST partial response and 27% (n=12) had RECIST stable disease, including 3 patients with prolonged stable disease for at least 6 months. Conclusions: The combination of paclitaxel and TAK-659 was well tolerated and showed preliminary modest efficacy which could be possibly overcoming resistance to taxane-based therapy in patients with advanced solid tumors. Clinical trial information: NCT03756818 .

A phase IIA clinical trial to evaluate a reversible Bruton’s tyrosine kinase inhibitor (BTKi) HBW-3220 capsules in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL).

e19042 Background: This clinical study is to evaluate HBW-3220, a novel BTKi with an improved in vitro profile than the existing non-covalent drugs pirtobrutinib (approved) and nemtabrutinib (Phase III). HBW-3220 shows superior inhibition against BTK wild-type and several common mutants, such as C481S, C481R, T474I, T316A, and L528W (enriched in pirtobrutinib resistance), and hematopoietic cell kinase (HCK, a key contributor to BTKi resistance due to kinase-defective BTK). Methods: This phase IIA clinical study is conducted in R/R B-NHL patients who had received two or more prior lines of treatment. The dose escalation study adopts accelerated titration and a "3+3" design, with a daily single dose of 15, 30, 60, 90, 120, or 150 mg. During the dose escalation phase, the sponsor and investigators determine whether to expand the cohort of the previous dose based on the existing data. Adverse events (AEs) are assigned according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response assessment is based on iwCLL 2018 guidelines for chronic lymphocytic leukemia (CLL), IWWM-7 consensus for Waldenstrom macroglobulinemia (WM), and Lugano 2014 guidelines for all other lymphomas, including small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and follicular lymphoma (FL). Results: 29 patients have been enrolled, and the dose escalation study has been completed. No dose-limiting toxicity (DLT) occurred in any patient, implicating good tolerability. Adverse events (AEs), similar to other BTKis, were mostly Grade 1 or 2, including fever (36%), diarrhea (32%), headache (18%), anemia (39%), infectious pneumonia (18%), decreased neutrophils count (39%), decreased platelet count (29%), increased alanine aminotransferase (21%), etc. Drug-related Grade 3 AEs included decreased neutrophil count (n=3, 11%), increased lymphocyte count (n=2, 7%), and infectious pneumonia (n=2, 7%). 23 patients underwent at least 1 response assessment. The overall response rate (ORR) in CLL/SLL (all with prior irreversible BTKi treatment, and 4 of them with additional BCL2 inhibitor treatment), MZL, MCL, and DLBCL patients were 83% (5/6), 50% (2/4), 40% (2/5) and 33% (1/3), respectively. Among the ORR, 90% (9/10) were in the 90 mg and above dose group, regardless of previous BTKi treatment history or mutation status of p53 and BTK. After oral administration, the drug exposures showed dose-dependent increases. The time to maximum plasma concentration (Tmax) was 2 hours, and the elimination half-life (T1/2) was 19 hours. Conclusions: The current data show that HBW-3220 is well tolerated with no DLT occurred at daily doses up to 150 mg, displaying most promising efficacy in patients with CLL/SLL, MZL, and MCL. Clinical trial information: ChiCTR2200062537.

A multicenter real-world study on the efficacy and safety of anlotinib-based treatment for metastatic breast cancer.

e13120 Background: Anlotinib is a multi-targeted small molecule receptor tyrosine kinase (RTK) inhibitor that inhibits angiogenesis. There is only one phase II study on the use of anlotinib in advanced breast cancer (MBC). Therefore, this study aims to analyze its efficacy and safety in the treatment of BC in the real world. It has been approved for the treatment of advanced non-small cell lung cancer and soft tissue sarcoma. There is limited research on the use of anlotinib in advanced breast cancer (MBC). Methods: This study retrospectively analyzed the clinical data of MBC patients who received anlotinib treatment at four domestic centers from January 2021 to December 2023. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Kaplan-Meier analysis was used to analyze PFS and OS, and Cox regression model was used to analyze the hazard ratios (HRs) of anlotinib-based treatment on PFS and OS in different subgroups of patients. A p-value <0.05 was considered statistically significant. Results: A total of 153 MBC patients receiving anlotinib-based treatment were included from four centers. The median age was 51 years (range: 22-76), and the median number of prior lines of therapy was 3. The median PFS was 7.7 months (range: 5.2-10.1 months), and the median OS was 28.0 months (range: 21.4-34.9 months). The median ORR and DCR were 19.6% and 60.1%, respectively. The ORR for HR+/HER2- and triple-negative breast cancer patients was 11.6% and 28.8%, respectively, DCR for HR+/HER2- and triple-negative breast cancer (TNBC) patients was 55.8% and 59.6%, respectively. The median PFS was 9.0 months (range: 6.0-11.9 months) for HR+/HER2- patients and 5.3 months (range: 3.5-7.0 months) for TNBC patients, while the median OS was 33.0 months (range: 24.4-41.5 months) and 14.0 months (range: 9.5-18.4 months), respectively. In the subgroup analysis, age <60 years, initial stage IV disease, Ki67≤60%, and treatment with PD-L1 monoclonal antibodies-based regimen were associated with PFS benefit. ECOG <2 and treatment with PD-L1 monoclonal antibodies-based regimen were associated with prolonged OS. Among the 31 patients with brain metastases receiving anlotinib treatment, 11 had active brain metastases and 20 had stable brain metastases. The median PFS was 8.0 months. The intracranial ORR was 12.9%, and the intracranial DCR was 61.3%. No serious adverse events or treatment-related deaths occurred. Grade I/II adverse reactions included hand-foot syndrome (22.2%) and fatigue (19.6%), while grade III/IV adverse reactions included fatigue (6.5%) and decreased neutrophil count (5.2%). Three patients required dose reduction due to intolerable adverse reactions, and nine patients discontinued treatment. Conclusions: Anlotinib demonstrates good antitumor activity and safety in the treatment of MBC. When combined with chemotherapy or immunotherapy, it can improve PFS and OS without significantly increasing toxicity. In particular, it shows promising intracranial ORR and PFS in patients with brain metastases. Clinical trial information: NCT04541420 .

A phase 1 study of HRS-1167 (M9466), a highly selective PARP1 inhibitor, in patients (pts) with advanced solid tumors.

3154 Background: The use of first-generation dual PARP1/2 inhibitors is limited due to their hematological toxicities and inevitable drug resistance. Given that loss of PARP1 is the primary driver of synthetic lethality in homologous recombination repair (HRR) deficient tumors, and PARP2 is largely associated with hematological toxicities, development of next-generation PARPi with selectivity for PARP1 is warranted. Here, we present results of the dose escalation (D-ESC) and dose expansion (D-EXP) parts of a first-in-human study of HRS-1167 (M9466), a highly selective PARP-1 inhibitor, in pts with advanced solid tumors. Methods: Pts were eligible for the D-ESC part if they had advanced solid tumors that had progressed on standard therapies or for which no standard therapies were available. The D-ESC part began with accelerated titration (30 mg; QD) and then switched to the BOIN design (50, 100, 200, and 300 mg; QD). In the D-EXP part, previously treated pts harboring germline or somatic BRCA1/2, PALB2, or RAD51C/D mutations received HRS-1167 at 50, 100, and 200 mg QD. Prior PARPi was allowed. The primary objectives were to assess the safety and tolerability of HRS-1167. Results: As of Nov 20, 2023, 40 pts were enrolled (median lines of prior treatment, 2 [range, 1–5]; prior PARPi, 15.0%). No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. Grade ≥3 treatment-related adverse events occurred in 12 (30.0%) pts, with the most common being anemia (6 [15.0%]), decreased neutrophil count (5 [12.5%]), and decreased WBC count (5 [12.5%]). Of the 24 pts with HRR mutations who had at least one post-baseline assessment for tumor response, 10 (41.7%) pts had objective responses (8 ovarian cancer, 1 prostate cancer, and 1 pancreatic cancer). PK exposures were approximately dose-proportional. The median Tmax was 1.0–1.5 h, and the mean t1/2 was 10.5–15.0 h following a single dose of HRS-1167 at 30–300 mg. No obvious drug accumulation was observed (Rac, 1.08–1.30 for Cmax; 1.29–1.62 for AUC0-24). Conclusions: HRS-1167 was well-tolerated and exhibited favorable safety and PK profiles in pts with advanced solid tumors, and demonstrated promising anti-tumor activity in pretreated pts with HRR mutations. Clinical trial information: NCT05473624 .