One-year Progression-free Survival Research Articles

The incidence of and risk factors for radiation pneumonitis in patients treated with simultaneous bevacizumab and thoracic radiotherapy

BackgroundFirst-line chemotherapy combined with bevacizumab is one of the standard treatment modes for patients with advanced non-small cell lung cancer (NSCLC). Thoracic radiotherapy (TRT) can provide significant local control and survival benefits to patients during the treatment of advanced NSCLC. However, the safety of adding TRT has always been controversial, especially because of the occurrence of radiation pneumonia (RP) during bevacizumab treatment. Therefore, in this study, we used an expanded sample size to evaluate the incidence of RP when using bevacizumab in combination with TRT.Patients and methodsUsing an institutional query system, all medical records of patients with NSCLC who received TRT during first-line chemotherapy combined with bevacizumab from 2017 to 2020 at Shandong Cancer Hospital and Institute were reviewed. RP was diagnosed via computed tomography and was classified according to the RTOG toxicity scoring system. The risk factors for RP were identified using univariate and multivariate analyses. The Kaplan–Meier method was used to calculate progression-free survival (PFS) and overall survival (OS).ResultsUltimately, 119 patients were included. Thirty-eight (31.9%) patients developed Grade ≥ 2 RP, of whom 27 (68.1%) had Grade 2 RP and 11 (9.2%) had Grade 3 RP. No patients developed Grade 4 or 5 RP. The median time for RP occurrence was 2.7 months (range 1.2–5.4 months). In univariate analysis, male, age, KPS score, V20 > 16.9%, V5 > 33.6%, PTV (planning target volume)-dose > 57.2 Gy, and PTV-volume > 183.85 cm3 were correlated with the occurrence of RP. In multivariate analysis, male, V20 > 16.9%, and PTV-volume > 183.85 cm3 were identified as independent predictors of RP occurrence. The mPFS of all patients was 14.27 (95% CI, 13.1–16.1) months. The one-year and two-year PFS rates were 64.9% and 20.1%, respectively. The mOS of all patients was 37.09 (95% CI, 33.8–42.0) months. The one-year survival rate of all patients was 95%, and the two-year survival rate was 71.4%.ConclusionsThe incidence of Grade ≥ 2 RP in NSCLC patients who received both bevacizumab and TRT was 31.9%. Restricting factors such as V20 and PTV will help reduce the risk of RP in these patients. For patients who receive both bevacizumab and TRT, caution should be exercised when increasing TRT, and treatment strategies should be optimized to reduce the incidence of RP.

Efficacy of total neoadjuvant chemotherapy in the FLOT regimen in patients with locally advanced gastric and gastroesophageal junction: results of a phase II study

Background. The established approach notably improving the therapeutic outcomes for locally advanced gastric cancer and gastroesophageal junction cancer, presently entails the amalgamation of perioperative chemotherapy aligned with the FLOT protocol and surgical intervention. However, this approach harbors limitations, as only half of the patient cohort successfully completes the entire prescribed course of drug therapy. The potential solution to this problem lies in the complete transfer of the chemotherapy volume to the preoperative period and the execution of total neoadjuvant chemotherapy with FLOT regimen.Aim. Aim is to conduct a comparative assessment of the efficacy and safety between total neoadjuvant and perioperative chemotherapy with FLOT regimen for patients with locally advanced gastric cancer and gastroesophageal junction cancer.Materials and methods. In a retrospective study we enrolled patients with histologically confirmed locally advanced gastric cancer and gastroesophageal junction cancer meeting clinical stage criteria T2–4 and N0–3, without of distant metastases, treated between 2014 and 2020 at Federal State Budgetary Institution “N. N. Blokhin National Medical Research Center of Oncology” оf the Ministry of Health of the Russian Federation and Moscow City Oncologic Hospital No. 62 Department of Healthcare of Moscow. Participants in the control group underwent 8 courses of perioperative chemotherapy (4 preoperatively and 4 postoperatively), while those in the experimental group received 8 courses of total neoadjuvant chemotherapy. Both groups received drug therapy according to the FLOT protocol: 5-fluorouracil 2600 mg/m2 , intravenous drip, over 24 hours, leucovorin 200 mg/m2 , intravenous drip, oxaliplatin 85 mg/m2 , intravenous drip, docetaxel 50 mg/m2 , intravenous drip, on day 1, with a 14-day intercourse interval. The primary endpoint was one-year progression-free survival.Results. In the study included 187 patients. Participants were divided into two groups: 95 in the total neoadjuvant chemotherapy group and 92 in the perioperative chemotherapy group. The one-year progression-free survival was higher in the total neoadjuvant chemotherapy group at 79 %, compared to 68 % in the perioperative chemotherapy group (HR 0.54, 95 % confidence interval 0.32–0.9, p = 0.02). Median disease-free survival was 27.2 and 19.5 months in the neoadjuvant and perioperative chemotherapy groups, respectively. The tolerability of the entire planned drug treatment regimen was superior in the total neoadjuvant chemotherapy group, reaching 88.4 %, as opposed to 57.6 % in the perioperative chemotherapy group (p = 0.0001).Conclusion. Among patients with locally advanced gastric cancer and gastroesophageal junction cancer, the application of total neoadjuvant chemotherapy according to the FLOT protocol, administered over 8 courses, demonstrated enhanced one-year progression-free survival and improved tolerability of the entire planned treatment regimen.

Anti-PD-1 antibody in combination with radiotherapy as first-line therapy for unresectable intrahepatic cholangiocarcinoma

BackgroundUnresectable intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis despite treatment with standard combination chemotherapy. We aimed to evaluate the efficacy and safety of radiotherapy in combination with an anti-PD-1 antibody in unresectable iCCA without distant metastases.MethodsIn this phase II study, patients with histopathologically confirmed unresectable primary or postoperative recurrent iCCA without distant metastases were enrolled. Patients received external radiotherapy with a dose of ≥45 Gy (2-2.5 Gy per fraction), followed by anti-PD-1 immunotherapy (camrelizumab 200 mg once, every 3 weeks) initiated within 7 days after completion of radiotherapy as first-line therapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The secondary end points included safety, objective response rate (ORR), disease control rate (DCR), and overall survival (OS).ResultsFrom December 2019 to March 2021, 36 patients completed radiotherapy and at least one cycle of immunotherapy and were included in efficacy and safety analyses. The median follow-up was 19.0 months (IQR 12.0-24.0), and the one-year PFS rate was 44.4% (95% CI, 30.8-64.0). The median PFS was 12.0 months (95% CI, 7.5-not estimable); the median OS was 22.0 months (95% CI, 15.0-not estimable). The ORR was 61.1% and the DCR was 86.1%. Seventeen of 36 (47.2%) patients experienced treatment-related adverse effects (AEs) of any grade. The most common AE was reactive cutaneous capillary endothelial proliferation (25.0%). Five (13.9%) patients experienced grade ≥3 treatment-related AEs, including decreased lymphocyte (5.6%), bullous dermatitis (2.8%), decreased platelet count (2.8%), and deep-vein thrombosis (2.8%).ConclusionsExternal radiotherapy plus camrelizumab, as first-line therapy, met its primary endpoint and showed antitumor activity and low toxicity levels in patients with unresectable iCCA without distant metastases, warranting further investigation.Trial registrationNCT03898895. Registered 2 April 2019.

An international phase II trial and immune profiling of SBRT and atezolizumab in advanced pretreated colorectal cancer

BackgroundImmuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients.MethodsEligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling.ResultsSixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20–81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9–11.6] and 1.4 months [95%CI:1.2–2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses.ConclusionsThis study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy.Trial registrationEudraCT N°: 2015–005464-42; Clinicaltrial.gov number: NCT02992912.

Retrospective assessment of neoadjuvant camrelizumab combined with induction chemotherapy: efficacy in laryngeal preservation for advanced hypopharyngeal and laryngeal squamous cell carcinoma

BackgroundHypopharyngeal and laryngeal squamous cell carcinoma (SCC) account for 25–30% of head and neck SCC. Total laryngectomy, while effective, compromises the quality of life. Immune checkpoint inhibitors such as Camrelizumab offer potential in laryngeal preservation. The study investigated Camrelizumab combined with TP regimen as a neoadjuvant therapy for laryngeal preservation in advanced hypopharyngeal and laryngeal SCC.MethodsA retrospective study was conducted at Sun Yat-sen University Cancer Center on patients diagnosed with locally advanced SCC of the hypopharynx and larynx from October 1, 2019, to October 25, 2022. The efficacy of a first-line treatment combining Camrelizumab (200 mg) and TP regimen (Albumin-bound paclitaxel at 260 mg/m2 and Cisplatin at 60 mg/m2) was evaluated using RECIST 1.1 criteria. Outcomes included overall survival (OS), progression-free survival (PFS), laryngectomy-free survival (LFS), and response rates.ResultsOf the 71 included patients, the median age was 60.7 years. Post the first-line treatment, 90.1% demonstrated an overall response. The one-year and two-year OS rates were 91.5% and 84.3%, respectively. One-year and two-year PFS rates were 92.9% and 83.9%, respectively, with LFS at 85.6% and 73.2%. The initial T4 stage as significantly associated with reduced OS and LFS. Skin reaction was the predominant adverse event.ConclusionThe Camrelizumab-TP regimen demonstrated promising results for advanced hypopharyngeal/laryngeal SCC patients, exhibiting high response rates, OS, and LFS, positioning it as a potential primary option for laryngeal preservation. Further comprehensive, randomized controlled studies are imperative to validate these initial observations and elucidate the regimen's full clinical efficacy in optimizing laryngeal outcomes.

Loco-regional radiotherapy in de novo metastatic nasopharyngeal carcinoma with chemotherapy and immunotherapy: A real-world retrospective study from two cancer centers.

Immunochemotherapy has become the first-line treatment for initial diagnosed metastatic nasopharyngeal carcinoma (mNPC). Loco-regional radiotherapy combined with systemic chemotherapy significantly improves the survival. However, the safety and efficacy of loco-regional radiotherapy combined with immunochemotherapy remained unknown. Patients with de novo mNPC who received immunochemotherapy followed by loco-regional radiotherapy were included from two cancer centers. Toxicity and treatment response were assessed using CTCAE 5.0 and RECIST 1.1, respectively. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. From 2019 to 2021, a total of 16 patients were retrospectively analyzed. The median follow-up was 28 months (range 14-47 months). No one died. One-year, 2-year, and 3-year PFS rate was 93.8%, 58.4% and 50.1%, respectively. Radiotherapy-related acute severe (grade 3 or higher) toxicity was dermatitis (1/16, 6.3%) and mucositis (2/16, 12.5%). Loco-regional radiotherapy provided a promising efficacy with modest toxicity for patients with mNPC who received immunochemotherapy.

Intracranial response pattern, tolerability and biomarkers associated with brain metastases in non-small cell lung cancer treated by tislelizumab plus chemotherapy.

Programmed cell death protein-1/programmed cell death protein-ligand 1 (PD-1/PD-L1) inhibitor and chemotherapy are the standard treatment for advanced non-small cell lung cancer (NSCLC) without sensitizing mutations. However, patients with untreated, symptomatic or recently-irradiated brain metastases (BMs) are mostly excluded from immunochemotherapy trials. This study aims to evaluate the intracranial response pattern, tolerability and biomarkers of tislelizumab plus chemotherapy in NSCLC with untreated, symptomatic or recently-irradiated BM. This multicenter, single-arm, phase 2 trial enrolled patients with treatment-naïve, brain-metastasized NSCLC. BM could be untreated or irradiated. Symptomatic or recently-irradiated BMs that were deemed clinically stable were allowed. Patients received tislelizumab (200 mg) plus pemetrexed (500 mg/m2) and carboplatin (AUC =5) on day 1 every 3 weeks for 4 cycles, followed by maintenance with tislelizumab plus pemetrexed. Primary endpoint was 1-year progression-free survival (PFS) rate. Secondary endpoints included intracranial efficacy and tolerability. PD-L1 expression, tumor mutational burden (TMB) and genomic alterations were evaluated as potential biomarkers. A total of 36 patients were enrolled, 19.2% had prior brain radiotherapy, 8.3% had symptomatic BMs that required corticosteroids ≤10 mg/d or antiepileptics. Confirmed systemic and intracranial ORR (iORR) was 43.8% and 46.7%, respectively. One-year systematic PFS rate and One-year iPFS rate was 36.8% and 55.8%, respectively. About 41.7% patients had neurological adverse events, 90% patients had concordant intracranial-extracranial responses. No intracranial pseudoprogression or hyperprogression occurred. Patients with prior brain radiation trended towards higher systemic (83.3% vs. 34.6%) and iORR (75.0% vs. 42.3%). Similar intracranial efficacy was observed in tumors with different PD-L1 and TMB levels, while alterations in cytokine receptors pathway predicted higher iORR (P=0.081), prolonged systematic PFS [hazard ratio (HR) =0.16, P=0.021] and overall survival (OS) (HR =0.71, P=0.029). Untreated or irradiated BMs in NSCLC follows a conventional response and progression pattern under immunochemotherapy with altered cytokine receptors pathway being a potential biomarker for systemic and intracranial outcomes.

Metastatic site and clinical outcome of patients with deficient mismatch repair metastatic colorectal cancer treated with an immune checkpoint inhibitor in the first-line setting.

55 Background: Nearly one-half of deficient mismatch repair (d-MMR) metastatic colorectal cancers (mCRC) demonstrate durable responses to immune checkpoint inhibitors (ICIs). Given preclinical data indicating that liver metastases sequester activated CD8+ T cells from systemic circulation, we examined clinical outcome by metastatic site. Methods: In a retrospective cohort of patients with d-MMR mCRCs treated at multiple centers in France (n=66), we sought to validate data from a U.S. cohort, and then performed pooled analysis (n=104). All patients received first-line ICI monotherapy. Metastatic site was analyzed in relationship to tumor response (RECIST version 1.1), and progression-free survival (PFS) by multivariable stratified Cox regression after adjustment for covariates. Results: Objective responses were achieved in 38/66 (58%) patients in the validation cohort. Best tumor response included 13 (20%) complete responses (CR), 25 (38%) partial responses (PR), 16 (25%) stable disease, and 11 (17%) progressive disease (PD). One-year and 5-year PFS rates were 73% and 67%, respectively; 18 (27%) patients progressed during immunotherapy. Best tumor response was attenuated in patients with liver metastasis ( P=0.03). Presence of liver metastasis, but not other sites, was associated with significantly poorer PFS after adjustment for covariates (HRadj 2.82; 95%CI, 1.08-7.39; Padj=0.03). In a pooled analysis, liver metastasis remained significantly and independently associated with poorer PFS (HRadj 3.18; 95%CI, 1.52-6.67; Padj=0.002) and with attenuated tumor best response (P=0.01). Conclusions: Metastasis to the liver, but not other sites, was validated as an independent factor associated with poorer response and survival after ICI treatment in d-MMR mCRCs. These data underscore the need for novel therapeutic strategies in these patients. [Table: see text]

Consolidative thoracic radiation therapy for extensive-stage small cell lung cancer in the era of first-line chemoimmunotherapy: preclinical data and a retrospective study in Southern Italy.

Consolidative thoracic radiotherapy (TRT) has been commonly used in the management of extensive-stage small cell lung cancer (ES-SCLC). Nevertheless, phase III trials exploring first-line chemoimmunotherapy have excluded this treatment approach. However, there is a strong biological rationale to support the use of radiotherapy (RT) as a boost to sustain anti-tumor immune responses. Currently, the benefit of TRT after chemoimmunotherapy remains unclear. The present report describes the real-world experiences of 120 patients with ES-SCLC treated with different chemoimmunotherapy combinations. Preclinical data supporting the hypothesis of anti-tumor immune responses induced by RT are also presented. A total of 120 ES-SCLC patients treated with chemoimmunotherapy since 2019 in the South of Italy were retrospectively analyzed. None of the patients included in the analysis experienced disease progression after undergoing first-line chemoimmunotherapy. Of these, 59 patients underwent TRT after a multidisciplinary decision by the treatment team. Patient characteristics, chemoimmunotherapy schedule, and timing of TRT onset were assessed. Safety served as the primary endpoint, while efficacy measured in terms of overall survival (OS) and progression-free survival (PFS) was used as the secondary endpoint. Immune pathway activation induced by RT in SCLC cells was explored to investigate the biological rationale for combining RT and immunotherapy. Preclinical data supported the activation of innate immune pathways, including the STimulator of INterferon pathway (STING), gamma-interferon-inducible protein (IFI-16), and mitochondrial antiviral-signaling protein (MAVS) related to DNA and RNA release. Clinical data showed that TRT was associated with a good safety profile. Of the 59 patients treated with TRT, only 10% experienced radiation toxicity, while no ≥ G3 radiation-induced adverse events occurred. The median time for TRT onset after cycles of chemoimmunotherapy was 62 days. Total radiation dose and fraction dose of TRT include from 30 Gy in 10 fractions, up to definitive dose in selected patients. Consolidative TRT was associated with a significantly longer PFS than systemic therapy alone (one-year PFS of 61% vs. 31%, p<0.001), with a trend toward improved OS (one-year OS of 80% vs. 61%, p=0.027). Multi-center data from establishments in the South of Italy provide a general confidence in using TRT as a consolidative strategy after chemoimmunotherapy. Considering the limits of a restrospective analysis, these preliminary results support the feasibility of the approach and encourage a prospective evaluation.

Multi-institutional experience of MR-guided stereotactic body radiation therapy for adrenal gland metastases

PurposeWhile dose escalation is associated with improved local control (LC) for adrenal gland metastases (AGMs), the proximity of gastrointestinal (GI) organs-at-risk (OARs) limits the dose that can be safely prescribed via CT-based stereotactic body radiation therapy (SBRT). The advantages of magnetic resonance-guided SBRT (MRgSBRT), including tumor tracking and online plan adaptation, facilitate safe dose escalation. MethodsThis is a multi-institutional review of 57 consecutive patients who received MRgSBRT on a 0.35-T MR linac to 61 AGMs from 2019 to 2021. The Kaplan-Meier method was used to estimate overall survival (OS), progression-free survival (PFS), and LC, and the Cox proportional hazards model was utilized for univariate analysis (UVA). ResultsMedian follow up from MRgSBRT was 16.4 months (range [R]: 1.1–39 months). Median age was 67 years (R: 28–84 years). Primary histologies included non-small cell lung cancer (N = 38), renal cell carcinoma (N = 6), and melanoma (N = 5), amongst others. The median maximum diameter was 2.7 cm (R: 0.6–7.6 cm), and most AGMs were left-sided (N = 32). The median dose was 50 Gy (R: 30–60 Gy) in 5–10 fractions with a median BED10 of 100 Gy (R: 48–132 Gy). 45 cases (74 %) required adaptation for at least 1 fraction (median: 4 fractions, R: 0–10). Left-sided AGMs required adaptation in at least 1 fraction more frequently than right-sided AGMs (88 % vs 59 %, p = 0.018). There were 3 cases of reirradiation, including 60 Gy in 10 fractions (N = 1) and 40 Gy in 5 fractions (N = 2). One-year LC, PFS, and OS were 92 %, 52 %, and 78 %, respectively. On UVA, melanoma histology predicted for inferior 1-year LC (80 % vs 93 %, p = 0.012). There were no instances of grade 3+ toxicity. ConclusionsWe demonstrate that MRgSBRT achieves favorable early LC and no grade 3 + toxicity despite prescribing a median BED10 of 100 Gy to targets near GI OARs.

Neoadjuvant PD-1 Plus Chemotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma.

Clinical studies have shown that programmed cell death-1 (PD-1) inhibitors can activate T cells and inhibit cancer growth. Therefore, the use of a PD-1 inhibitor plus chemotherapy as neoadjuvant chemotherapy for locally advanced esophageal cancer is worth further exploration. Patients with locally advanced esophageal squamous cell carcinoma were enrolled in this study to receive two cycles of a preoperative combination of toripalimab, paclitaxel, and cisplatin. Efficacy was evaluated after two treatment cycles. The patients' postoperative pathological staging was analyzed and compared. Surgery was performed within 42 days of the start date of the last chemotherapy cycle. Neoadjuvant immunochemotherapy achieved a high pathologic complete response (pCR) rate (29.0%), major pathological response rate (41.9%), and objective response rate (80.6%) and demonstrated statistically significant downstaging after neoadjuvant therapy (P < .05) with manageable treatment-related adverse effects. No significant association was found between PD-L1 level and pCR (P = .365). In addition, R0 resection was achieved in all 31 (100%) patients during surgery. For all the included patients, the one-year progression-free survival rate was 87.1% (95% CI: 75.3%-98.9%), the one-year overall survival (OS) rate was 96.8% (95% CI: 79.8%-95.9%), and the two-year OS rate was 83.9% (95% CI: 71.6%-92.2%). Our findings indicate that this combination may be a potential neoadjuvant therapy regimen in this setting.

Clonal Hematopoiesis Is Associated with Severe Cytokine Release Syndrome in Patients Treated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

Background: Among patients receiving CD19 or B-cell maturation antigen (BCMA) CAR-T therapy, inflammation pre- and post-CAR-T infusion is attributed in the development of toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and prolonged cytopenias. Clonal hematopoiesis (CH), the clonal expansion of hematopoietic stem cells with somatic mutations, has been associated with inflammatory disorders such as rheumatoid arthritis and graft-versus-host disease, as well as clonal cytopenias of undetermined significance. In the setting of CAR-T, others have reported an association between CH and both ICANS and treatment-associated myeloid neoplasms. Herein, we examined the prevalence of pre-CAR-T CH in a predominantly transplant-naïve cohort of recipients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), and assessed the relationship between CH and CAR-T related outcomes including CRS, ICANS, prolonged cytopenia, progression-free survival (PFS), and overall survival (OS). Methods: This study included 62 patients with NHL or MM who underwent CD19 or BCMA CAR-T therapy from 2017 to 2022 at City of Hope and had available pre-CAR-T cryopreserved peripheral blood mononuclear cells (PBMCs). DNA was isolated with QIAamp DNA Mini Kit (Qiagen) from PBMC samples (94% collected &amp;lt;30d of CAR-T infusion), on which we performed targeted exome sequencing (108 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CH (variant allele frequency [VAF] ≥2%). Multivariable logistic regression was used to examine the association between CH (Yes/No) and absolute neutrophil count (ANC) recovery at day +60 (Y/N), maximum grade CRS and ICANS, grade &amp;lt;2 vs 2+, and OS and PFS at 1y. Covariables considered were age at CAR-T, baseline ANC, sex, race, CAR-HEMATOTOX (Rejeski et al. 2021), bridging therapy (Y/N), and number of prior lines of therapy. ANC recovery was defined as grade 2 or better for 3 measurements without growth factor support &amp;gt;2 weeks. Those without ANC recovery and who started new treatment before day +60 were excluded from that analysis. Results: Overall, the median age was 64y (range 21y-85y); 37 (60%) had de novo diffuse large B-cell lymphoma, 17 (27%) had transformed follicular lymphoma, 2 (3%) had MM, 2 (3%) had mantle cell lymphoma, and the remaining patients had other transformed indolent lymphomas. Median prior lines of therapy was 3 (1-12), and only 6% had previously undergone autologous hematopoietic cell transplantation. Systemic bridging therapy prior to CAR-T was required in 27 (44%), and 8 (13%) received radiation as bridging. All received fludarabine and cyclophosphamide for lymphodepleting chemotherapy. Axicabtagene ciloleucel was the most common (76%) CAR-T product, followed by tisagenlecleucel in 16% of patients. Overall, 51 (82%) and 29 (47%) patients experienced CRS and ICANS, respectively. had delayed ANC recovery. One-year PFS was 50% and 1y OS was 73%. Clonal hematopoiesis: 15 (24%) patients had at least one pathogenic CH mutation; 4 (6.5%) had ≥2 CH mutations. Of the 28 CH mutations identified, the most common were DNMT3A (18%), CHEK2 (11%), PMS2 (7%) and ASXL1 (7%); 29% of mutations had VAFs &amp;gt;10%. Outcomes after CAR-T: Patients with CH were significantly more likely to develop grade ≥2 CRS (60% vs. 28%, p=0.03) compared to those without CH (odds ratio [OR] 3.9, 95% CI 1.2-13.2; p=0.027). Accounting for baseline ANC (which was unexpectedly higher among the CH cohort and associated with delayed ANC recovery, p=0.02) patients with CH did not have a significantly different rate of delayed ANC recovery compared to those without CH (adjusted OR 0.37, 95% CI 0.09-1.5; p=0.17). There was no association between CH and ICANS, nor with 1y PFS and OS. Conclusion: CH was frequent (24%) in this cohort of CAR-T recipients and was associated with a higher risk of ≥2 CRS after CAR-T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR-T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis Acknowledgements: Funding through the CoH Hematological Malignancies Program Pilot Project Award. The authors acknowledge the work provided by CoH Center for Informatics, notably Research Informatics, and the utilization of the POSEIDON platform and the Honest Broker process.

A Pilot Study of Reduced Intensity HLA-Haploidentical Hematopoietic Cell Transplantation (HaploHCT) with Post-Transplant Cyclophosphamide in Patients with Advanced Myelofibrosis

Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for patients with myelofibrosis (MF); however, a significant obstacle to proceed to HCT is availability a matched donor, especially since MF is most often diagnosed in older adults. The effective development of haploidentical transplant (haploHCT), with post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, has been a major therapeutic advance for patients without an available matched donor. Based on the excellent survival rates seen in older patients with myeloid malignancies using fludarabine/Melphalan-based (Flu/Mel) regimen with PTCy GVHD prophylaxis, we designed a pilot trial (NCT03118492) to evaluate safety and tolerability of reduced intensity condition (RIC) regimen of Flu/Mel and TBI (2Gy) for peripheral blood stem cells (PBSC) HaploHCT with PTCy in patients with advanced MF (Figure 1a). At the time of this report, we have enrolled 17 patients (out of 22) in two cohorts. After treating the first 4 patients in cohort 1 (CH-1), eligibility was updated to exclude accelerated disease, severe pulmonary hypertension, with stricter fluid management for a stricter monitoring and eligibility criteria (cohort 2; CH-2). Our primary objective was to determine safety of this regimen in patients with MF. Key secondary endpoints were grade 2-4 acute GVHD, chronic GVHD, engraftment, overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), and relapse. Detailed patient/HCT characteristics are listed in Table 1. Briefly, median age at the time of HCT was 59 years (range: 48-70), and 53% of patients were male. MF diagnosis was primary MF in 53% of patients, and 71% had intermediate-2 risk level. Karnofsky performance status was 80-100 in 94.1% of patients and HCT comorbidity index was 0-2 in 82.4%. Median time from MF diagnosis to HCT was 935 days (range: 27-7651). In CH-1, unacceptable toxicity (UT) was defined as any of the following considered at least possibility related to PTCy: any death; grade 3-4 adverse events (AEs) that does not improve to grade ≤2 within 4 weeks except for hematologic toxicities. For hematologic toxicities, UTs were primary graft failure. Two out of the 4 patients in CH-1 experienced UTs. [UPN1: grade 3 anorexia that did not improve to grade ≤2 within 4 weeks; UPN4: grade 3 kidney injury (per Bearman Scale), and grade 4 neutropenia lasting more than 42 days]. Since &amp;gt;1/6 patients had UTs, per protocol monitoring rules and after a full IRB review, the definition of UT was updated to the following in CH-2: any regimen-related grade 3-4 toxicity per Bearman scale, or for hematologic toxicities, per NCI CTCAE v4.03 toxicity scale, any grade 4 neutropenia associated with fever or infection and lasting for more than 21 days, or grade 4 neutropenia lasting for more than 42 days, or death. In CH-2, one out of 16 patients experienced a UT of acute kidney injury. UPN17 has not reached the 100-day UT period, at the time of this report. One-year OS, PFS and NRM for all patients were 80% (95%CI: 39-95), 68% (95%CI: 30-89) and 21% (95%CI: 3-50), respectively. All patients engrafted (n=12), with the median time to neutrophils engraftment of 19 days (range: 13-23) for CH-1 and 16 days (range: 12-22) for the CH-2. One-year OS for CH-2 was 91% compared to 50% in CH1 and was reduced to 78% and 50% at 2 years, respectively. RFS in CH-2 was 91% at 1 year, and 62% at 2 years compared to 50% in CH-1 at both time points. Relapse was not seen at 1 and 2 years in CH-1, whereas in CH-2 there were no relapses at 1-year but 15% of patients relapsed by the end of year 2. NRM at 100-days was 25% in CH1 vs non in CH-2 and at 2 years-NRM were 50% and 22% in CH-1 and CH-2, respectively. Grade 3-4 GVHD was not seen in either cohort. Similarly moderate and severe chronic GVHD was not seen in either cohort at 1 or 2 years. One and 2 years GRFS was 81 and 61% respectively. In conclusion, early results of this pilot study indicate that HaploHCT in MF patients undergoing HCT is safe and feasible, with low NRM and higher grade acute and chronic GVHD. We are currently accruing in CH2. If successful, this approach can be tested in a multi-center setting as a phase II trial, and likely extend this potentially curative procedure to most patients of minority populations in the United States and to a significant proportion of the Caucasian population without an HLA matched.

Metastatic site and clinical outcome of patients with deficient mismatch repair metastatic colorectal cancer treated with an immune checkpoint inhibitor in the first-line setting

PurposeOnly one-half of deficient mismatch repair (d-MMR) metastatic colorectal cancers (mCRC) demonstrate durable responses to immune checkpoint inhibitors (ICIs). Given preclinical data indicating that liver metastases sequester activated CD8+ T cells from systemic circulation, we examined clinical outcome by metastatic site. Patients and methodsIn a retrospective cohort of patients with d-MMR mCRCs treated at multiple centers in France (n = 66), we sought to validate data from a U.S. cohort, and performed pooled analysis (n = 104). All patients received first-line ICI monotherapy. Metastatic site was analyzed in relationship to tumor response (RECIST version 1.1), and with progression-free survival (PFS) by multivariable stratified Cox regression after adjustment for covariates. ResultsObjective responses were achieved in 38/66 (58%) of patients in the validation cohort. Best tumor response included 13 (20%) complete responses (CR), 25 (38%) partial responses (PR), 16 (25%) stable disease, and 11 (17%) progressive disease (PD). One-year and 5-year PFS rates were 73% and 67%, respectively; 18 (27%) patients progressed during immunotherapy. Best tumor response was attenuated in patients with liver metastasis (P = 0.03). Presence of liver metastasis, but not other sites, was associated with significantly poorer PFS after adjustment for covariates (HRadj 2.82; 95%CI, 1.08–7.39; Padj=0.03). In a pooled analysis, liver metastasis remained significantly and independently associated with poorer PFS (HRadj 3.18; 95%CI, 1.52–6.67; Padj=0.002) and with attenuated tumor best response (P = 0.01). ConclusionsMetastasis to the liver, but not other sites, was validated as an independent factor associated with poorer response and survival after ICI treatment in d-MMR mCRCs. These data underscore the need for novel therapeutic strategies in these patients.

CAR T- Cell Therapy Provides an Opportunity for Further Consolidation Treatment for Relapsed or Refractory Adult Burkitt Lymphoma Patients

Background: Adult Relapsed and refractory Burkitt's progresses rapidly, and there is limited data on CART therapy. The available data also indicates poor survival rates. Aims: Exploring the efficacy of CAR-T therapy for adult relapsed/refractory Burkitt's lymphoma, and analyzing the factors affecting the efficacy and survival of CART treatment. Methods: This single-centre, retrospective study analysed patients with Burkitt's lymphoma who received CAR-T therapy at the Beijing GoBroad Boren Hospital between December 2018 and February 2023. The inclusion criteria were adult relapsed and refractory Burkitt's lymphoma. Nineteen patients were included: 13/19 (68%) male; Median age is 37 (19-56).6/18 (33%) patients get standard intense chemotherapy（not R-CHOP）.17/19 (89.4%) patients were at stage IV at the time of salvage therapy. 9/19 (47.4%) patients IPI score was ≧3 .9/19 (47.4%) patients had &amp;gt; 7.5 cm bulky disease. Midian Leukapheresis LDH is 547.9 U/L. Patients had received a median of 4 cycles (range 3-14) prior to treatment. 2/19 (10.5%) and 2/19 (10.5%) patients had failed prior autologous hematopoietic stem cell transplantation and prior allogeneic hematopoietic cell transplant, respectively. 17/19 (89.4%) patients received bridging therapy before CAR-T，which only have 1 patient CR and 1 patient achieve a PR. Analyzing whether a sequential consolidation treatment strategy for patients who respond to CART therapy can prolong survival. Results: The median CAR-T infusion dose is 1.46*10^6/kg（0.0126-7.22）. The median of CAR-T peak expansion is 89.5（3.84-710）*10^6/L , which occurred on day 7（7-11）after CAR-T cell therapy. 16/19（84.2%） of patients experienced CRS, with 3/19 (15.8%) of them classified as grade III-IV.Besides,5/19(15.8%) of patients experienced iCANS, with 3/19 (26.3%) of them classified as grade III-IV. The median follow-up time was 4.274 (0.2-43.4) months.Three months ORR and CRR were 31.6% and 21.1%. The best ORR and the best CRR were 47.4% and 26%, respectively. One-year progression free survival and overall survival were 15.8% and 21.1%. For individuals who achieved CR/PR to CART therapy in three months, their survival curves were significantly better than those of individuals with SD/PD. The univariate analysis of PFS showed that risk factors included the high LDH at the time of leukapheresis(p=0.0182,HR 1.001) ,three months response is SD/PD (p=0.0045,HR 20.8) and initial treatment with R-CHOP based chemotherapy(p=0.0319,HR 5.46) .Among the 19 patients, 12 patients continued to receive other treatments for consolidation or salvage, including 5 cases of other target CAR-T therapies, 5 cases of autologous transplants, and 2 cases of allogeneic transplants. However, only 4 of these all patients remained disease-free. Among them, 2 patients received allogeneic transplants, 1 patient received autologous transplant, and no subsequent other treatments in one patient. Summary/Conclusion: CAR-T therapy should be recommended as soon as possible after Burkitt becomes relapsed or refractory due to the ineffectiveness of multi-drug chemotherapy. Upon reaching remission, the transition to autologous or allogenic stem cell transplantation may be considered. Due to the small number of cases, further validation of our findings is still needed.

Time-Limited Therapy with Zanubrutinib Plus Rituximab in Treatment-Naïve Chronic Lymphocytic Leukemia: Early Results of an Ongoing Phase 2 Trial

Introduction: The Bruton tyrosine kinase inhibitor (BTKi) zanubrutinib has recently been approved for treatment of chronic lymphocytic leukemia (CLL). Zanubrutinib induces durable remissions in most patients with CLL, and treatment is typically given as continuous monotherapy, until disease progression or toxicities prohibit further use. We developed time-limited therapy with zanubrutinib in combination with rituximab as an alternative to long-term BTKi monotherapy. Here, we report early results from the first 17 treatment-naïve patients with CLL who enrolled in this ongoing phase 2 trial (NCT04458610) between July 2020 and April 2023 at MD Anderson Cancer Center. Patients and Study Design: Patients with treatment-naïve CLL requiring therapy per iwCLL criteria receive zanubrutinib 160 mg orally twice daily and rituximab (375 mg/m 2 intravenously) on days 1, 8, 15, 22 of cycle 1, and then on day 1 of cycles 2 - 6 (one cycle is 28 days). Patients who achieve a complete remission (CR) by iwCLL 2018 criteria after 6 cycles of combination therapy continue with zanubrutinib alone for another 6 cycles. Patients who achieve a partial remission (PR) or stable disease (SD) after 6 cycles continue for another 6 cycles of the combination. Patients who achieve a CR after 12 cycles will receive 6 additional cycles of zanubrutinib alone, and then stop treatment. Patients who achieve a PR or SD after 12 cycles will continue zanubrutinib alone for 12 cycles and the stop therapy after a total of 24 cycles. After this time-limited therapy, patients transition to observation and can resume therapy if they relapse and fulfill iwCLL criteria for salvage therapy. The primary objective of the trial is to determine the proportion of patients who have treatment-free remission 6 months after discontinuation of zanubrutinib. Secondary objectives are to determine the length of treatment-free remission, identify clinical factors associated with long versus short remissions, and to evaluate the efficacy of re-treatment with zanubrutinib plus rituximab in patients who relapse. Results: The median age of the patients was 68 years (range, 54 - 77 years), 47% had unmutated IgHV and 41% advance stage disease (RAI stage III and IV). The median baseline absolute lymphocyte count (ALC) and β2 microglobulin were 51.9x10 9/L (range, 1.7 - 231.0x10 9/L) and 3.9 mg/L (range, 2.5 - 6.8 mg/L), respectively. After a median follow-up of 13 months (range, 0.5 - 29 months), all patients remain on study, and the estimated one-year progression-free (PFS) and overall survival (OS) is 100%. Seven patients completed therapy (1 patient after 12 cycles, 6 patients after 24 cycles) and have moved on to observation (median observation time post-therapy 4.5 months). So far, we have not observed any progression events after treatment discontinuation. Overall response rate is 100%, with 9% CR and 91% PR after 6 months (n=11), 11% CR and 89% PR after 12 months (n=9), and 33% CR and 67% PR after 24 months of therapy (n=6). The median levels of bone marrow involvement by CLL cells, quantified by flow cytometry, declined from 81.6% at baseline (range, 25.8 - 93.2%, n=16) to 20.3% after 6 cycles (range, 0.07 - 82%, n=11, p&amp;lt;0.0001), to 12.1% after 12 cycles (range, 0.04 - 55.60%, n=9, p&amp;lt;0.0001), and to 7.23% after 24 cycles (range, 0.2 - 41.4%, n=6, p=0.001). Grade ≥3 adverse events (AE) were observed in 9 patients (52.9%), which included hypertension (n=4) and decreased neutrophil counts (n=3). The most frequent grade 1-2 AE were decreased neutrophil (59%) and platelet counts (47%), bruising (41%), chills, increased creatinine, arterial hypertension, nausea (35% each), fatigue, and headache (29% each). No atrial fibrillation events were observed. Conclusion: This early analysis indicates that time-limited therapy with zanubrutinib and rituximab is well tolerated and induces remissions with a major reduction in bone marrow disease burden in patients with treatment-naïve CLL. The first 7 patients who stopped therapy so far have not progressed, but longer follow-up in more patients is needed to determine the durability of responses after therapy discontinuation, and how those compare to more intensive CLL combination regimens.

PD-1 Inhibitors combined with paclitaxel (Albumin-bound) and cisplatin for larynx preservation in locally advanced laryngeal and hypopharyngeal squamous cell carcinoma: a retrospective study.

laryngeal and hypopharyngeal squamous cell carcinoma (SCC) is a common head and neck cancer with significant impact on quality of life due to its crucial roles in vocalization, airway protection, and swallowing. This retrospective study aims to evaluate the efficacy and larynx organ preservation of neoadjuvant treatment with PD-1 inhibitors in combination with paclitaxel (Albumin-bound) and cisplatin for locally advanced laryngeal and hypopharyngeal SCC. Medical records of consecutive patients diagnosed with histologically or cytologically confirmed locally advanced SCC of the larynx and hypopharynx, who received PD-1 inhibitor therapy at a single tertiary care center, were reviewed from January 1, 2019, to December 15, 2022. The patients were treated with a combination of PD-1 inhibitors, paclitaxel (Albumin-bound) 260mg/m2, and cisplatin 60mg/m2 (TP) as their first-line therapy. Survival outcomes, laryngectomy-free survival (LFS) rates and response rates were assessed. The study cohort comprised 156 patients, predominantly male, with a median age of 60.4 years. The estimated one-year overall survival (OS) rate was 94.1%, two-year OS rate was 82.5%, one-year progression-free survival (PFS) rate was 80.4%, and two-year PFS rate was 66.3%. The one-year LFS was 86.4%, and the two-year LFS rate was 73.0%. The overall response rate after TP + PD-1 inhibitors therapy was 88.5%. Common treatment-associated adverse events included rash, thyroid function abnormalities, myelosuppression, and colitis. Neoadjuvant therapy with PD-1 inhibitors in combination with paclitaxel (Albumin-bound) and cisplatin showed promising efficacy and tolerability for larynx preservation in locally advanced laryngeal and hypopharyngeal SCC. The high response rates and favorable survival outcomes suggest this approach as a potential treatment option. Prospective randomized controlled trials are needed to further validate these findings and establish the role of immunotherapy in larynx preservation.

Combining Radiotherapy with Chemotherapy and Immunotherapy as First-Line Treatment for De Novo Metastatic Nasopharyngeal Carcinoma: A Dual-Center Retrospective Analysis

Local regional radiotherapy combined with systemic chemotherapy significantly improves the prognosis of patients with metastatic nasopharyngeal carcinoma (NPC). Immunochemotherapy has become the first-line treatment for initial metastatic NPC. This study evaluated the safety and efficacy of local regional radiotherapy combined with immunochemotherapy as the first-line treatment of metastatic NPC. Patients with histologically proven de novo metastatic NPC who received immunotherapy and chemotherapy followed by local-regional radiotherapy were included from 2 cancer centers. Toxicity and treatment response were assessed using CTCAE 5.0 and RECIST 1.1, respectively. Overall survival (OS) and progression free survival (PFS) were analyzed using the Kaplan-Meier method. From 2019 to 2021, a total of 16 patients were retrospectively analyzed. The median age was 44.5-year-old (range 16-76). Patients with ≥3 metastatic lesions accounts for 58.8%. Bone metastasis was the most common metastatic site. The chemotherapy regimens were paclitaxel/gemcitabine and cisplatin. Toripalimab, camrelizumab and sintilimab were used for immunotherapy. All patients completed the local regional radiotherapy with 69.96Gy for primary nasopharyngeal tumor and positive lymph nodes, 60.06Gy for high-risk region and 50ཞ54.45Gy for low-risk region. Seven patients underwent radiotherapy for metastatic lesions. The median follow-up was 20.5 months (range 6-38 months). Two-year OS was 100%. Three patients experienced distant progression. One-year and 2-year PFS rate was 93.8% and 76.7%, respectively. After combination of chemotherapy and immunotherapy, the overall response rate (ORR) was 93.7% with a complete response (CR) of 6.3%. At the end of radiotherapy, the ORR was 100%. Nine patients (56.3%) achieved CR. Radiotherapy related acute severe (grade 3 or higher) toxicity was dermatitis (1/16, 6.3%) and mucositis (2/16, 12.5%). Immunotherapy related hypophysitis and capillary hyperplasia was 6.3% and 6.3%, respectively. No long-term toxicity was observed. Loco-regional radiotherapy provided a promising efficacy with modest toxicity for patients with metastatic nasopharyngeal carcinoma who received immunochemotherapy.

Prospective Phase II Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy (SBRT) Followed By Concurrent Mediastinal Chemoradiation and Adjuvant Immunotherapy for Locally-Advanced Non-Small Cell Lung Cancer (LA NSCLC)

To report the efficacy and toxicity outcomes of a prospective phase II trial of primary tumor SBRT followed by conventional chemoradiation to the lymph nodes and adjuvant immunotherapy in patients (pts) with unresectable LA NSCLC. Eligible pts included stage II-III LA NSCLC with peripheral primary tumors ≤ 7cm or centrally based tumors that had at least 2 cm separation from involved nodal disease. Pts received SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by standard radiation to 60 Gy in 30 fractions to the involved lymph nodes with concurrent platinum doublet chemotherapy. The trial was amended to allow pts without disease progression after chemoradiation to receive adjuvant durvalumab per the PACIFIC trial. The primary endpoint was 1 year progression free survival (PFS), evaluated as a binary variable. Frequencies and proportions were used for reporting this primary endpoint, in addition to adverse events and patterns of failure. Median PFS and OS were estimated using Kaplan Meier methods. Safety and efficacy is reported on the first 50 pts enrolled in the trial with a median follow-up of 24 months (mos) (range, 1-54 mos). Pts were primarily stage IIIA (60%) or stage IIIB (34%), with 6% of pts stage IIB. Overall grade 3 or higher toxicity related to SBRT and/or mediastinal radiation was 8% with two pts (4%) developing grade 3 pneumonitis and one pt having a grade 5 lung infection possibly related to radiation. Overall grade 2 pneumonitis related to SBRT or mediastinal radiation was 20%. Only one pt (2%) developed grade 3 esophagitis. No late cardiac events have been observed. The one-year PFS for all pts was 62% with a median PFS of 26.3 mos and median overall survival of 40.8 mos. Of the 50 pts enrolled, 37 received at least one dose of adjuvant durvalumab. The one-year PFS for pts who received at least one dose of durvalumab was 70.3% with a median PFS not yet reached in this group (median follow-up 24 mos). Patterns of failure were mostly distant with 26% of pts experiencing distant failure, 6% regional, and 2% distant and regional. There was only one local failure (2%) after SBRT in all 50 pts. SBRT to the primary tumor followed by conventional chemoradiation to the involved lymph nodes and adjuvant immunotherapy was well tolerated and showed improved 1-year PFS compared to prior conventional chemoradiation trials for locally advanced NSCLC. The results of this trial will be further evaluated in a randomized phase III study, NRG LU-008. Pts will receive either conventional chemoradiation vs. SBRT to the primary tumor followed by chemoradiation to the involved lymph nodes followed by consolidative immunotherapy to evaluate the possibility of utilization of SBRT as a new standard of care for LA NSCLC.

Stereotactic Radiotherapy or Whole Brain Radiotherapy Combined with Pyrotinib and Capecitabine in HER2-Positive Advanced Breast Cancer Patients with Brain Metastases (BROPTIMA): A Prospective, Phase Ib/II Single-Arm Clinical Study

Approximately half of patients with advanced HER2-positive breast cancer (BC) will develop brain metastases (BM) over time. Local therapy including stereotactic radiotherapy (SRT) and whole brain radiotherapy (WBRT) is the main initial treatment in malignant tumor patients with BM. However, more than 50% patients after radiotherapy in one year suffered intracranial recurrence. Pyrotinib, a small molecule, irreversible, pan-ErbB receptor tyrosine kinase inhibitor (TKI), has a high potency for controlling BM and reducing the occurrence of brain metastases in advanced HER2-positive BC patients. We hypothesized that SRT or WBRT combined with pyrotinib and capecitabine could decrease intracranial progression in HER2 positive BC with newly diagnosed BM. In this prospective single-arm phase Ib/II trial (NCT04582968), eligible patients were assigned to either fractionated stereotactic radiotherapy (FSRT) or whole-brain radiation therapy (WBRT), combined with pyrotinib and capecitabine. The primary endpoint was one-year CNS progression-free survival (PFS) rate. Secondary endpoints included intracranial objective response rate (IC-ORR) according to RANO-BM criteria, progression-free survival (PFS), overall survival (OS) and evaluation of safety and neurocognitive function. From January 2020 to August 2022, 40 patients were enrolled. Twenty-nine patients were treated with FSRT in 8 Gy per fraction with 3 to 5 fractions and 11 were treated with WBRT in 3 Gy per fraction with 10 fractions, and then received chemotherapy in a time frame starting from 0 to 7 days after radiotherapy. At a median follow-up of 17.3 months, 1-year CNS-PFS rate was 74.9% (95% CI 61.9-90.7%) and median CNS-PFS was 18 months (95% CI, 15.5 to NA months). One-year PFS rate was 66.9% (53.1-84.2%) and median PFS time was 17.6 months (95% CI 12.8-34.1 months). The best intracranial response rate (IC-ORR: complete response and partial response) was 92.5% (37/40). The most common grade 3 or worse toxicity was diarrhea (7.5%) and asymptomatic radiation necrosis was detected in 4 of 67(6.0%) lesions treated with FSRT. No differences of neurocognitive function evaluated by MMSE (Mini-Mental State Exam) were observed between different groups at any time point. Radiotherapy combined with pyrotinib and capecitabine resulted in a promising efficacy that crossed the pre-specified boundary in patients with HER2-positive advanced breast cancer with brain metastases. This is the first prospective study showing the efficacy and safety of CNS radiotherapy concurrent with pyrotinib and capecitabine in patients with BM from HER2-positive breast cancer. Further investigation in a randomized controlled study is warranted.