5-year PFS Research Articles

Efficacy and safety of the combination of tisleizumab with chemoradiotherapy in oligorecurrence esophageal squamous cell carcinoma: A prospective phase II study.

4057 Background: The postoperative recurrence and metastasis rate of esophageal squamous cell carcinoma (ESCC) remains high and prognosis is poor. PD-1 immune checkpoint inhibitors have shown efficacy in targeting advanced esophageal cancer. This phase II study aims to explore the efficacy and safety of concurrent chemoradiotherapy and immunotherapy for ESCC patients with oligometastatic recurrence after radical surgery. Methods: This phase II study enrolled ESCC patients from 3 hospitals in China, diagnosed oligometastatic recurrence after radical surgery. The 1st stage, with 10 patients enrolled, was designed to explore the safety level and the 2nd stage was to explore efficacy. The oligorecurrence is defined as progression occurring three months after the operation with no more than three metastatic regions. The local recurrence was defined as tumor bed or anastomotic recurrence. The regional lymph node recurrences were regarded as mediastinal region and celiac lymph, respectively. The distal recurrences were considered as supraclavicular, retroperitoneal region and other distal organs. All of the positive regional lymph nodes were collectively counted as one lesion if regional lymph node recurrences existed. Tisleizumab was delivered on D1,22. Nab-paclitaxel 150mg/m2 (starting on D2,23) and cisplatin, 75mg/m2(starting on D2-4,22-24) were administered for two cycles. The radiotherapy was delivered with 50.4-60Gy, 1.8-2Gy per fraction. After CRT, patients received Tisleizumab every 3 weeks for 3-6 months and 2-4 cycle consolidation chemotherapy. The primary endpoint was 1-year OS, the second endpoints were 1-year PFS, ORR and toxicities. Results: Between Jan 2021 and May 2023,50 patients were screened for enrolment and 44 patients met the eligibility criteria. The metastatic regions were made up by the local (15.9%),regional (47.7%), distal (13.6%) and mixed recurrence (22.7%). In the 1st stage, one patient had a grade-3 Immune-related erythra out of ten patients. All patients were delivered chemoradiotherapy, 36(81.8%) patients had completed two cycles of immunotherapy. The ORR rate was 84.1%. During concurrent chemoradiotherapy, the incidence of grade≥3 treatment-related adverse events was nausea (9.1%), vomit (4.5%), anorexia (4.5%), leukopenia (13.6%), hepatitis (2.3%), radiation esophagitis (1.4%), erythra (4.5%). There were 5 cases of Immune-related adverse, including 2 cases of erythra, 1 case of hypothyroidism, hepatitis, gastroenteritis, respectively. With the median follow-up time of 19 months (range:4-30 months), 1-year OS and PFS was 83.2% and 79.2%. The median OS and the median PFS were not reached. Conclusions: Concurrent chemoradiotherapy and immunotherapy yielded satisfactory 1-year OS rate and manageable toxicities in oligometastatic recurrence patients with ESCC after radical surgery. Clinical trial information: NCT04821765 .

Combination of pirtobrutinib and lentiviral transduced bispecific anti-CD20/CD19 (LV20.19) CAR T-cell therapy to improve outcomes in patients with relapsed/refractory lymphoma.

7043 Background: Combination trials of BTK inhibitors (BTKi) with CAR-T have suggested potential synergistic benefit by improving CAR-T immunophenotype and clinical outcomes but are limited by increased toxicity. We report immunophenotype, cytokine profile, and patient outcomes with the new non-covalent BTKi, pirtobrutinib (pirto) when given prior to LV20.19 CAR-T and compare the final CAR product to pts who did not receive pirtobrutinib prior to CAR. Methods: Pts received LV20.19 CAR-T as part of a phase 1/2 trial (NCT04186520). Only pts who received pirto £4 weeks prior to apheresis were included. To determine the impact of pirto on LV20.19 CAR-T, we calculated both polyfunctionality (PFA) and polyfunctional strength index (PSI) for each product using the Isoplexis. Descriptive statistics, t-tests and Kaplan-Meier method were used as appropriate. Results: 11 pts received pirto prior to LV20.19 CAR-T (Table). Median age was 65 (50-80) yrs and median prior lines of therapy were 4 (2-8). There were 4 MCL pts, 5 Richter’s (RT)/CLL, 1 MZL and 1 DLBCL. Median duration of pirto was 4 (1-20) mo. Pts were on pirto for a median of 12 (1-22) days prior to apheresis. All except 1 pts received target CAR-T dose. The day 28 ORR was 82% (CR=7, PR=2). After a median follow up of 13 mo, 3 pts died (PD, Covid, Guillain Barre). The median PFS and OS were both 30.8 mo while the 1-year PFS and OS rates were 9 and 15 mo respectively. 9 pts had CRS and 2 had ICANS, all grades 1-2, while 4 had IEC-HS. One pt had afib recurrence and 1 pt had CMV viremia within 30 days of CAR-T. Among the pts with immunophenotypic data (n=10), there were no differences in naïve or more differentiated T-cell percentages in apheresis and final CAR-T products when compared to pts who did not receive pirto before LV20.19 CAR-T (n=57). Although not statistically significant, both PFA (CD4=61.8 vs 59, CD8= 49.8 vs 46.9) and PSI (CD4= 1752 vs 1608, CD8=1299 vs 1079) were higher with pirto pre-treated pts, suggesting a potential trend towards improved CAR-T functionality. Conclusions: These data represent the largest experience of pirto prior to CAR-T apheresis and demonstrate that pirto can be safely used as a bridge to LV20.19 CAR-T without negatively impacting their immunophenotype and potentially improving functionality. These data support our planned phase 1 clinical trial to assess the safety of pirto as bridging and maintenance therapy with LV20.19 CAR-T (NCT05990465). [Table: see text]

Long term results of a new treatment strategy for follicular low grade lymphoma (FLGL).

e19035 Background: FLGL usually presents with widespread but asymptomatic lymphadenopathy, low SUVs on PET and normal LDH. It's considered incurable and standard of care has been 'watch and wait' (W&W) followed later by treatment if necessary. We have described a subset of patients that we termed clinically discordant indolent histology (“CDIH”) whose behavior is more aggressive. CDIH is defined as presence of any of these: B symptoms, high LDH, SUV >14 on PET, Ki-67 index >30% or involvement of areas such as lung, pleura, soft-tissue, CNS and bones. Our study aims to assess real-world long-term outcome of managing FLGL with and without CDIH. Methods: We analyzed 186 previously untreated FLGL cases treated at our center from June 2002-July 2023, without opting for W&W. CDIH cases typically received R-CHOP x6, then 4 FND. Non-CDIH mainly received FND-R. All received 2 years maintenance rituximab. Main objective was to assess 10-year PFS and OS of stage IV cases, comparing it in a real-world setting against our previously published MD Anderson (MDACC) data. Secondary objectives were to compare our 10-year PFS and OS in stage IV cases against historical controls based on the FLIPI-2 score. We also sought to determine prognostic value of CDIH as compared to FLIPI-2, evaluate early relapse rate (2 yrs), and assess rate of transformation to aggressive lymphoma. Results: Median age: 58 (26-93). Median follow up: 96 mos (6-261). Stage III-IV: 76%. CDIH was present in 56%. Our PFS 10 yrs for non-CDIH=96% vs CDIH=77% (p=0.002). For stage IV, PFS 10 yrs = 82% vs MDACC's 50% using FND-R. OS 10-yr= 90% vs MDACC's 85%. 67 pts were followed >10 years; a relapse occurred in only 5 (7%). Our PFS 10 yr for favorable FLIPI-2 (score 0)= 97%, for intermediate (1-2) =88%, unfavorable (3-5)= 72% (p=.15). Our PFS results were consistently superior to literature data across all FLIPI-2 scores. Transformation to DLBCL= 6/186 (3%) compared to 20-30% historical controls; 5 of 6 transformations were in cases with CDIH and 4 occurred within 3 yrs. Early (<2 yr) relapse rate= 2% in contrast with 20% literature data; all 4 early relapses were CDIH. Conclusions: Our findings emphasize several advantages of initiating treatment early and basing it on presence or absence of CDIH. Our data highlight the need to 1- identify CDIH for potential use of doxorubicin treatment. 2- CDIH as prognostic factor seems more effective than FLIPI-2. 3- PFS 10 yr results are remarkably superior to both literature controls and to our previous experience at MDACC with FND-R. 4- Only 7% relapses beyond 10 yrs suggest potential for cure, according to our results and those from MDACC. [Table: see text]

Long-term follow-up of patients with hairy cell leukemia treated with different modalities at a single institution: Real-life experience over 25 years.

e19023 Background: Hairy cell leukemia (HCL) is an uncommon and indolent leukemia of mature B cells, accounting for 2% of all lymphoid neoplasms. We analyzed characteristics, treatment modalities, response rates, and survival of HCL patients followed at our institution. Methods: We retrospectively reviewed data from the medical records of 56 consecutive HCL patients evaluated in our Hematology/Oncology clinic between 1998 and 2023. Results: The median age at diagnosis was 59 years (range, 37-94). Forty-nine patients (87%) were male. First-line therapy was cladribine in 30 patients (54%), cladribine + rituximab in 6 patients (11%), observation in 5 patients (9%), and another modality (fludarabine, pentostatin, single agent-rituximab, and other) in the rest of patients. The median follow-up was 122 months (1-291). The overall response rate was 96%. CR and PR rates were 68% and 28%, respectively. Relapses were observed in 44% of patients. The median OS was not reached, and the median PFS was 181 months (95% CI, 128-252). The 5-year and 10-year PFS were 78% and 29%, respectively. Only 3 patients (5%) died as a result of HCL, either indirectly from immune suppression (pneumonia, 2 patients) or directly (cachexia in 1 patient, untreated because of advanced age and comorbidities). Conclusions: Treatment with purine analogues such as cladribine, plus or minus rituximab, achieves deep and durable responses in most HCL patients. Although relapses were commonly observed, the vast majority of HCL patients did not die as a result of HLC.

Phase II study of tislelizumab combined with concurrent chemoradiotherapy for locally advanced cervical cancer.

e17523 Background: Concurrent chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical cancer (LACC). However, local recurrence and distant metastasis are the main modes of treatment failure in LACC, especially for patients with stage IIIA ~IVA as well as patients with large masses (>4cm) and regional lymph node metastasis. This study aimed to evaluate the efficacy and safety of tislelizumab (anti-PD-1 antibody) combined with concurrent chemoradiotherapy for locally advanced cervical cancer. Methods: Eligible patients were age 18-75 years, ECOG performance status of 0-1 and untreated cervical cancer (2018 FIGO stage IIIA, IIIB, IVA, or cervical tumor diameter > 4cm with regional lymph node metastasis, or paracervical invasion with regional lymph node metastasis). All patients received CRT plus tislelizumab 200mg Q3W for 1 year or disease progression or intolerable toxicity. The CRT includes at least 4 cycles of cisplatin 40mg/m2 QW + EBRT 45~50Gy/25f then BT 28~30Gy/4~5f. The primary endpoint was tumor regression ratio before brachytherapy. Secondary endpoints were 3-month and 6-month objective response rate (ORR), 1-year and 3-year OS and PFS, safety. Results: From August 24, 2022 to February 4, 2024, 30 patients were enrolled. 25 patients completed CRT and were available for evaluation. The median age was 59 years (range 40-75). The tumor regression ratio before brachytherapy was 90.6%. The ORR at 3 and 6 months were 100%, The OS and PFS rate at 1 year were 100%. The main adverse effect was neutropenia (36% for grade 3-4 and 20% for grade 1-2). Radiation enteritis incidence was 64% and were grade 1-2. Other adverse effect such as nausea, vomiting, and dizziness occurred during CRT and could be alleviated after symptomatic treatment. No immune-related adverse events were observed. Conclusions: Our results suggest that Tislelizumab combined with concurrent chemoradiotherapy showed valuable antitumor activity and controllable safety in LACC. We will keep strictly implementing our study protocol for further PFS and OS. Clinical trial information: NCT05588219 .

The efficacy and safety of ulinastatin in the prevention and treatment of radiotherapy-induced oral mucositis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC): A multicenter, open-label, randomized controlled clinical trial.

6105 Background: Severe oral mucositis is a common radiation-induced toxicity in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients treated with concurrent chemo-radiotherapy (CCRT). Ulinastatin (UTI) can reduce the inflammatory response by inhibiting the release of inflammatory factors, but its role in radiotherapy-induced oral mucositis (RTOM) is unclear. Therefore, we conducted a multicenter, open-label, randomized controlled clinical trial to investigate the efficacy and safety of UTI in the prevention and treatment of RTOM in LA-NPC patients. Methods: Patients with histologically confirmed LA-NPC who met the eligibility criteria were randomly assigned to UTI group and control group. All patients received radical intensity modulated radiation therapy (IMRT) and concurrent chemotherapy (cisplatin 100 mg/m2/3 weeks for 2 or 3 cycles). UTI of 100,000 units three times daily (5 days/week) was intravenously administrated from day 1 to the end of radiotherapy for UTI Group. The primary endpoint was the incidence of grade ≥ 3 acute RTOM during CCRT (Radiation Therapy Oncology Group, RTOG grading). The secondary endpoints included the cumulative incidence of RTOM, recovery rate (proportion of patients with grade ≥ 3 RTOM who recovered to grade ≤ 2 during CCRT), the onset time and duration of grade ≥ 3 RTOM, oral pain (Numerical rating scale, NRS), safety and survival outcomes. Results: From January, 2018, to December, 2021, 182 patients from 5 hospitals were enrolled. 179 patients were included for efficacy, safety and survival analysis (89 in the UTI group and 90 in the control group). All UTI group patients completed UTI treatment as planned, and both groups completed scheduled CCRT. The incidence of grade ≥ 3 RTOM was significantly lower in UTI group compared with control group (25.8% vs. 41.1%; P = 0.030). The recovery rate in UTI group was higher than that in control group (39.1% vs. 10.8%; P = 0.023). However, the onset time and the duration of grade ≥ 3 RTOM were similar between the two groups (Median [IQR] 26.00 [19.00, 33.00] days vs. 32.00 [20.50, 36.00] days; P= 0.621 and 12.00 [7.00, 18.00] days vs. 15.00 [8.00, 25.50] days; P= 0.209). The incidence of severe oral pain ( NRS score≥ 7 ) was significantly reduced in UTI group compared with the control group (22.5% vs. 36.7; P = 0.038). No UTI related adverse events were observed during treatment. With a median follow-up time of 41.6 months (IQR, 38.2 - 45.0 months), The 3-year OS, LRRFS, DMFS and PFS in UTI group and Control group were 96.5% vs. 94.3%, 91.2% vs. 87.2%, 95.2% vs. 92.1% and 89.9% vs. 85.1%, respectively (all P > 0.05). Conclusions: Our study revealed that UTI can effectively reduce the incidence of graded ≥ 3 RTOM and severe oral pain without increasing adverse events and compromising survivals. Clinical trial information: NCT03387774 .

Neoadjuvant treatment with camrelizumab in combination with doxorubicin and ifosfamide: A phase II clinical study of high-risk soft tissue sarcoma.

e23548 Background: Surgery remains the cornerstone in the management of non-metastatic soft tissue sarcomas. However, high rate of recurrence and metastasis are not uncommon in patients(pts) with high-risk soft tissue sarcoma. Although doxorubicin plus ifosfamide resulted in better tumor shrinkage which facilitate surgical resection, approaches of reducing recurrence and metastasis are still needed. Chemotherapy combined with PD-1 antibodies showed promising activity in several tumors. To date, there is no study to evaluate the efficacy and safety of camrelizumab combined with chemotherapy for high-risk Soft Tissue Sarcoma. Methods: This is a phase II, open-label single-arm study (NCT04606108), aimed to include pts aged 14-65 with histopathologically confirmed high risk soft tissue sarcoma and ECOG 0-1, at least one measurable lesion. One course of treatment every three weeks (camrelizumab 200 mg on day 1, doxorubicin 37.5 mg/m2 or liposomal doxorubicin 25 mg/m2 on days 1-2, and ifosfamide 3 g/m2 on days 1-3). After completing the 2nd course of chemotherapy, the drug will be stopped for 14 days, and surgery or the next stage of treatment will be carried out according to the efficacy of the treatment. Six courses of preoperative chemotherapy will be administered 2 weeks ± 5 days after surgery based on the effectiveness, followed by radiotherapy (50 Gy in 25 fractions or 60 Gy in 30 fractions.) within 3 months after surgery. The primary objective is the Objective response rate (ORR). Using the Simon minimax 2 stage design, planned sample size is 62 pts with 80% power and alpha of 5% to detect an increase in ORR from 27% to 42%. Interim analysis requiring at least 9 confirmed responses in the first 30 pts to proceed to full accrual. Results: 35 pts completed neoadjuvant therapy and surgery, 30 pts received postoperative adjuvant therapy and 1 patient achieved partial response (PR). Median age was 36.4 years (14-61), 62.8% were females, and 57.1% were ECOG-PS 0. Surgery was performed in 35 pts including 16/35 Synovial Sarcoma (SS), 5/35 Liposarcoma (LPS), 2/35 Myxofibrosarcoma (MFS), 2/35 Undifferentiated pleomorphic sarcoma (UPS), 1/35 Leiomyosarcoma (LMS), 5/35 Malignant mesenchymal tumors and 4/35 other pathologic subtype. The 2-year PFS rate was 84.9%, the 2-year OS rate was 96.77%, and the 2-year RFS rate was 72.6%. The most common grade 3-4 adverse events included leukopenia (37.7%), Neutrophil count decreased (37.7%), Platelet count decreased (20.0%), Blennisthmia (3.1%), and Aspartate aminotransferase increased (0.8%). Conclusions: Camrelizumab combined with doxorubicin, liposomal doxorubicin, and ifosfamide in the perioperative treatment of soft tissue sarcoma pts were safe and tolerable. Survival follow-up is still ongoing to analyze the effect of perioperative immunotherapy combined with chemotherapy on long-term outcomes of pts with soft tissue sarcoma. Clinical trial information: NCT04606108 .

Pyrotinib in HER2-altered advanced salivary gland carcinomas: Analysis of two cohorts from an exploratory study.

6108 Background: The HER2 altered in a subset of salivary gland cancers (SGCs). Pyrotinib is an oral irreversible pan-HER receptor tyrosine kinase inhibitor targeting HER1, HER2, and HER4. In this study, we assessed the efficacy and safety of pyrotinib in patients with HER2-amplified/overexpressed/mutated advanced SGCs, including recurrent/metastatic(R/M) and locally advanced (LA) patients with high-risk of recurrence. Methods: R/M and high-risk LA SGCs with HER2-alteration were enrolled. Pyrotinib (400 mg) was given orally once daily. In LA cohort, pyrotinib were given as adjuvant therapy after standard surgery and postoperative radiation. Results: Between August 2019 and August 2023, 18 patients were enrolled (10 in R/M cohort and 8 in LA cohort). In R/M cohort, the median age was 58.5 years, and all patients were grade III. The ORR was 90%, including 2 CRs, 7 PRs and 1PD; median DOR was 5.7 months (range: 3.1-13.7) and median PFS was 7.6 months (range: 2.7-16.8). In LA cohort, the median age was 59.0 years, and all patients but one were grade III. All patients but one had T4 disease; 5 patients had N3 and 2 had N2b disease; 5 patients had ENE and 5 patients had positive margin. With a median follow up 21.3 months, only 3 patients experienced recurrence, and one patient died due to non-tumor reasons. The estimated 2-years PFS and 2-years OS were 75% and 100%. The most common adverse event was diarrhea, which occurred in 11/18 (61.1%) patients and 3/18 (16.7%) were grade III. Conclusions: Pyrotinib showed promising antitumor activity in recurrent/metastatic HER2-altered SGCs, and had a potential to prolong survival outcome as adjuvant treatment in LA patients setting, which needs further randomized studies. Clinical trial information: NCT05087706 .

Clinical features and outcomes of patients with follicular lymphoma grade 3A: A real-world study in single center.

e19058 Background: Follicular lymphoma (FL) was classified into three grades based on the number of centroblasts (FL1-2, FL3A, and FL3B). Guidelines suggest that FL1-2 should be treated according to the treatment recommendations for classical FL. FL3B is usually treated as diffuse large B-cell lymphoma (DLBCL).There is no consensus yet on the management of FL3A. In order to explore the relationship between clinical features and outcomes of FL3A, we conducted this study. Methods: We conducted a retrospective study of newly diagnosed FL patients who were admitted to our hospital from January 2013 to December 2022. The data were collected from the hospital electronic medical record system, including but not limited to: demographic characteristics, pathological information, clinical features at diagnosis, treatment, and efficacy evaluation. The survival curve was calculated through Kaplan-Meier method and compared with Log Rank test.The prognostic factors of PFS was compared by COX regression analysis. Results: There were 253 FL3A patients admitted, accounting for 27.55% of all FL patients. After screening, a total of 223 FL3A patients were included in this study. Among 223 patients, the male to female ratio was close to 1:1; The median age is 57 years old. At diagnosed, 33 patients in early stage and 190 in advanced stage. Among advanced patients, 144 had no treatment indications according to the GELF criteria. 86.1% (192/223) of patients received systemic treatment, with the majority of rituximab contained regimens. The overall response rate (ORR) was 96%, and 62.9% of patients who responded to chemotherapy received maintenance therapy with CD20 monoclonal antibody. A median follow-up of 41 months, with an estimated 5-year OS of 91.3% and 5-year PFS of 73%. The PFS of advanced FL patients treated with RCHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) was significantly longer than that of non-RCHOP regimen patients (P<0.05). The PFS of patients receiving maintenance treatment was better than that of those not (P<0.05). Conduct prognostic analysis on advanced FL3A patients. Univariate analysis showed that treatment plan selection, maintenance of treatment, PET scan of FDG metabolic maximum uptake value (SUVmax), Ki-67, lactate dehydrogenase (LDH), white blood cell count (WBC), IgA, IgM, all significantly affected PFS; Multivariate analysis shows SUVmax ≥ 15 and platelet count<100 × 109/L and LDH>210U/L are all correlated with poor PFS. Conclusions: This study found that FL3A accounts for 27.55% of all FLs, with a median age of 57 years old and mostly in the advanced stage. FL3A has a long survival period, with a 5-year PFS of 73%. COX regression analysis showed that SUVmax, platelet count, and LDH were all associated with PFS in advanced FL3A patients.Those may explore new clinical prognosis prediction models.

Plasma mutational burden in PIK3CA and TP53 independently predicts early progression in patients with HR+/HER2- metastatic breast cancer (MBC) enrolled in the GEICAM/2014-12 FLIPPER trial.

1029 Background: There is an unmet need for molecular diagnostics to predict therapy outcomes using blood-based biomarker monitoring to guide treatments in HR+/HER2- MBC patients. Here, we report initial results of serial ctDNA analyses in a trial of Fulvestrant (F) + CDK4/6 inhibitor (CDK4/6i) Palbociclib (Pa) vs. F + Placebo (Pl). Endocrine therapy + CDK4/6i are currently the cornerstones of treatment for HR+/HER2- MBC. However, between 10–30% of patients suffer primary resistance. Thus, early identification of HR+/HER2- MBC patients that progress during CDK4/6i treatment is required. Methods: The GEICAM FLIPPER trial (NCT02690480) is a multicenter, double-blind, randomized, phase II study comparing F+Pa vs F+Pl in postmenopausal women with HR+/HER2- MBC. Sequential plasma was collected from 187 patients at baseline, 12, 24, 36, and 48 weeks on treatment and at progression. In total, 903 samples were analyzed using the Plasma-SeqSensei BC IVD kit (Sysmex Inostics) that identifies and quantifies ctDNA mutations in six BC-related genes. The mutant allele frequency (MAF) of PIK3CA and TP53 variants was assessed in baseline samples (median value as cutoff). These variants, identified as the most prevalent, were used as surrogate markers for mutational burden. The Kaplan-Meier method was used to estimate median (m) PFS and overall survival (OS). Hazard ratio (HR) and odds ratio (OR) were calculated with 95% confidence interval (CI) using Cox proportional hazards regression model and logistic regression respectively, unadjusted or adjusted by age, site of disease, disease presentation at study entry and clinical subtype. Results: Previously we showed that F+Pa improved 1-year PFS (83.5% vs. 71.9%, p=0.064) and mPFS (31.8 vs. 22.0 months, p=0.001) vs F+Pl. Here, ctDNA analyses revealed that having ≥1 mutation in PIK3CA + TP53 was prognostic of early (≤12 months) progression (OR 2.37; 95% CI 1.1-5.12, p=0.0274) independent of treatment arm. Furthermore, having ≥2 mutations was associated with treatment resistance (not achieving objective response; OR 3.55; 95% CI 1.28-9.87, p=0.0151). Additionally, worse mPFS and mOS were seen in patients with ≥2 mutations in PIK3CA + TP53 (PFS: HR 3.6; 95% CI 2.25-5.76, p<0.0001; OS: HR 2.92; 95% CI 1.66-5.12, p=0.002) and in patients with high MAF (PFS: HR 2.43; 95% CI 1.6-3.68, p<0.0001; OS: HR 2.83; 95% CI 1.75-4.58, p<0.0001). Finally, having ≥2 mutations in PIK3CA + TP53 was predictive of early progression (OR 22.32; 95% CI 4.12-120.9, p<0.0001) and worse mOS (61.8 vs. 34.79 months) in the F+Pl arm (HR 5.91; 95% CI 2.65-13.16, p<0.0001) but not in the F+Pa arm. Conclusions: Baseline plasma mutational burden in both PIK3CA and TP53 genes was significantly associated with Fulvestrant +/- Palbociclib treatment outcome in HR+/HER2- MBC and appeared to be predictive of Palbociclib benefit. Clinical trial information: NCT02690480 .

Preliminary results of a randomized controlled, open-label, multi-center phase II study of camrelizumab combined with chemotherapy followed by concurrent chemoradiotherapy and camrelizumab consolidation therapy versus standard chemoradiotherapy as first-line treatment for limited-disease small cell lung cancer.

e20132 Background: Immune checkpoint inhibitors combined with chemotherapy have significant clinical benefits in extensive-stage small cell lung cancer (SCLC). However, for patients with limited-disease SCLC (LD-SCLC), the data on immunotherapy combined with chemoradiotherapy is insufficient. Methods: In this open-label, multi-center, phase 2 trial, we randomly 1:1 assigned patients with previously untreated LD-SCLC to receive camrelizumab combined with chemotherapy followed by concurrent chemoradiotherapy (CCRT) and camrelizumab consolidation therapy or standard chemoradiotherapy. Patients with ECOG performance status of 0 to 1, and adequate organ function were eligible. For thoracic radiation, 45 Gy in 3 weeks (1.5 Gy, BID) was given on the first day of the third cycle of chemotherapy. An etoposide plus platinum-based regimen was given 4 cycles in total. Patients who had a good response to initial treatment were offered prophylactic cranial irradiation. The primary endpoint was the 1-year progression-free survival rate. We assumed that the 1-year PFS rate in the experimental group was expected to reach 65% compared to chemoradiotherapy alone group 45%, and planned to enroll 112 patients with 56 in each group. Results: Up to date, we have enrolled 40 patients. The median follow-up was 10.6 months. Safety was evaluated in all treated patients. No Grade 5 adverse event was observed. Grade 3 or 4 treatment-related adverse events occurred in 58.8% of the patients in the camrelizumab plus chemoradiotherapy and in 52.9% of those in the chemoradiotherapy alone group. The most frequent grade 3 or 4 adverse events were hematologic toxicities (70.6% vs. 58.8%). Acute esophagitis and pneumonitis of grade 3 occurred in both groups were 1/17 (5.9%) and 1/17 (5.9%), respectively. In the experimental group, only one patient was developed grade 3 immune pneumonia 1/17 (5.9%). The 1-year PFS rate was 54.5% (95% confidence interval [CI] 19.5%-89.6%) with camrelizumab plus chemoradiotherapy and 44.4% (95% CI 3.9%-88.0%) with chemoradiotherapy alone. Among the 17 patients who received camrelizumab, the median PFS time was not reached, as compared with 14.35 (95% CI, 8.15-20.91) months among the 17 patients with chemoradiotherapy alone. Conclusions: In patients with LD-SCLC, the addition of camrelizumab to chemoradiotherapy did not increase the incidence of adverse events. Camrelizumab plus chemoradiotherapy resulted in an encouraging 1-year PFS rate. Larger sample sizes and longer follow-up times are required to validate our preliminary results. Clinical trial information: ChiCTR2000032275.

Use of liquid biomarker thymidine kinase activity (TKa) to predict outcome and progression in patients with metastatic breast cancer (MBC) in the GEICAM/2014-12 FLIPPER trial.

1028 Background: There is a need for more precise blood-based tumor biomarkers in MBC. TKa is a liquid proliferation biomarker providing prognostic, predictive and monitoring information in MBC. TKa can be measured in blood using the DiviTum TKa assay. Here we report the results of TKa in a trial of endocrine therapy (ET) fulvestrant (F) + the CDK4/6 inhibitor (CDK4/6i) Palbociclib (Pa) vs. F + Placebo (Pl), the GEICAM FLIPPER trial (NCT02690480), a multicenter, double-blind, randomized (1:1) study. F+Pa showed 1-year PFS rates of 83.5% vs. 71.9% (p=0.064) and better median (m)PFS (31.8 vs. 22.0 months, p=0.001) than F+Pl in first line treatment of HR+/HER2- MBC patients. F+Pa also significantly improved ORR and CBR. ET+CDK4/6i are currently the cornerstone of treatment for HR+/HER2- MBC. However, 10-30% of these patients display primary resistance to treatment. Early identification of patient subsets with different risk of progression during treatment with CDK4/6i may help tailor clinical management and disease monitoring. Methods: Sequential plasma was collected from 187 patients (pts) at baseline (BL) and at 12, 24, 36, 48 weeks (w) on treatment, and at progression. 910 samples were analyzed for TKa with the FDA approved and CE labelled DiviTum TKa assay (Biovica, Sweden) using DuA (DiviTum unit of Activity) as measuring unit. The cutoff for categorizing in high vs low is 250 DuA. The Kaplan-Meier method was used to estimate mPFS and mOS. Unadjusted and adjusted hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were calculated with the Cox proportional hazards regression model and with logistic regression respectively, considering relevant confounders. Results: Low BL TKa predicted better PFS (30.5 months mPFS in low vs 19.8 in high, HR 1.62; 95% CI 1.11-2.35, p=0.011) and OS (HR 1.81; 95% CI 1.15-2.85, p=0.0099). Higher TKa at BL and at 12w was detected in pts that progressed before 12 months. Conversely, low BL TKa, maintained throughout week 12-48, were associated with objective response (HR 2.58; 95% CI 1.38-4.81, p=0.0029) and OS (HR 5.74; 95%CI 2.06-16, p=0.0008). At progression, pts on F+Pa tended to have higher TKa levels than F+Pl (246 vs. 138 DuA), reflecting faster growing tumors, not achieving statistical significance (p=0.0585). TKa monitoring and dynamics from BL and on treatment timepoints (week 12-48) show that the group of pts with low TK at BL that remain low during treatment is enriched with non-progressors and pts that progress after 12 months (p=0.0108). High TKa at BL predicted shorter OS in the F+Pa arm (HR 4.39; 95% CI 2.15-8.99, p<0.0001). Conclusions: Measuring blood TKa levels can monitor and predict efficacy of F+/-Pa at BL and during therapy in MBC. TKa dynamics before and during therapy are associated with PFS and OS. Future studies will provide additional knowledge on the utility of TKa in MBC. Clinical trial information: NCT02690480 .

F.3 Multicentre prospective validation of integrated molecular classification of meningiomas and prediction of recurrence risk using DNA methylation

Background: Meningiomas have significant heterogeneity between patients, making prognostication challenging. For this study, we prospectively validate the prognostic capabilities of a DNA methylation-based predictor and multiomic molecular groups (MG) of meningiomas. Methods: DNA methylation profiles were generated using the Illumina EPICarray. MG were assigned as previously published. Performance of our methylation-based predictor and MG were compared with WHO grade using generalized boosted regression modeling by generating time-dependent receiver operating characteristic (ROC) curves and computing area under the ROC curves (AUCs) along with their 95% confidence interval using bootstrap resampling. Results: 295 meningiomas treated from 2018-2021 were included. Methylation-defined high-risk meningiomas had significantly poorer PFS and OS compared to low-risk cases (p<0.0001). Methylation risk increased with higher WHO grade and MG. Higher methylome risk (HR 4.89, 95%CI 2.02-11.82) and proliferative MG (HR 4.11, 95%CI 1.29-13.06) were associated with significantly worse PFS independent of WHO grade, extent of resection, and adjuvant RT. Both methylome-risk and MG classification predicted 3- and 5-year PFS and OS more accurately than WHO grade alone (ΔAUC=0.10-0.23). 42 cases were prescribed adjuvant RT prospectively although RT did not significantly improve PFS in high-risk cases (p=0.41). Conclusions: Molecular profiling outperforms conventional WHO grading for prognostication in an independent, prospectively collected cohort of meningiomas.

Estimating the long-term survival of unresectable stage III non-small cell lung cancer based on cure model analysis

BackgroundThe predictors of long-term survival and appropriate surrogate endpoints in unresectable stage III non-small cell lung cancer (NSCLC) treated with radiotherapy remain unclear, especially in the immune therapy era. MethodsThis study retrospectively analyzed a prospective cohort of 822 patients treated at the Chinese National Cancer Center from 2013 to 2022. Cure fractions, surrogates for long-term survival, and associated factors were assessed using a mixture cure model, with validation against a matched Surveillance, Epidemiology, and End Results (SEER) dataset. Results27.3% of patients with unresectable stage III NSCLC can achieve long-term survival after treated by radiotherapy. 4-year PFS and 5-year OS, when 80% of patients were considered cured, showed significant correlations with cure rates based on background mortality-adjusted PFS and relative survival, with R-squared values exceeding 0.85. Independent predictors of long-term survival included non-squamous cell carcinoma (non-SCC) pathological type, N category, gross tumor volume, and treatment combination with immune checkpoint inhibitors (ICIs). ConclusionsRadiotherapy, especially when combined with ICIs, offers a potential cure for a proportion of patients with unresectable stage III NSCLC. Tumor burden and ICIs are key predictors of long-term survival. The study suggested 4-year PFS and 5-year OS as surrogate endpoints for cure and long-term survival assessment.

The safety and efficacy of bevacizumab in treatment of recurrent low-grade glioma: a systematic review and meta-analysis.

Central nervous system (CNS) tumors are among the most common malignancies in various age ranges. Low-grade glioma (LGG) can account for nearly 30% of pediatric CNS malignancies. Progression or recurrence after the first-line treatments is common among these patients. Therefore, more treatments are required. Bevacizumab as an anti-VEGF antibody has come into the spotlight recently and is especially used in relapse or recurrence settings. This review aims to study the safety and efficacy of bevacizumab for patients with recurrent LGG. This study was conducted according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PubMed, Scopus, Web of Science, and Embase were comprehensively searched using the relevant key terms until 24th August 2023 to retrieve the studies that investigated clinical outcomes of bevacizumab in patients with recurrent LGG. All statistical analysis was performed by STATA v.17. A total of 1306 papers were gathered, out of which 13 were incorporated in the meta-analysis. The pooled incidence rate of treatment according to the RANO scale was 70% (95% CI = 43-98%) for objective response rate, 26% (95% CI = 58-96%) for partial response, 21% (95% CI = 15-28%) for minor response, 14% (95% CI = 3-24%) for complete response, 48% (95% CI = 37-59%) for stable disease, and 8% (95% CI = 4-11%) for progressive disease. Furthermore, according to progressive survival after treatment, it was 4% (95% CI = -1 to 9%) for 6-month PFS, 41% (95% CI = 32-50%) for 2-year PFS, and 29% (95% CI = 22-35%) for 3-year PFS. According to the RANO scale and PFS, clinicians should be aware that Bevacizumab could be a favorable alternative therapy for recurrent LGG. Furthermore, bevacizumab exhibits minimal toxicity and high tolerability in recurrent LGG.

Outcomes of patients in nasopharyngeal adenoid cystic carcinoma in the IMRT era: a single-center experience

ObjectiveNasopharyngeal adenoid cystic carcinoma (NACC) is a rare malignancy with special biological features. Controversies exist regarding the treatment approach and prognostic factors in the IMRT era. This study aimed to evaluate the long-term outcomes and management approaches in NACC.MethodsFifty patients with NACC at our institution between 2010 and 2020 were reviewed. Sixteen patients received primary radiotherapy (RT), and 34 patients underwent primary surgery.ResultsBetween January 2010 and October 2020, a total of 50 patients with pathologically proven NACC were included in our analysis. The median follow-up time was 58.5 months (range: 6.0–151.0 months). The 5-year overall survival rate (OS) and progression-free survival rate (PFS) were 83.9% and 67.5%, respectively. The 5-year OS rates of patients whose primary treatment was surgery and RT were 90.0% and 67.3%, respectively (log-rank P = 0.028). The 5-year PFS rates of patients whose primary treatment was surgery or RT were 80.8% and 40.7%, respectively (log-rank P = 0.024). Multivariate analyses showed that nerve invasion and the pattern of primary treatment were independent factors associated with PFS.ConclusionsDue to the relative insensitivity to radiation, primary surgery seemed to provide a better chance of disease control and improved survival in NACC. Meanwhile, postoperative radiotherapy should be performed for advanced stage or residual tumours. Cranial nerve invasion and treatment pattern might be important factors affecting the prognosis of patients with NACC.

REPeated mAgnetic resonance Image-guided stereotactic body Radiotherapy (MRIg-reSBRT) for oligometastatic patients: REPAIR, a mono-institutional retrospective study

BackgroundOligo-progression or further recurrence is an open issue in the multi-integrated management of oligometastatic disease (OMD). Re-irradiation with stereotactic body radiotherapy (re-SBRT) technique could represent a valuable treatment option to improve OMD clinical outcomes. MRI-guided allows real-time visualization of the target volumes and online adaptive radiotherapy (oART). The aim of this retrospective study is to evaluate the efficacy and toxicity profile of MRI-guided repeated SBRT (MRIg-reSBRT) in the OMD setting and propose a re-SBRT classification.MethodsWe retrospectively analyzed patients (pts) with recurrent liver metastases or abdominal metastatic lesions between 1 and 5 centimeters from liver candidate to MRIg-reSBRT showing geometric overlap between the different SBRT courses and assessing whether they were in field (type 1) or not (type 2).ResultsEighteen pts completed MRIg-reSBRT course for 25 metastatic hepatic/perihepatic lesions from July 2019 to January 2020. A total of 20 SBRT courses: 15 Type 1 re-SBRT (75%) and 5 Type 2 re-SBRT (25%) was delivered. Mean interval between the first SBRT and MRIg-reSBRT was 8,6 months. Mean prescribed dose for the first treatment was 43 Gy (range 24–50 Gy, mean BEDα/β10=93), while 41 Gy (range 16–50 Gy, mean BEDα/β10=92) for MRIg-reSBRT. Average liver dose was 3,9 Gy (range 1–10 Gy) and 3,7 Gy (range 1,6–8 Gy) for the first SBRT and MRIg-reSBRT, respectively. No acute or late toxicities were reported at a median follow-up of 10,7 months. The 1-year OS and PFS was 73,08% and 50%, respectively. Overall Clinical Benefit was 54%.ConclusionsMRIg-reSBRT could be considered an effective and safe option in the multi-integrated treatment of OMD.

Predictors of Survival, Treatment Modalities, and Clinical Outcomes of Diffuse Large B-Cell Lymphoma in Patients Older Than 70 Years Still an Unmet Medical Need in 2024 Based on Real-World Evidence.

Diffuse large B-cell lymphoma (DLBCL) especially affects the older population. Old (≥60 years) and very old age (≥80 years) DLBCL patients often present high-risk molecular alterations, lower tolerability to conventional immunochemotherapy, and poor clinical outcomes. In this scenario, attenuated therapeutic strategies, such as the R-MiniCHOP and R-MiniCHOP of the elderly regimens, have emerged for this particularly fragile population. However, the responses, clinical outcomes, and toxicities of these regimens currently remain poorly understood, mainly because these individuals are not usually included in controlled clinical trials. This retrospective, observational, and single-center real-world study included 185 DLBCL, NOS patients older than 70 years treated at the largest oncology center in Latin America from 2009 to 2020. We aimed to assess the outcomes, determine survival predictors, and compare responses and toxicities between three different primary therapeutic strategies, including the conventional R-CHOP regimen and the attenuated R-MiniCHOP and R-MiniCHOP of the elderly protocols. The median age at diagnosis was 75 years (70-97 years), and 58.9% were female. Comorbidities were prevalent, including 19.5% with immobility, 28.1% with malnutrition, and 24.8% with polypharmacy. Advanced clinical stage was observed in 72.4%, 48.6% had bulky disease ≥7 cm, 63.2% had B-symptoms, and 67.0% presented intermediate-high/high-risk IPI. With a median follow-up of 6.3 years, the estimated 5-year OS and PFS were 50.2% and 44.6%, respectively. The R-MiniCHOP of the elderly regimen had a lower ORR (p = 0.040); however, patients in this group had higher rates of unfavorable clinical and laboratory findings, including hypoalbuminemia (p = 0.001), IPI ≥ 3 (p = 0.013), and NCCN-IPI ≥ 3 (p = 0.002). Although associated with higher rates of severe neutropenia (p = 0.003), the R-CHOP regimen promoted increased OS (p = 0.003) and PFS (p = 0.005) in comparison to the attenuated protocols. Additionally, age ≥ 75 years, high levels of LDH, B-symptoms, advanced clinical stage (III/IV), neutrophilia, and low lymphocyte/monocyte ratio were identified as poor prognostic factors in this cohort. In this large and real-life Latin American cohort, we demonstrated that patients with DLBCL, NOS older than 70 years still do not have satisfactory clinical outcomes in 2024, with half of cases not reaching 5 years of life expectancy after diagnosis. Although the conventional R-CHOP offers response and survival advantages over attenuated regimens, its myelotoxicity is not negligible. Therefore, the outcomes reported and the prognostic factors here identified may assist clinicians in the appropriate selection of therapeutic strategies adapted to the risk for old and very old DLBCL patients.

Patterns of Treatment Failure in Primary Central Nervous System Lymphoma.

Progression of PCNSL remains a challenge with salvage therapies, including the risk of substantial morbidity and mortality. We report patterns of first tumor progression to inform opportunities for improvement. This is an institutional retrospective review from 2002 to 2021 of 95 consecutive patients with pathologically confirmed PCNSL, of whom 29 experienced progressive disease. Kaplan-Meier method, log-rank test, and Cox proportional hazard models are used to characterize associations of patient, tumor, and treatment variables with LC, PFS, and patterns of first failure. Most patients were below 65 years old (62%) with KPS >70 (64%) and negative CSF cytology (70%). In 70 patients with MRIs, the median tumor volume was 12.6 mL (range: 0.5 to 67.8 mL). After a median follow-up of 11 months, 1-year PFS was 48% and 1-year LC was 80%. Of the 29 patients with progression, 24% were distant only, 17% were distant and local, and 59% were local only. On MVA, LC was associated with age (HR: 1.08/y, P =0.02), KPS (HR: 0.10, P =0.02), completion of >6 cycles of HD-MTX (HR: 0.10, P <0.01), and use of intrathecal chemotherapy (HR: 0.03, P <0.01). On UVA, local only first failure trended to be increased with >14 mL tumors (OR: 5.06, P =0.08) with 1-year LC 83% (<14 mL) versus 64% (>14mL). There were no significant associations with LC and WBRT ( P =0.37), Rituximab ( P =0.12), or attempted gross total resection ( P =0.72). Our findings reaffirm the importance of systemic and intrathecal therapies for local control in PCNSL. However, bulky tumors trend to fail locally, warranting further investigation about the role of local therapies or systemic therapy intensification.

Brentuximab Vedotin Plus Ibrutinib in Relapsed and Refractory Hodgkin Lymphoma

IntroductionBrentuximab vedotin (BV) is an antibody-drug conjugate that delivers monomethyl auristatin E (MMAE) to CD30+ cells and is safe and effective in relapsed/refractory (r/r) Hodgkin lymphoma (HL). Although most patients respond to BV, only a minority will obtain a complete response (CR), and almost all patients eventually progress.Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor highly active in multiple subtypes of non-Hodgkin lymphoma; limited data exist regarding its use in HL. It irreversibly inhibits interleukin-2-inducible kinase (ITK) with Th1 based immune responses. As we previously observed preclinical synergy between ibrutinib and BV, we hypothesized ibrutinib may enhance the antitumor activity of BV in HL. We designed and conducted a phase II trial of ibrutinib plus BV in patients with R/R HL, and herein report the final primary analysis of safety and efficacy. MethodsThis was a multicenter phase II trial with a lead-in cohort in patients with r/r HL. Eligibility criteria included age ≥ 15 years with r/r HL after at least one prior line of therapy. Treatment consisted of 1.8 mg/kg BV intravenously every 3 weeks and ibrutinib 560 mg PO daily (420 mg PO daily in the lead-in cohort). Prior BV was allowed if patients were not refractory. The primary endpoint was the CR rate according to Lugano 2014. Secondary endpoints included toxicities, overall response rate (ORR), and duration of response (DOR). ResultsThe 39 patients were enrolled onto the study, of which 67% were male; the median age was 33 (range: 17-71). 38% had extranodal disease at baseline, 51% had advanced stage disease, 51% were refractory to the prior therapy, and 21% had prior BV. Of 36 patients who were evaluable for response, the CR rate was 33% and ORR 64%; median DOR was 25.5 months. Thirteen patients proceeded to autologous transplant and 3 patients proceeded to allogeneic transplant for consolidation after response. The most common adverse events were nausea (67%), peripheral neuropathy (62%), diarrhea (59%), fatigue (46%), thrombocytopenia (46%), headache (41%), rash (41%), elevated ALT (38%), anemia (36%), vomiting (36%), abdominal pain (33%), fever (33%), and hypertension (33%). Six patients experienced unacceptable toxicity, defined as Gr 3/4 non-hematologic toxicity or non-resolving Gr 3/4 hematologic toxicity including one patient who died of multiorgan failure from suspected COVID-19 infection during cycle 1. DiscussionThe combination of BV and ibrutinib was active in r/r HL; however, given significant toxicity, it cannot be recommended for future development.