Toxicity Grade Research Articles

Results of a retrospective study on the efficacy and safety of alpelisib in patients with HR+/HER2- metastatic breast cancer in real-world clinical practice.

e13058 Background: The combination of alpelisib and fulvestrant is an optimal therapy option for patients with hormone receptor-positive (HR+), HER2-negative (HER2–) metastatic breast cancer with PIK3CA gene mutations. The aim of this work to retrospectively analyze the efficacy and safety of alpelisib in real-world clinical practice in patients with pre-treated luminal HER2– negative metastatic breast cancer. Methods: The study included an analysis of 33 patients with widespread luminal HER2- negative breast cancer with detected PIK3CA gene mutation. The median age was 57 ± 13 months (95% CI 52-62). In 12 (36.4%) patients, the PIK3CA gene mutation was detected in exon 9, and in 21 (63.6%) – in exon 20. Alpelisib was prescribed to pre-treated patients in different lines. Most women (32/33; 97%) had received ET combined regimens with CDK4/6 inhibitors before starting alpelisib therapy: 14 (42.4%) patients underwent palbociclib therapy in combination with fulvestrant; 4 (12.1%) – palbociclib with aromatase inhibitors; 13 (39.5%) – ribociclib in combination with fulvestrant; 1 (3.0%) – ribociclib with aromatase inhibitors. It is important to note that 63.6% of patients had previous progression on fulvestrant monotherapy and 72.7% on aromatase inhibitor therapy. Patients with luminal B-subtype of breast cancer dominated - 72.7% (24/33). Results: The median overall survival (OS) in this study was 14 ± 2.5 months (95% CI: 9-18.9), and the median progression-free survival (PFS) was 6 ± 2.7 months (95% CI: 0.7-11.3). The rate of objective response was 30.3%, and prolonged disease stabilization was observed in 24.2% of cases. Prognostic factors were brain metastases (increasing the risk of death by 18 times) and discontinuation of the drug for any reason (increasing the risk of death by 8 times). It should be noted that the main reason for discontinuation or disruption of the drug's timing was unmanageable toxicity. All patients registered adverse events of varying degrees, with 21 (63.6%) patients experiencing hyperglycemia (grade 3-4 – 30.3%) and 14 (42.4%) patients experiencing skin toxicity (grade 3-4 – 15.2%). In the SOLAR-1 study, the frequency of hyperglycemia was comparable (64.8%), and rash was noted in a third of all patients, which is comparable to our data. Conclusions: The results of using alpelisib with fulvestrant confirm its effectiveness in real-world clinical practice in patients with pre-treated HR+HER2- negative widespread breast cancer with the presence of somatic PIK3CA gene mutation. Brain involvement is an unfavorable prognostic factor in patients with PIK3CA mutation and increases the risk of death by 18 times, requiring the need to optimize the therapeutic algorithm, including through radiation methods. Discontinuation of the drug, which increases the risk of death by 8 times.

Results of a phase 1/2 study of MHB036C: A potential best-in-class TROP2 antibody-drug conjugate (ADC) incorporating a potent DNA topoisomerase I inhibitor in locally advanced or metastatic solid tumors.

e15007 Background: MHB036C, an investigational ADC, comprises a humanized anti-TROP2 monoclonal antibody engineered to minimize potential toxicities mediated by non-specific uptake, and a highly potent DNA topoisomerase I inhibitor (5~10 times more potent than DXd) conjugated via a stable cleavable linker. In preclinical studies, MHB036C demonstrated superior tumor killing activities (5~10 times more potent than the DS-1062a analog) and a favorable safety profile with no unique toxicities as compared to other TROP2 ADCs and no occurrences of interstitial lung disease (ILD). We here present the safety and efficacy results from a first-in-human phase 1/2 study of MHB036C. Methods: Patients with locally advanced or metastatic solid tumors were enrolled in dose-escalation (D-Esc) and dose-expansion (D-Exp) segments. The D-esc study, utilizing an accelerated titration followed by the traditional 3+3 design, assessed MHB036C at doses ranging from 0.25-2.25 mg/kg administered intravenously (IV) every 3 weeks. Results: At data cutoff (Dec 31, 2023), 26 pts were enrolled and received at least one dose of MHB036C (D-Esc, n=11, D-Exp, n=15). Two pts experienced dose-limiting toxicities (Grade 3 stomatitis) at 2.25 mg/kg. The MTD was determined to be 1.5 mg/kg. The most common TRAEs overall in ≥25% of pts were stomatitis, anemia, decreased appetite, vomiting, white blood cell (WBC) count decreased, fatigue, nausea, and neutrophil count decreased. The most common Grade ≥3 TRAEs (occurred in ≥5% of pts) were stomatitis (34.6%), WBC count decreased (11.5%), neutrophil count decreased (7.7%), and anemia (7.7%). No ILD was reported. Of 21 response-evaluable pts, 7 experienced partial responses. In the subset of 12 NSCLC pts treated with doses ranging from 1.3 to 2.25 mg/kg, the ORR was 33.3% (4/12) and the DCR was 83.3%. In the subset of 5 HER2-negative breast cancer pts encompassing 4 TNBC pts and 1 HR+/HER2- breast cancer patient, the ORR was 60.0% (3/5). Conclusions: MHB036C demonstrated a manageable safety profile without either major hematologic side effects or ILDs and encouraging efficacy in NSCLC and HER2- breast cancer, representing a potential best-in-class TROP2 ADC. The dose optimization and expansion study is ongoing to establish the RP2D for MHB036C. Clinical trial information: CTR20231246.

9MW2821, a nectin-4 antibody-drug conjugate (ADC), in patients with advanced solid tumor: Results from a phase 1/2a study.

3013 Background: 9MW2821 is a monoclonal ADC that delivers monomethyl auristatin E to cells expressing Nectin-4. Nectin-4 is an adhesion molecule that highly expressed in variety of solid tumors, especially urothelial cancer (UC), cervical cancer (CC), esophageal cancer (EC) and breast cancer. Here we report the updated safety and efficacy data of 9MW2821. Methods: 9MW2821 was administered by intravenous infusion at doses of 0.33-1.5mg/kg on days 1, 8 and 15 of each 28-day cycle. The study included dose escalation, dose expansion and cohort expansion period which included UC, CC, EC, triple negative breast cancer (TNBC) and other Nectin-4 positive solid tumors that progressed after ≥1 systemic treatments (Tx). Primary objectives were assessment of safety and preliminary efficacy. Results: As of Jan 15, 2024, 260 patients (pts) were enrolled with doses ranging from 0.33 to 1.5mg/kg. Only 1 out of 6 pts in 1.5mg/kg group had dose limiting toxicity (grade 4 neutropenia lasted more than 5 days). The maximum tolerated dose was not reached up to 1.5mg/kg and the RP2D was selected as 1.25mg/kg for tolerance. 240 pts were enrolled at dose of 1.25mg/kg. The most common TRAEs of 1.25mg/kg dose group (≥20%, all grade/≥5%, ≥G3) were white blood cell (WBC) count decreased (50.8%, 23.3%), neutrophil count decreased (46.3%, 27.9%), anemia (43.8%, 8.3%), aspartate aminotransferase increased (42.1%, 2.9%), alanine aminotransferase increased (35.4%, 2.1%), asthenia (32.1%, 2.9%), rash (30.0%, 5.0%), decreased appetite (28.8%, 1.3%), nausea (26.7%, 0%), hyperglycemia (25.4%, 2.1%), platelet count decreased (24.2%, 4.6%), alopecia (24.2%, 0%), hypoaesthesia (22.5%, 1.7%), constipation (21.3%, 0%), vomiting (20.9%, 1.3%), hypertriglyceridemia (20.4%, 2.1%), gamma-glutamyltransferase increased (15.8%, 5.4%). Among 190 pts treated with 9MW2821 at 1.25mg/kg or above and reached tumor assessment, objective response rate (ORR) and disease control rate (DCR) was 35.3% and 78.4%, respectively. 37 UC pts, 45 CC pts, 27 EC pts and 16 TNBC pts were enrolled at 1.25mg/kg and evaluable for tumor assessment. Median prior lines of Tx were 2 (range, 1-4). All UC, 51% CC and 93% EC pts progressed after platinum-based chemotherapy and immune checkpoint inhibitors, respectively. Objective responses were also observed in pts with other solid tumor types. Conclusions: The data indicated encouraging efficacy of 9MW2821 in advanced UC, CC, EC and TNBC. 9MW2821 is the first Nectin-4 targeting ADC showed antitumor activity in patients with CC, EC and TNBC. The safety profile showed adequate tolerability. Clinical trial information: NCT05216965 . [Table: see text]

Results of a first-in-human, dose-escalation phase 1 study of the ERK1/2 inhibitor ATG-017 in patients with advanced solid tumors.

e15114 Background: This open-label, first-in-human, phase 1 study evaluates the safety, pharmacokinetics, and maximum tolerated dose (MTD) of ATG-017, an oral, potent, and highly selective inhibitor of ERK1/2, in patients with refractory advanced solid tumors. Methods: Twenty-one patients with solid tumors harboring activating alterations in the RAS-MAPK pathway were enrolled in the 3+3 design dose-escalation phase for continuous dosing: 5 mg QD (n=1), 5 mg BID (3), 10 mg BID (3), 20 mg BID (7), 30 mg BID (4), and 40 mg BID (3). Results: Safety: All patients reported at least 1 treatment-emergent adverse event (TEAE). Fourteen patients (66.7%) experienced serious adverse events. At 40mg BID, 2 of 3 patients experienced a dose-limiting toxicity (DLT) (grade 3 diarrhea and grade 3 retinopathy). At 30mg BID, 2 of 4 patients experienced a DLT (grade 3 acneiform dermatitis and grade 2 blurred vision). All DLTs resolved with drug interruption. At 20mg BID, a potentially biologically active dose, 7 patients were treated with no DLTs observed. At all dose levels, the most commonly observed TEAEs were consistent with previously reported toxicities with other ERK pathway inhibitors (gastrointestinal, skin, and ocular adverse events). Pharmacokinetics: Between 5mg BID and 30mg BID, exposure increased proportionally. At doses 20mg BID or higher, the concentration in the whole dosing interval (≥ 328ng/mL, geometric mean) was higher than the target concentration (231 ng/mL) for effective ERK inhibition derived from preclinical PK/PD models. Efficacy: Of the 21 treated patients, one patient (4.8%) with mesonephric-like ovarian adenocarcinoma (KRAS G12V mutation) in the 30 mg BID cohort achieved a best response of partial response (sustained for six cycles of treatment), and 8 (38%) patients were assessed as having stable disease (sustained over an average of five cycles), based on RECIST v1.1. Conclusions: In patients with solid tumors, 20mg BID continuous dosing of ATG-017 was identified as the MTD and delivers exposure that is likely to be active in inhibiting ERK. This dose is currently being explored in a dose expansion phase. A combination regimen with nivolumab is also being investigated. Clinical trial information: NCT04305249 .

A phase 1 study of liposomal irinotecan in patients with advanced breast cancer.

1080 Background: Liposomal irinotecan (HE072) is a liposomal formulation that encapsulates irinotecan in a lipid bilayer vesicle, and as a generic drug, had been approved in China, recently, in patients with pancreatic cancer after gemcitabine treatment. Advanced triple negative breast cancer (TNBC) has very poor prognosis and limited treatment choices. Here we present results of breast cancer treated with HE072 in patients with highly pre-treated metastatic TNBC and HER2 negative breast cancer brain metastasis (BCBM). Methods: HE072-CSP-002 was a phase 1 study, consisting of two parts, dose escalation and expansion part (part 1) and expansion cohort part (part 2). In part 1, standard 3+3 design was used to investigate up to three dose levels of HE072 (50 mg/m2, 70 mg/m2 and 90 mg/m2), up to 6-9 additional subjects may be enrolled for dose expansion. In part 2, patients were enrolled in two cohorts (TNBC cohort and BCBM cohort), and received HE072 70 mg/m2 every two weeks (Q2W). The primary endpoints were the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), and the incidence and severity of treatment emergent adverse events (TEAEs). Secondary endpoints included progression free survival (PFS), objective response rate (ORR), overall survival (OS). Results: As of June 5th, 2023, 119 patients were enrolled, including 101 patients with TNBC and 18 patients with HER2 negative BCBM (part 1: n=27; part 2: n=92). In the part 1, one dose-limiting toxicity (grade 3 nausea and grade 3 vomiting) was observed at 70 mg/m2 dose level, and MTD was not reached. A total of 115 patients (96.6%) had at least one TEAEs of any grade, and 55 patients (46.2%) had ≥grade 3 TEAEs. The most common ≥grade 3 TEAEs related to HE072 included neutropenia (21.0%), leukopenia (18.5%), diarrhea (10.1%), anemia (9.2%) and hypokalemia (8.4%). Eighty-three (82.2%) of the 101 patients with TNBC were evaluable for response. After a median follow-up of 10.1 months (range 8.8-10.8), 22 patients (26.5%, 95%CI 17.4-37.3) achieved overall response, which were all partial response and 58 patients (69.9%, 95%CI 58.8-79.5) achieved disease control. The median PFS and OS were 4.8 months (95%CI 3.9-5.8) and 14.1 months (95%CI 11.2-not reached), respectively. 12(66.7%) of the 18 patients with HER2 negative BCBM were evaluable for response. 1 patient (8.3%, 95%CI 0.2, 38.5) achieved overall response, which is partial response and 8 patients (66.7%, 95%CI 34.9, 90.1) achieved disease control. The median PFS was 5.6 months (95%CI 1.4~ not reached), 12-month OS rate was 55.5%. Conclusions: HE072 exhibited excellent antitumor activity in heavily pre-treated patients with TNBC and HER2 negative BCBM with acceptable safety profiles. 70 mg/m2 Q2W was determined as the RP2D. Further clinical trials are under plan. Clinical trial information: NCT04728035 .

Efficacy and safety of apatinib combined with nab-paclitaxel for second-line treatment of metastatic triple negative breast cancer (TNBC): An open-label phase II trial.

e13127 Background: Apatinib is an oral, highly potent tyrosine-kinase inhibitor targeting VEGFR2. Preclinical studies have demonstrated that apatinib can enhance the anti-tumor effect of taxanes in TNBC via promoting apoptosis and suppressing migration and invasion of tumor cells. Previous studies have also shown the role of apatinib in combination with chemotherapy for treating TNBC. However, combinational treatment of apatinib and nab-paclitaxel for metastatic TNBC has not been reported. Therefore, the objective of this study was to evaluate the safety and efficacy of apatinib in combination with nab-paclitaxel as a second-line treatment for TNBC. Methods: This is a single-center, single-arm, and open-label prospective study. The patients enrolled in this study had metastatic TNBC, ECOG PS 0-2, at least one measurable lesion, and had previously received one systemic therapy except apatinib and nab-paclitaxel. They were treated with apatinib (250mg, PO, QD) plus nab-paclitaxel (125mg/m2, IV, day 1, 8 and 15) every 3 weeks as second-line treatment until disease progression, unacceptable toxicity, or consent withdrawal. The study utilized RECIST v1.1 to assess efficacy and NCI-CTCAE 5.0 to report adverse events. The study's primary endpoints were tolerability and progressive free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Results: Twenty patients were enrolled by the cut-off date of December 1st, 2023. The median age was 55 years (range 31-76) and all had an ECOG PS of 0-1. Ninety percent of the sample had a Ki67 of 30% or higher, while 85% tested negative for PD-L1. All patients had distant metastases, with 35.0% having visceral metastasis and 35% having metastatic sites of 3 or more. 70% of patients had undergone surgery on the primary tumor. All patients received apatinib plus nab-paclitaxel treatment, with a median of 9 cycles (range 2-25), were included in the safety dataset. All patients experienced grade 1-2 treatment-related adverse events (TRAEs). Haematological toxicity of grade 3-4 with neutropenia occurred in 25.0% of patients. In addition, non-haematological toxicities were observed in 10% of patients, including abnormal hepatic function (5.0%) and hypertension (5.0%). No treatment-emergent adverse event (TEAE) resulted in death during the study. Out of the 20 evaluated patients, the median progression-free survival (PFS) was 6.7 months (95% CI: 6.0-NR). The objective response rate (ORR) was 65.0% (13/20), and the disease control rate (DCR) was 90.0% (18/20), according to RECIST v1.1. The median overall survival (OS) has not yet been reached. Conclusions: The combination of apatinib and nab-paclitaxel showed promising antitumor activity in patients with metastatic TNBC as a second-line treatment, with a manageable safety profile. Clinical trial information: NCT05019690 .

Long-term survival, toxicities, and the role of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma treated with intensity-modulated radiation therapy: A retrospective study with a 5-year follow-up.

e18003 Background: This study aimed to evaluate 5-year outcomes and the late toxicity profile of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma (NPC). Methods: Our retrospective analysis included 70 patients with locally advanced NPC stages III and IVB (according to the 2010 American Joint Committee on Cancer staging system). Patients were treated with two cycles of induction chemotherapy (IC) before concurrent chemoradiotherapy (CCRT) at the affiliated cancer hospital of Guizhou medical university. The IC with docetaxel, cisplatin (DDP) and fluorouracil regimen. Patients were divided into two groups during CCRT. Using a “MELODIE” multi-channel programmed pump, DDP (100 mg/m2) was administered for 12 hours from 10:00 am to 10:00 pm and repeated every 3 weeks for 2-3 cycles. DDP was administered at the peak period of 4:00 pm in the sinusoidal chrono-modulated infusion group (Arm A, n = 35). The patients in Arm B received a constant rate of infusion. Both arms received radiotherapy through the same technique and dose fraction. The long-term survival and disease progression were observed. Results: After a median follow-up of 82.8 months, the 5-year progression-free survival rate was 81.3% in Arm A and 79.6% in Arm B (P = 0.85). The 5-year overall survival rate was not significantly different between Arm A and Arm B (79.6% vs 85.3%, P = 0.79). The 5-year distant metastasis-free survival rate was 83.6% in Arm A and 84.6% in Arm B (P = 0.75). The 5-year local recurrence-free survival rate was 88.2% in Arm A and 85.3% in Arm B (P = 0.16). There were no late toxicities of grade 3-4 in either group. Both groups had grade 1-2 late toxicities. Dry mouth was the most common late toxic side effect, followed by hearing loss and difficulty in swallowing. There was no statistically significant difference between Arm A and Arm B in terms of side effects. Conclusions: Long-term analysis confirmed that in CCRT, cisplatin administration with sinusoidal chrono-modulated infusion was not superior to the constant infusion rate in terms of long-term toxicity and prognosis.

Immunotherapy toxicity prediction in patients with melanoma using machine learning algorithms.

e21567 Background: Immune checkpoint inhibitor (ICI) related toxicity is common in melanoma patients, but identifying who will experience toxicity can be challenging. Precision medicine tools that accurately predict ICI toxicity could improve patient outcomes. This study aimed to use Machine Learning (ML) to predict ICI toxicity in patients with melanoma. Methods: 384 datasets were available for patients started on immunotherapy between 2014-2023 in a single, large regional cancer center in Kent, U.K. Raw data was preprocessed using a standard scaling function and one hot encoding, followed by SMOTE to balance the imbalanced classes. Six ML algorithms were developed using 80% of the training data, tested on 20% of validation data and used the Grid Search Cross-Validation technique for hyperparameter optimization. Shapley Additive Explanations (SHAP) explainable artificial intelligence was used to interpret the toxicity prediction model to improve the interpretation and transparency of the decision boundary. Results: Of the 384 patients, 112 patients (29%) had completely resected disease and then had adjuvant treatment while 272 (71%) were unresectable or had metastatic disease and had palliative treatment intent. In the metastatic setting, the commonest immunotherapy regimen was Pembrolizumab (155, 57%), followed by Ipilimumab/Nivolumab (85, 31%). The commonest regimen in the adjuvant setting was Pembrolizumab (86, 77%). 95 patients (25%) experienced ICI-related toxicity. The number of patients with Grades 1-4 toxicity was 2 ,4, 18 and 4 respectively, the remaining had unspecified toxicity grades. The commonest class of toxicity (CTCAE v5) was gastrointestinal (36, 38%), followed by endocrine (20, 21%) and skin (19, 20%). Linear Regression and Gaussian Naïve Bayes predicted toxicity with the most accuracy, 92% (Table 1). The model showed that increasing age, female gender and not receiving Nivolumab predicted toxicity. Regardless of the regimen or treatment intent, our ML model could also predict immunotherapy response with 90% accuracy. Conclusions: These ML algorithms used clinically available data to predict ICI toxicity accurately. Key predictors of toxicity included increasing age, female gender and not receiving Nivolumab in the setting of both adjuvant and palliative intent. Future work will aim to externally validate these models in other centers. We will also explore if models could be trained for use in patients treated with nivolumab in combination with new anti-LAG-3(relatlimab). [Table: see text]

Update on the prognostic value of a novel immune-related toxicity grading system (OST score) in patients with advanced solid tumours treated with immune checkpoint inhibitors (ICI).

e14696 Background: Toxicity grading systems have been an asset in managing cancer patients undergoing systemic treatment. In the era of ICI treatment, correlation between toxicity and treatment response is becoming more apparent. A new toxicity score was developed with the aim of better defining the profile of immune-related toxicities (irAEs). Initial analyses also demonstrated its potential in predicting patient outcomes. Here we provide an update on the survival analyses. Methods: Data were collected from the Pathobiology of Adverse Immune Reactions (PAIR) prospective cohort study at Guy’s Hospital from February 2018 until December 2023. Patients with advanced solid tumours naïve to ICI who received at least 1 dose were included. Minimum 6 months of follow-up was required. IrAEs were captured based on the OST score which evaluates the number of affected Organs (O), number of Severe (S) CTCAE (≥G3) toxicities, and Total sum of all grade toxicities (T). OST was calculated as a cumulative score at the end of follow-up or death. Patients were divided in high and low toxicity groups, defined by the median value for each parameter. For the composite OST score analysis, patients were divided in 2 groups based on a point system; 1 point was attributed for each individual OST high parameter; high toxicity OST group included patients with score >1. Descriptive statistics and crude and multivariate survival Cox Proportional Hazards regression analyses were performed accounting for age, tumour type, treatment, and steroid exposure. Results: A total of 148 patients fulfilled the criteria. Median age was 68 years (range 23-87), the majority were white Caucasian (81.8%) and male (56%). Melanoma was the most common tumour type (32.4%) followed by NSCLC (21.6%) and RCC (19.2%). 37.8% of patients received Ipilimumab/Nivolumab, 30.4% Pembrolizumab and 31.8% received other PD(L)-1 monotherapies. Twenty-eight patients (18.9%) had an autoimmune disorder at baseline; hypothyroidism was most common (5.4%). At end of follow-up, 82 deaths (55.4%) had occurred. Across the three OST parameters, Organ (O) was the strongest predictor of survival [HR (95%CI) 0.480 (0.265-0.869)]. After adjustment, multivariate analysis showed that risk of death was significantly lower in the high vs low Organ and Total toxicity groups [HR (95%CI) 0.379 (0.216-0.663) and 0.544 (0.302-0.982) respectively], but not for Severity [0.664 (0.338-1.306)]. In the OST combined score, the high toxicity group had favourable prognosis compared to low groups (mOS 56.6 vs 13 months) [HR (95%CI) 0.439 (0.275-0.702)]. Conclusions: Our new score manages to efficiently capture immune-mediated toxicity profile of patients treated with ICI as well as predict their outcomes. Further prospective evaluation, integration of laboratory markers and external validation is currently ongoing.

N9: Pilot study of novel shortened induction for high-risk neuroblastoma.

10052 Background: N9 induction for high-risk neuroblastoma was designed to limit non-hematological toxicity (especially ototoxicity) and to prevent relapse in the central nervous system (CNS). N9 builds on 2 novel regimens: high-dose cyclophosphamide-topotecan-vincristine (CTV) and ifosfamide-carboplatin-etoposide (ICE), each with good penetration across the blood-brain barrier. Methods: N9 is a pilot study (Clinicaltrials.gov.NCT04947501) to assess feasibility and safety. Secondary/exploratory objectives include response, collection of peripheral blood stem cells (PBSCs; ≥5x106/kg CD34(+) cells sufficient for ≥2 rescues), tumor resection, and assessment of central nervous system relapse. Early stopping rules centered on excessive delay in timing of chemotherapy. Eligibility criteria included age >1-to-<13 years; 1 prior chemotherapy cycle was allowed. CTCAE Version 5.0 and International Neuroblastoma Response Criteria are used.N9 comprises 4 cycles of chemotherapy. Cycles start after absolute neutrophil count is >500/μL, platelets >100,000/μL, and non-hematologic toxicities grade ≤2. Intervals of 21-28 days between start of cycles are foreseen. PBSC collection and surgery follow >3 cycles. Cycles #1 and #4 (CTV): cyclophosphamide 70mg/kg/day, days 1-2, topotecan 2mg/m2/day, days 1-4, and vincristine 0.067mg/kg, day 1. Cycle #2 (ICE): ifosfamide 1500mg/m2/day, days 1-5, carboplatin 400mg/m2/day, days 1-2, and etoposide 100mg/m2/day, days 1-5. Cycle #3: cyclophosphamide (as in CTV) and 72-hr infusions of doxorubicin 75mg/m2 and vincristine 0.067mg/kg. Results: The target number of 15 patients were enrolled: 10/2021-9/2023; age 1.5–9.8 (median 3.3) years; 14 stage M, 1 stage L2; and 10 post-1 cycle of other chemotherapy. They completed N9 without undue toxicity: all cycles started on time, organ functions remained intact, 11/11 patients tested had no ototoxicity, and acute toxicities were typical for myelosuppression (including uncomplicated fever/neutropenia). Responses were complete (n=6), partial (n=5), and stable disease (n=4). The target number of PBSCs was collected in 12 patients (9-75, median 14 x106/kg CD34(+) cells), 4x106/kg in 2 patients, and pending in 1. All patients had gross total resections of the primary tumor. Post-N9, patients did not undergo transplant, but proceeded to immunotherapy (naxitamab) or chemoimmunotherapy (naxitamab+irinotecan-temozolomide). Of 9 with residual disease post-N9, 7 achieved CR (median of 5.6 months from study entry) and 1 achieved metabolic CR (16 months), though 3 subsequently relapsed (no CNS). Conclusions: N9 shows promise for reducing chemotherapy and long-term toxicity. Less chemotherapy without compromising survival is a realistic goal by virtue of the advances with anti-GD2 monoclonal antibodies which, in combination with GM-CSF+low-dose chemotherapy, are highly effective against chemo-resistant disease in bone/bone marrow. Clinical trial information: NCT04947501 .

Real-world immune-related adverse events in patients with early triple negative breast cancer who received pembrolizumab.

1099 Background: The addition of pembrolizumab to chemotherapy (KEYNOTE-522 regimen) in high risk early triple negative breast cancer (TNBC) has improved clinical outcomes. However, this treatment can result in immune-related adverse events (irAEs) involving any organ and in some cases, life-long toxicities or even death. This retrospective study describes real-world patterns of irAEs in patients (pts) with early TNBC who received pembrolizumab at two academic centers. Methods: We evaluated irAEs in pts with stage II-III TNBC from MD Anderson Cancer Center and Lyndon B Johnson diagnosed between January 2018 and May 2023 who received neoadjuvant pembrolizumab plus chemotherapy. We excluded those enrolled on clinical trials. We utilized ASCO irAE and CTCAE v5 guidelines for toxicity grading. Logistic regression assessed the effect of clinical variables on irAEs, adjusting for covariates. Results: We identified 233 pts with a median age of 51 ± 12 years; 62% with stage II and 35% with stage III TNBC; 25% were Hispanic/Latino, 21% non-Hispanic Black and 42% were non-Hispanic White. In total, 80 pts (34%) developed 100 separate irAEs (94 with definite and 6 with possible/probable attribution). The most common irAEs were endocrine (52%) followed by gastrointestinal (23%). Grade ≥ 3 irAE occurred in 26 instances, with the most common being gastrointestinal (13 instances). A fatal irAE occurred in 2 pts where both were colitis. A total of 26 irAEs resulted in hospitalization, 45 required systemic steroids, and 15 required additional immunosuppressive therapy. Most (66) irAEs were unresolved at last follow up, although the majority had improved to grade 1 (37/66) and 32 patients discontinued pembrolizumab early due to irAEs. No clinical factor (race, stage, tumor grade, age, body mass index) was associated with development of an irAE. Conclusions: In this real-world diverse population, we identified a similar rate and severity of irAEs as reported in the KEYNOTE-522 trial. Hospitalizations occurred in 26% of irAEs while most developed persistent immune toxicity. Gastrointestinal irAEs were more common compared to KEYNOTE-522 reported data. Research is needed to better predict and mitigate the burden of irAEs and to improve the long-term survivorship care of pts with early TNBC pts who receive pembrolizumab. [Table: see text]

Effect of nivolumab combined with definitive chemoradiotherapy on response rate for esophageal cancer: An immune active intrinsic subtype could be its biomarker—The NOBEL trial.

4068 Background: The usefulness of combined therapy with immune checkpoint inhibitors (ICI) and chemoradiotherapy (CRT) and its potential biomarker of treatment efficacy for esophageal cancer remains unclear. We investigated the safety, efficacy, and associated biomarkers of combined therapy with ICI and definitive CRT in operable and inoperable esophageal squamous cell carcinoma (ESCC). Methods: This prospective single-arm phase 2 trial was performed at five hospitals in Japan. Patients aged 20–75 years with histologically confirmed ESCC, an ECOG PS score of 0 or 1, and adequate organ and bone marrow functions were eligible. Inoperable patients did not have distant organ metastasis. Patients did not receive any chemotherapy or surgical resection as an initial therapy. Concurrent radiotherapy (50.4 Gy/28 fractions to the primary lesion and 41.4 Gy/23 fractions to the regional LN area) consisted of 4 courses of CF (cisplatin, 75 mg/m2/day, day 1; 5-fluorouracil, 1000 mg/m2/day, days 1–4) plus nivolumab (240 mg/m2/day, every 2 weeks for up to 1 year). The primary endpoint was safety. The incidence rates of nonhematological toxicity grade ≥ 4 and pneumonitis grade ≥ 3 were ≤10% and ≤15%, respectively. The secondary endpoints included overall survival (OS), progression-free survival (PFS), complete response (CR) rate, and time to esophagectomy-free survival (EFS). Sixty patients were to be accrued, but the trial enrollment was terminated because of slow accrual. This trial was registered as jRCT1091220408. Results: Between January 2019 and September 2021, 42 patients were enrolled. Twenty-five patients had operable disease and 16 had inoperable disease. Two patients (4.8%) experienced grade 3 pneumonitis, suggesting that the primary endpoint was met. The median relative dose intensity of nivolumab was 92.4%. One-year OS, PFS, and EFS rates in all cases were 92.7%, 65.4%, and 78.0%, respectively. One-year OS, PFS, and EFS rates in operable and inoperable cases were 100%, 79.6%, and 84.0% and 81.3%, 43.8%, and 68.8%, respectively. The CR and objective response rates were 73.2% (95% confidence interval [CI]: 58.1%–84.3%) and 87.8% (95% CI: 74.5%–94.7%), respectively. The CR rates in operable and inoperable cases were 84% (95% CI: 65.3%–93.6%) and 56.3% (95% CI: 33.2%–76.9%), respectively. Immune high-active intrinsic subtype before treatment (n=4) with an expression score > 80 of 51 immune-related genes showed a high CR rate (100%, n=4), whereas the immune low-active intrinsic subtype (n=37) with an expression score < 80 showed a relatively high CR rate (70%). Conclusions: Nivolumab combined with definitive CRT provided encouraging efficacy and acceptable toxicity in patients with ESCC. Immune high-active intrinsic subtype before treatment has the potential to predict a high CR rate for this combination treatment. Clinical trial information: jRCT1091220408 .

STRIvE-02 Arm C: Phase 1 study of concurrent PD-1 inhibition with B7-H3 CAR T cell immunotherapy for recurrent/refractory pediatric solid tumors.

e14626 Background: B7-H3 expression by a broad range of pediatric solid tumors has led to development of B7-H3-directed chimeric antigen receptor (B7-H3-CAR) T cells. However, early phase clinical trials of B7-H3-CAR T cells in recurrent/refractory solid tumors demonstrated inconsistent CAR T cell expansion and limited anti-tumor activity. We subsequently developed a dual transduced CAR product expressing B7-H3-CAR and CD19-CAR (CARB7H3x19) to enhance CAR T cell expansion with antigenic stimulation by normal B cells (STRIvE-02 Arm B). Augmented expansion was observed but CAR T cell persistence was variable, leading to a hypothesis that concurrent use of pembrolizumab (pembro), a PD1-inhibitor, would help prolong persistence, leading to improved anti-tumor activity. Methods: Patients up to age 26 years with recurrent/refractory solid tumors (excluding primary CNS) enrolled onto Arm C of STRIvE-02 to examine safety and feasibility of CARB7H3x19 at a dose of 0.5 x 106 CD19-CAR T/kg followed by pembro 2 mg/kg (max 200 mg) either 7- (Dose regimen (DR) 1) or 21-days (DR 2) post-CAR T cell using a 3+3 statistical design. All subjects received lymphodepletion with fludarabine and cyclophosphamide prior to CAR T cells. CTCAEv5 was used for toxicity grading. Results: Of six patients (pts) enrolled (age range 11–25 yrs, median 20 yrs, four received CAR T cell+pembro; three received DR1 pembro (day (D)+7), and one received DR2 (D+21). A pt on DR2 with nonseminomatous germ cell tumor developed grade (gr) 5 immune effector cell-associated hyperinflammatory syndrome (IEC-HS) on D+17 prior to pembro, resulting in trial suspension. One pt did not receive CAR T cells and is unevaluable. Adverse effects occurring in pts who received pembro included gr 3 fever in setting of neutropenia (n=1), and gr 2 hyperthyroidism (n=1), with no dose limiting toxicity attributed to CAR T cell+pembro. Maximum circulating CAR T expansion for Arm C was 192.18 cells/uL (range 6.86 – 192.18 cells/uL) with median persistence of 28 days (range 28 - 84), compared to a maximum circulating CAR T expansion of 740.95 cells/uL (range 8.29 – 740.95 cells/uL) and median persistence of 65 days (range 21 - 274) in pts treated on Arm B receiving the same CAR dose level (n=8). D+28 disease restaging in the four Arm C pts who received CAR T cells+pembro demonstrated stable disease (n=1) and disease progression (n=3). Conclusions: Although we observed tolerable toxicity among patients who received CAR T cell+pembro, the small number of patients limit full toxicity assessment. T cell expansion and persistence was observed, but the effects of pembro on CAR T cell fitness are unclear. Phenotypic characterization of circulating CAR T cells is underway to further assess impact of pembro. Of note, this is the first reported death attributed to IEC-HS in a patient after receiving B7-H3-CAR T cells. Investigations into etiology are ongoing. Clinical trial information: NCT04483778 .

A phase II trial of olaparib and durvalumab in patients with recurrent IDH-mutated gliomas.

2013 Background: Isocitrate dehydrogenase mutations (IDHmt) define astrocytomas and oligodendrogliomas. IDHmt results in accumulation of R-2-hydroxyglutarate (2HG), leading to epigenetic dysregulation and defective homologous recombination repair, providing a rationale for poly (adenosine 5’-diphophate-ribose) polymerase (PARP) inhibitors. PARP inhibition upregulates PD-L1 so the combination with immune checkpoint inhibition is potentially synergistic. Methods: Patients (pts) with recurrent high-grade IDHmt gliomas were enrolled in this phase II open-label study (NCT03991832). Eligibility included progressive disease with up to 2 prior lines of systemic therapies and ECOG 0–1. Pts received olaparib 300 mg twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Simon’s optimal two-stage design was used. The primary objective was overall response rate (ORR) and disease control rate (DCR) by RANO criteria. Secondary objectives included overall survival (OS), progression free survival (PFS) and safety.Exploratory biomarkers of response and resistance were assessed with serial blood samples using cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) as well as multiplex-immunohistochemistry. Results: In the 29 pts enrolled between January 2020–February 2023, median age was 40.5 (range 23–66) and 41% were female. Initial tumor grade was 2 in 9, 3 in 8 and 4 in 12 pts, respectively. Median time to enrollment from tumour diagnosis was 5.9 years. All had prior resection and median number of prior systemic therapies was 2. One patient clinically deteriorated before starting treatment. ORR was 10%, 95% CI 2.2–27%, with responses in 3 pts. One pt with grade 4 astrocytoma had a complete response and remains on treatment after 33 months. The other 2 responders with grade 4 astrocytoma had response durations of 4.1 and 9.8 months. DCR was 28% (95% CI 12.7–47.2%) with 5 additional pts demonstrating stable disease. With a median follow-up of 33 months, mOS was 9.5 months (95% CI 4.3–19.3) and mPFS was 1.9 months (95% CI 1.8–3.0). There was no treatment-related grade 3–4 toxicities. Any grade toxicities included fatigue (48%), nausea (17%), diarrhea (10%), and cytopenias (3%). Using serial cfMeDIP-seq, cell free DNA methylomes comparing responders versus progressors using the top differentially methylated regions can predict treatment response with high accuracy (AUC 0.833). Post progression, differentially methylated genes converge on TGF-β and signal transduction pathways, suggesting possible mechanisms of resistance. Multi-modal analysis of long-term responders will additionally be presented. Conclusions: Combination treatment with olaparib and durvalumab for pts with IDHmt glioma is well tolerated but has limited efficacy in unselected pts. cfMeDIP-seq can reliably predict tumour progression providing a blood-based biomarker of treatment response. Clinical trial information: NCT03991832 .

#425 Felzartamab (anti-CD38) in patients with IgA Nephropathy—interim results from the IGNAZ study

Abstract Background and Aims Most patients with IgA nephropathy (IgAN) will progress to kidney failure within 10-15 years of diagnosis. Sustained proteinuria is the best predictor of adverse long-term kidney outcomes and is a surrogate marker for efficacy. CD38+ plasma cells are likely the main source of pathogenic Gd-IgA1, and the related autoantibodies in IgAN. Felzartamab (felza; HIB202) is a recombinant purified human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to CD38 on plasma cells and is being studied across immune-mediated kidney diseases such as IgAN, Primary Membranous Nephropathy, Lupus Nephritis, and Antibody Mediated Rejection. The primary aims of the IGNAZ study were to assess: 1) efficacy of felza compared to placebo on urine protein:creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) change from baseline, and 2) the relationship between exposure, safety, and efficacy in each of 3 dose groups vs. placebo. Interim results with 15 months of follow-up from this 24-month trial are presented. Method In Part 1, 48 IgAN subjects were randomized in a 1:1:1:1 ratio across a placebo and 3 active arms in this multicenter, double-blind placebo-controlled, phase IIa trial. The M1, M2, and M3 active arms received 2 doses in 15 days, 5 doses in 2 months, and 9 doses in 5 months, respectively. In Part 2, 6 Japanese subjects received the M3 regimen, open-label, and have been followed for 9 months. Key inclusion criteria included ages 18-80 years, biopsy confirmed diagnosis of IgAN within the past 8 years, proteinuria at screening ≥1.0 g/d, eGFR ≥30 ml/min/1.73 m2 (by CKD-EPI), and background stable and maximally tolerated renin angiotensin system inhibitors. Results 48 randomized subjects were enrolled at 28 sites in the US and in 14 different countries in Europe and in Asia, of which 46 completed the treatment phase. Mean (SD) baseline characteristics (Parts 1 and 2 combined): age 41.6 (12.3) yrs, UPCR 1.67 (1.0) g/g, eGFR 74.6 (30.3) ml/min/1.73 m2. 67% of subjects were male. Intention-to-treat with felza demonstrated rapid, clinically meaningful reductions in UPCR with the maximal treatment effect being observed in the M3 9-dose regimen. In Part 1, percentage change from baseline in UPCR was −14% for placebo and −25% for M3 9-dose arm at month 3, and +9% for placebo and −35% for M3 at month 6 (Fig. A). Reductions in proteinuria observed at month 6 persisted until Month 15, 10 months after the last dose: +6% and −38% mean UPCR change from baseline for placebo and the M3 9-dose arm, respectively (Fig. B). Relatively stable eGFR values were observed for the felza arms compared to loss of eGFR in the placebo arm. Rapid, durable reductions in IgA and Gd-IgA1 levels were seen across the dosing arms, with reductions lasting 10 months after the last dose (Fig. C). IgG recovery occurred faster off-treatment than IgA. Results in the Part 2 subjects were similar to the Part 1 M3 cohort through 9 months. There were no apparent dose-dependent adverse events and no exposure-safety relationship. Treatment-emergent adverse events (TEAEs) were generally of mild or moderate intensity or toxicity grade. The most common TEAE assessed as related by study investigator was infusion related reactions (IRR), most of which occurred on the first infusion. There was one treatment-related serious AE due to an IRR. Five subjects discontinued treatment due to IRRs or drug hypersensitivity; for four of the five subjects, the infusion rate was higher than protocol-specified or had an error in pre-medication. TEAE infections were comparable between placebo and felza arms: Placebo (33.3%), M1 (33.3%), M2 (36.4%), M3 (38.5%), Part 2 (50.0%); all were Grades 1 or 2, and non-serious. Conclusion This proof-of-concept study highlights the potential for disease modification in IgAN with the anti-CD38 mAb felza and supports continued research as a potential treatment for high-risk IgAN patients. Felza treatment resulted in clinically meaningful, prolonged UPCR reductions and eGFR stabilization sustained ≥10 months after dosing was completed. Felza was generally well tolerated with rapid recovery of IgG with durable reductions in IgA and pathogenic Gd-IgA1 levels.

Rechallenge with Anti-EGFR Treatment in RAS/BRAF wt Metastatic Colorectal Cancer (mCRC) in Real Clinical Practice: Experience of the GITuD Group.

There are few third- and fourth-line therapeutic options for metastatic colorectal cancer (mCRC). In RAS/BRAF wild-type (wt) mCRC previously treated with anti-epidermal growth factor receptor (anti-EGFR) (first-line) and relapsed after a good response, retreatment with anti-EGFR (rechallenge) emerges as a therapeutic alternative. The aim was to show the activity and safety of anti-EGFR rechallenge in RAS/BRAF wt mCRC in real-world practice. A multicenter, retrospective, observational study (six hospitals of the Galician Group of Research in Digestive Tumors) was conducted. Adult patients with RAS/BRAF wt mCRC, evaluated by liquid biopsy, were included. They received anti-EGFR rechallenge (cetuximab, panitumumab) as monotherapy, or combined with chemotherapy, in third- or subsequent lines. Efficacy (overall response rate [ORR], disease control rate [DCR], overall survival [OS], and progression-free survival [PFS]) and safety (incidence of adverse events [AEs]) were assessed. Thirty-one patients were analyzed. Rechallenge (median 6 cycles [range 1-27], mainly cetuximab [80.7%]), started at a median anti-EGFR-free time of 18.4 months (1.7-37.5months) after two (38.7%) or more (61.3%) lines of treatment; 64.5% of patients received a full dose. Median OS and PFS were 9.8 months (95% confidence interval [CI] 8.2-11.4) and 2.6 months (95% CI 1.7-3.4), respectively. ORR was 10%, and DCR was 30%. The most common AEs were diarrhea (35.5%), anemia (29%), emesis (6.4%), and neutropenia (6.4%); <5% grade ≥3; 48.4% of patients reported anti-EGFR-related skin toxicity (grade >1). Hypomagnesemia required supplements in 29% of patients. Dose delays (≥3 days) and reduction (≥20%) were reported in 11 (35.5%) and seven patients (22.6%), respectively. In RAS/BRAF wt mCRC patients, an anti-EGFR rechallenge provides a feasible therapeutic option with clinical benefit (survival) and a manageable safety profile.

Mechanisms and management of CAR T toxicity.

Chimeric antigen receptor (CAR) T cell therapies have dramatically improved treatment outcomes for patients with relapsed or refractory B-cell acute lymphoblastic leukemia, large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma. Despite unprecedented efficacy, treatment with CAR T cell therapies can cause a multitude of adverse effects which require monitoring and management at specialized centers and contribute to morbidity and non-relapse mortality. Such toxicities include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, neurotoxicity distinct from ICANS, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, and immune effector cell-associated hematotoxicity that can lead to prolonged cytopenias and infectious complications. This review will discuss the current understanding of the underlying pathophysiologic mechanisms and provide guidelines for the grading and management of such toxicities.

Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team—a multicenter phase II trial

BackgroundThe purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as “fit” by comprehensive geriatric assessment (CGA).MethodsA single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of “fit” (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22).ResultsOne hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47).ConclusionThis phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA.Trial registrationThe registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial.

Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer. This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fractionation regimens and the anticipated small sample size typical for a Phase 1 clinical trial. MRgFUS-MB is an innovative radioenhancement therapy associated with a safe profile, potentially promising responses, and durable LC. These results warrant validation in Phase 2 clinical trials. clinicaltrials.gov, identifier NCT04431674.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.