Progression-free Rates Research Articles

Advanced Renal Cell Cancer Combination Immunotherapy Clinical Trial (ARCITECT; HCRN GU 22-587)

Abstract Background First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods ARCITECT is a phase II, multicenter study evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has > 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR > 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806. Results

Retrospective registry of patients with locally advanced/metastatic HR+/HER2- breast cancer treated in clinical practice in Andalusia.

Limited data are available regarding the real-world effectiveness and safety of Cyclin Dependent Kinase 4/6 inhibitor (CDK4/6i) (palbociclib/ribociclib) just as a first-line treatment for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2‒) metastatic breast cancer (MBC). To assess whether clinical or demographic characteristics limit access to first-line CDK4/6i treatment in clinical practice in the Autonomous Community of Andalusia (Spain) between November 2017 and April 2020. In addition, effectiveness will be described in an exploratory analysis. Physicians from 12 centers participated in selecting demographic and clinical characteristics, treatment, and outcome data from women with HR + /HER2- MBC treated with or without CDK4/6i in addition to hormonal in the first-line setting, in a 3:1 proportion. Kaplan-Meier analysis estimated progression-free rates (PFRs) and survival rates (SRs). A total of 212 patients were included, of whom 175 (82.5%) were in the CDK4/6i treatment group and 37 (17.5%) were in the non-CDK4/6i treatment group (control group). Patients in the CDK 4/6i treatment group were younger (p = 0.0011), the biopsies of the metastatic site at the moment of the relapse were most commonly performed (p = 0.0454), and had multiple metastatic sites (p = 0.0025). The clinical benefit rate (CBR) was 82.3% in the CDK4/6i group and 67.8% in the control group. Median time to a progression event or death (PFS) was 20.4months (95%CI 15.6-28) in the CDK4/6i group and 12.1months (95%CI 7.9-not reached) in the control group. Younger patients, biopsies of metastatic disease and with multiple metastatic sites were more frequently treated with CDK4/6i in our daily clinical practice.

A phase II study of nivolumab in patients with recurrent or metastatic carcinosarcomas.

6041 Background: We aimed to determine the activity of anti-PD-1 inhibitor, nivolumab in metastatic and/or recurrent carcinosarcoma. Methods: In this phase 2 trial, eligible patients had histologically confirmed metastatic and/or recurrent carcinosarcoma, measurable disease, 1-3 prior chemotherapy, and adequate renal/hepatic/hematologic function. In this single arm phase 2 trial, treatment consisted of nivolumab 3 mg/kg every 2 weeks. Primary outcome was progression free rate (PFR) at 6 months and secondary outcomes included overall response rate, progression-free survival (PFS), overall survival, and safety. Results: Between July 2020 and Nov 2023, 28 patients enrolled and received trial treatment. As of the time of data cut-off (Feb 1, 2024), 4 remains on treatment. Of the 28 patients evaluable, 4 (14.3%) achieved confirmed partial response, and 9 (32.1%) had stable disease, yielding and disease control rate of 46.4%. The median PFS was 2.6 months. The pre-specified primary endpoint was met with 6-months PFR of 30.8%. The common-treatment related adverse events included urticaria (5 [17.9%]), dyspepsia (4 [14.3%]), elevated aspartate aminotransferase (3 [10.7%]), and anemia (3 [10.7%]). The genomic analysis will be available at the meeting. Conclusions: Nivolumab demonstrated promising efficacy with favourable toxicity profile in metastatic/recurrent carcinosarcoma. Clinical trial information: NCT05224999 .

Efficacy and safety of SHR-2554 in advanced epithelioid sarcoma: A phase 2 trial.

11549 Background: Epithelioid sarcoma (ES) is a rare and aggressive subtype of soft-tissue sarcoma. The loss of SMARCB1 (INI1) expression which leads to oncogenic dependence on the transcriptional repressor EZH2 has been observed in over 90% of ES. Patients (pts) with metastatic ES have a poor prognosis. We investigated the efficacy and safety of SHR-2554, an oral selective EZH2 inhibitor, in pts with refractory ES. Methods: To be eligible for inclusion, pts had to fulfill the following criteria: 8 years or older; histologically confirmed advanced or metastatic ES with loss of INI1 or upregulated mRNA level of EZH2; progressive disease after at least one line of doxorubicin-containing chemotherapy; the presence of measurable disease according to RECIST 1.1; an ECOG performance status of 0-1. Pts received SHR2554 (350 mg, bid, po) until disease progression or unacceptable toxicity. The primary endpoint was progression-free rate at 12 weeks. A Simon two-stage design was applied. If there were 3 pts remaining progression-free at 12 weeks within the first 9 pts, the cohort would expand to 17 pts and the outcome would be positive if more than 7 pts remained progression-free at 12 weeks. Results: Between Jul 2021 and Dec 2023, a total of 17 pts were enrolled and received at least 1 dose of SHR-2554. The median age was 32 years (range 8-57) and 41.2% were males. 9 (52.9%) pts had received immunotherapy targeting PD-1/L1 and 6 (35.3%) pts had received anti-angiogenesis therapy before enrollment. The median line of previous treatment was 2 (range 1-4). Loss of INI1 was confirmed in 14 (82.4%) pts. Tumor response was evaluated in 14 pts at data cutoff. 9 (64.3%) of 14 pts remained progression-free at 12 weeks. The primary endpoint was met. Based on investigator assessment, 3 (21.4%) of 14 pts achieved partial response and 8 (57.1%) pts had stable disease as best response. Adverse events (AEs) were generally mild. The most common treatment-related hematological AEs were anaemia, platelet count decreased and hyperuricaemia. Conclusions: SHR-2554 showed promising efficacy and an acceptable safety profile in pts with refractory ES, warranting further investigation. Clinical trial information: ChiCTR2100046099.

A phase 2 study of regorafenib in metastatic/unresectable, refractory synovial sarcomas.

e23551 Background: Current therapeutic options for advanced synovial sarcomas remain limited. Adoptive T-cell therapies against NY-ESO-1 and MAGE-4 benefit a subset of patients, but is of limited value in Asian patients due to the absence of the HLA-A*02 genotype. Methods: The trial had a single arm, Simon two-stage design that included patients with advanced synovial sarcomas who had progressed on 2 lines of therapy, one of which could be an anti-VEGF therapy. Regorafenib was administered orally in a continuous regimen with 80mg and 120 mg doses on alternate days. The primary end point was 3-month progression-free rate (PFR). A 3-month PFR of greater than 40% was taken to be a marker of drug efficacy. Secondary end points included median PFS, OS and safety analysis. Quality of life assessment was carried out at baseline and at 3 months using the EORTC C-30 questionnaire. Radiological responses were assessed using RECIST 1.1 criteria after independent review by 2 radiologists. Results: A total of 22 patients were included in the study during the period from January 2022 to December 2023 with baseline characteristics as shown in Table 1. 18 patients were eligible for assessment of the primary outcome. The 3-month PFR with regorafenib was 57% with an ORR of 5%. At a median follow up of 9 months, the median PFS was 5.0 (2.9-7.0) months, and the median OS was 10.0 (7.8-11.2) months. In an exploratory analysis, the subset of patients previously exposed to pazopanib showed a 3-month PFR of 46% and a median PFS of 3 months. The grade ¾ toxicities seen included HFSR (52%), diarrhea (5%) and oral mucositis (5%). The quality-of-life analysis showed symptom burden to be highest in the fatigue, pain and financial difficulties domain at baseline. No worsening of symptom burden scores was seen over the study period. The global health status score showed a numerical improvement at 3 months. Conclusions: The study had a significant number of patients with poor PS. Regorafenib in the above-mentioned dosing regimen demonstrated meaningful clinical activity in a heavily pre-treated population of patients with synovial sarcoma, including those previously exposed to pazopanib, with a preserved quality of life. The treatment was associated with manageable toxicities and no new safety signals, albeit with higher HFSR rates. [Table: see text]

A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer (GIANT): ECOG-ACRIN EA2186.

4003 Background: Evidence-based data is lacking to guide the care of vulnerable older adults with newly diagnosed metastatic pancreatic ductal adenocarcinoma (mPDAC) resulting in extrapolation of the treatment approach utilizing data from younger patients. EA2186 is a phase II randomized controlled trial, and the first prospective study aiming to define the optimal treatment approach for vulnerable older adults with newly diagnosed mPDAC. Methods: EA2186 enrolled vulnerable patients ≥70 years of age with histologically confirmed mPDAC, ECOG PS 0-2 and adequate organ function. Vulnerability was defined by a screening geriatric assessment (GA) demonstrating mild abnormalities in functional status, comorbidities, cognition, or age ≥80 years. Patients were randomized to Arm A: Gemcitabine (1000mg/m2) and Nab-Paclitaxel (125mg/m2) every 14 days or Arm B: 5-Fluorouracil (2400mg/m2 over 46hr) Leucovorin (400mg/m2) and Liposomal Irinotecan (50mg/m2) every 14 days. A comprehensive GA and quality of life (QOL) evaluation were completed at baseline and 3 time points. Primary endpoint was overall survival (OS); secondary endpoints included progression free survival (PFS), response rate (RR), safety, and QOL. The study had 90% power to detect a difference in median OS of 7.7 vs. 10.7 months (HR of 0.72) using a one-sided log-rank test at the 0.10 significance level. Stratification factors included age 70-74 vs ≥75, and ECOG PS 0-1 vs 2. The study met the planned futility boundary for OS at its single interim analysis (60.6% information) and was closed early by the DSMC. Results: 176 patients were enrolled at 92 US sites between 6/2020 – 10/2023, 88 patients per arm. Median age of enrolled patients was 77 (range 70-90), 49% females, 24% ECOG-0, 64% ECOG-1 and 12% ECOG-2. Majority of patients were deemed vulnerable by cognition (46%), age (36%) or co-morbidities (31.4%), with some patients meeting vulnerability criteria in multiple domains. No significant difference was seen in median OS between the arms (4.7 vs. 4.4 months in Arms A and B respectively; p = 0.72). PFS, RR, and factors contributing to early treatment discontinuation and affecting the lower-than-expected survival will be presented at the meeting. At the time of data cut off rates of ≥grade 3 toxicity was 45.6% in Arm A and 58.7% in Arm B (p = 0.10); rates of ≥grade 4 toxicity were 7.6% in Arm A vs 14.7% in Arm B (p = 0.16). Most common ≥grade 3 toxicities included anemia, neutropenia, fatigue in both Arms, and diarrhea in Arm B. Conclusions: EA2186 did not demonstrate a significant difference in efficacy or overall toxicity between two attenuated regimens tested in vulnerable older adults with mPDAC. These results provide important data to guide treatment decisions and goals of care discussions in this vulnerable patient population. Clinical trial information: NCT04233866 .

Efficacy of alpelisib (ALP) + fulvestrant (FUL) with rational use of metformin (MET) in patients with HR+/HER2- advanced breast cancer (ABC).

1049 Background: Hyperglycemia (HG) is an on-target effect of ALP, and prophylactic with metformin was shown to decrease the rate and severity of HG. Here we present efficacy and safety of ALP in a large cohort of patients with rational approach to metformin usage based on risk factors of HG. Methods: Patients (pts) with HR+/HER2- PIK3CAmut ABC were treated with ALP 300mg orally and FUL 500mg IM until disease progression or intolerance. The primary endpoints were progression free survival (PFS) and rate of grade 3/4 HG in different risk groups. Pts were stratified to risk groups of HG based on the algorithm (table 1) before starting ALP and received MET for prevention of HG. Results: A cohort comprised 139 pts, median lines of previous treatment in ABC was 3 (1-9): 88% received CDK4/6i, 60% - FUL, and 55% - chemotherapy (77) prior to ALP. The median PFS (mPFS) on ALP - was 7.0 (CI 95%: 5.0-8.9). The risk of HG was assessed in 138 pts: low (47), moderate (46), and high (42) risk, and 3 pts with type 2 diabetes mellitus. Any grade HG was reported in 62% pts, no cases HG G4 were detected. HG G3 was reported in 13% pts; 10% pts required ALP dose reduction to 250 mg due to HG G3; 3 pts (2%) discontinued ALP due to HG. The mPFS in our analysis was longer than in BYlieve trial in cohort C: 7.0 vs 5.6 mo. We suggest that prophylactic of HG allowed maintenance of full dose of ALP in most patients and thus increased the efficacy of ALP. Furthermore, in contrast to the METALLICA trial we distinguished a low risk group (33%) of pts who don’t need the prophylactic use of MET. Conclusions: Rational use of MET in pts with moderate and high risk of HG reduces the frequency and severity of HG, decreases the rate of ALP dose reductions and as a result may increase the efficacy of ALP. Pts with low risk of HG don’t need MET for HG prevention. [Table: see text]

Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).

TPS4614 Background: First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods: ARCITECT is a phase II, multicenter investigator initiated trial evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has > 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR > 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806 .

Abstract PO3-16-02: Trastuzumab and taxane chemotherapy in the first-line in MBC patients with a HER2-negative primary tumor and HER2-positive circulating tumor cells: a phase II trial

Abstract Purpose: HER2 overexpressing circulating tumor cells (CTCs) are observed in up to 20% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically increased the outcome of patients with HER2 positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy. Methods: In this single-arm, phase II trial, HER2 negative patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy (trastuzumab group). Patients with detectable CTCs but without HER2 overexpression and that received taxane chemotherapy only, were used as internal control group (taxane monotherapy group). The primary outcome measure was progression-free rate at 6 months (PFR6). The study was powered to reach a PFR6 of 80%; in this case this strategy was considered worth further investigation. In November 2022, the study was terminated early due to slow patient accrual. Results: 63 HER2 negative patients with metastatic disease were screened, of which 8 patients had HER2-positive CTCs and were treated in the first line with trastuzumab in addition a taxane. Patients receiving taxane monotherapy were used as a control group (n = 27). The median number of CTCs was 15 (range 1 – 131) in patients with HER2-positive CTCs, compared to median 5 (range 1-1047) in the control group. PFR6 was 50% in the trastuzumab group and 64% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p=0.51). Excluding the patients that had no measurable CTCs, there was a borderline significant difference between median CTC count in the patients that did and that did not have HER2 positive CTCs (p=0.05). We confirmed a significant higher CTC-count in samples that had at least one HER2-postive CTC in an independent patient set (n=233, p< 0.001). Conclusions: Although this study was performed in a limited number of patients, no clinical benefit of trastuzumab was observed. Firstly, we conclude that our strategy was not feasible for clinical implementation due to high numbers needed to screen. And, second, due to the strong correlation between CTC numbers and detected CTC HER2 positivity, the prognostic value of the CTC numbers precludes judgement of any predictive value of the HER2 status of CTCs. Citation Format: Noortje Verschoor, Manouk Bos, Inge de Kruijff, Ngoc M Van, Jaco Kraan, Jan Drooger, Johanna Zuetenhorst, Saskia M Wilting, Stefan Sleijfer, Agnes Jager, John WM Martens. Trastuzumab and taxane chemotherapy in the first-line in MBC patients with a HER2-negative primary tumor and HER2-positive circulating tumor cells: a phase II trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-16-02.

Long-term clinical and radiological trajectories of craniocervical vasculopathy in children with PHACE syndrome.

To describe the rates of stroke and craniocervical vasculopathy progression in children with posterior fossa malformations, hemangioma, arterial anomalies, coarctation of the aorta/cardiac defects, and eye abnormalities (PHACE) syndrome. A single-center, retrospective natural history study of children with PHACE syndrome. Clinical and sequential neuroimaging data were reviewed to study the characteristics and progression of vasculopathy and calculate the rates of arterial ischemic stroke (AIS) and transient ischemic stroke (TIA). Vasculopathy progression was defined as worsening or new vascular findings on follow-up magnetic resonance angiography. Thirty-four children with cerebrovascular abnormalities at the PHACE syndrome diagnosis were studied (age range = 2 to 18 years, 85% females). Median age at the initial diagnosis was 5.5 months (interquartile range = 1-52 months); median age at the last follow-up was 8 years 6 months (range = 2-18 years). Overall, 10 (29%) patients had radiological progression of their vasculopathy, with a cumulative progression-free rate of 73% (95% confidence interval [CI] = 0.57-0.89), and a cumulative TIA-free and AIS-free rate of 87% (95% CI = 0.745-0.99). Vasculopathy was continuously progressive in six patients (18%) at the last follow-up. Three patients (9%) had TIA and all had progressive vasculopathy. One patient had presumed perinatal AIS at the initial PHACE diagnosis, while no other patient experienced an AIS during the follow-up. In children with PHACE syndrome, craniocervical vasculopathy is non-progressive and asymptomatic in the majority of cases. The risk of ischemic stroke in these children is very low. Larger and prospective studies are necessary to confirm these findings.

The effect of a single dose of nivolumab prior to isolated limb perfusion for patients with in-transit melanoma metastases: An interim analysis of a phase Ib/II randomized double-blind placebo-controlled trial (NivoILP trial)

ObjectiveILP has shown to achieve high response rates in patients with melanoma ITM. Possibly there is a synergistic mechanism of action of ILP and anti-PD1. The aim of this trial was to investigate the safety and efficacy of adding a single dose of systemic anti-PD1 to isolated limb perfusion (ILP) for patients with melanoma in-transit metastases (ITM). MethodsIn this placebo controlled double-blind phase Ib/II trial, patients with melanoma ITM were randomized 1:1 to either a single systemic dose of nivolumab or placebo one day prior to ILP. The primary endpoint was complete response (CR) rate at three months, and safety in terms of incidence and severity of adverse events (AEs). ResultsA total of 20 patients were included. AEs of any grade occurred in 90% of patients in the nivolumab arm and in 80% in the placebo arm within three months after ILP. Grade 3 AEs were reported in 40% and 30% respectively, most commonly related to wound infection, wound dehiscence, or skin necrosis. There were no grade 4 or 5 AEs reported. The CR rate was 75% in the nivolumab arm and 60% in the placebo arm. The 1-year local progression-free rate was 86% in the nivolumab arm and 67% in the placebo arm. The 1-year OS was 100% in both arms. ConclusionFor patients with melanoma ITM, the addition of a single systemic dose of nivolumab the day before ILP is considered safe and feasible with promising efficacy. Accrual will continue in a phase 2 trial.

Ki-67 labeling index predicts tumor progression patterns and survival in patients with atypical meningiomas following stereotactic radiosurgery

PurposeThis study investigated whether Ki-67 labeling index (LI) correlated with clinical outcomes after SRS for atypical meningiomas.MethodsThis retrospective study examined 39 patients with atypical meningiomas who underwent SRS over a 10-year study period. Ki-67 LI was categorized into 3 groups: low (< 5%), intermediate (5%–10%), and high (> 10%). Local tumor control rates (LCRs), progression-free rates (PFRs), disease-specific survival (DSS) rates, and adverse radiation-induced events (AREs) were evaluated.ResultsThe median follow-up periods were 26 months. SRS was performed at a median prescription dose of 18 Gy for tumors with a median Ki-67 LI of 9.6%. The 3-year LCRs were 100%, 74%, and 25% in the low, intermediate, and high LI groups, respectively (p = 0.011). The 3-year PFRs were 100%, 40%, and 0% in the low, intermediate, and high LI groups (p = 0.003). The 5-year DSS rates were 100%, 89%, and 50% in the low, intermediate, and high LI groups (p = 0.019). Multivariable Cox proportional hazard analysis showed a significant correlation of high LI with lower LCR (hazard ratio [HR], 3.92; 95% confidence interval [CI] 1.18–13.04, p = 0.026), lower PFR (HR 3.80; 95% CI 1.46–9.88, p = 0.006), and shorter DSS (HR 6.55; 95% CI 1.19–35.95, p = 0.031) compared with intermediate LI. The ARE rates were minimal (8%) in the entire group.ConclusionPatients with high Ki-67 LI showed significantly more tumor progression and tumor-related death. Ki-67 LI might offer valuable predictive insights for the post-SRS management of atypical meningiomas.

Nivolumab monotherapy or combination with ipilimumab with or without cobimetinib in previously treated patients with pancreatic adenocarcinoma (CheckMate 032)

BackgroundPancreatic cancer is one of the deadliest cancer types and represents a major unmet medical need. CheckMate 032 investigated safety and efficacy of nivolumab monotherapy and nivolumab plus ipilimumab with/without...

Trastuzumab and first-line taxane chemotherapy in metastatic breast cancer patients with a HER2-negative tumor and HER2-positive circulating tumor cells: a phase II trial

PurposeHER2 overexpressing circulating tumor cells (CTCs) are observed in up to 25% of HER2-negative metastatic breast cancer patients. Since targeted anti-HER2 therapy has drastically improved clinical outcomes of patients with HER2-positive breast cancer, we hypothesized that patients with HER2 overexpressing CTCs might benefit from the addition of trastuzumab to chemotherapy.MethodsIn this single-arm, phase II trial, patients with HER2-positive CTCs received trastuzumab as addition to first-line treatment with taxane chemotherapy. Patients with detectable CTCs but without HER2 overexpression that received taxane chemotherapy only, were used as control group. The primary outcome measure was progression-free rate at 6 months (PFR6), with a target of 80%. In November 2022, the study was terminated early due to slow patient accrual.Results63 patients were screened, of which eight patients had HER2-positive CTCs and were treated with trastuzumab. The median number of CTCs was 15 per 7.5 ml of blood (range 1–131) in patients with HER2-positive CTCs, compared to median 5 (range 1–1047) in the control group. PFR6 was 50% in the trastuzumab group and 54% in the taxane monotherapy group, with no significant difference in median PFS (8 versus 9 months, p = 0.51).ConclusionNo clinical benefit of trastuzumab was observed, although this study was performed in a limited number of patients. Additionally, we observed a strong correlation between the number of evaluable CTCs and the presence of HER2-positive CTCs. We argue that randomized studies investigating agents that are proven to be solely effective in the HER2-positive patient group in patients with HER2-positive CTCs and HER2-negative tissue are currently infeasible. Several factors contribute to this impracticality, including the need for more stringent thresholds, and the rapidly evolving landscape of cancer treatments.

Long-term outcomes of stereotactic radiosurgery for intracranial schwannoma in neurofibromatosis type 2: a genetic analysis perspective.

Neurofibromatosis type 2 (NF2) is intractable because of multiple tumors involving the nervous system and is clinically diverse and genotype-dependent. Stereotactic radiosurgery (SRS) for NF2-associated schwannomas remains controversial. We aimed to investigate the association between radiosurgical outcomes and mutation types in NF2-associated schwannomas. This single-institute retrospective study included consecutive NF2 patients with intracranial schwannomas treated with SRS. The patients' types of germline mutations ("Truncating," "Large deletion," "Splice site," "Missense," and "Mosaic") and Halliday's genetic severity scores were examined, and the associations with progression-free rate (PFR) and overall survival (OS) were analyzed. The study enrolled 14 patients with NF2 with 22 associated intracranial schwannomas (median follow-up, 102 months). The PFRs in the entire cohort were 95% at 5 years and 90% at 10-20 years. The PFRs tended to be worse in patients with truncating mutation exons 2-13 than in those with other mutation types (91% at 5 years and 82% at 10-20 years vs. 100% at 10-20 years, P = 0.140). The OSs were 89% for patients aged 40 years and 74% for those aged 60 years in the entire cohort and significantly lower in genetic severity group 3 than in the other groups (100% vs. 50% for those aged 35 years; P = 0.016). SRS achieved excellent PFR for NF2-associated intracranial schwannomas in the mild (group 2A) and moderate (group 2B) groups. SRS necessitates careful consideration for the severe group (group 3), especially in cases with NF2 truncating mutation exons 2-13.

TAS0313 plus Pembrolizumab for Post-Chemotherapy Immune Checkpoint Inhibitor-Naïve Locally Advanced or Metastatic Urothelial Carcinoma.

We evaluated the efficacy and safety of TAS0313, a multi-epitope long peptide vaccine, plus pembrolizumab in post-chemotherapy immune checkpoint inhibitor-naïve patients with locally advanced/metastatic urothelial carcinoma (la/mUC). TAS0313 9 mg was administered subcutaneously followed by pembrolizumab 200 mg on Day 1, and as monotherapy on Day 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Biomarkers of response were assessed. In 36 patients enrolled, the ORR was 33.3% (complete response: 7 patients; partial response: 5 patients). Median PFS was 5.0 months; 6- and 12-month progression-free rates were 46.4% and 36.5%, respectively. Median OS was not reached; 6-, 12-, and 24-month OS rates were 83.3%, 72.2%, and 55.1%, respectively. In post hoc analysis, patients with a tumor infiltrating CD8+ lymphocyte (CD8+ TIL) count ≥99 and/or programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥50 and lymphocyte count >1,380 cells/μL had higher ORRs and prolonged PFS versus patients with a CD8+ TIL count <99, PD-L1 CPS <50, and lymphocyte count ≤1,380 cells/μL. Thirty-four (94.4%) patients receiving combination therapy experienced treatment-related adverse events (AE), with pyrexia (n = 15, 41.7%), injection-site reactions (n = 15, 41.7%), injection-site induration (n = 6, 16.7%), and malaise (n = 6, 16.7%) the most common. No grade ≥3 treatment-related AEs occurred in ≥10% of patients. TAS0313 plus pembrolizumab combination therapy showed promising efficacy and manageable safety in la/mUC. Clinical Trial Registration: JapicCTI-183824.

MicroRNAs as biomarkers for trastuzumab-based therapy in HER2-positive advanced oesophago-gastric cancer patients

BackgroundThis study aimed to identify microRNAs (miRs) as circulating biomarkers of resistance to first-line trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.MethodsA high-throughput 1015 Exiqon miRCURY LNA™ microRNA inhibitor library screen was performed in trastuzumab-treated HER2-positive NCI-N87 and HER2-negative FLO-1 oesophago-gastric cancer cell lines. NanoString nCounter® miR analysis was performed in NCI-N87, FLO-1, and MAGIC trial (ISRCTN93793971) formalin-fixed paraffin-embedded (FFPE) oesophago-gastric cancer patient samples. MiR-148a-3p copies in plasma samples were quantified using digital droplet polymerase chain reaction (ddPCR) from HER2-positive oesophago-gastric cancer patients treated with standard-of-care trastuzumab-based therapy within the FOrMAT (NCT02112357) and PLATFORM (NCT02678182) clinical trials. The primary endpoints were overall survival (OS) for plasma miR-148a-3p HIGH (&amp;gt;median) versus LOW (≤median). The secondary endpoints were progression-free survival (PFS) and 3-month progression-free rates (PFRs) miR-148a-3p HIGH versus LOW. PLATFORM sensitivity analysis normalised miR-148a-3p (NmiR-148a-3p).ResultsThe inhibition of miR-148a-3p reduced NCI-N87 relative cell viability (&amp;lt;0.6) and expression was high (&amp;gt;242) in NCI-N87 and HER2-positive MAGIC trial patients (n=5). Normalised-miR-148a-3p (NmiR-148a-3p) LOW versus HIGH demonstrated a statistically significant difference in 3-month PFRs (n=23; OR, 0.11 [0.02–0.78]; p=0.027; aOR, 0.03 [0.001–0.71], p=0.029) but no difference in OS or PFS. There was no statistically significant relationship between miR-148-3p LOW versus HIGH for OS (PLATFORM, n=62; hazard ratio [HR], 0.98 [0.57–1.66]; p=0.933; FOrMAT, n=8; HR, 0.54 [0.13–2.31]; p=0.322), PFS (n=62; HR, 1.08 [0.65–1.81]; p=0.759; FOrMAT, n=8; HR, 1.26 [0.31–5.07]; p=0.714), or PFRs (PLATFORM, n=31; odds ratio [OR], 0.67 [0.2–2.8]; p=0.577).ConclusionNormalised miR-148a-3p may be a relevant biomarker for trastuzumab-based therapy in advanced HER2-positive oesophago-gastric cancer patients.

Kinetics and Biology of Circulating Tumor Cells (CTCs) and Measurable Residual Disease (MRD): Two Dynamic High-Risk Clones in Multiple Myeloma (MM)

BACKGROUND CTCs and MRD are two small clones associated with a high risk of progression in smoldering MM (SMM) and post treatment relapse in active MM. Despite growing knowledge about their clinical significance and biological features, these questions remain unanswered: 1) What is the prognostic value of CTC and MRD kinetics? 2) Is MM dissemination and on-treatment resistance driven by specific genomic alterations? 3) Are CTCs and MRD genetically related? AIM Analyze the kinetics and molecular features of CTCs and MRD in SMM and MM patients. METHODS CTC kinetics were investigated using NGF in 164 SMM patients with ≥3 assessments collected every 6 months in the iMMunocell study. MRD kinetics were investigated using NGF in 277 MM patients with ≥4 assessments in BM aspirates after induction, transplant, consolidation, and yearly during maintenance (GEM2012MENOS65-GEM2014MAIN trials). Unsupervised clustering based on CTC and MRD kinetics was performed using CONNECTOR. Molecular features of BM tumor cells at diagnosis were compared to paired CTCs in 94 SMM and MM patients and to paired MRD in 96 MM patients. In 10 cases, genomic data from tripartite BM tumor cells, CTCs, and MRD was available. Tumor samples were isolated based on patient-specific aberrant phenotypes using FACS. Whole exome and RNA-seq were performed in 343 and 217 samples, respectively. RESULTS Based on the assessment of CTCs in 754 PB samples, SMM patients clustered into 3 groups: sustained undetectable (n = 20), stable (n = 71) and evolving (n = 73) CTC levels. With a median follow-up of 2 years, the respective 2y progression-free rates were 100%, 94% and 81% ( P =.003). Risk stratification based on CTC kinetics (C-index 0.68) outperformed a single baseline assessment (C-index 0.61) and, along with the IMWG 20/2/20 model, had independent prognostic value (HR 3.4; P = .01). Patients with high risk cytogenetics showed more frequently evolving CTC levels. Studying genetic drivers of tumor egress, we found CTCs to closely resemble BM tumor cells (88% concordance at copy number [CNA] and somatic mutational [SNV] level). No recurrent cell-specific SNV or CNA was identified. CTC's transcriptional profile revealed 268 DEGs enriched in interferon alpha, gamma response and cell-adhesion pathways. Next, the prognostic value of MRD dynamics was analyzed according to 1,759 assessments, identifying 3 patient clusters: sustained undetectable (n = 100), stable (n = 104), and evolving (n = 73) MRD levels. Respective 6-year rates of PFS after consolidation were 90%, 75% and 5% ( P &amp;lt;.001), and of OS were 94%, 95% and 66% ( P&amp;lt;.001). Risk stratification based on MRD kinetics (C-index 0.82) outperformed a single MRD assessment before maintenance (C-index 0.62), the R-ISS (C-index 0.57) and R2-ISS (C-index 0.61) at diagnosis. MRD cells showed heterogeneous genomic evolution (60% median concordance) diverging from BM tumor cells at diagnosis due to de novo CNA and SNV that emerged at a subclonal level, particularly after transplant. After induction, MM driver mutations were detected or remained clonal in 13/19 (68%) MRD, whereas after transplant, this was true for only 5/13 (38%) MRD. No recurrent cell-specific SNV or CNA was identified. The transcriptional signature of MRD was treatment dependent, with common molecular features of on-treatment resistance found in all 96 patient-paired samples analyzed after various treatment stages. The 334 DEGs were commonly enriched in KRAS signaling hallmarks. Genomic profiles of tripartite BM tumor cells, CTCs and MRD from 10 MM patients confirmed a patient-specific mutational landscape with genomic heterogeneity in MRD. For instance, one patient exhibited BRAF &amp; DIS3 mutations and del(13q) detected at baseline in BM tumor cells and CTCs, which persisted in MRD. After induction, de novo clonal SNVs, including a NEK11 mutation, emerged, followed by the appearance of 3 subclonal CNA after transplant, possibly contributing to resistance. CONCLUSIONS This is the largest dataset analyzing the kinetics and molecular features of CTCs and MRD in SMM and active MM. We showed superior prognostic value of CTC and MRD kinetics over single assessments. Tumor dissemination seems to be driven by transcriptional priming rather than acquired secondary genetic events, while on-treatment resistance is linked to genomic and transcriptional evolution, without recurrent genetic alterations and with common molecular signatures of resistance.

RADT-24. A PROSPECTIVE TRIAL EVALUATING THE EFFICACY OF REIRRADIATION TO BONY METASTASES WITH STEREOTACTIC BODY RADIATION THERAPY

Abstract INTRODUCTION Bone metastasis is common in advanced-stage cancer patients. While reirradiation of metastatic tumors offers significant symptom control, major limits exist on the possible dose delivered to previously irradiated disease sites. Stereotactic body radiation therapy (SBRT) offers the potential to avoid delivering toxic radiation doses to the spinal cord and other organs at risk by delivering large doses with steep dose gradients. METHODS We developed a prospective study including 44 patients with recurrent bone metastasis that were treated to assess the effectiveness of SBRT on local control at or before 6 months as a primary endpoint and local progression-free survival (LPFS), Progression-free survival (PFS), and overall survival (OS) as a secondary objective. RESULTS Patients median age was 62.5 years (22.7% female and 77.3% male). The majority of patients received reirradiation to a spinal lesion (29/44, 65.9%) of various primary disease sites predominantly prostate (13/44, 29.5%), lung (8/44, 18.2%), and renal cell (5/44, 11.4%). The most common dose prescriptions were 30 Gy in 5 fractions (24/44, 54.5%). Of the participants, 41 (93.2%) experienced local control at or before 6 months, with 3.6 median months to local progression for those who progressed. 48% and 36.5% of the cohort maintained LPFS at 2 years, and 3 years respectively with a local progression-free rate of 89.5% at 2 and 3 years. OS was maintained in 50.9% and 38.8% of patients at 2 years and 3 years respectively. CONCLUSION SBRT offers an effective and less toxic approach for the reirradiation of recurrent metastatic tumors as it can prevent associated toxicities to the surrounding normal tissues and maintain a local progression-free rate in a large percentage of patients. We believe that more clinicians should offer SBRT as an effective option for recurrent metastatic bone tumors especially involving the spinal vertebrae.

The safety and response of CT guided percutaneous cryoablation for lung nodules by 17-gauge needles

BackgroundThe safety and efficacy of 17-gauge needles used in CT-guided percutaneous cryoablation for lung nodules were explored in this study. The purpose of the study was to compare the findings with earlier research and multi-center clinical trials that used various needle sizes.MethodsBetween 2016 and 2020, a retrospective study was conducted with approval from the institutional review board. A total of 41 patients were enrolled, and 71 lung nodules were treated in 63 cryoablation procedures using local anesthesia. Complication rates were recorded, and overall survival rates as well as tumor progression-free rates were calculated using the Kaplan-Meier method.ResultsSelf-limited hemoptysis was caused by 12.9% of the procedures, and drainage was required for pneumothoraces resulting from 11.3% of them. The overall survival rates at one, two, three, and four years were 97%, 94%, 82%, and 67%, respectively. The tumor progression-free rates at one, two, three, and four years were 86.2%, 77%, 74%, and 65%, respectively.ConclusionCryoablation for lung nodules using 17-Gauge needles can achieve similar rates of survival and tumor control rates, similar or even lower complication rates as compared with other studies and multi-center trials using mixed sized needles.