Trials Of Systemic Therapy Research Articles

KIRROS: A phase II trial in progress of first-line atezolizumab (atezo) with or without bevacizumab (bev) in patients with unresectable hepatocellular carcinoma (HCC) and Child-Pugh B (CPB) cirrhosis.

TPS647 Background: HCC treatment is more complex for the sizable proportion of patients with CPB cirrhosis. These patients have poor survival due to both the cancer and underlying liver dysfunction. As such, they are typically excluded from pivotal clinical trials for first-line systemic therapy for unresectable HCC. The IMbrave150 trial established atezo + bev as a global standard of care for unresectable HCC, demonstrating a statistically significant improvement in overall survival (OS), progression-free survival (PFS) and confirmed objective response rate (ORR) of atezo + bev vs sorafenib (Finn N Engl J Med 2020; Cheng J Hepatol 2022). Real-world studies have consistently suggested benefit of atezo + bev in patients with HCC and CPB cirrhosis (e.g., Tanaka Hepatol Res 2022, D’Alessio Hepatol [Baltimore, Md] 2022). However, prospective clinical trial data are needed to comprehensively characterize safety and efficacy in this population. Single-agent immunotherapy is often used in patients with HCC and CPB cirrhosis given potential safety concerns of combination therapy. Safety data from real-world studies are limited by ascertainment and measurement biases. Therefore, a prospective study is warranted to address the unmet need for safety and efficacy data for first-line atezo ± bev in patients with CPB cirrhosis. Methods: KIRROS (NCT06096779) is a prospective, open-label, multicohort, multicenter phase II study in patients aged ≥18 years who have measurable and confirmed unresectable HCC, and CPB-7 or -8 cirrhosis who have not received prior systemic therapy. Eligible patients will be recruited into 2 cohorts for which endpoints will be non-comparatively assessed: Cohort A (n=60) patients will be treated with atezo 1200 mg intravenous (IV) + bev 15 mg/kg every 3 weeks (Q3W), and Cohort B (n=60) patients, those who do not meet Cohort A inclusion criteria (e.g., main portal vein tumor thrombus and proteinuria), will receive atezo 1200 mg IV Q3W only. Patients will receive treatment until unacceptable toxicity or loss of clinical benefit. The primary objective is to evaluate the safety of the treatment regimens as determined by incidence, nature and severity of adverse events and laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Secondary objectives are to estimate efficacy with ORR, duration of response, and PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and HCC modified RECIST, as well as OS. Quality-of-life secondary endpoints include patient-reported tolerability of the treatment regimens assessed by PRO-CTCAE and EORTC IL46, and health-related quality of life per EORTC QLQ-C30 and QLQ-HCC18 scores. As of September 2024, the KIRROS study is recruiting patients at 40 sites in the US and Puerto Rico. Clinical trial information: NCT06096779 .

Efficacy and Safety of Four Weeks of Moderately Hypofractionated Chemoradiation for Unresectable, Stage 3 Non-Small Cell Lung Cancer: A Systematic Review.

Shortening treatment time with moderately hypofractionated radiotherapy benefits patients by reducing inconvenience and costs, but its use in the definitive treatment of unresectable Stage 3 non-small cell lung cancer is controversial due to lack of level one evidence and toxicity concerns. Pivotal systemic therapy trials utilize conventionally fractionated chemoradiation at 2Gy per fraction given over 6weeks. In practice, 4weeks of chemoradiation at 2.75Gy per fraction is sometimes employed to reduce the treatment burden for selected patients, especially those who are older or have comorbidities. It is uncertain if the two fractionation regimens are similar in biologically effectiveness, especially with varying systemic therapy. This systematic review aimed to collate the survival and toxicity outcomes for 4weeks of moderately hypofractionated chemoradiation, using >50-60Gy in 20 fractions. Eight studies met the eligibility criteria; seven studies were from a database search of MEDLINE, EMBASE, Cochrane Library, and Web of Science and one study was added later. Two studies were prospective randomized trials and six were retrospective cohort studies. No study included immunotherapy. The historical evidence has been limited, but emerging data is promising, especially when compared to outcomes of standard chemoradiation. Thus, further investigation of this strategy is justified.

Quantitative evaluation of the efficacy and safety of first-line systemic therapies for advanced hepatocellular carcinoma.

This study aimed to quantitatively evaluate the efficacy and safety of first-line systemic therapies for treating advanced hepatocellular carcinoma (aHCC). The study included clinical trials of first-line systemic therapies for aHCC since the approval of sorafenib in 2007. Hazard function models were used to describe changes in overall survival (OS) and progression-free survival (PFS) over time. Monte Carlo simulation was used to compare OS and PFS for different treatments, including sorafenib, antiangiogenic therapies (AATs) (except sorafenib), immune checkpoint inhibitor (ICI) monotherapy, AAT + targeted therapy, AAT + chemotherapy, AAT + ICIs, and ICIs + ICIs. Furthermore, the objective response rate (ORR) and incidence of grade ≥ 3 adverse events were analyzed. Fifty studies comprising 12,918 participants were included. AAT + ICIs demonstrated a significant benefit in median OS (mOS), median PFS (mPFS), and ORR (20.5 [95% CI 17.5-24] months, 7.5 [95% CI 6.5-8.8] months, and 24% [95% CI 17%-30%], respectively). ICIs + ICIs and ICI monotherapy ranked second and third, respectively with an mOS of 20 (95% CI 18.5-21.5) months and 14.5 (95% CI 13.5-16) months, respectively. The OS, PFS, and ORR of patients treated with AAT, AAT + targeted therapy, and AAT + chemotherapy were similar to those of patients treated with sorafenib. A higher proportion of patients with Barcelona Clinic Liver Cancer (BCLC) stage C had a shorter OS. OS was associated with publication year, and PFS was associated with the proportion of patients with BCLC stage C. The incidence of grade ≥ 3 adverse events in the ICIs and ICIs + ICIs treatment groups was low. The study results provide valuable information from which to base rational clinical drug use and serves as a reliable external control for evaluating new treatments for aHCC.

Benchmarks of Success in Radiotherapy versus Systemic Therapy National Clinical Trials Network (NCTN) Randomized Controlled Trials Sponsored by the National Cancer Institute (NCI).

The National Clinical Trials Network (NCTN) is the largest government sponsored organization in the United States tasked with funding randomized controlled trials (RCTs) in oncology. It is unknown whether there are differences in study design by treatment modality. We evaluated differences in methodology between trials testing radiotherapy versus systemic therapy. The Clinical Trials Support Unit website was used to identify active RCTs of systemic or radiotherapy across NCTN cooperative groups through December 31, 2023. Studies in disease sites with > 5 radiotherapy trials were included. Each trial's protocol was reviewed to obtain key design information that were descriptively compared: primary endpoint, hypothesis testing type (superiority vs non-inferiority), non-inferiority margin, hypothesized effect size, power, and significance level. A total of 186 RCTs (142 systemic therapy, 44 radiotherapy) were examined. Comparing primary endpoints, 59.1% vs 26.8% of radiotherapy vs systemic therapy trials, respectively, had a primary endpoint of overall survival. Nearly 1/3 of radiotherapy trials (31.2%) were non-inferiority vs 6.3% of systemic therapy trials. Among breast cancer trials, 75% of radiotherapy studies were non-inferiority vs 11.1% systemic. Target effect size, power, and significance level were similar by treatment modality within tumor types and disease settings. Among NCTN cooperative group RCTs, there were marked differences in study design between radiotherapy vs systemic therapy trials. A higher benchmark for defining success for radiotherapy interventions was observed with greater emphasis on overall survival as primary endpoint. This may reflect differences in therapeutic mechanism by modality and types of study questions posed.

Adjuvant rituximab and elevated intratumoural CD8 expression are associated with sustained disease control after radiotherapy in a randomised trial of systemic therapy in early-stage follicular lymphoma

We report extended follow-up of TROG99.03, a randomised phase III trial in early-stage follicular lymphoma (ESFL) including new information on the role of adjuvant rituximab and translational studies. Patients with ESFL were randomised to involved field radiotherapy (IFRT) or IFRT plus 6-cycles cyclophosphamide/vincristine/prednisolone (IFRT+CVP). From 2006 rituximab was added to IFRT+CVP (IFRT+R-CVP). Clinical and multi-omic parameters were evaluated. Findings were validated in two independent ESFL cohorts (99 and 60 patients respectively). Between 2000 and 2012, 150 (75 per arm) patients were recruited. 48% were positron emission tomography (PET)-staged. By protocol, at median follow-up 11.3-years, progression-free survival (PFS) remained superior for IFRT+(R)CVP vs. IFRT (hazard ratio [HR]=0.60, 95% CI=0.37-0.98, p=0.043; 10-year PFS 62% vs. 43%) respectively. Although no significant difference in overall survival was observed (HR=0.44, 95% CI=0.16-1.18, p=0.11, 10-year OS 95% vs. 84%), patients receiving IFRT+(R)CVP experienced fewer composite (histological transformation and death) events (p=0.045). PFS of IFRT+R-CVP-treated patients compared with all other treatments lacking rituximab (IFRT alone plus IFRT+CVP) was superior (HR=0.36, 95% CI=0.13-0.82, p=0.013). Amongst PET-staged patients, PFS differences between IFRT+R-CVP vs. IFRT were maintained (HR=0.38, 95% CI=0.16-0.89, p=0.027) indicating benefit distinct from stage migration. FL-related mutations and BCL2-translocations were not associated with PFS. However, by multivariate analysis elevated CD8A gene expression in diagnostic biopsy tissue was independently associated with improved PFS (HR=0.45, 95% CI=0.26-0.79, p=0.037), a finding confirmed in both ESFL validation cohorts. CD8A gene expression was raised (p=0.02) and CD8+ T-cell density higher within follicles in ESFL vs. advanced-stage FL (p=0.047). Human leucocyte antigen class I specific neoantigens were detected in 43% of patients, suggesting neoantigen-specific CD8+ T-cells have a role in confining the spread of the disease. Adjuvant R-CVP and elevated intratumoural CD8 expression were independently associated with sustained disease control after radiotherapy in ESFL. Cancer Council Victora; National Health and Medical Research Council; Leukaemia Foundation; Mater Foundation.

Perioperative systemic therapy, current paradigm and ongoing clinical trials in upper tract urothelial cancer.

To provide a comprehensive overview of existing and future paradigms for perioperative systemic therapy in the treatment of upper tract urothelial carcinoma. Contemporary treatment paradigms for the management of upper tract urothelial carcinoma focus on use of neoadjuvant cisplatin based chemotherapy for high grade disease primarily based on two small single arm phase II clinical trials. More robust evidence from a phase III randomized clinical trial exists for the use of adjuvant platinum based chemotherapy for invasive disease after radical nephroureterectomy, but there are significant concerns about renal function and platinum eligibility after nephroureterectomy. There are currently ongoing clinical trials for nonplatinum based perioperative systemic therapies including checkpoint inhibitors/immunotherapy as well as antibody-drug conjugates, but currently no recommendation can be made for these approaches. Current evidence supports neoadjuvant cisplatin chemotherapy in the setting of high grade disease or concern for significant renal dysfunction after radical nephroureterectomy or platinum based adjuvant chemotherapy in eligible patients with advanced disease after surgery. While there is no established role for nonplatinum based therapies yet, multiple ongoing trials exploring use of immunotherapies and antibody-drug conjugates as monotherapy or combination may provide new therapeutic options in this population.

Clinical benefit and fragility evaluation of systemic therapy trials for advanced soft tissue sarcoma.

The clinical benefit of systemic anticancer therapies can be unclear despite positive trials, and outcomes may not translate to real-world practice. This study evaluated the benefit of soft tissue sarcoma (STS) treatments using the European Society of Medical Oncology Magnitude of Clinical Benefit Scale (MCBS) v1.1 and measured the robustness of STS trial results using Fragility Index (FI). Database searches for adult phase II or III trials in advanced STS (January 1998-December 2023) were performed. Therapies with trial outcomes that met the criteria for MCBS were scored 1-5 (≥4 represents substantial clinical benefit). For randomized clinical trials with positive time-to-event endpoints, the number of additional events that would render results nonsignificant, FI, was calculated and expressed as a proportion of the experimental arm size (fragility quotient [FQ]). Higher FI/FQ implies more robust results. Among 194 trials, 19 (9.8%) were phase III. Most phase II trials (146/175; 83.4%) had single-arm or non-comparative design. Trials that were eligible for MCBS scoring (n=78; 40.2%) evaluated 56 different agents/regimens. Median MCBS score was 2. Only three agents/regimens (all cytotoxic therapies) had an MCBS score ≥4. Among 47 randomized clinical trials, 16 (8 phase II; 8 phase III) trials had positive outcomes. Median FI was 7 (range, 2-52) and 10 trials (62.5%) had an FQ < 10%, with median of 7% (range, 1%-59%). Most systemic therapies in STS trials did not confer substantial clinical benefit per European Society of Medical Oncology-MCBS. Additionally, positive randomized trials were often fragile. Novel STS therapy trials should use clinically meaningful endpoints and real-world efficacy confirmation is essential, especially for less robust trials.

Off-Protocol Radiation Therapy in Phase 3 Metastatic Solid Tumor Trials

Increasing data suggest that radiation therapy, particularly ablative radiation therapy, alters the natural history of metastatic disease. For patients with metastatic disease enrolled in prospective trials testing systemic therapy, the use of off-protocol radiation therapy to improve clinical symptoms or extend the duration of study systemic therapy may influence study endpoints. We sought to evaluate how often off-protocol radiation therapy was permitted among systemic therapy phase 3 trials, how often off-protocol radiation therapy is used, and whether off-protocol radiation therapy correlated with study outcomes. Two-arm, superiority-design, phase 3 randomized trials testing systemic therapy were screened from ClinicalTrials.gov. Protocol availability was required to assess the trial approach to off-protocol radiation therapy if not described in the manuscript. Adjusted odds ratios with 95% CI were calculated by logistic regression. A total of 112 trials enrolling 80,134 patients were included, with publication dates between 2010 and 2019. Of these, off-protocol radiation therapy was allowed, not discussed, or prohibited during study systemic therapy in 52% (N =58), 25% (N = 28), and 23% (N = 26) of trials, respectively. However, only 2% (2 of 112) of trials reported off-protocol radiation therapy utilization rates, although no data were reported on the use of ablative off-protocol radiation therapy. No trials evaluated or adjusted for the potential influence of off-protocol radiation therapy on study endpoints. Among the subset of open-label studies, trials permissive toward off-protocol radiation therapy were more likely to meet their primary endpoint (adjusted odds ratio, 4.50; 95% CI, 1.23-20.23; P = .04). Although most trials allowed off-protocol radiation therapy during the receipt of the study systemic therapy, the influence of off-protocol radiation therapy, especially ablative radiation therapy, on study outcomes is underevaluated among phase 3 systemic therapy trials.

Evaluation of American Urological Association Renal Cell Carcinoma Risk Groups for Chromophobe Renal Cell Carcinoma

ObjectivesTo develop and compare various models for risk stratification in chromophobe renal cell carcinoma (chrRCC). Models have been developed to predict progression-free (PFS) and cancer-specific survival (CSS) following surgery for localized renal cell carcinoma (RCC). Notably, chromophobe RCC (chrRCC) is not included in American Urological Association (AUA) risk stratification, as nuclear grading is not recommended. MethodsWe queried our institutional registry to identify patients managed surgically for unilateral, sporadic, M0, chrRCC from 1970-2012. AUA risk groups were defined using reported criteria, excluding grade, and were compared to the Mayo system incorporating nodal involvement, perinephric/renal sinus fat invasion, and sarcomatoid differentiation. PFS and CSS were estimated using the Kaplan-Meier method. Predictive ability was summarized using c-indexes from Cox proportional hazard regression models. ResultsA total of 257 patients were identified. Thirty-nine patients experienced disease progression at a median 30 months (IQR 5.0-84) and 25 died from chrRCC at a median 34 months (IQR 15-79) following surgery. PFS and CSS rates at 10 years after surgery were 84% and 90%, respectively. C-indexes for modified AUA and Mayo risk groups were similar at 0.76 and 0.75, respectively, for PFS, and 0.77 and 0.76, respectively for CSS. ConclusionsThe modified AUA and Mayo risk stratification systems have similarly robust c-indexes for PFS and CSS in chrRCC. These models can be used to counsel patients based on pathologic features, inform clinicians on appropriate follow-up pathways, and identify patients at risk of disease progression for enrollment in adjuvant systemic therapy trials.

BMScope: A scoping review to chart the evolving clinical study landscape in brain and leptomeningeal metastasis.

Recent studies have challenged the notion that patients with brain metastasis (BM) or leptomeningeal metastasis (LM) should be excluded from systemic therapy clinical trials. This scoping study summarizes the BM/LM clinical studies published between 2010 and 2023. MEDLINE, CINAHL, CAB Abstracts, PsycINFO, Cochrane Library, HINARI, International Pharmaceutical Abstracts, PubMed, Scopus, Web of Science, and EMBASE electronic databases were searched on June 21, 2021. An updated search was performed on February 21, 2023. Eligible studies investigated a therapeutic intervention in solid tumor patients with BM and/or LM and reported a patient outcome. Extracted study-level data, including study type, publication date, geographical location, number of BM/LM patients in the study, primary tumor type, and type of therapeutic intervention, were collected. 4921 unique studies were eligible for analysis. The key finding is that BM/LM clinical research is expanding globally, both in observational studies and clinical trials. Despite the shift over time toward a higher proportion of systemic therapy trials, the majority still do not include patients with symptomatic disease and lack reporting of BM/LM-specific endpoints. Globally, there has been a trend to more international collaboration in BM/LM clinical studies. Our analysis of the BM/LM literature charts the evolving landscape of studies involving this previously excluded population. Given the increasing clinical research activity, particularly involving late-stage systemic therapy trials, it is imperative that due consideration is given to the intracranial activity of new investigational agents. Wider adoption of standardized reporting of intracranial-specific endpoints will facilitate the evaluation of relative intracranial efficacy.

Benefit assessment of novel systemic therapies for bone and soft tissue sarcomas: a cross-sectional study.

Bone and soft tissue sarcomas are rare malignancies, and their heterogeneity has limited the development of novel drugs. This study aimed to apply two validated tools to evaluate the clinical benefits of novel drug therapies for sarcoma developed over the last decade. The PubMed and Embase databases were searched for randomized controlled trials (RCTs) of systemic therapies for sarcomas published between 2013 and 2023. Each trial was scored according to the European Society of Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) and the American Society of Clinical Oncology-Value Framework version 2 (ASCO-VF). We included 52 RCTs in this study, of which 17 (32.7%) reported positive results that favored the experimental arm. The ESMO-MCBS grades were determined in 14/17 positive trials, and three of them (21.4%) met the threshold for meaningful clinical benefit. Likewise, ASCO-VF scores were calculated for 11/17 positive trials, and three of them (27.3%) met the threshold for meaningful clinical benefit. Weak correlation (r = 0.38, P = 0.277) and agreement (κ = 0.211, P = 0.490) were observed between the two frameworks. Only a few RCTs with positive results have demonstrated substantial patient benefits for bone and soft tissue sarcomas over the past decade.

Contemporary survival in metastatic bladder cancer patients: A population-based study.

The overall survival (OS) improvement after the advent of several novel systemic therapies, designed for treatment of metastatic urothelial carcinoma of the urinary bladder (mUCUB), is not conclusively studied in either contemporary UCUB patients and/or non-UCUB patients. Within the Surveillance, Epidemiology, and End Results database, contemporary (2017-2020) and historical (2000-2016) systemic therapy-exposed metastatic UCUB and, subsequently, non-UCUB patients were identified. Separate Kaplan-Meier and multivariable Cox regression (CRM) analyses first addressed OS in mUCUB and, subsequently, in metastatic non-UCUB (mn-UCUB). Of 3443 systemic therapy-exposed patients, 2725 (79%) harbored mUCUB versus 709 (21%) harbored mn-UCUB. Of 2725 mUCUB patients, 582 (21%) were contemporary (2017-2020) versus 2143 (79%) were historical (2000-2016). In mUCUB, median OS was 11 months in contemporary versus 8 months in historical patients (Δ = 3 months; p < .0001). After multivariable CRM, contemporary membership status (2017-2020) independently predicted lower overall mortality (OM; hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.60-0.76; p < .001). Of 709 mn-UCUB patients, 167 (24%) were contemporary (2017-2020) and 542 (76%) were historical (2000-2016). In mn-UCUB, median OS was 8 months in contemporary versus 7 months in historical patients (Δ = 1 month; p = .034). After multivariable CRM, contemporary membership status (2017-2020) was associated with HR of 0.81 (95% CI = 0.66-1.01; p = .06). In conclusion, contemporary systemic therapy-exposed metastatic patients exhibited better OS in UCUB. However, the magnitude of survival benefit was threefold higher in mUCUB and approximated the survival benefits recorded in prospective randomized trials of novel systemic therapies.

Diagnostic Value of Short Course Low-dose Prednisolone in Patients with Clinically Suspected Seronegative Inflammatory Arthritis - A Retrospective Study.

We aim to establish the utility of a trial of low-dose systemic glucocorticoid therapy in the assessment of new clinically suspected inflammatory arthritis patients. We retrospectively identified patients from a private rheumatology practice in Melbourne, Australia between January 1st, 2019, and December 31st, 2021, who presented with clinically suspected inflammatory arthritis and subsequently underwent a trial of low-dose prednisolone (15 mg daily weaned over three weeks in 5 mg increments). We excluded patients with known autoimmune/ inflammatory disorders or concurrent immunosuppression at presentation. We collected basic participant demographic details and clinical details of their presentation, glucocorticoid response, investigations, and treatment. We recruited 177 participants with a median age of 52, and 69.5% were female gender. The median symptom time to presentation was 12 months. Hands were the most affected joint in 63.3% and 85% had bilateral disease. Among the participants, 29.4% had synovitis on clinical review and 75.7% had imaging performed as part of the initial assessment. At presentation, the median CRP was 11 and the median ESR was 16. 79.7% of the cohort experienced significant improvement in their arthritis symptoms from low-dose glucocorticoids and 83.6% of the cohort required long-term immunosuppression for an underlying inflammatory condition. Of those who responded to glucocorticoids, 92.1% were diagnosed with an inflammatory condition. Rheumatoid arthritis was the most common overall diagnosis in 28%. An initial trial of low-dose glucocorticoids in undifferentiated arthritis patients is useful in predicting the diagnosis of inflammatory arthritis. It is also a predictor of further long-term steroid-sparing therapy.

Postrecurrence Treatment in Neoadjuvant or Adjuvant FDA Registration Trials

In oncology randomized clinical trials, suboptimal access to best available care at recurrence (or relapse) may affect overall survival results. To assess the proportion and the quality of postrecurrence treatment received by patients enrolled in US Food and Drug Administration (FDA) registration trials of systemic therapy in the adjuvant or neoadjuvant setting. For this systematic review, all trials leading to an FDA approval from January 2018 through May 2023 were obtained from the FDA website and drug announcements. Randomized clinical trials of an anticancer drug in the neoadjuvant or the adjuvant setting were included. Trials of supportive care treatment and treatments given in combination with radiotherapy were excluded. Information abstracted for each trial included tumor type, setting, phase, type of sponsor, reporting and assessment of postrecurrence, and overall survival data. A total of 14 FDA trials met the inclusion criteria. Postrecurrence data were not available in 6 of 14 registration trials (43%). Of the 8 remaining trials, postrecurrence treatment was assessed as suboptimal in 6 (75%). Overall, only 2 of 14 trials (14%) had data assessed as appropriate. This systematic review found that 43% of randomized clinical trials of anticancer treatment in the adjuvant or neoadjuvant context failed to present any assessable postrecurrence treatment data. In instances in which these data were shared, postrecurrence treatment was suboptimal 75% of the time. The findings suggest that regulatory bodies should enforce rules stipulating that patients have access to the best standard of care at recurrence.

NRG-LU002: Randomized phase II/III trial of maintenance systemic therapy versus local consolidative therapy (LCT) plus maintenance systemic therapy for limited metastatic non-small cell lung cancer (NSCLC).

8506 Background: First line therapy options for advanced NSCLC without actionable molecular alterations include immunotherapy (IO) -/+ chemotherapy or chemotherapy alone. NRG-LU002 was a randomized phase II/III study assessing the benefits of local consolidative therapy (LCT) when added to systemic therapy as maintenance in management of oligometastatic NSCLC. Methods: Eligible patients had metastatic NSCLC with 3 or fewer extracranial metastatic sites (excluding primary) exhibiting at least stable disease after 4 cycles of 1st line systemic therapy. Patients were randomized 1:2 to maintenance systemic therapy or LCT (radiation and/or surgery) followed by maintenance systemic therapy until progression, death, or intolerable toxicity. Stratification factors included histology and IO use. In the randomized phase II (RPhII) portion of the study, the primary endpoint was progression-free survival (PFS) with a planned decision analysis after 216 patients were enrolled and 138 PFS events observed. Secondary endpoints included overall survival (OS), quality of life, and toxicity. The RPhII portion was designed to provide at least 95% power to detect a PFS hazard ratio (HR) of 0.60 at 1-sided significance level of 0.15, and the phase III portion warranted only if the estimated HR was less than 0.83. Results: NRG-LU002 accrual was initiated in 4/2017 and suspended in 11/2021 when the RPhII portion sample size was met. Following the planned interim analysis, the study was closed in 12/2023. Overall, 215 patients (81 -LCT arm, 134 +LCT arm) were enrolled from 68 sites with a median age of 65 years (40-86), 77% white, 95% PS 0/1, 78% non-squamous histology, and 90% having received IO-based systemic therapy. Median follow-up among all/surviving patients were 21.9/29.4 months, respectively. With 138 PFS events from both arms, estimated 1-yr and 2-yr PFS rates were 48% (95% CI: 35.9, 59.0) and 36% (95% CI: 24.8, 47.2) in the maintenance systemic therapy arm and 52% (95% CI: 42.5, 59.8) and 40% (95% CI: 31.5, 48.6) in the LCT + maintenance systemic therapy arm, respectively (2-sided log-rank test p-value = 0.66). Corresponding HR was 0.93 (95% CI: 0.66, 1.31). Of 185 patients treated with IO-containing regimens, the PFS HR was 0.90 (95% CI: 0.61, 1.32). OS HR between two arms was 1.05 (0.70, 1.56) among all patients and 1.05 (0.68, 1.63) among IO-treated patients. For adverse events reported as definitely, probably or possibly related to treatment, there were more LCT + maintenance systemic therapy patients with overall grade 2 or higher toxicities (73% vs 84%) and grade 3 or higher pneumonitis (1% vs 10%). Conclusions: LCT added to IO-based 1st line systemic therapy was associated with a PFS HR of 0.90. Reducing toxicity and increasing biologically-driven patient selection may optimize this therapeutic ratio. Clinical trial information: NCT03137771 .

Veterans Affairs seamless phase II/III randomized trial of standard systemic therapy with or without PET-directed local therapy for oligometastatic prostate cancer (VA STARPORT).

TPS5120 Background: The concept of metastasis-directed therapy (MDT) using radiation or surgery for oligometastatic (OM) prostate cancer (pCa) has evolved from an anecdotal hypothesis to a promising approach that may optimally balance toxicity and oncologic efficacy. Recently, there have been multiple smaller phase II randomized trials that have shown a signal of efficacy for MDT in OM pCa. Most studies have compared MDT to observation alone as the control arm, included only recurrent OM patients, and included up to 3-5 sites of metastasis. It is in this context, that the VA STARPORT trial was initiated in 2021 to definitively determine the role of MDT in Veterans with oligorecurrent pCa in 1-5 sites. Yet, the diagnosis and management of metastatic pCa have since evolved. The SABR-COMET-10 trial recently completed enrollment and compares systemic therapy alone or with MDT in patients with 1-10 metastases from various histologies. While pCa PET/CT imaging was only available for Veterans with biochemical recurrence in 2021, PSMA PET/CT now allows for the improved diagnosis of OM in Veterans with de novo pCa—a growing cohort of patients without a clear standard of care. Therefore, to maximize the impact and generalizability of the trial, VA STARPORT has been amended to allow for de novoOM and 1-10 metastases. The primary goal of VA STARPORT is to determine if adding PET-directed local therapy (PDLT) to standard systemic therapy (SST) improves disease control compared to SST alone in Veterans with recurrent and de novooligometastatic pCa. Methods: VA STARPORT is a phase II/III randomized trial open at 18 VA medical centers comparing SST alone (Arm 1) or with PDLT (Arm 2) in Veterans with OM pCa. Key eligibility criteria include recurrent or de novohormone-sensitive metastatic pCa and 1-10 metastatic lesions on any FDA-approved pCa PET/CT. The primary endpoint is castration-resistant prostate cancer-free survival (CRPC-free survival). Secondary endpoints include radiographic PFS, clinical PFS, freedom from index lesion progression, toxicity, quality of life, and prostate cancer-specific and overall survival. SST is delivered using any NCCN guideline-concordant regimen in both arms. PDLT can be either radiation or surgery to all sites of cancer. Regarding local therapy, de novo patients in Arm 1 receive prostate-directed RT, and in Arm 2 receive PDLT to all metastases and the prostate. For recurrent patients in Arm 1 there is no local therapy, while in Arm 2 patients receive PDLT. All participants undergo somatic tumor sequencing using the VA National Precision Oncology Program. Assuming a hazard ratio of 0.60 for SST + PDLT vs SST, two-sided alpha = 0.05 and 90% power, a total of 464 participants will be randomized to generate 166 CRPC-free survival events by the end of the active study phase. Recruitment is ongoing and 150 patients have been enrolled. Clinical trial information: NCT04787744 .

PATH-HHT, a Double-Blind, Randomized, Placebo-Controlled Trial in Hereditary Hemorrhagic Telangiectasia Demonstrates That Pomalidomide Reduces Epistaxis and Improves Quality of Life

Introduction Hereditary hemorrhagic telangiectasia (HHT), the second most common bleeding disorder worldwide, affects 1 in 5000 people and is characterized by extensive formation of telangiectasia and arteriovenous malformations (AVM) in mucosa, lung, brain, and liver. The primary clinical manifestation is recurrent, often severe epistaxis which commonly results in iron deficiency anemia, emergency room visits, hospitalizations, and reduced quality of life (QOL). Though non-randomized and/or underpowered studies have suggested that systemic bevacizumab or thalidomide may be effective in treating HHT, there have been no pivotal studies and therefore no FDA or EMA approved therapies. Methods PATH-HHT was an NHLBI-funded, randomized, placebo-controlled clinical trial conducted at 13 centers in the US to determine the safety and efficacy of pomalidomide for bleeding in HHT. Pomalidomide was supplied by Celgene and Bristol Myers Squibb. Patients were randomized in a 2:1 ratio to receive pomalidomide 4 mg daily or matching placebo for 6 months. Dose reductions were allowed for toxicity. The primary endpoint was the change in the Epistaxis Severity Score (ESS), a well-validated bleeding score in HHT, from baseline (randomization) to the end of the six-month treatment period, analyzed using a mixed model for repeated measures with adjustment for baseline value, center, treatment, visit, and treatment by visit interaction. Key secondary endpoints included 1) change in the average daily self-reported epistaxis duration from the four weeks preceding the baseline visit to weeks 20-24 of treatment, 2) amount of parenteral iron infused or blood transfused, and 3) change in QOL measurements, including an HHT-specific QOL score. Results PATH-HHT opened in November 2019 and was closed to enrollment by the NHLBI in June 2023 after a planned 75% interim analysis met a prespecified threshold for efficacy. A total of 144 patients were randomized and treated (95 pomalidomide, 49 placebo). Early study discontinuation was 25% in pomalidomide: 14% AE, 11% withdrawn, 1 unrelated death, compared with placebo (4% withdrawn). Across groups, 8% were terminated after 12 weeks for early study closure. Participants included 48% females, 11% non-white race; mean (± SD) age was 58.8±12.2 years. The mean ESS at baseline was 5.0±1.5 (4.9 pomalidomide, 5.2 placebo), consistent with moderate to severe epistaxis. At 24 weeks, the ESS in patients treated with pomalidomide decreased by a mean [95% CI] of -1.84 [-2.24, -1.44] and in the placebo group decreased by -0.89 [-1.39, -0.39] (mean difference -0.95 [-1.58, -0.32], p = 0.003) (Figure, Panel A). Difference between groups was apparent by 12 weeks (mean difference -0.52, 95% CI [-1.04, -0.01], p = 0.045). The HHT-specific QOL score, which ranges from 0 to 16 with higher scores indicating more limitations, also decreased more in the pomalidomide (mean -2.6, 95% CI [-3.3, -1.9]) vs the placebo group at 24 weeks (mean -1.2, 95% CI [-2.1, -0.3], p = 0.015) (Figure, Panel B). Adverse events that occurred more in the pomalidomide group included mild to moderate neutropenia (45% vs. 10%), constipation/diarrhea (60% vs. 37%), and rash (36% vs. 10%). Venous thrombosis occurred in 2% of patients in each group. Conclusion PATH-HHT is the largest and the first adequately powered, randomized trial of systemic therapy in HHT. The study demonstrated a significant and highly clinically relevant reduction in epistaxis in pomalidomide-treated patients as well as an improvement in the HHT-specific QOL score. Pomalidomide may offer a novel approach to management of HHT. Since plasma was collected from patients in this study before and at the end of treatment, additional studies may identify biomarkers predicting pomalidomide responses.

Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies

For people with atopic dermatitis (AD) refractory to topical therapies, treatment with phototherapy and systemic therapies can be considered. Multiple biologic therapies and Janus kinase (JAK)inhibitors have been approved since 2014 to treat AD. These guidelines update the 2014 recommendations for management of AD with phototherapy and systemic therapies. To provide evidence-based recommendations on the use of phototherapy and systemic therapies for AD in adults. A multidisciplinary workgroup conducted a systematic review and applied the GRADE approach for assessing the certainty of evidence and formulating and grading recommendations. The workgroup developed 11 recommendations on the management of AD in adults with phototherapy and systemic agents, including biologics, oral JAK inhibitors, and other immunomodulatory medications. Most randomized controlled trials of phototherapy and systemic therapies for AD are of short duration with subsequent extension studies, limiting comparative long-term efficacy and safety conclusions. We make strong recommendations for the use of dupilumab, tralokinumab, abrocitinib, baricitinib, and upadacitinib. We make conditional recommendations in favor of using phototherapy, azathioprine, cyclosporine, methotrexate, and mycophenolate, and against the use of systemic corticosteroids.

Gender Disparities in the Clinical Trials and Real-World Utilization of Systemic Therapy in the Management of Urothelial Carcinoma

Objectives: The objectives of this study was (1) to examine the representation of women in clinical trials for systemic therapy in muscle-invasive (MIBC) or metastatic bladder cancer (BC) and (2) to determine the association between sex and systemic therapy in the treatment of MIBC or metastatic BC. Methods: A review of bladder cancer systemic therapy clinical trials cited by the National Comprehensive Cancer Network guidelines was performed. Proportions of women were compared with the corresponding proportions in the US population with bladder cancer between 1975 and 2018, based on the Surveillance, Epidemiology, and End Results database. We also used the National Cancer Database (NCDB) to identify 55,951 patients with American Joint Committee on Cancer clinical stage II, III, and IV bladder cancer between 2004 and 2015. We determined the predictors of systemic therapy for bladder cancer treatment using a multivariable logistic regression model. Results: 26.9% of the US bladder cancer population were women; however, only 17.7% of participants in US clinical trials and 19.9% of participants in all clinical trials were female, indicating an absolute difference of 9.2% (95% confidence interval [CI]: 6.2%-12.1%; P &lt; .001) and 7.0% (95% CI: 6.1%-7.9%; P &lt; .001), respectively. Multivariable analysis of the NCDB showed that women had decreased odds of receiving systemic therapy compared with male patients with MIBC or metastatic BC (odds ratio: 0.93, 95% CI: 0.89-0.96; P &lt; .001). Conclusion: Women are underrepresented in MIBC and/or metastatic BC systemic therapy clinical trials. In addition, women are less likely than men to receive systemic therapy for the treatment of MIBC or metastatic BC. Further research is needed to investigate the reasons for gender disparities in treatment of MIBC or metastatic BC as well as the participation in clinical trials.

P03.15.B SURGICALLY TARGETED RADIATION THERAPY (START) FOR RECURRENT GLIOBLASTOMA: INITIAL OUTCOMES FROM A PROSPECTIVE MULTICENTER REGISTRY

Abstract BACKGROUND Surgically targeted radiation therapy (STaRT), using a novel bioresorbable collagen brachytherapy device containing 4 Cesium-131 sources, is FDA-cleared for use as adjuvant radiation therapy (RT) post-resection in both newly diagnosed and recurrent intracranial neoplasms. Intraoperative initiation of brachytherapy potentially minimizes post-resection tumor regrowth with a favorable dosimetric profile compared to external beam radiation. This work sought to determine early patterns of care and the safety of this approach in recurrent glioblastoma (GBM). MATERIAL AND METHODS This prospective multi-institutional observational study (NCT04427384) included recurrent GBM patients who underwent maximum safe resection (MSR) and permanent implantation of the device(s) (GammaTile, GT Medical Technologies, Tempe, AZ, US). Descriptive and comparative analyses regarding patient characteristics and early clinical outcomes were performed. Toxicities were categorized using the CTCAE v5.0 adverse event (AE) criteria. RESULTS During 10/2020-01/2023, 14 participating sites enrolled 45 patients with recurrent GBM for STaRT; 2 patients had two sites treated for a total of 47 implants. 67% of patients were treated at the first recurrence, 24% at the second, and 13% at the third, respectively. The median age was 61 (range 28-75), 36% were female, and 23% were &amp;gt;65 years. 85% of patients received prior same-site RT with the median time from last RT to implantation of 14.6 months (range 3.5-57). The median maximum preoperative size was 4.2 cm (range 1.6-7.0), and the median volume was 20.8 cm3 (range 0.8-130). 68% of resections were gross-total, 17% near-total, and 15% sub-total; the median time needed for device implantation was 5 minutes (range 1.0-13). Median follow-up was 5.2 months (range 0.6-23.2). Median Karnofsky performance status (KPS) at screening, at initial postoperative assessment, and 3 months were all 80 (range 40-100). 7 attributed AEs occurred in 13% (6/45) of patients, all grade 3 AEs: 2 CSF leaks, 2 seizures, 1 cerebral edema, 1 pseudomeningocele, and 1 left hemiparesis. All except one were coded as related to both radiation and surgery; the patient with pseudomeningocele experienced a seizure at 47 days that was considered related to radiation alone. CONCLUSION Early data from this prospective registry demonstrate the feasibility and safety of STaRT in recurrent GBM. Data on 6-month progression-free survival will be presented at the conference. A prospective randomized trial of adjuvant systemic therapy (AST)+MSR+STaRT versus MSR+AST is planned for initiation in 2023.