Showing papers by "Karla V. Ballman published in 2023"

Prognostic and Predictive Value of Immune-Related Gene Expression Signatures vs Tumor-Infiltrating Lymphocytes in Early-Stage ERBB2/HER2-Positive Breast Cancer

Abstract: Key Points Question Which immune-related biomarker provides the most valuable information to predict pathologic complete response and event-free survival in patients with early-stage ERBB2/HER2-positive breast cancer: tumor-infiltrating lymphocytes, immune-related gene expression signatures, or both? Findings In this predictive prognostic study in which a combined correlative analysis of the CALGB 40601 and PAMELA trials was conducted, 305 patients with early-stage ERBB2/HER2-positive breast cancer, 6 B-cell–related signatures were more strongly associated with pathologic complete response than were tumor-infiltrating lymphocytes. In a multivariable Cox model performed in the CALGB 40601 trial, the immunoglobulin G signature, but not tumor-infiltrating lymphocytes, was independently associated with event-free survival. Meaning Findings suggest that when both tumor-infiltrating lymphocytes and gene expression are available, the prognostic and predictive value of RNA sequencing–based immune signatures is superior.

MAIN-CAV: Phase III randomized trial of maintenance cabozantinib and avelumab versus avelumab after first-line platinum-based chemotherapy in patients (pts) with metastatic urothelial cancer (mUC; Alliance A032001).

Abstract: TPS4609 Background: First-line platinum-based chemotherapy followed by maintenance avelumab (Av) is the current preferred standard of care in patients (pts) with mUC who do not progress after platinum-based chemotherapy. There is an unmet need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. CABO is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitors. We hypothesize that CABO-Av combination will be synergistic in pts with mUC with an acceptable safety profile and will improve upon the benefit seen with Av maintenance in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for locally advanced/mUC pts (including N3 only disease) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adult pts will be randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or combination of Av and CABO 40 mg orally daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of immunotherapy (exception of BCG), no central nervous system metastases, no major surgery within 4 wk, no uncontrolled hypertension or cardiovascular disorders. Pts will be stratified based on 1) best response to 1L therapy: complete response vs partial response vs stable disease and 2) presence or absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of one-sided alpha of 0.025, power of 80%, median OS of 21 months (mo) on Av arm and hazard ratio (HR) of 0.75, thus hypothesizing a median OS of 28 mo on CABO-Av combination arm. Key secondary endpoints include progression-free survival, safety, tolerability, and activity of CABO-Av compared to Av alone based on RECIST 1.1 and iRECIST criteria and PD-L1 status of pts’ tumors. Quality of life (QOL) will be assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-avelumab vs avelumab alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test correlation of established and new radiomic signatures with OS, adverse events and QOL and incorporate both radiologic and biologic features to predict outcomes. This trial would be the first to systematically address whether adding a multitargeted TKI, CABO to Av leads to improved clinical outcomes compared to Av alone. Clinical trial information: NCT05092958 .

Abstract GS4-01: Impact of Breast Conservation Therapy on Local Recurrence in Patients with Multiple Ipsilateral Breast Cancer – Results from ACOSOG Z11102 (Alliance)

Abstract: Background Breast conserving therapy (BCT) is accepted as a preferred option for unifocal breast cancer. However, the oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC), has not been demonstrated in a prospective study. The ACOSOG (Alliance) Z11102 phase II single arm prospective trial was designed to evaluate outcomes with BCT for MIBC. Methods Women age 40+ with 2 or 3 foci of biopsy proven breast cancer (BC) (each site < 5cm in size with at least 1 site invasive) separated by >2-3 cm of normal breast tissue and disease limited to two quadrants of the breast with cN0 or cN1 disease were eligible. All patients had pre-operative mammogram and breast MRI was initially required and subsequently made optional. Neoadjuvant therapy was not allowed. Patients were treated with lumpectomy resected to negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary endpoint of Z11102 is the cumulative incidence of local recurrence (LR, defined as histologic evidence of ductal carcinoma in situ or invasive BC in the ipsilateral breast or chest wall) at 5 years (treating death and distant and nodal/regional recurrence as competing risks) to assess whether the rate is greater than 8%. Data were frozen 5/25/2022. Results From 11/2012-8/2016, 270 women were enrolled. Of these, 33 were ineligible, 14 converted to mastectomy, 11 were unable to meet protocol-specific radiation endpoints, 1 had no definable tumor, 1 had 4 sites of cancer and 16 withdrew before completing surgery and radiation, leaving 194 patients [median age 61 (range 40-87)] eligible who completed breast conserving surgery and radiation therapy. With median follow-up of alive patients of 66.6 months (range: 4.1, 90.6), 6 patients have developed LR (5 ipsilateral breast and 1 chest wall), corresponding to an estimated cumulative incidence of local recurrence of 3.2% (95% CI: 1.3, 6.4) at 5 years. No patients have developed regional recurrence, 5 patients developed distant recurrence, 0 patients developed local and distant recurrence, 5 patients developed contralateral BC, 3 new non-BC primaries and 8 patients have died (1 related to BC). The rate of local recurrence in patients without a breast pre-op MRI (n=14) was 22.6% at 5 years compared to 1.7% among the 180 patients with a preop MRI (p=0.002). Patient age, number of sites of preoperative biopsy proven BC, HER2 status, pathologic T and N category were not statistically significantly associated with risk of LR. Conclusion The Z11102 clinical trial demonstrates that for women with MIBC breast conserving surgery with adjuvant radiation with lumpectomy site boosts has an acceptably low LR rate (3.2% at 5 years), making this a reasonable consideration for women with 2-3 ipsilateral foci. The LR rate was significantly higher in the small cohort of patients without preoperative breast MRI. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT01556243 Table 1: Factors associated with LR after BCT for MIBC Citation Format: Judy C. Boughey, Kari M. Rosenkranz, Karla V. Ballman, Linda McCall, Bruce G. Haffty, Laurie W. Cuttino, Charlotte D. Kubicky, H. T. Carisa Le-Petross, Kimberly Van Zee, Armando E. Giuliano, Olwen M. Hahn, Kelly K. Hunt, Lisa Carey, Ann Partridge. Impact of Breast Conservation Therapy on Local Recurrence in Patients with Multiple Ipsilateral Breast Cancer – Results from ACOSOG Z11102 (Alliance) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-01.

A phase I/II dose-escalation study of fractionated 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC) in patients with prior treatment with 177Lu-PSMA.

Abstract: TPS288 Background: As prostate-specific membrane antigen targeted radiotherapy (PSMA-TRT) is now an active standard-of-care treatment in mCRPC, ongoing studies with alternative approaches to targeting PSMA will increasingly need to consider the consequences of sequential PSMA-TRT exposure. Our past and ongoing investigations into antibody-based targeting (e.g., J591) and potent alpha emitting payloads (e.g., 225Ac) impact drug kinetics, biodistribution, and resultant clinical toxicities. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg without achievement of maximal tolerated dose (MTD). One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of Gr 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had Gr > 3 heme toxicity or Gr > 2 non-heme toxicity. Although not intentionally preselected for prior exposure, 55% (12/22) of patients had 177Lu-PSMA previously. With approval of 177Lu vipivotide tetraxetan, we amended an ongoing phase I dose-escalation study to include a post-177-Lu-PSMA cohort. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function, and prior receipt of AR pathway inhibitor and chemotherapy (or refused/ineligible). There is no limit to prior lines of therapy except alpha-emitting therapies (i.e., PSMA-TRT, 223Ra) and in this amended dose-escalation cohort, all patients must have had prior treatment with 177Lu-PSMA. Treatment will be given in a single fractionated cycle of 225Ac-J591 administered on D1 and D15. The phase I component is a 3+3 dose-escalation study design with up to 18 patients, with the goal of identifying MTD. The phase II component will include up to 16-19 patients in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG3-modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment to the post-177Lu-PSMA cohort began in August 2022. Clinical trial information: NCT04506567 .

Outcome of Patients With Malignant Peripheral Nerve Sheath Tumors Enrolled on Sarcoma Alliance for Research Through Collaboration (SARC) Phase II Trials.

Abstract: BACKGROUND Evaluation of prior phase II trials for malignant peripheral nerve sheath tumors (MPNST) may help develop more suitable trial endpoints in future studies. METHODS We analyzed outcomes of patients with recurrent or unresectable/metastatic MPNST enrolled on prior Sarcoma Alliance for Research through Collaboration (SARC) phase II trials and estimated the progression-free survival (PFS). PFS from SARC006 (NCT00304083), the phase II trial of upfront chemotherapy in chemotherapy naïve patients, was analyzed separately. Impact of baseline enrollment characteristics on PFS was evaluated. RESULTS Sixty-four patients (29 male, 35 female, median age 39 years (range 15-81)) with MPNST were enrolled on 1 of 5 trials of single agent or combination therapy that were determined to be inactive. Patients had received a median of 1 (range 0-5) prior systemic therapy, and most had undergone prior surgery (77%) and radiation (61%). Seventy-three percent had metastatic disease at enrollment. Median PFS was 1.77 months (95% CI, 1.61-3.45), and the PFS rate at 4 months was 15%. Greater number of prior systemic therapies and worse performance status were associated with inferior PFS. There was no significant difference in PFS based on age at enrollment, treatment trial, response criteria, presence of metastatic disease, disease site at enrollment, and prior surgery or radiation. In comparison, on the SARC006 trial the PFS rate at 4 months was 94% in 40 patients. CONCLUSION These data provide a historical baseline PFS that may be used as a comparator in future clinical trials for patients with MPNST.

Bolus versus Continuous Intravenous Delivery of Doxorubicin in Soft Tissue Sarcomas: Post Hoc Analysis of a Prospective Randomized Trial (SARC021/TH CR-406).

Abstract: PURPOSE Continuous intravenous infusion (CIV) of doxorubicin (DOX), versus bolus (BOL), may minimize dose-dependent DOX cardiomyopathy, but it is unclear whether this advantage is evident as employed in typical soft tissue sarcoma (STS) treatment. The impact of administration mode on adverse events (AEs) and efficacy were compared using data from a randomized trial of DOX-based therapy (SARC021/TH CR-406). EXPERIMENTAL DESIGN In this post hoc analysis, CIV vs. BOL was at discretion of the treating physician. Likelihood of AEs, and objective responses were assessed by adjusted logistic regression. Progression-free (PFS) and overall survival (OS) were compared using Kaplan-Meier, log-rank test, and adjusted Cox regression. RESULTS DOX was administered by BOL to 556 and by CIV to 84 patients. Proportions experiencing hematologic, non-hematologic or cardiac AEs did not differ by administration mode. Hematologic AEs were associated with age, performance status, and cumulative DOX. Non-hematologic AEs were associated with age, performance status, and cumulative evofosfamide. Cardiac AEs were only associated with cumulative DOX; there was no interaction between DOX dose and delivery mode. PFS and OS were similar (median 6.14 months BOL vs. 6.11 months CIV, p=0.47; mOS 18.4 months BOL vs. 21.4 months CIV, p=0.62). PFS, OS, and objective responses were not associated with delivery mode. CONCLUSIONS CIV was not associated with superior outcomes over BOL within DOX dosing limits of SARC021. Cardiac AEs were associated with increasing cumulative DOX dose. While not randomized with respect to DOX delivery mode, the results indicate that continued investigation of AE mitigation strategies is warranted.

Local Recurrence After Breast-Conserving Therapy in Patients With Multiple Ipsilateral Breast Cancer: Results From ACOSOG Z11102 (Alliance)

Abstract: PURPOSE Breast-conserving therapy (BCT) is the preferred treatment for unifocal breast cancer (BC). The oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC) has not been demonstrated in a prospective study. ACOSOG Z11102 (Alliance) is a phase II, single-arm, prospective trial designed to evaluate oncologic outcomes in patients undergoing BCT for MIBC. PATIENTS AND METHODS Women age 40 years and older with two to three foci of biopsy-proven cN0-1 BC were eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary end point was cumulative incidence of local recurrence (LR) at 5 years with an a priori rate of clinical acceptability of <8%. RESULTS Among 270 women enrolled between November 2012 and August 2016, there were 204 eligible patients who underwent protocol-directed BCT. The median age was 61 years (range, 40-87 years). At a median follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4). Patient age, number of sites of preoperative biopsy–proven BC, estrogen receptor status and human epidermal growth factor receptor 2 status, and pathologic T and N categories were not associated with LR risk. Exploratory analysis showed that the 5-year LR rate in patients without preoperative magnetic resonance imaging (MRI; n = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189; P = .002). CONCLUSION The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with disease evaluated with preoperative breast MRI.

Whole-food plant-based diet (WFPBD) to control weight and metabo-inflammation in overweight/obese men with prostate cancer (PC) receiving androgen deprivation therapy (ADT): A multi-center randomized control trial.

Abstract: TPS5098 Background: Obesity promotes a chronic inflammatory state that is associated with PC progression. ADT can cause significant side effects including weight gain, accumulation of body fat, insulin resistance, and an increased risk of diabetes and cardiovascular disease. A WFPBD has been shown to promote weight loss, decrease chronic inflammation, and shift gut microbial profiles to a microbiome that promotes insulin sensitivity. We hypothesize that a WFPBD and behavior intervention will promote weight loss and a reduction in adiposity in overweight/obese patients with PC on ADT and will decrease biomarkers of metabo-inflammation; and that a WFPBD, which is enriched in fiber, will modulate the fecal microbiota and metabolites, and alter study participants’ serum metabolome. Correlative studies will offer insight into the impact of nutrition on metabolic pathways that are known to be affected by PC, ADT and/or excess body fat, including steroid metabolism, ketogenesis, and fatty acid metabolism. Methods: Key eligibility criteria include pts with PC with a BMI ≥ 27 receiving ADT with an LHRH/GnRH analogue for >24 weeks pre-study (+ androgen receptor pathway inhibitor for >3 mos) with anticipation of >26 more weeks of ADT. 60 patients randomized 1:1 between two cohorts. Cohort 1: pts receive 12 prepared meals (provided by Plantable) per weeks 1-4 and 6 meals weeks 5-8 plus Plantable coaching, nutritional counseling and education to assist in self-prepping plant-based meals (weeks 9-26); Cohort 2 (control): pts receive general nutritional counseling from a Registered Dietician weekly for 8 weeks, then monthly x 4. Collection of baseline and serial measurements (pre-intervention, weeks 4, 8 and 26) including weight, serum carotenoid levels (to monitor dietary compliance), dual energy x-ray absorptiometry (DXA) scans, MnSOD polymorphisms, and biomarkers of inflammation and metabolism. The primary comparison is weight loss at 4 weeks (with an 80% power to detect an effect size 0.74 standard deviations with a 2-sided significance level of 0.05 using a two-sample t-test). Secondary objectives will assess and compare changes in: a) biomarkers of metabolic disorders (Hemoglobin A1c, fasting insulin/glucose) and cardiovascular risk (LDL cholesterol, HDL cholesterol, triglycerides); b) pro-inflammatory markers (IL-6, hsCRP) and adipokines (leptin, adiponectin); c) fecal microbiota; and d) quality of life measurements. Exploratory objectives will assess the effects of a WFPBD on serum and fecal metabolomics and on clonal hematopoiesis. Trial is open at Weill Cornell Medicine (WCM), John Hopkins University and Columbia University. First pt enrolled at WCM September 2022. Funding support from the Prostate Cancer Foundation; PC Clinical Trials Consortium c22-301. Clinical trial information: NCT05471414 .

SARC041: A phase 3 randomized double-blind study of abemaciclib versus placebo in patients with advanced dedifferentiated liposarcoma.

Abstract: TPS11587 Background: Recurrent or metastatic dedifferentiated liposarcoma (DDLS) remains a difficult disease to treat. Available agents such as doxorubicin, eribulin, trabectedin, ifosfamide, dacarbazine, or gemcitabine-based regimens are associated with low response rates and only modest improvements in progression free or overall survival. The oncogene CDK4 is ubiquitously amplified in this disease and represents a rational therapeutic target. In single-arm phase 2 studies, treatment with selective CDK4 inhibitors resulted in clinical benefit (12-week progression-free survival (PFS) of 57% with palbociclib and 74% with abemaciclib). We hypothesize that treatment with abemaciclib will improve PFS compared to placebo in patients with recurrent or metastatic DDLS. Methods: This is a phase 3 randomized double-blind study of abemaciclib versus placebo. Eligible patients have recurrent or metastatic dedifferentiated liposarcoma (purely well-differentiated liposarcoma excluded), progression of disease by RECIST 1.1 in the 6 months prior to study entry, any number of prior systemic therapies, and adequate organ function and performance status. Patients are stratified by number of prior lines of therapy (0 vs 1 or more) and randomized 1:1 between abemaciclib 200 mg PO twice a day and matching placebo. Patients are followed with scans every 6 weeks (every 12w after 36w) and those with progression of disease on placebo may cross over to open label abemaciclib. The primary endpoint is PFS. Target enrollment is 108 evaluable patients which provides 80% power with two-sided 10% significance level to detect a hazard ratio of 0.6. Secondary endpoints include response rate, PFS and response rate after crossover, and overall survival. Archival tissue will be collected to explore potential biomarkers. As of Feb 1, 2023, 43 patients have been accrued at 9 participating centers. Clinical trial information: NCT04967521 .

Effect of a telephone-based weight loss intervention (WLI) on weight at 12-months in women with early breast cancer: Results from the Breast Cancer Weight Loss (BWEL) trial.

Abstract: 12001 Background: Obesity is a poor prognostic factor in early breast cancer. The Breast Cancer Weight Loss (BWEL) trial (Alliance for Clinical Trials in Oncology A011401; NCT02750826) evaluates the impact of a WLI on invasive disease-free survival in breast cancer patients (pts) with a body mass index (BMI) ³27 kg/m2. Here we report the impact of the WLI on weight change. Methods: Eligible pts were within 14 months of diagnosis of stage 2-3 HER2-negative breast cancer, had completed chemotherapy and radiation (if administered), and were randomized 1:1 to a telephone-based WLI plus health education (HE) or an HE alone control group. The WLI was delivered by telephone-based health coaching and focused on caloric restriction and increased exercise. Height and weight were measured at baseline and 12 months. Changes in weight were compared between groups. Analysis was performed with univariable and multivariable (including arm, baseline weight, menopausal status, race/ethnicity, and hormone receptor [HR] status) regression models. A 0.05 level of significance was used. Results: 3181 women were randomized between 8/2016 and 2/2021. At baseline, mean BMI was 34.5 (±5.74) kg/m2, mean age was 53.4 (±10.58) years, and 57% of pts were postmenopausal at the time of diagnosis. 80.3% of participants were White, 12.8% were Black, and 7.3% were Hispanic. Follow-up weight was available from 2293 pts alive and disease-free at 12 months. The WLI led to a significant decrease in weight relative to controls; pts randomized to WLI lost an average of 4.8% (±7.9) of baseline body weight at 12 months vs. 0.8% (± 6.4) weight gain in controls (p<0.0001). Pts randomized to WLI experienced significant weight loss (vs controls) across demographic and tumor factors (Table). WLI effect differed significantly by menopausal status (interaction p value = 0.0057) and race/ethnicity (interaction p-value = 0.019), but not HR status (interaction p-value = 0.17). Conclusions: A telephone-based WLI induced significant, clinically meaningful weight loss in breast cancer pts with overweight and obesity across demographic and tumor factors. Additional tailoring of the WLI could be useful to enhance weight loss in Black and younger pts. Further follow-up of the BWEL trial will evaluate whether the WLI improves disease outcomes. Support: U10CA180821, U10CA180882, UG1CA189823; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02750826 . [Table: see text]

Association of tumor infiltrating lymphocyte quantity with survival in patients (pts) with metastatic breast cancer (MBC) receiving microtubule-targeting agents: Post hoc analysis CALGB 40502 (Alliance).

Abstract: 1010 Background: Stromal tumor infiltrating lymphocyte (sTIL) quantity is prognostic in primary breast cancer, yet MBC is characterized by lower sTILs. No study has definitively evaluated the association of sTIL quantity with survival outcome in the metastatic (met) setting without checkpoint blockade. CALGB (Alliance) 40502 was a randomized phase 3 trial of 799 MBC pts receiving first-line chemotherapy, comparing paclitaxel, nab-paclitaxel or ixabepilone with or without bevacizumab. We hypothesized that sTILs quantity is associated with outcome in MBC. Methods: 582 submitted hematoxylin and eosin slide images from 443 unique pts were evaluable for sTILs in accordance with International TILs Working Group methods. Analysis of sTILs was based on most recent available tissue, with 161/443 (36.3%) having recurrent/met tissue. Using prespecified thresholds of <5% (low) vs ≥5% (high) for sTIL distribution in the met setting, associations between sTILs low/high or as a continuous variable were evaluated with baseline characteristics and outcome. The primary objective was to evaluate the association of sTILs with progression-free survival (PFS) and overall survival (OS), with chemotherapy arm as a covariate. Results: High sTILs were more frequent among pts with hormone receptor (HR)-negative disease (64% HRneg vs 34% HRpos, p<0.001), with no significant association with treatment arm, age, menopausal status, race/ethnicity, or body mass index (BMI). Among all evaluable slides, mean sTILs were higher for primary tumors than met (mean 13.3% primary vs 8.4% met, p=3e-4). Among non-lymph node met sites, sTILs ranged from 1.3% (bone) to 9.5% (lung). Among 100 unique pts with paired primary and met slides, the primary had significantly greater mean sTILs (10.5% vs 7.7%, p=0.008). For the primary objective, Cox proportional hazard model of sTILs low vs high was significantly associated with worse PFS (HR 1.34; 95% CI 1.1-1.63, p=0.004) and OS (HR 1.32; 95% CI 1.07-1.63, p=0.009) when controlling for treatment arm. When controlling for both treatment arm and HR status, association of sTILs low vs high demonstrated similar trends but did not reach statistical significance for PFS (HR 1.2; 95% CI 0.97-1.47, p=0.09) or OS (HR 1.14; 95% CI 0.91-1.43, p=0.2). There was no significant interaction between sTILs and chemotherapy arm (all p-interaction >0.05). Conclusions: Immune activation measured by sTILs is significantly lower in met tumors than primary breast cancer and varies by met site. In this trial, sTILs were associated with progression-free and overall survival in chemotherapy-treated MBC, with a trend toward independent value adjusted for other prognostic features. Clinical trial information: NCT00785291 .

Radiation therapy and irreversible electroporation for intermediate risk prostate cancer (RTIRE).

Abstract: TPS403 Background: The objective of the RTIRE clinical trial (NCT05345444) is to demonstrate the feasibility, safety, and early oncologic efficacy of combining MRI-guided stereotactic body radiation therapy (MRgSBRT) with irreversible electroporation (IRE) for men with intermediate-risk localized prostate cancer. Methods: Inclusion criteria: 1) Men aged ≥18, 2) ECOG 0 –1, 3) Histologically confirmed intermediate risk prostate cancer per NCCN guidelines, 4) Focal grade group 2 (GG2) or 3 (GG3) cancer in multi-parametric magnetic resonance imaging (mpMRI) target, 5) Gland size < 80cc, 6) Ability to undergo IRE, 7) Ability to receive MRI-guided SBRT, 8) Ability to complete the HRQOL assessment surveys, 9) Willingness to undergo 12 month follow up biopsy. Exclusion criteria: 1) Prior TURP, 2) Prior history of focal therapy, 3) Prior history of receiving pelvic radiotherapy, 4) Patient with history of inflammatory bowel disease, 5) History of bladder neck or urethral stricture. Study Design/Endpoints: This is a feasibility and safety study assessing the ability to perform IRE followed by real-time MRgSBRT. Subjects will undergo focal IRE followed by MRgSBRT (>6 weeks after IRE) to the prostate +/- seminal vesicles prescribed to 32.5 Gy in 5 fractions. The primary endpoint of the first portion of the trial is feasibility, defined as at least 80% of subjects (8 of 10 subjects) undergoing assessment at 12-weeks post-IRE and at 6-weeks post-MRgSBRT within 1 year from enrollment of the first subject. The expansion phase will include an additional 40 subjects to assess side effect profile and early oncologic efficacy (n=50) at 12 months post RTIRE. RTIRE has enrolled 8 subjects in 3 months and will proceed to the expansion phase. Secondary endpoints include: 1) short-term safety as measured by treatment-related adverse events, 2) oncologic efficacy as measured by number of subjects with presence of ≥GG2 cancer at 12 months post-RTIRE therapy, 3) health-related quality of life (HRQOL) as measured by Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP), International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5) 4) post-RTIRE prostate-specific antigen (PSA) kinetics including time to PSA nadir and post-nadir PSA stability, 5) assessment of pre and post-RTIRE mpMRI changes to evaluate the area of necrosis and presence of residual tissue, 6) rates of biochemical and clinical progression and the need for secondary or adjuvant treatment following RTIRE. Clinical trial information: NCT05345444 .

Abstract CT014: Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer

Abstract: Background: PSMA-based targeted radionuclide therapy is now a standard of care for mCRPC since approval of 177Lu-PSMA-617. Use of antibodies (e.g., J591) to target PSMA with higher potency radionuclides (e.g., 225Ac) impacts kinetics, biodistribution, clinical efficacy, and toxicities. In our first-in-human ph I dose-escalation study of single dose 225Ac-J591 in patients with mCRPC, no MTD was reached (max dose 93.3 KBq/kg). Following this, we developed ph I/II parallel dose-escalation studies of fractionated (D1, D15) single cycle and multiple (q6w) dose regimens. Here we present safety data from the initial fractionated study in predominantly 177Lu-naive. Methods: Eligible patients had adequate organ function, ECOG performance status 0-2, and progressive mCRPC following potent AR pathway inhibitor (ARPI) and chemo (or unfit/refusing). Prior 177Lu-PSMA was allowed until an amendment developed a separate study for post-177Lu-PSMA. Baseline 68Ga-PSMA PET scans were performed, but not used to determine eligibility. A 3+3 dose-escalation design was used. Phase I primary objective: determination of dose-limiting toxicity (DLT) and recommended phase II dose (RP2D). DLT was defined as within 8 weeks of first dose: neutropenia (Gr 4 or febrile neutropenia), thrombocytopenia (TCP) (Gr 4, or Gr 3 with clinically significant bleeding), any Gr >2 non-hematologic toxicity deemed to be at least possibly related to 225Ac-J591, or any attributable toxicity precluding or delaying the second dose by >2 weeks. Secondary/exploratory objectives: efficacy measures (e.g., PSA decline, radiographic RR, biochemical/radiographic PFS, OS, CTCs, patient reported outcomes), safety (CTCAE v5), and correlatives (plasma and tissue genomics, PSMA imaging). Results: 24 patients were enrolled in phase I. Median age 73.5 (57-91), PSA 25.78 (3.39-2133.41); 53% (n=13) >1 prior ARPI, 58% (n=14) taxane chemo, 8% (n=2) anti-PSMA therapy, 12.5% (n=3) prior 223Ra. CALGB prognostic groups: Good 4 (16%), Intermediate 8 (33%), Poor 12 (50%). No DLTs were observed in Cohort 1 (n=3) or 2 (n=6). In C3, 2/6 subjects experienced DLTs (Gr 3 weakness, Gr 2 TCP with >2 week delay in second fraction). 8 patients were enrolled in an intermediate dose cohort (2.5) with 1 DLT (Gr 4 TCP). Two patients withdrew before the second dose (intercurrent illness; interruption of 225Ac supply). Most common low gr non-hematologic treatment emergent AEs: fatigue (95%), xerostomia (69%), and nausea (57%). Among evaluable patients for PSA change (n=22), 21 (95%) experienced PSA decline with 14 (67%) with decline of 50% and 6 (37%) with decline of 90%. 13/21 patients had CTCs samples collected at baseline and 12 wks; 5 were unfavorable at baseline (≥5/7.5 mL); 10/13 (77%) remained favorable or converted from unfavorable to favorable; 6/12 (50%) had 50% decline in CTC count; and 5/13 (38%) converted from detectable to undetectable. Conclusions: A single fractionated cycle of 225Ac-J591 was delivered with few high grade AEs and with evidence of preliminary efficacy by PSA and CTC changes across all dose levels. Citation Format: Jones T. Nauseef, Michael Sun, Charlene Thomas, Mahelia Bissassar, Escarleth Fernandez, Zachary Davidson, Amie Patel, Angela Tan, Tessa A. Chamberlain, Kara Earle, Rebecca Wunder, Sabrina Guervil, Sandra H. Castellanos, Judith Stangl-Kremser, Peter S. Gregos, Joseph R. Osborne, Karla V. Ballman, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Neil H. Bander, Scott T. Tagawa. Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT014.

Alliance A032002 (ART): Phase II randomized trial of atezolizumab versus atezolizumab and radiation therapy for platinum-ineligible/refractory metastatic urothelial cancer.

Abstract: TPS589 Background: In patients (pts) with metastatic unresectable urothelial cancer, platinum-based chemotherapy remains the standard of care for first-line treatment followed by switch maintenance avelumab if disease control is achieved with chemotherapy. Outside of this setting, single agent immunotherapy is often used in pts that have recurrence after platinum-based chemotherapy or are platinum ineligible. Atezolizumab is a PD-L1 inhibitor currently approved for pts that have urothelial cancers expressing positive PD-L1 or pts ineligible for receiving platinum-based chemotherapy. Tumor-targeted radiotherapy can generate immune-stimulating effects without immune suppression as was previously thought. Moreover, it has become clear that radiotherapy can induce profound effects on tumor cells and the tumor microenvironment that can enhance or trigger an anticancer immune response. While numerous trials have investigated the abscopal effect, this trial will have specific parameters regarding drug type, radiation dose and administration. Methods: A032002 is a phase 2 trial addressing pts that are platinum ineligible or refractory to platinum-based chemotherapy. 144 pts will be randomized to receive either atezolizumab or atezolizumab and single site radiation therapy. The atezolizumab regimen is 1200 mg every 3 weeks. Administration of radiotherapy will occur to one non-target site (8 Gy x 3) for pts randomized to the atezolizumab + radiotherapy arm. All pts will undergo centralized PD-L1 testing (SP142 monoclonal primary antibody), which can be performed on archival tissue; a new biopsy is only required if no archival tissue is available. Key eligibility criteria include age ≥ 18 years, ECOG performance status 0-2, histologically confirmed metastatic urothelial cancer, having at least one measurable site per RECIST 1.1 to monitor for abscopal response, one site targetable for radiation, and tissue available for PD-L1 testing. The primary endpoint is tumor response within 6 months of randomization. Tumor response is defined as a complete response (CR) or partial response (PR) as assessed by the treating physician using RECIST 1.1 criteria. For a one-sided log rank test with a type 1 error rateof 0.10, the study has 90% power to detect a 20% increase in response rate. Key secondary endpoints include tumor response using iRECIST, progression-free survival and overall survival. Quality of life assessments include EORTC QLQ-C30, QLQ-BLM30 and PROMIS-Fatigue. Tissue, urine and blood samples will be collected and biobanked for future correlative science. Enrollment to ART began in December 2021. The study is available for participation at all US NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882. Clinical trial information: NCT04936230 .

Randomized, double-blinded phase II study of ketoconazole (keto), hydrocortisone (HC), and anti-PSMA antibody J591 labeled with 177Lu or 111In in patients (pts) with high-risk non-metastatic (met) castration-resistant prostate cancer (M0 CRPC).

Abstract: LBA21 Background: Up to 1/3 of pts develop biochemical relapse following primary therapy. Many are not cured with salvage local therapy, likely because of undetectable distant disease. PSMA is expressed on most PC and can be targeted by radiolabeled J591. 177Lu is a predominantly β-emitting radionuclide and also has γ emission which allows imaging. 111In is predominantly a γ emitter, also with some auger emission for therapy. Hormonal therapy is effective and may increase PSMA expression and radiosensitize. In this DOD-funded study initiated in the pre-PSMA PET and AR signaling inhibitor era, we hypothesized that 177Lu prolongs 18-month (mo) met-free survival (MFS) more than 111In in pts with high risk, M0 CRPC when targeting PSMA via J591 in combo with keto and HC. Methods: Pts with high-risk M0 CRPC defined by PSA DT < 8 mo and/or absolute PSA > 20 ng/mL and serum testosterone < 50 ng/mL with no evidence of metastatic disease on CT/MRI and bone scan were eligible. Treatment included a minimum 4 week lead-in with keto 400 mg TID and HC 20 mg AM, 10 mg PM (both of which could be continued until unacceptable toxicity or development of mets) and a single infusion of J591 with 2:1 randomization to 177Lu (70 mCi/m2) or 111In (5 mCi) in double-blinded fashion. The final version of the protocol was designed to randomize 55 pts for 80% power to detect a difference in 18-mo MFS with one-sided alpha of 10%. Secondary endpoints include median MFS, PSA response, overall survival, and toxicity. Results: 55 pts with median age 68 (range 52 - 88), 75% prostatectomy, 23% primary radiation, 2% primary ADT; 19% local salvage therapy. Median PSA doubling time 3 mo (range 0.87 – 7.85), median baseline PSA 8.0 (range 1-78). In intent to treat analysis (5 without imaging and 4 lost to follow up by 18 mo), 50% developed mets by 18 mo with 177Lu vs 76% with 111In (p=0.066). Median MFS was 23.8 mo vs 20.8 mo, and biochemical PFS was 18.67 vs 8.87 mo, favoring 177Lu in analyses censoring start of new treatment. Confirmed >50% PSA decline occurred in 82% with 177Lu and 71% with 111In. Grade >3 heme AEs were more common with 177Lu vs 111In, including neutropenia (57% vs 11%, with 1 febrile neutropenia) and thrombocytopenia (77% vs 11%, with 25% vs 6% platelet transfusions), whereas Gr >3 non-heme AEs were less common with 177Lu vs 111In, including abdominal pain (0 vs 11%), ALT increase (3.3% vs 22%), and diarrhea (0 vs 22%). Conclusions: Anti-PSMA mAb J591 with keto/HC when radiolabeled with 177Lu leads to improved 18-month met-free survival vs 111In. Most pts had significant PSA decline with either version of radiolabeled J591 with keto/HC. Hematologic toxicity is more common with 177Lu. This supports the development of anti-PSMA radioimmunotherapy for low volume advanced PC, though the optimal radionuclide and targeting agent is unknown. Clinical trial information: NCT00859781 .