Study Design of a Phase 2 Trial of the Aldosterone Synthase Inhibitor BI 690517 Alone and in Combination With Empagliflozin in Patients With Diabetic and Non-Diabetic CKD

Elevated aldosterone levels are strongly associated with chronic kidney disease (CKD) progression. BI 690517 is an aldosterone synthase inhibitor that may reduce the deleterious mineralocorticoid receptor-dependent and -independent actions of aldosterone. Disruptions to aldosterone signalling increase the risk of hyperkalaemia, which may be mitigated by the addition of sodium–glucose cotransporter-2 inhibitors such as empagliflozin (EMPA). Thus, BI 690517 and EMPA may have a favourable safety profile and synergistic kidney protective activity.This randomised, double-blind, placebo-controlled, parallel-dose Phase II trial (NCT05182840) will enrol ≥552 adults with CKD with or without type 2 diabetes; this will provide 90% power to detect a ≥15% change in urine albumin:creatinine ratio measured in first morning void urine (UACRFMV) with a one-sided 5% α at Week (W) 14. Eligible patients will have an estimated glomerular filtration rate (eGFR) ≥30 and \u3c90 mL/min/1.73 m2, UACR ≥200 and \u3c5000 mg/g, serum potassium ≤4.8 mmol/L and be receiving with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.Following an 8-week run-in period to assign background medication (EMPA 10 mg or matched placebo randomised 1:1), patients will be randomised 1:1:1:1 to receive BI 690517 (low, medium, or high dose) or matched placebo for 14 weeks (Figure).The primary endpoint is change in UACRFMV from baseline to W14. Secondary endpoints are the proportion of patients with ≥15% and ≥30% decrease from baseline in UACRFMV at W14. Further endpoints include safety findings and change from baseline in eGFR and serum potassium at W14.The trial is recruiting in 30 countries and 117 patients have been enrolled to date

381 Intratumoral oncolytic virus V937 plus ipilimumab in patients with advanced melanoma: the phase 1b MITCI study

Background Intratumoral administration of V937, a bioselected genetically unmodified Coxsackievirus A21, has shown antitumor activity both as a monotherapy and in combination with the anti–PD-1 antibody pembrolizumab.1–3 V937 induces lytic tumor cell infection and upregulation of members of immune checkpoint pathways.2 We present the results from the phase 1b MITCI study that evaluated V937 plus ipilimumab for advanced melanoma. Methods Eligible patients had unresectable or metastatic stage IIIB/C or IV melanoma amenable to intratumoral injection. Patients received intratumoral V937 3×108 TCID50 on days 1, 3, 5, 8, and 22, then Q3W for 14 more injections plus intravenous ipilimumab 3 mg/kg Q3W administered 4 times starting on day 22. Imaging was done Q6W beginning at day 106; response was assessed per immune-related response criteria (irRC). The primary endpoints were safety and ORR in the overall population and in patients whose disease progressed on prior anti–PD-1 therapy. Results 50 patients were enrolled and received ≥1 dose of study treatment. At data cutoff (February 21, 2020), all had discontinued the study and study therapy. Median (range) age was 64.5 (28–88) years. Fourteen patients (28%) had stage III disease. Forty patients (80%) had received prior systemic treatment, 33 of whom had received anti–PD-1 therapy. The median number of cycles of ipilimumab was 4 (range, 1–4), and the number of intratumoral injections of V937 was 9 (range, 5–19). Among the 94% of patients who had ≥1 treatment-related AE, 14% had grade 3/4 treatment-related AEs, none of which were considered related to V937. The most common grade 3/4 treatment-related AEs were dehydration, diarrhea, and hepatotoxicity (4% each). No grade 5 treatment-related AEs occurred. The most common treatment-related AEs were pruritus (50%), fatigue (44%), diarrhea (32%), and nausea (22%). Efficacy outcomes for the overall population and by prior anti-PD-1 therapy use are presented in table 1. Tumor regression was observed in injected and noninjected lesions. VIEW INLINE VIEW POPUP DOWNLOAD POWERPOINT Abstract 381 Table 1 Conclusions V937 plus ipilimumab was safe and the toxicities were manageable and consistent with that anticipated for the individual treatment components. ORR was robust and significantly higher than anticipated with ipilimumab monotherapy, including in patients who had received prior anti–PD-1 therapy. Most responses were durable (≥26 weeks), and responses seen in noninjected metastases provided evidence of probable systemic immune activation. The combination of V937 plus ipilimumab warrants further investigation in a larger trial in patients with advanced melanoma. Acknowledgements Medical writing assistance was provided by Kathleen Estes, PhD, of ICON plc (North Wales, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Trial Registration NCT0230714

A Pilot Study to Assess the Integration of a Unique PROQOL Tool and Early Palliative Care Intervention in the Care of High Grade Glioma Patients and their Caregivers (2633)

Objective: Appraise the feasibility of a novel patient reported outcomes (PRO) quality of life (QOL) tool administered by smart device in routine office visits (OV) and of early integration of palliative care (PC) for pwHGG and caregivers to improve QOL for both. Background: Early involvement of palliative care (PC) in patients with metastatic cancer has been associated with improved quality of life (QOL). Patients with high grade glioma (pwHGG) and their caregivers have unique needs such that similar results are anticipated in this population but cannot be extrapolated. Recognizing that pwHGG often require a caregiver early in the course of disease, this patient population also experiences significant personal and caregiver distress that has been given limited attention and resources. Design/Methods: Prospective, single-center cluster-randomized pilot conducted for 6 months during completion of adjuvant therapy for newly diagnosed high grade glioma. After informed consent was obtained, 15 pwHGG and their caregivers were randomized to: routine OV with basic QOL survey; OV with PROQOL; or PC consultation, in addition to OV with PROQOL. Results: All clusters have completed the study at this time. Two elderly patients with declining performance status transitioned to hospice after initial visit, two moved out of state prior to adjuvant visits, one withdrew due to appointment burden and one withdrew after an infection complication. The PROQOL appears to be easily integrated into OV without significant patient, caregiver, or provider burden. Providers confirmed utility in prioritizing symptoms and concerns. Thus far, it appears that patients (and caregivers) appeared to benefit from the PROQOL and PC support as evidenced by longitudinal improvement in QOL scores over the control group. Conclusions: A unique PROQOL tool and early PC may be easily integrated into practice, and may improve the QOL of pwHGG and their caregivers. Challenges include appointment burden and costs related to PC

Longitudinal Perception of Prognosis of Patients with High Grade Glioma Compared to their Caregivers and Clinicians (2588)

Objective: Evaluate the longitudinal perception of prognosis of patients compared to their caregivers and their providers during the adjuvant treatment of newly diagnosed high grade glioma. Background: Treatment options and prognosis are limited for patients with high grade glioma (pwHGG), underscoring the importance of patient and caregiver understanding to prioritize goals of care and quality of life (QOL). Although addressed by multiple providers, patients and caregivers may experience discordance in understanding the prognosis. This may be related to patient/caregiver perception, cognitive decline as a result of the tumor and/or treatment, or failure by the clinician to clearly articulate this information under emotional circumstances. Design/Methods: After IRB approval, 16 pwHGG, their caregivers and their providers reported an overall survival estimate at each monthly visit during adjuvant treatment, as part of a larger survey. Options included “weeks,” “weeks to several months,” “several months to years,” “indefinite number of years”, or “I do not wish to answer.” Results: The majority of the patient/caregiver clusters have completed the study with estimated closure in November 2019. The perception of the patient differs from the caregiver at almost each visit. Regardless of the counseling provided by provider, the perception of both tends to change at each visit and can vary from dismal to overtly optimistic. There does not appear to be dramatic discrepancy between the neuro-oncology and palliative care provider’s perception of prognosis. Conclusions: Newly diagnosed pwHGG and caregivers vary in their perception of prognosis, deviating not only from each other but also differing at each visit throughout the course of their illness. The providers’ perception appeared to remain consistent but often varied from that of the patient and caregiver. Providers need to be aware that prognostic understanding appears to fluctuate throughout the course of illness and cannot be clarified via a single discussion. Disclosure: Dr. Sharma has nothing to disclose. Dr. Wolfe has nothing to disclose. Dr. Barrera has nothing to disclose. Dr. Williamson has nothing to disclose. Dr. Farfour has nothing to disclose. Dr. Mrugala has received research support from Arbor Pharmaceuticals. Dr. Edwin has nothing to disclose. Dr. Sloan has nothing to disclose. Dr. Porter has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Boston biomedical data safety monitoring board

3380 / 8 - Seven autoantibody panel, validated in two independent patient serum collections, can detect women with DCIS and invasive breast cancer

Mammography is essential to identify early breast cancer but the sensitivity is dependent on breast characteristics. A serum-based biomarker used along with mammography to identify lesions that need to be biopsied may improve the sensitivity of mammography and reduce the number of biopsies needed. We have identified a panel of autoantibodies found in early breast cancer. An autoantibody biomarker is ideal because antibody immunity can be detected with very low levels of antigen with direct antigen recognition by B cells resulting in clonal amplification of antigen specific plasma cells. Work in our laboratory has identified tumor-associated proteins present in pre-malignant tumors that are necessary for survival of human breast cancer cells across breast cancer subtypes. Increased autoantibodies to seven of these early tumor-associated proteins (PDIA6, KRT8, SERBP1, ARPC2, RRM2, AURKA, and NDC80) were present in the sera of women with DCIS and invasive breast cancer in two independent serum collections but not in control women with no known breast lesions.The presence of autoantibodies in the discovery set was evaluated in 185 individuals: 42 control women, 12 women with hyperplasia, 36 patients with fibroadenoma, 59 patients with ductal carcinoma in situ (DCIS), and 36 patients with invasive breast cancer (IBC). The validation set was evaluated in 228 individuals: 50 control patients, 50 patients with fibroadenoma, 18 patients with hyperplasia, 50 patients with DCIS, and 60 patients with IBC, 20 with hormone receptor positive (HR+) HER2 negative, 20 with HER2+, and 20 triple negative (TN). We defined a positive autoantibody response as over 2 standard deviations above the mean found in control women. All seven autoantibodies could predict patients with hyperplasia, fibroadenoma, DCIS, and IBC in both the discovery and validation sets. For example, the seven-antibody panel could identify DCIS from control women with AUC of 0.95 (95% CI 0.912 to 0.995, p\u3c0.0001) and validation set AUC 0.63 (95% CI 0.52 to 0.74, p=0.026). The seven-antibody panel could identify IBC from control women with AUC of 0.85 (95% CI 0.73 to 0.97, p\u3c0.0001) and validation 0.70 (95% CI 0.60 to 0.79, p\u3c0.0001). Furthermore, the seven-antibody panel could identify women with each of the breast cancer subtypes as compared to control women. Women with HR+HER2- breast cancer could be detected with AUC 0.69 (95% CI 0.55 to 0.83 p=0.014), women with HER2+ breast cancer could be detected with AUC 0.69 (95% CI 0.52 to 0.90, p=0.02), and women with triple negative breast cancer could be detected with AUC 0.69 (95% CI 0.55 to 0.83, p=0.002) in the validation set. Future studies will evaluate this panel in a prospective study at the time of mammography to identify a serum biomarker that will improve sensitivity of mammography

2166 / 8 - Analysis of ctDNA next generation sequencing (NGS) for predicting response to amivantamab and lazertinib among patients with EGFR-mutant NSCLC after progression on osimertinib and platinum-based chemotherapy (CHRYSALIS-2 Cohort A)

Background: Among post-osimertinib (osi), chemotherapy-naïve patients (pts) treated with amivantamab (ami) and lazertinib (laz) in CHRYSALIS Cohort E, NGS of baseline ctDNA and tumor tissue revealed pts with identified EGFR/MET-based resistance (eg, EGFR C797S or MET amplification) were slightly more likely to respond versus those without EGFR/MET-based resistance (ORR=47% vs 29%), but about half of responders had unknown resistance mechanisms (Bauml JCO 2021; 39:15_suppl, 9006). In CHRYSALIS-2 Cohort A (NCT04077463), ami + laz demonstrated an ORR of 33% in the post-osi and platinum-based chemotherapy population (Shu JCO 2022; 40:16_suppl, 9006). This analysis investigated whether EGFR/MET-dependent resistance by ctDNA correlated with response.Methods: Cohort A examined ami + laz in EGFR exon19del or L858R mutated advanced NSCLC whose disease progressed on osi as well as platinum-based chemotherapy. ORR was verified through blinded independent central review. Plasma samples were collected prior to treatment; ctDNA was analyzed by Guardant360.Results: A total of 162 pts were enrolled; of these, 110 (68%) had analyzable ctDNA data, with most common mutations observed in EGFR and TP53. Twenty-eight (25%) pts had resistance categorized as EGFR/MET-dependent and 31 (28%) as EGFR/MET-independent; no genetic resistance mechanism was identified in 51 (46%). The ORRwas 29% and 26% in EGFR/MET-dependent and independent pts, respectively. ORR in pts with an unknown resistance mechanism was 39% (Table).Conclusions: Among pts who progressed on osi and platinum-based chemotherapy, genetic profiling of osi resistance by ctDNA did not predict response, with many responders having unknown resistance mechanisms. These results suggest alternative biomarker approaches are needed to identify pts most likely to benefit from ami + laz. Table. ORR by type of resistance mechanism Resistance mechanism n PR ORRa EGFR/MET-dependentb 28 8 29% EGFR/MET-independent 31 8 26% Unknown 51 20 39% All patients 110 36 33% aResponses were assessed by blinded independent central review per RECIST v1.1. bIncludes co-occurring ‘independent’ resistance mechanisms. EGFR, epidermal growth factor receptor; MET, mesenchymal epithelial transition factor; ORR, objective response rate; PR, partial response