5019 Background: In TALAPRO-2, talazoparib (TALA) + enzalutamide (ENZA) significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) vs ENZA + placebo (PBO) in patients (pts) with mCRPC harboring HRRm assessed prospectively. Here we report exploratory biomarker analyses which assessed HRR by gene subgroup and potential associations with efficacy in pts enrolled in the HRR-deficient cohort from TALAPRO-2. Methods: Pts were randomized 1:1 to TALA 0.5 mg (N=200) or PBO (N=199) + ENZA 160 mg QD. HRRm testing used a 12-gene HRR panel (HRR12; clinical trial assays based on FoundationOne CDx and FoundationOne Liquid CDx). HRRm status categorization by gene incorporated all available tumor and prescreening/screening ctDNA records using an algorithm similar to that previously used by others (Fallah et al, JCO 2024 PMID: 38484203). For non- BRCA gene analyses, pts with co-occurring BRCA1/2 alterations were excluded. For BRCA1 , pts with co-occurring BRCA2 alterations were excluded. The efficacy endpoints assessed were overall response rate (ORR), rPFS, and OS. Data cutoff Sept 3, 2024. Results: For all HRRm pts, TALA + ENZA was superior to ENZA + PBO across all efficacy endpoints: ORR, 69.4% vs 39.1% (odds ratio [OR], 0.28 [95% CI, 0.13–0.61]); rPFS, median 30.7 vs 12.3 months (mo) (hazard ratio [HR]=0.47 [0.36–0.62]); OS, median 45.1 vs 30.8 mo (HR=0.60 [0.46–0.78]). TALA + ENZA vs ENZA + PBO demonstrated benefit for BRCA2m across endpoints: ORR, 86.4% vs 31.0% (OR, 0.07 [95% CI, 0.01–0.35]); rPFS, median not reached (NR) vs 10.9 mo (HR=0.25 [0.15–0.42]); OS, median NR vs 28.5 mo (HR=0.47 [0.29–0.76]). Similar rPFS and OS benefit was seen for BRCA1m and PALB2m (allowing for small n in the groups); for ORR, evaluable n of 8 across arms for each gene was too low to meaningfully assess ORR differences. Benefit for TALA + ENZA was also evident for CDK12m : ORR, 63.6% vs 22.2% (OR, 0.16 [95% CI, 0.01–1.61]); rPFS, 19.3 vs 13.8 mo (HR=0.36 [0.19–0.70]); OS, 36.4 vs 22.8 mo (HR=0.41 [0.23–0.74]). ATMm also showed benefit for TALA + ENZA: ORR, 75.0% vs 33.3% (OR, 0.17 [95% CI, 0.02–1.32]); rPFS, 30.4 vs 18.3 mo (HR=0.66 [0.37–1.18]); OS, 45.1 vs 39.5 mo (HR=0.70 [0.38–1.29]). CHEK2m showed modest overall benefit for TALA + ENZA: ORR, 53.3% vs 42.9% (OR, 0.66 [95% CI, 0.07–5.59]); rPFS, 24.8 vs 18.3 mo (HR=0.65 [0.34–1.22]); OS, 34.2 vs 39.5 mo (HR=0.96 [0.51–1.81]). The remaining six HRR12 genes could not be meaningfully assessed for efficacy benefit by gene with TALA + ENZA vs ENZA + PBO due to low mutational prevalence. Conclusions: An efficacy benefit was evident for TALA + ENZA vs PBO + ENZA across multiple mutational subgroups assessed by gene, and was most pronounced for the BRCA1-PALB2-BRCA2 axis and CDK12 , with benefit also apparent for ATM . Analyses of additional efficacy endpoints are planned and will be presented. Clinical trial information: NCT03395197 .

IntroductionTumor acidity is emerging as a hallmark of cancer and carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) expression is frequently increased in acidic tumors. L-DOS47, a novel antibody-drug conjugate (ADC), consists of jack bean urease cross-linked to anti-CEACAM6 nanobodies. L-DOS47 is thus both targeted to CEACAM6-expressing tumors and designed to improve tumor control by neutralizing the acidic tumor microenvironment (TME) through ammonia and bicarbonate production from local urea.MethodsThis open-label, non-randomized study evaluated safety and tolerability of L-DOS47 in Stage IIIB/IV non-small cell lung cancer (NSCLC) patients. The Phase I 3 + 3 dose escalation aimed to determine the maximum tolerated dose (MTD) of L-DOS47 administered once/week over 14 days followed by seven days rest. Phase II explored twice-weekly dosing.Results55/90 patients enrolled in Phase I received L-DOS47 up to 13.55 μg/kg. Although one dose-limiting toxicity (DLT) occurred in a patient at 5.76 μg/kg, MTD was not reached. Common treatment-emergent adverse events (TEAEs), reported by 38% of patients, were respiratory/thoracic/mediastinal disorders including dyspnea. No complete (CR) or partial responses (PR) were observed in Phase I or Phase II, despite the latter’s intensified dosing regimen; however, Phase I post-hoc exploratory analyses found that progression-free survival (PFS) was significantly extended at doses ≥5.76 μg/kg (P=0.0203). Anti-L-DOS47 antibody (ADA) titers were not associated with AE or shorter PFS. Immunohistochemistry (IHC) screening of an unrelated cohort revealed high CEACAM6 expression in 45.2% NSCLC cases.ConclusionsL-DOS47 monotherapy was well tolerated at doses up to 13.55 μg/kg. No CRs or PRs were observed but extended PFS was associated with higher doses. Screening for CEACAM6 expression may select patients who are more likely to derive benefit from L-DOS47.Clinical Trial Registrationhttps://www.clinicaltrialsregister.eu/ctr-search/search; EudraCT Identifier: 2010-020729-42 (May 6, 2010).

LBA18 Background: The Phase 3 TALAPRO-2 trial met its primary endpoint, showing improved radiographic progression-free survival (rPFS) for TALA + ENZA vs placebo (PBO) + ENZA as 1L treatment in pts with mCRPC unselected for homologous recombination repair (HRR) gene alterations (all-comers; cohort 1). Here we report final OS data, a descriptive update of rPFS, and extended safety follow-up in cohort 1. Methods: In cohort 1, pts were randomized 1:1 to ENZA 160 mg + either TALA 0.5 mg (0.35 mg if moderate renal impairment) or PBO once daily and stratified by prior abiraterone or docetaxel (yes/no) for castration-sensitive PC and HRR gene alteration status. Key eligibility criteria included asymptomatic or mildly symptomatic mCRPC, ECOG PS ≤1, ongoing androgen deprivation therapy, and no prior life-prolonging therapy for CRPC. The primary endpoint was rPFS by blinded independent central review. OS was an alpha-protected key secondary endpoint. For statistical significance at the final OS analysis, the stratified log-rank 2-sided P value needed to be ≤0.022 using a group sequential design with O’Brien-Fleming spending function. Results: Overall, 805 pts were randomized, 402 to TALA+ENZA and 403 to PBO+ENZA. At data cutoff (Sept 3, 2024), 211 pts (52%) in the TALA + ENZA arm and 243 pts (60%) in the PBO + ENZA arm had died; median follow-up was 52.5 and 53.0 months, respectively. Hazard ratio (HR) for OS with TALA + ENZA vs PBO + ENZA was 0.796 (95% CI, 0.661–0.958; 2-sided P =0.0155); median OS (95% CI), 45.8 months (39.4–50.8) vs 37.0 months (34.1–40.4 months), respectively. In prespecified subgroup analyses, OS favored TALA + ENZA vs PBO + ENZA in pts who were HRR-deficient (n=169; HR, 0.549; 95% CI, 0.364–0.826; P =0.0035) or HRR–non-deficient/unknown (n=636; HR, 0.878; 95% CI, 0.713–1.080; P =0.218). In exploratory analyses of pts with results available for both circulating tumor DNA and tumor tissue, OS favored TALA + ENZA vs PBO + ENZA in pts without BRCA1/2 alterations (n=439; HR, 0.749; 95% CI, 0.582–0.963; P =0.024) and in pts without HRR alterations (n=314; HR, 0.782; 95% CI, 0.582–1.050; P=0.101). Consistent with the primary analysis, updated rPFS data favored TALA + ENZA vs PBO + ENZA (HR, 0.667; 95% CI, 0.551–0.807; P <0.0001); median rPFS, 33.1 vs 19.5 months, respectively. Consistent with primary results, the most common grade ≥3 TEAEs with TALA + ENZA were anemia (49%) and neutropenia (19%). TEAEs were generally manageable; 86 pts (22%) discontinued TALA due to TEAEs. Conclusions: TALA + ENZA demonstrated a statistically significant and clinically meaningful improvement in OS vs standard-of-care ENZA as 1L treatment in pts with mCRPC unselected for HRR gene alterations. rPFS continued to favor TALA + ENZA. No new safety signals were identified with extended follow-up. Clinical trial information: NCT03395197 .

Introduction:Discrepancies between preclinical tests and clinical results raise serious concerns about the appropriateness of the current methodologies. In particular, cell biology approaches neglect fundamental physical parameters despite their relevance to in vivo conditions. Oxygen availability is critical for cell reactions; thus, the lack of consideration of hypoxia as the main regulator of the tumor microenvironment (TME) leads to misinterpreted data with consequences for translational applications. In this study, we show that mitomycin C (MMC), an antineoplastic antibiotic, is rarely used in ovarian cancer (OC) treatment despite its potential efficacy; we use MMC as an example of a treatment that warrants reevaluation under microenvironmental conditions, particularly during in vitro testing. Methods:To evaluate the effects of MMC and oxygen tension (pO2) on OC cells (SKOV3), HTA 2.0 microarrays were used, which demonstrated that hypoxia and MMC induced transcriptomic changes in OC cells. Their combination particularly emphasized the effect of pO2 modification on MMC activity. The most significant findings were verified in three other OC cell lines, namely, TOV112D, ES-2, and A2780. Results:Under normoxic conditions, MMC mostly affected several pathways associated with ribosome-related processes, whereas under hypoxic conditions, it induced modifications in the extracellular matrix (ECM). The most significantly upregulated gene in response to hypoxia-MMC treatment was MMP1, regulated by both MMC and hypoxia. Low pO2 levels during MMC treatment allowed the identification of important regulators, such as SPP1, and the corresponding processes, including cholesterol biosynthesis. Conclusion:Hypoxia modulated the effects of MMC on OC cells and identified genes that may serve as promising targets to enhance the effectiveness of MMC treatment.

2610 Background: Immune checkpoint inhibitor (ICI) monotherapy has shown limited activity against advanced EGFR mut NSCLC. However, combinatorial approaches may enhance the clinical outcomes and are under evaluation. AFM24 is a tetravalent, bispecific ICE that binds CD16A on NK cells and macrophages and EGFR on solid tumors, redirecting and enhancing immune responses towards EGFR-expressing tumors. Atezolizumab, an anti-PD-L1 antibody, has been approved in patients with various solid tumors. The EGFR mut NSCLC expansion cohort of this Phase 1/2a study explores a possible synergistic effect of AFM24 in combination with atezolizumab in heavily pretreated patients with NSCLC EGFR mut (NCT05109442). Methods: AFM24 is given weekly at 480 mg intravenously (IV) in combination with 840 mg atezolizumab IV fortnightly to patients with advanced or metastatic EGFR mut NSCLC who progressed on ≥1 prior line of therapy, including ≥1 prior TKI. The primary endpoint is overall response rate (ORR) by RECIST v1.1 by Investigator assessment. Secondary endpoints include safety, pharmacokinetics, and immunogenicity. Treatment is given in 28-day cycles until disease progression, intolerable toxicity, investigator discretion, or patient withdrawal of consent. Results: As of 15 January 2025, 28 patients received AFM24 and atezolizumab for a mean (range) duration of 21.7 (2–65) weeks. Median (range) age is 65 years (32–83); 67.9% were female. All patients had received prior EGFR- specific TKI, 82% had received platinum-based chemotherapy and 75% 3 rd gen TKIs. Patients received a median (range) of 3 (1–8) prior lines of treatment. The combination was well tolerated with no new or unexpected toxicities observed compared to each single agent. The most common treatment-related adverse events (TRAE) were infusion-related reactions in 64% of patients (19 Grade 1–2, 1 Grade 3). 9 patients had ≥G3 TRAEs, the most common being neutropenia/neutrophil count decrease, with no associated infections. No other immune TRAEs were reported. The 22 response-evaluable patients achieved an ORR of 23% (1 CR, 3 PRs, 1 unconfirmed PR), a DCR of 64% and tumor shrinkage in 50% of patients. Responses were deepening over time in 3 patients. With a median follow-up of 9 months, the median PFS was 5.5 months (95% CI 1.9–not-evaluable). 6 (27%) patients have received treatment for over 10 months. Conclusions: AFM24 combined with atezolizumab demonstrated encouraging clinical efficacy in patients with EGFR mut NSCLC who had exhausted prior lines of therapy. Treatment showed a well-managed safety profile. This approach potentially offers a feasible, chemotherapy-free therapeutic option for the EGFR mut NSCLC patients who have progressed to prior TKIs and platinum-based chemotherapy and warrants further evaluation. Clinical trial information: NCT05109442 .

Right ventricular (RV) function and eventually failure determine outcome in patients with pulmonary arterial hypertension (PAH). Initially, RV responds to an increased load caused by PAH with adaptive hypertrophy; however, eventually RV failure ensues. Unfortunately, it is unclear what causes the transition from compensated RV hypertrophy to decompensated RV failure. Moreover, at present, there are no therapies for RV failure; those for left ventricular (LV) failure are ineffective, and no therapies specifically targeting RV are available. Thus there is a clear need for understanding the biology of RV failure and differences in physiology and pathophysiology between RV and LV that can ultimately lead to development of such therapies. In this paper, we discuss RV adaptation and maladaptation in PAH, with a particular focus of oxygen delivery and hypoxia as the principal drivers of RV hypertrophy and failure, and attempt to pinpoint potential sites for therapy.

5023 Background: In TALAPRO-2 (NCT03395197), pts unselected for homologous recombination repair (HRR) gene alterations received TALA + ENZA or PBO + ENZA in 1L mCRPC. TALA + ENZA significantly improved radiographic progression-free survival (rPFS) vs PBO + ENZA. In a previous analysis of five randomized phase 3 mCRPC trials, CTC reduction from ≥5 to <5 per 7.5 mL of blood (CTC conversion) or from >0 to 0 (CTC0) at a Week 13 timepoint was shown to be prognostic for overall survival, with higher discriminatory power than PSA reduction (Heller et al. J Clin Oncol. 2018;36:572-580). We examined CTC conversion and CTC0 as candidate prognostic biomarkers for rPFS in TALAPRO-2. Methods: Blood was serially collected and shipped real-time for CTC enumeration using CELLSEARCH (Menarini Silicon Biosystems) at a central laboratory (Covance). Collection timepoints were screening, Weeks 1, 9, 17, and 25, and safety follow-up visit. Baseline CTC counts were based on Week 1 (screening results were used if Week 1 results were unavailable). CTC reductions were assessed in the safety population as CTC conversion or as CTC0. Data cutoff date was August 16, 2022. Results: At baseline, 653 pts in the intent-to-treat population were evaluable for CTC counts: 213/653 (33%) had CTC counts ≥5 per 7.5 mL of blood, and 353/653 (54%) had CTC counts >0. At Week 9, 144 pts were evaluable for CTC conversion (71 TALA + ENZA, 73 PBO + ENZA), with 254 evaluable for CTC0 (119 TALA + ENZA, 135 PBO + ENZA). CTC conversion at Week 9 proved prognostic for rPFS benefit for TALA + ENZA (hazard ratio [HR]=0.13, 95% CI [0.06–0.32], 2-sided P<0.0001) and PBO + ENZA (HR=0.16 [0.07–0.40], P<0.0001). Similarly, CTC0 at Week 9 was prognostic for TALA + ENZA (HR=0.33 [0.19–0.57], P<0.0001) and PBO + ENZA (HR=0.41 [0.24–0.69], P=0.0006). At Week 17, 132 pts were evaluable for CTC conversion (64 TALA + ENZA, 68 PBO + ENZA), with 227 evaluable for CTC0 (114 TALA + ENZA, 113 PBO + ENZA). CTC conversion at Week 17 proved prognostic for rPFS benefit for TALA + ENZA (HR=0.28 [0.10–0.73], P=0.0065) and for PBO + ENZA (HR=0.26 [0.11–0.59], P=0.0006). CTC0 at Week 17 was also prognostic for TALA + ENZA (HR=0.16 [0.09–0.30], P<0.0001) and for PBO + ENZA (HR=0.36 [0.20–0.64], P=0.0004). Conclusions: CTC reduction at Week 9 and 17 proved prognostic of improved rPFS in both treatment arms in TALAPRO-2. To our knowledge, this is the first time such an association has been demonstrated in a phase 3 trial featuring a PARP inhibitor. Not all regions supported CTC collection, and missing results mainly reflected technical and logistical limitations. These results support the broad prognostic utility of CTC enumeration in mCRPC, particularly in the context of PARP inhibitor therapy. Clinical trial information: NCT03395197 .

178 Background: TALAPRO-2 demonstrated statistically significant improvement in radiographic PFS with 1L talazoparib (TALA) + enzalutamide (ENZA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without HRR gene alterations (HRRm). Tumors were prospectively determined to harbor HRRm. Pts were randomized 1:1 to TALA 0.5 mg (N=200) or placebo (PBO; N=199) + ENZA 160 mg QD. Exploratory biomarker analyses assessed HRR gene subgroups and potential associations with secondary efficacy endpoints in pts with HRRm tumors. Methods: Prospective testing used a 12-gene HRR panel (HRR12) of FoundationOne CDx/FoundationOne Liquid CDx.For single gene groups, only pts bearing alteration(s) in that gene and no other HRR12 genes were analyzed. Gene cluster alteration dominance hierarchy: any BRCA1/2 alteration ( BRCA cluster); any PALB2 ( PALB2 cluster); any CDK12 ( CDK12 cluster); any ATM ( ATM cluster); all other HRR12 genes (each pt counted once). Endpoints: ORR, time to progression or death on first subsequent antineoplastic therapy (PFS2), PSA response ≥50%, time to PSA progression (TTPP), and time to initiation of cytotoxic chemotherapy (TTCC). Results: TALA + ENZA demonstrated differential benefit for BRCA2 single gene group across endpoints: ORR, 78.9% vs 33.3% (odds ratio [OR], 0.13 [95% CI, 0.03–0.63]); PFS2, median not reached (NR) vs 26.1 mo (HR, 0.44 [0.20–0.97]); PSA response >50%, 87.0% vs 58.3%; TTPP, NR vs 9.2 mo (HR, 0.20 [0.10–0.41]); TTCC, NR vs 17.0 mo (HR, 0.27 [0.13–0.57]). Similar broad benefit was seen for BRCA cluster and BRCA1 single gene groups and to a lesser extent PALB2 single gene and cluster groups (allowing for small n in the latter 3 groupings). Broad differential benefit was evident for CDK12 single gene group : ORR 70.0% vs 28.6% (OR 0.17 [0.01–2.03]); PFS2, 36.4 vs 18.8 mo (HR, 0.29 [0.11–0.75]); PSA response ≥50%, 85.7% vs 53.3%; TTPP, 13.8 vs 11.1 mo (HR 0.61 [0.29–1.26]); the exception was TTCC, NR vs NR (HR 1.32 [0.43–4.06]). Similar benefit was seen for CDK12 cluster. For ATM single gene group, differential numerical benefit was seen for ORR, 81.8% vs 20.0% (OR 0.06 [0.00–1.17]); TTPP, 26.8 vs 15.9 mo (HR, 0.61 [0.25–1.47]); TTCC, NR vs NR (HR 0.60 [0.18–1.96]); no differential benefit was seen in other endpoints (similar for ATM cluster). The CHEK2 single gene group showed numerically differential benefit for PSA endpoints and TTCC. The other HRR12 gene cluster typically showed comparable efficacy between arms with potential exception of TTPP, 28.6 vs 14.0 mo (HR 0.65 [0.33–1.31]), and TTCC, NR vs NR (HR 0.65 [0.26–1.62]). Conclusions: Broad differential efficacy benefit was evident for TALA + ENZA vs PBO + ENZA across multiple molecular subgroups and was most pronounced for the BRCA1- PALB2- BRCA2 axis and CDK12. Additional analyses are warranted. Clinical trial information: NCT03395197 .

WHAT IS THIS SUMMARY ABOUT?:This summary describes the results from the TALAPRO-2 research study (also known as a clinical trial). The TALAPRO-2 study tested the combination of two medicines called talazoparib plus enzalutamide. This combination of medicines was used as the first treatment for adult patients with metastatic castration-resistant prostate cancer. The combination of talazoparib plus enzalutamide was compared with a placebo plus enzalutamide. WHAT IS METASTATIC CASTRATION-RESISTANT PROSTATE CANCER?:Metastatic castration-resistant prostate cancer is a type of cancer that starts in the prostate and has spread to other parts of the body. Castration-resistant means that the cancer continues to grow even when testosterone levels in the blood are reduced to very low levels. Taking medicines to lower testosterone levels in the blood is a standard treatment for men with advanced prostate cancer. WHAT ARE THE AIMS OF THE TALAPRO-2 TRIAL?:TALAPRO-2 looked at if combining talazoparib plus enzalutamide would increase the length of time patients lived before their cancer got worse or they died compared with a placebo plus enzalutamide. Researchers looked at how treatment affected the size and number of tumors and the length of time before patients needed to change to a new cancer medicine. Researchers also looked at any side effects patients had during the study. WHAT ARE THE KEY TAKEAWAYS?:A total of 805 patients with metastatic castration-resistant prostate cancer took part in the study. Compared with patients who took a placebo plus enzalutamide, the group of patients who took talazoparib plus enzalutamide had a 37% reduced risk of their cancer getting worse or dying. Some patients had tumors that at the start of the study could be measured with scans. Sixty-two percent of patients who took talazoparib plus enzalutamide had their tumors decrease or shrink to the point that they could no longer be seen on scans versus 44% of patients who took a placebo plus enzalutamide. Patients who took talazoparib plus enzalutamide were more likely to have a longer time before they needed to change to a new cancer medicine. The most common side effects of talazoparib plus enzalutamide were low levels of red blood cells (66% of patients) and neutrophils (36% of patients), and excessive tiredness or exhaustion (34% of patients).Clinical Trial Registration: NCT03395197 (TALAPRO-2) (ClinicalTrials.gov).

High-grade gliomas are aggressive, deadly primary brain tumors. Median survival of patients with glioblastoma (GBM, WHO grade 4) is 14 months and <10% of patients survive 2 years. Despite improved surgical strategies and forceful radiotherapy and chemotherapy, the prognosis of GBM patients is poor and did not improve over decades. We performed targeted next-generation sequencing with a custom panel of 664 cancer- and epigenetics-related genes, and searched for somatic and germline variants in 180 gliomas of different WHO grades. Herein, we focus on 135 GBM IDH-wild type samples. In parallel, mRNA sequencing was accomplished to detect transcriptomic abnormalities. We present the genomic alterations in high-grade gliomas and the associated transcriptomic patterns. Computational analyses and biochemical assays showed the influence of TOP2A variants on enzyme activities. In 4/135 IDH-wild type GBMs we found a novel, recurrent mutation in the TOP2A gene encoding topoisomerase 2A (allele frequency [AF] = 0.03, 4/135 samples). Biochemical assays with recombinant, wild type (WT) and variant proteins demonstrated stronger DNA binding and relaxation activity of the variant protein. GBM patients carrying the altered TOP2A had shorter overall survival (median OS 150 vs 500 days, P = .0018). In the GBMs with the TOP2A variant we found transcriptomic alterations consistent with splicing dysregulation. luA novel, recurrent TOP2A mutation, which was found exclusively in four GBMs, results in the TOP2A E948Q variant with altered DNA binding and relaxation activities. The deleterious TOP2A mutation resulting in transcription deregulation in GBMs may contribute to disease pathology.

Deregulation of fibroblast growth factor receptors (FGFRs) is related to the initiation and progression of multiple cancers. CPL304110 is a new tyrosine kinase inhibitor of FGFR 1–3 administered orally in phase I clinical study, aimed to evaluate safety, tolerability, and determination of the recommended phase II dose (RP2D), the dose-response relationship for efficacy, and pharmacokinetics of CPL304110. Patients with advanced solid malignancies, received escalating doses of CPL304110, ranging from 12.5mg to 100mg qd in cohorts 1-4 (patients without screening for the presence of FGFR aberrations) and 175mg qd or bid in cohorts 5-6 (patients with FGFR aberrations), on 28-day cycle during phase IA of the trial. Twenty-one patients were enrolled during phase IA. The most common treatment-related adverse events (AE) included anemia (19%), ocular toxicity (19%, at median time of 48 dosing days), and dry eye (14.3%). Only one patient (4.8%) experienced ≥grade 3 drug-related AE, and no patients experienced dose-limiting toxicity so far. Using computed tomography-based RECIST 1.1 performed at baseline and at 22-day of every even cycle intervals from the start of treatment, 3 patients achieved partial responses (squamous lung cancer, basal cell carcinoma, cholangiocarcinoma) and 11 others had stable disease as the best response. The objective response rate (ORR; 3 partial responses) for cohorts 1-6 was 14.3% however, referring to the group of patients with FGFR aberration (cohorts 5-6), the ORR was 37.5%. Preliminary results of the study suggest low potential for CPL304110 accumulation and linear pharmacokinetics, however, these results need to be confirmed by data from more patients. The above early study observations suggest that CPL304110 administration is associated with acceptable toxicity and encouraging response rate in heavily pretreated patients with FGFR-aberrant advanced solid malignancies. The final selection of RP2D will take place after the end of phase IB.

155 Background: Lorigerlimab (MGD019) is an investigational, bispecific Fc-bearing (IgG4) DART molecule designed to enhance CTLA-4 blockade on dual expressing, tumor infiltrating lymphocytes, while maintaining maximal PD-1 blockade on PD-1 expressing cells. Lorigerlimab has approximate dose proportional PK across 1–10 mg/kg IV dosing Q3W, with sustained PD-1 receptor occupancy evident at doses ≥1 mg/kg Q3W. MGD019-01 is a global first-in-human dose finding and activity estimating study of lorigerlimab in advanced solid tumors (AST). Methods: The exp phase of MGD019-01 evaluates single agent safety, PK, and antitumor effects of lorigerlimab at the recommended dose for exp of 6 mg/kg IV Q3W in 4 tumor specific cohorts. Confirmed responses were noted in each cohort. Preliminary results of the mCRPC cohort are reported here. Response evaluable pts received ≥1 dose and had ≥1 postbaseline imaging evaluation. Measurable lesions were evaluated per RECIST v1.1 and skeletal metastases assessed by bone scan. Prostate specific antigen (PSA) response was defined as a ≥50% (PSA50) or ≥90% (PSA90) PSA decline from baseline with confirmation ≥3 weeks later. Expression of proliferation marker, Ki67, and inducible costimulator (ICOS) by peripheral T cells was assessed by flow cytometry. Results: At data cutoff (9/10/22), 127 pts with AST received ≥1 dose of lorigerlimab 6 mg/kg. Median exposure was 10 weeks (range, 0.1, 94.4) with median of 4 infusions. 6 pts remain on therapy; 36 discontinued for PD (n=13), AEs (n=17), or patient/physician decision (n=6). Treatment related adverse events (TRAE) occurred in 109/127 (85.8%) pts. TRAEs occurring in ≥15% of pts were fatigue, pruritus, hypothyroidism, pyrexia. Rates of grade ≥3 TRAEs and immune-related AEs were 32.3% and 7.9%, respectively. AEs leading to drug discontinuation occurred in 22.8% of pts. There were no fatal AEs related to lorigerlimab. In the mCRPC exp cohort (n=42), pts had a median of 2 prior lines of therapy for CRPC, >80% received prior ART or taxanes; 88% had visceral (liver, 26%; lung, 26%) or nodal disease and 95% had bone metastases. 42 pts were PSA response evaluable; 35 were RECIST evaluable. ORR was 25.7% (9/35; 9 confirmed PRs). Median duration of response was 16.1 weeks (range 6–25+ weeks). 5 responders remain on study, 4 discontinued for unrelated fatal AEs: COVID-19 (2) cardiac arrest (1) C. difficile infection (1). Confirmed PSA50 and PSA90 response rates were 28.6% (12/42) and 21.4% (9/42), respectively. Increased frequencies of Ki67+ and ICOS+ T cells were observed on day 8 posttreatment compared to pretherapy per the flow cytometry analyses from 35 pts. Conclusions: Lorigerlimab demonstrates a manageable safety profile with evidence of encouraging and durable antitumor activity in a chemotherapy refractory mCRPC population. Randomized evaluation of lorigerlimab in mCRPC is warranted. Clinical trial information: NCT03761017 .

Purpose A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-α) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. Patients and Methods Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-α 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. Results Median overall survival was greater in the sunitinib group than in the IFN-α group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test (P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-α group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor–signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-α (P < .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-α (P < .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). Conclusion Sunitinib demonstrates longer overall survival compared with IFN-α plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.

BackgroundAbiraterone acetate (ABI) and Enzalutamide (ENZA) are second-generation hormone drugs that show breakthrough activity in post-chemotherapy, metastatic castration-resistant prostate cancer (mCRPC). The leading oncological and urological guidelines indicate both drugs with the same strong recommendation. There is a lack of randomized trials which compare the efficacy of ABI and ENZA. The current study aimed to compare the effectiveness of the drugs with an analysis of prognostic factors related to those drugs.Patients and methodsThe study included 420 patients with docetaxel (DXL) pretreated mCRPC from seven Polish cancer centers. Patients were treated according to inclusion and exclusion criteria in the Polish national drug program (1000 mg ABI and 10 mg prednisone, n=76.2%; ENZA, 160 mg; n=23.8%). The study retrospectively analyzed the overall survival (OS), time to treatment failure (TTF), PSA 50% decline rate (PSA 50%) and selected clinic-pathological data.ResultsIn the study group, the median OS was 17 months (95% CI: 15.6-18.3). The median OS (26.1 vs. 15.7 mo.; p<0.001), TTF (14.2 vs. 7.6 mo.; p<0.001) and PSA 50% (87.5 vs. 56%; p<0.001) were higher in ENZA than in ABI treatment. Multivariate analysis shows that ENZA treatment and PSA nadir <17.35 ng/mL during or after DXL treatment were related to longer TTF. ENZA treatment, DXL dose ≥750 mg, PSA nadir <17.35 ng/mL during or after DXL treatment was related to longer OS.ConclusionsENZA treatment may be related to more favorable oncological outcomes than ABI treatment in the studied Polish population of patients. A 50% decline in PSA is an indicator of longer TTF and OS. Due to the non-randomized and retrospective nature of the analysis, the current results require prospective validation.

Natural compounds, such as resveratrol (Res), are currently used as adjuvants for anticancer therapies. To evaluate the effectiveness of Res for the treatment of ovarian cancer (OC), we screened the response of various OC cell lines to the combined treatment with cisplatin (CisPt) and Res. We identified A2780 cells as the most synergistically responding, thus optimal for further analysis. Because hypoxia is the hallmark of the solid tumor microenvironment, we compared the effects of Res alone and in combination with CisPt in hypoxia (pO2 = 1%) vs. normoxia (pO2 = 19%). Hypoxia caused an increase (43.2 vs. 5.0%) in apoptosis and necrosis (14.2 vs. 2.5%), reactive oxygen species production, pro-angiogenic HIF-1α (hypoxia-inducible factor-1α) and VEGF (vascular endothelial growth factor), cell migration, and downregulated the expression of ZO1 (zonula occludens-1) protein in comparison to normoxia. Res was not cytotoxic under hypoxia in contrast to normoxia. In normoxia, Res alone or CisPt+Res caused apoptosis via caspase-3 cleavage and BAX, while in hypoxia, it reduced the accumulation of A2780 cells in the G2/M phase. CisPt+Res increased levels of vimentin under normoxia and upregulated SNAI1 expression under hypoxia. Thus, various effects of Res or CisPt+Res on A2780 cells observed in normoxia are eliminated or diminished in hypoxia. These findings indicate the limitations in using Res as an adjuvant with CisPt therapy in OC.

Purpose Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). Patients and Methods Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo ( P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. Conclusion Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.

Endothelial cells (ECs) select, recognize and stop circulating cells on the vascular endothelium surface which allows homing, making them key players of recruitment selectivity into normal vs pathologic organs. While endothelium organospecificity is the first selectivity level by which ECs interact with extra- and intravasating cells, ECs adapt to environmental signals which strongly influences the surface phenotype of the concerned endothelium. ECs express sets of homing receptors/adhesion molecules, a pattern enabling them to retain or exclude normal or pathologic circulating cells. At EC interactions level, cross-recognitions molecules are endogenous lectins: Selectins, Siglecs, galectins, with their glycosylated ligands. As first interacting partners, they finely tune adhesion by their rapid and dynamic modifications reflecting microenvironment. ECs functions require variability and adaptation to site changes to report the local and temporal biological state. Among modulatory effects which respond to the dynamic reactions needs, post-translational modifications by glycosylation provide the molecular answers orchestrating specific and efficient cell cross-talk. Quantitative and qualitative variations of glycoconjugates composition, in response to microenvironmental pressures is a fast, strongly sensitive means to modulate interactions and molecular reactivity. Mediated by the glycosyltransferases/glycosidases balance, dependent on microenvironmental conditions as tumor hypoxia, glycoconjugate recognitions are responsible for immune cells recruitment in normal conditions with deep consequences in diseases. Deleterious extravasation/intravasation of dysfunctional immune and pathologic cells like metastases, result from similar mechanisms. Consequently, control of glycoconjugates composition, expression and recognitions, open to new therapeutic approaches for the improvement of therapies efficacy.

Background Abiraterone acetate (AA) is a drug used in advanced prostate cancer. However, known clinical factors with predictive and prognostic value are scarce. This study evaluated cardiovascular (CV) factors and geriatric scales as potential markers of superior response during AA therapy. Methods This is a prospective observational study. Serum levels of high sensitivity troponin T (hsTnT), D-dimer, NT-proBNP and left ventricle ejection fraction (LVEF) were used for CV evaluation. Questionnaires of G8, VES-13, Activities of Daily Living (ADL), Instrumental Activities of Daily Living (iADL), and Geriatric Depression Scale (GDS) were included in the geriatric screening assessment. All measures were taken before AA initiation. Survival curves and Cox proportional hazard models (univariate and multivariate) were used to determine the predictors for a longer time to treatment failure (TTF). Results Forty nine patients were included in the study. Overall median TTF was 7.9 months (95% CI: 5.9-12.4). In univariate analysis, factors associated with inferior TTF were ( P -value < .05): visceral metastases - HR 2.34; 95% CI: 1.24-4.45, history of coronary artery disease - HR 3.02; 95% CI: 1.19-7.66; LVEF < 50% - HR 2.53; 95% CI: 1.03-6.17; P = .041; age-adjusted D-dimer > upper reference limit (URL) - HR 3.53; 95% CI: 1.81-6.85; P < .001; hsTnT > URL - HR 2.17; 95% CI: 1.13-4.16; P = .016; NT-proBNP ≥ 300 pg/mL - HR 2.3; 95% CI: 1.22-4.34; P = .01; G8 score ≤14 points - HR 2.47; 95% CI: 1.29-4.74; P = .007. In multivariate analysis, age-adjusted D-dimer > URL, G8 score ≤ 14 points and visceral metastases remained statistically significant in prediction of inferior TTF. The number of these factors was associated with shorter median TTF: 0-1 factor – 14.1 months; 2 factors – 5.9 months; 3 factors – 2.7 months; P < .001, log-rank). Conclusions Age-adjusted D-dimer, and geriatric G8 scores may predict TTF in men with metastatic castration-resistant prostate cancer during AA therapy. These observations require further study in a larger population.

The environmental and metabolic pressures in the tumor microenvironment (TME) play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition and activation. Hypoxia triggers a cascade of events that promote tumor growth, enhance resistance to the anti-tumor immune response and instigate tumor angiogenesis. During growth, the developing angiogenesis is pathological and gives rise to a haphazardly shaped and leaky tumor vasculature with abnormal properties. Accordingly, aberrantly vascularized TME induces immunosuppression and maintains a continuous hypoxic state. Normalizing the tumor vasculature to restore its vascular integrity, should hence enhance tumor perfusion, relieving hypoxia, and reshaping anti-tumor immunity. Emerging vascular normalization strategies have a great potential in achieving a stable normalization, resulting in mature and functional blood vessels that alleviate tumor hypoxia. Biomarkers enabling the detection and monitoring of tumor hypoxia could be highly advantageous in aiding the translation of novel normalization strategies to clinical application, alone, or in combination with other treatment modalities, such as immunotherapy.