Kanesvaran, Ravindran

Abstract Background Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors. Methods This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons. Results Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node–only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher. Conclusions Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.

Prostate cancer is a disease of older adults that has undergone a significant therapeutic paradigm shift in the last decade with the emergence of novel androgen receptor pathway inhibitors (ARPis). One of the more commonly used ARPis is enzalutamide. This drug, along with darolutamide and apalutamide, initially received approvals in the metastatic castrate-resistant prostate cancer setting but is now utilized frequently in the metastatic castrate-sensitive and non-metastatic castration-resistant settings. Landmark phase III data illustrating ARPi efficacy in older adults are limited to those with excellent performance status. However, its role in unfit older prostate cancer patients remains to be explored in the context of a narrative review. This first-of-its-kind drug review aims to shed light on the most up-to-date evidence behind the unique toxicity profile of ARPis in the context of geriatric vulnerabilities such as cognitive and functional impairment, along with potential solutions and supporting evidence that exists to circumvent these issues in the vulnerable older adult.

475 Background: The vascular disrupting agent (VDA) BNC105P shows synergy with everolimus in preclinical models. The DisrupTOR-1 trial included a phase I component exploring this combination and a randomized phase II component comparing everolimus with BNC105P (Arm A) to everolimus monotherapy (Arm B) (Pal et al. ESMO 2014). Methods: Pts with clear cell mRCC and 1-2 prior therapies (including ≥1 VEGF-TKI) were randomized in the phase II study component. In Arm A, patients received a 7 day lead-in dose of everolimus followed by dosing with BNC105P. Patients in Arm A had optional blood collections prior to administration of BNC105P and 3 hours after receiving BNC105P. A fluorescence-based assay was used to characterize a broad panel of analytes at each time point. Biomarkers were assessed in both a static and dynamic fashion. For the former, biomarkers were stratified by median value, and progression-free survival (PFS) was compared in resulting subgroups using the Kaplan-Meier method. For the latter, change in biomarker level before and after BNC105P infusion was stratified by median difference, and PFS was compared in resulting subgroups using the Kaplan-Meier method. Results: 139 pts were randomized with 69 and 67 evaluable pts in Arms A and B, respectively. Dynamic biomarkers were assessed in a total of 44 patients who received everolimus with BNC105P. Increases in matrix metalloproteinase-9 (MMP-9) and stem cell factor (SCF) were associated with improved PFS (p=0.0421 and p=0.0291, respectively). Decreases in sex hormone binding globulin (SHBG) and serum amyloid protein (SAP) were associated with improved PFS (p=0.0184 and p=0.0063). With respect to static biomarkers, elevated baseline ferritin and lower baseline IL-8 were associated with improved PFS (p=0.0291 and p=0.0149, respectively). Conclusions: Several static and dynamic biomarkers in the DisrupTOR-1 trial were associated with PFS. A prospective biomarker-driven study examining everolimus with BNC105P selected by baseline IL-8 and ferritin is in development. Clinical trial information: NCT01034631.

Abstract Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). Experimental Design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. Results: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. Conclusions: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. Clin Cancer Res; 21(15); 3420–7. ©2015 AACR.