Iglesias, José

Abstract The Phase 2 IMPRIME 1 study evaluated the combination of the pathogen-associated molecular pattern (PAMP) Imprime with the immune checkpoint inhibitor (ICI) pembrolizumab as second or later line of treatment (2 L+) for patients with metastatic triple-negative breast cancer (mTNBC). Eligible patients with mTNBC received weekly Imprime (4 mg/kg) intravenously in combination with pembrolizumab (200 mg every 3 weeks). Primary endpoints were overall response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression free survival (PFS), and overall survival (OS). Exploratory endpoints included correlations between immune cell activation markers in tumor tissues and blood and response to therapy. Of the 42 evaluable patients, six had a response (one complete, five partial), with an ORR of 14.3% by RECIST v1.1. Median PFS was 2.7 months, median OS was 16.4 months, and DCR was 54.8%, with responders achieving a median DoR of 15.2 months. Therapy was generally well tolerated and resulted in an increase of immune activation markers, with higher levels of activation in peripheral blood associated with response and improved survival. The combination of Imprime and pembrolizumab was safe and demonstrated immune activation in tumor tissues and peripheral blood in patients with TNBC. Improved response rates were observed compared to historical studies of ICI monotherapy in similar patient populations. Study number (ClinicalTrials.gov trial registration): NCT02981303.

Background Although myocardial infarction with nonobstructive coronary arteries (MINOCA) is more common in women, it is unknown whether sex is a risk factor for adverse outcomes in patients with MINOCA. We aimed to investigate the relationship between sex differences and outcomes of patients with MINOCA. Methods and Results A systematic literature search was performed in PubMed, Embase, and Cochrane databases from their inception until August 2023 for relevant studies. End points were pooled using the Hartung–Knapp–Sidik–Jonkman random‐effects model as odds ratio (OR) with 95% CIs. Nine studies, involving 30 281 patients with MINOCA (comprising 18 079 women and 12 202 men), were included in the study. Women were older and had a higher prevalence of hypertension, diabetes, and stroke compared with men. The median duration of follow‐up was 3.5 years, with an interquartile range of 2.2 to 4.2 years. Pooled analysis revealed no statistically significant difference in the risk of all‐cause mortality (OR, 1.03 [95% CI, 0.87–1.22]), major adverse cardiovascular events (OR, 1.18 [95% CI, 0.89–1.58]), heart failure (OR, 1.32 [95% CI, 0.57–3.03]), stroke (OR, 1.13 [95% CI, 0.56–2.26]), and myocardial infarction (OR, 1.04 [95% CI, 0.29–3.76]) between the 2 groups. Regarding short‐term outcomes, women had a significantly higher risk of in‐hospital major adverse cardiovascular events compared with men (OR, 1.33 [95% CI, 1.16–1.53]) whereas there was no significant difference in the risk of in‐hospital mortality (OR, 0.90 [95% CI, 0.64–1.28]) between the 2 patient groups. Conclusions Despite the differences in demographics and comorbidity profiles, there was no significant difference in the long‐term outcomes for patients with MINOCA between sexes. However, it is noteworthy that women experienced a higher risk of in‐hospital major adverse cardiovascular events compared with men.

4525 Background: Pancreatic cancer cells and surrounding stroma are known to overexpress SPARC (secreted protein acid rich in cysteine), which is associated with poor clinical outcomes. nab-P, an albumin-bound nanoparticle form of paclitaxel increased tumor accumulation of paclitaxel through binding of albumin to SPARC. This disease specific phase 1 study was designed to evaluate the safety and efficacy of G + nab-P and the correlation of response with tumor SPARC and serum CA19–9 levels. Methods: nab-P doses (100–150 mg/m2) + (G) (1000 mg/m2) were given on days 1, 8, and 15 of a 28-day cycle to pts with metastatic pancreatic adenocarcinoma and with no prior chemotherapy for their metastatic disease. Level 3 SPARC staining by immunohistochemistry was considered positive. Results: 63 pts received treatment. The most common grade 3 and 4 adverse event that occurred in >20% of pts was neutropenia. Nine (18%) pts and 4 (8%) pts had a grade 3/4 event, respectively. Neuropathy was also observed. One combination-associated death due to sepsis occurred at the 150 mg/m2 nab-P level. Serial PET scans of 53 pts with outside adjudication to date showed 12 (23%) complete responses, 29 (55%) partial responses (PRs) and 4 (8%) stable disease (SD). By RECIST criteria, of the 49 pts evaluable to date, 1(2%) had CR, 12 (24%) had PR, and 20 (41%) had SD. The median survival was 9 months to date. SPARC data were available for 35 pts, of which 10 (29%) were SPARC+ and 25 (71%) were SPARC-. Of these, 27 pts had evaluable response data. Pts that were SPARC+ (8/27) were more likely to be responders (6/8, 75%) than pts who were SPARC- (5/19, 26%), P = 0.03, Fisher's exact test. Median progression-free survival (PFS) increased from 4.8 months for SPARC- pts (22 pts) to 6.2 months for SPARC+ pts (9 pts); however, these data are still immature. Of 45 pts with elevated CA19–9 at baseline, 42 (93%) had maximum decrease of >40% with a median maximum decrease of 92%. Conclusions: The combination of nab-P and G was generally well tolerated and had substantial enough antitumor activity in patients with pancreatic cancer to warrant a phase III clinical trial. SPARC+ status in these patients was associated with higher response rate and longer PFS. [Table: see text]

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.