Phase 2 trial of CV301 vaccine plus atezolizumab (Atezo) in advanced urothelial carcinoma (aUC).

511 Background: PD(L)1 inhibitors can achieve durable responses in aUC but only in a minority of patients (pts). Combination strategies with agents that “prime and stimulate” the immune system may improve outcomes. CV301 comprises 2 recombinant poxviruses, Modified Vaccinia Ankara (MVA) and Fowlpox (FPV), encoding the human transgenes for CEA, MUC-1, and a Triad of Co-stimulatory Molecules (TRICOM: ICAM-1, LFA-3, and B7-1). MVA-CV301 is used for priming and FPV-CV301 is used for booster doses. Preliminarily, BN-platform vaccine plus PD-(L)1 inhibitors exhibited synergistic preclinical anti-tumor efficacy and the combination of CV301 and anti-PD-(L)1 agent demonstrated an acceptable safety profile. We hypothesized that this combination would be safe and effective in cisplatin-ineligible or platinum-refractory pts with aUC. Methods: A Phase 2, single-arm multicenter trial was designed to study CV301 + atezo as 1st-line treatment in pts with aUC ineligible for cisplatin-based chemotherapy regardless of PD-L1 status (Cohort 1; C1) and in pts progressing on/after platinum-based chemotherapy (Cohort 2; C2). MVA-CV301 was given subcutaneously (SC) on Days 1 and 22 and FPV-CV301 SC from day 43 every 21 days for 4 doses, then every 6 weeks until 6 months, then every 12 weeks until 2 years. Atezo 1200mg IV was given every 21 days. Primary endpoint: objective response rate (ORR). Secondary endpoints: OS, PFS, response duration, AEs and antigen-specific T-cell responses to CEA and MUC-1 by ELISPOT. Using 1-sided α 2.5%/cohort, a 2-stage design with 14/19 and 13/22 stage 1/2 subjects, respectively, will achieve ≥70% power if the true ORR for C1 is 43% and C2 is 33%. 3 C1 and 2 C2 responders were required in stage 1 to move forward. Results: 43 evaluable pts were enrolled and received therapy: 19 in C1; 24 in C 2. Overall, 9 pts experienced ≥ Grade 3 AEs related to the combination of treatment: 5 in C1, and 4 in C2. In C1, 1 pt had partial response (PR), for ORR 5.3% (90%CI: 0.3, 22.6) and 5 (26.3%, 90%CI: 11.0, 47.6) had stable disease (SD) as best response. In C2, 1pt had CR and 1 had PR, for ORR 8.3% (90%CI: 1.5, 24.0) and 3 (12.5%, 90%CI: 3.5, 29.2) had SD as best response. Median PFS and OS in C1 were 2.0 mo and 13.8 mo, and in C2 1.95 and 8.13 mo, respectively. The trial was halted for futility. Responding pts in C2 exhibited T-cell responses to CEA and pts with SD exhibited responses to MUC-1. Conclusions: CV301 + atezo exhibited an acceptable safety profile but did not demonstrate sufficient efficacy in pts with aUC as 1st-line therapy in cisplatin-ineligible pts or in the platinum-refractory setting. The development of effective vaccines to generate robust and durable responses as single agents and/or combined with anti-PD(L)1 remains an unmet need in aUC. Clinical trial information: NCT03628716. </jats:p

Surgery and outcome of infective endocarditis in octogenarians: prospective data from the ESC EORP EURO-ENDO registry

Purpose: High mortality and a limited performance of valvular surgery are typical features of infective endocarditis (IE) in octogenarians, even though surgical treatment is a major determinant of a successful outcome in IE. Methods: Data from the prospective multicentre ESC EORP EURO-ENDO registry were used to assess the prognostic role of valvular surgery depending on age. Results: As compared to &lt; 80&nbsp;yo patients, ≥ 80&nbsp;yo had lower rates of theoretical indication for valvular surgery (49.1% vs. 60.3%, p &lt; 0.001), of surgery performed (37.0% vs. 75.5%, p &lt; 0.001), and a higher in-hospital (25.9% vs. 15.8%, p &lt; 0.001) and 1-year mortality (41.3% vs. 22.2%, p &lt; 0.001). By multivariable analysis, age per se was not predictive of 1-year mortality, but lack of surgical procedures when indicated was strongly predictive (HR 2.98 [2.43-3.66]). By propensity analysis, 304 ≥ 80&nbsp;yo were matched to 608 &lt; 80&nbsp;yo patients. Propensity analysis confirmed the lower rate of indication for valvular surgery (51.3% vs. 57.2%, p = 0.031) and of surgery performed (35.3% vs. 68.4%, p &lt; 0.0001) in ≥ 80&nbsp;yo. Overall mortality remained higher in ≥ 80&nbsp;yo (in-hospital: HR 1.50[1.06-2.13], p = 0.0210; 1-yr: HR 1.58[1.21-2.05], p = 0.0006), but was not different from that of &lt; 80&nbsp;yo among those who had surgery (in-hospital: 19.7% vs. 20.0%, p = 0.4236; 1-year: 27.3% vs. 25.5%, p = 0.7176). Conclusion: Although mortality rates are consistently higher in ≥ 80&nbsp;yo patients than in &lt; 80&nbsp;yo patients in the general population, mortality of surgery in ≥ 80&nbsp;yo is similar to &lt; 80&nbsp;yo after matching patients. These results confirm the importance of a better recognition of surgical indication and of an increased performance of surgery in ≥ 80&nbsp;yo patients

Characteristics, management, and outcomes of patients with left-sided infective endocarditis complicated by heart failure: a substudy of the ESC-EORP EURO-ENDO (European infective endocarditis) registry

Aims: To evaluate the current management and survival of patients with left-sided infective endocarditis (IE) complicated by congestive heart failure (CHF) in the ESC-EORP European Endocarditis (EURO-ENDO) registry. Methods and results: Among the 3116 patients enrolled in this prospective registry, 2449 (mean age: 60years, 69% male) with left-sided (native or prosthetic) IE were included in this study. Patients with CHF (n&nbsp;=&nbsp;698, 28.5%) were older, with more comorbidity and more severe valvular damage (mitro-aortic involvement, vegetations &gt;10 mm and severe regurgitation/new prosthesis dehiscence) than those without CHF (all p ≤ 0.019). Patients with CHF experienced higher 30-day and 1-year mortality than those without (20.5% vs. 9.0% and 36.1% vs. 19.3%, respectively) and CHF remained strongly associated with 30-day (odds ratio[OR] 2.37, 95% confidence interval [CI] [1.73-3.24; p &lt; 0.001) and 1-year mortality (hazard ratio [HR] 1.69, 95% CI 1.39-2.05; p &lt; 0.001) after adjustment for established outcome predictors, including early surgery, or after propensity matching for age, sex, and comorbidity (n&nbsp;=&nbsp;618 [88.5%] for each group, both p &lt; 0.001). Early surgery, performed on 49% of these patients with IE complicated by CHF, remained associated with a substantial reduction in 30-day mortality following multivariable analysis, after adjustment for age, sex, Charlson comorbidity index, cerebrovascular accident, Staphylococcus aureus IE, streptococcal IE, uncontrolled infection, vegetation size &gt;10 mm, severe valvular regurgitation and/or new prosthetic dehiscence, perivalvular complication, and prosthetic IE (OR 0.22, 95% CI 0.12-0.38; p &lt; 0.001) and in 1-year mortality (HR 0.29, 95% CI 0.20-0.41; p &lt; 0.001). Conclusion: Congestive heart failure is common in left-sided IE and is associated with older age, greater comorbidity, more advanced lesions, and markedly higher 30-day and 1-year mortality. Early surgery is strongly associated with lower mortality but is performed on only approximately half of patients with CHF, mainly because of a surgical risk considered prohibitive