Long-term Follow-up of the The Danish Study to Assess theEfficacy of ICDs in Patients with Non-ischemic Systolic HeartFailure on Mortality (DANISH)

Background: The Danish Study to Assess the Efficacy of Implantable Cardioverter-Defibrillators (ICDs) in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) found that primary-prevention ICD implantation was not associated with an overall survival benefit in patients with non-ischemic systolic heart failure during a median follow-up of 5.6 years, though there was a beneficial effect on all-cause mortality in patients ≤70 years. This study presents an additional four years of follow-up data from DANISH. Methods: In DANISH, 556 patients with non-ischemic systolic heart failure were randomized to receive an ICD and 560 to receive usual clinical care and followed until June 30, 2016. In this long-term follow-up study, patients were followed until May 18, 2020. Analyses were conducted for the overall population and according to age (≤70 and >70 years). Results: During a median follow-up of 9.5 years (25 th -75 th percentile, 7.9-10.9 years), 208/556 patients (37%) in the ICD group and 226/560 patients (40%) in the control group died. Compared with the control group, the ICD group did not have significantly lower all-cause mortality (HR 0.89 [95%CI,0.74-1.08]; P=0.24). In patients ≤70 years (n=829), all-cause mortality was lower in the ICD group than the control group (117/389 [30%] vs 158/440 [36%]; HR 0.78 [95%CI,0.61-0.99]; P=0.04), whereas in patients >70 years (n=287), all-cause mortality was not significantly different between the ICD and control group (91/167 [54%] vs 68/120 [57%]; HR 0.92 [95%CI,0.67-1.28]; P=0.75). Cardiovascular death showed similar trends (overall, 147/556 [26%] vs 164/560 [29%], HR 0.87 [95%CI,0,70-1.09], P=0.20; ≤70 years, 87/389 [22%] vs 122/440 [28%], HR 0.75 [95%CI,0.57-0.98], P=0.04; >70 years, 60/167 [36%] vs 42/120 [35%], HR 0.97 [95%CI,0.65-1.45], P=0.91). The ICD group had a significantly lower incidence of sudden cardiovascular death in the overall population (35/556 [6%] vs 57/560 [10%]; HR 0.60 [95%CI,0.40-0.92]; P=0.02) and in patients ≤70 years (19/389 [5%] vs 49/440 [11%]; HR 0.42 [95%CI,0.24-0.71]; P=0.0008), but not in patients >70 years (16/167 [10%] vs 8/120 [7%]; HR 1.34 [95%CI,0.56-3.19]; P=0.39). Conclusions: During a median follow-up of 9.5 years, ICD implantation did not provide an overall survival benefit in patients with non-ischemic systolic heart failure. In patients ≤70 years, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00542945.

OP440 Comparison Of Evidence Supporting Cancer Drug Approvals And Prices In The US And Brazil

IntroductionCancer drug prices are high on the policy agenda worldwide. Previous research found no association between cancer drug benefits and prices at the time of regulatory approval. Drugs approved in the US with uncertain benefits may have spill-over effects in other settings. Our objective was to compare the evidence supporting cancer drug approvals in the US and Brazil, and to examine the association between cancer drug prices and availability of added therapeutic benefit.MethodsWe matched all novel cancer drugs approved in the US from 2010–2019 to approvals in Brazil. We extracted data on pivotal study design characteristics and outcomes in the US and Brazil, and evidence supporting price approval in Brazil, including availability of added therapeutic benefit.ResultsFrom 2010–2019, fifty-six cancer drugs with matching indications were approved in US and Brazil and had their prices authorized in Brazil by December 2020. Drug were available in Brazil following a median 522 days after US approval (IQR: 351–932). In the US, thirty-four (60.7 percent) of the drugs had pivotal randomized controlled trials (RCTs) and Twelve (21.4 percent) had overall survival benefit. By the time of Brazilian approval, forty-one (73.2 percent) drugs had pivotal RCTs and twenty-two (39.3 percent) had overall survival benefit. A total of twenty-eight (50 percent) drugs did not demonstrate added therapeutic benefit over other authorized drugs for the same indication and had a median reduction from requested to approved price of 6.1 percent (IQR: 0–27.8 percent) in Brazil. The twenty-seven (48.2 percent) drugs with added therapeutic benefit had a median price reduction of 2.0 percent (IQR: 0–9.2 percent).ConclusionsHalf of new cancer drugs approved in Brazil failed to demonstrate added therapeutic benefit. The Brazilian pricing system secured considerable price reductions, ensuring that prices for medicines with no added therapeutic benefit were not higher than existing treatments for the same approved indication. Although evidence was more mature by the time of Brazilian review, pivotal studies often lacked randomization and overall survival endpoints.

Gp-100 as a Novel Therapeutic Target in Uveal Melanoma

Uveal melanoma is a rare neoplasm with poor prognosis in the metastatic setting. Unlike cutaneous melanoma, treatment with kinase inhibitors or immune checkpoint inhibitors is not effective. Glycoprotein 100 (Gp-100) is a protein highly expressed in melanocytes and melanoma that has recently been effectively targeted by tebentafusp, a first-in-class bispecific protein of the immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs) family. Tebentafusp targets tumor cells that express a peptide of Gp-100 presented by HLA*A0201, creating an immune synapse that kills targeted tumor cells. Recently, a randomized phase III trial reported an overall survival benefit for tebentafusp in patients with untreated metastatic uveal melanoma. The aim of this comprehensive review is to summarize evidence of Gp-100 as a therapeutic target in melanoma, and the preclinical and clinical development of tebentafusp as a novel therapeutic strategy for patients with uveal melanoma.

Superior Overall Survival in Patients with Colorectal Cancer, Regular Aspirin Use, and Combined Wild-Type PIK3CA and KRAS-Mutated Tumors

The impact of aspirin use after the diagnosis of colorectal cancer is unknown. Among others, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutational status was proposed as a molecular biomarker for the response to adjuvant aspirin therapy. However, prognostic data on aspirin use after a colorectal cancer diagnosis in relation to KRAS mutational status is limited. In a single-center retrospective study, we obtained KRAS and PIK3CA mutational status in a cohort of 153 patients with a first diagnosis of colorectal cancer receiving tumor surgery with curative intent. PIK3CA mutational status was determined by pyrosequencing, and KRAS mutational status was determined by next-generation sequencing. Clinicopathological data and survival data were assessed using patient records and reporting registers. We observed a significant 10-year overall survival benefit in patients with aspirin use and combined wild-type PIK3CA and mutated-KRAS tumors (HR = 0.38; 95% CI = 0.17–0.87; p = 0.02), but not in patients without aspirin use. Our data indicate a benefit of aspirin usage particularly for patients with combined wild-type PIK3CA and mutated-KRAS tumor characteristics.

Perioperative Systemic Chemotherapy for Colorectal Liver Metastasis: Recent Updates

The liver is the most common site of metastases for colorectal cancer. Complete resection in some patients with resectable liver metastases (LM) can lead to long-term survival and cure. Adjuvant systemic chemotherapy after complete resection of LM improves recurrence-free survival; however, the overall survival benefit is not clear. In selected patients, preoperative systemic treatment for metastatic colorectal cancer can convert unresectable to resectable cancer. This review will focus on patient selection, and integration of perioperative and postoperative systemic treatment to surgery in resectable and initially unresectable LM. Additionally, new drugs and biomarkers will be discussed.

Patterns of therapy initiation during the first decade for patients with follicular lymphoma who were observed at diagnosis in the rituximab era

Immediate treatment for asymptomatic, low-tumor burden follicular lymphoma (FL) has not shown an overall survival benefit over “watch and wait” (W/W) strategy. We estimated incidence of treatment initiation at specific time points and assessed its association with the presence of any criteria such as GELF, BNLI, GITMO at diagnosis. FL patients managed by W/W strategy were identified from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE between 2002 and 2015. Cumulative incidence estimates of treatment initiation were calculated using transformation (as the first event) and death as competing risks. 401 FL patients were identified on W/W strategy. At a median follow-up of 8 years, 256 (64%) initiated treatment. For patients on the W/W strategy for 5 years, the likelihood of treatment initiation in the next 5 years was 12% compared to 43% at diagnosis unlike transformation rates which remained steady. Patients with any of popular treatment criteria at diagnosis did not have increased therapy initiation rates (44% vs. 42%) during the first 5 years or lymphoma-related death rates at 10 years (6% vs. 7%). Identifying biological differences in patients with early vs. late or no progression is a critical next step in understanding outcomes in W/W patients.