Yazdanpanah, Omid

121 Background: In the Phase 3 VISION trial, treatment with the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) + protocol-permitted standard of care (SoC) significantly improved median radiographic progression-free survival (rPFS; 8.7 vs 3.4 months [mo]) and overall survival (OS; 15.3 vs 11.3 mo) in patients with metastatic castration-resistant prostate cancer (mCRPC) vs SoC alone. However, it is unclear how the addition of androgen receptor pathway inhibitors (ARPIs) affected 177 Lu-PSMA-617 treatment outcomes. Here we compared the efficacy and safety of 177 Lu-PSMA-617 in patients treated with vs without concomitant ARPIs. Methods: In VISION, adult patients with PSMA-positive mCRPC previously treated with ≥1 prior ARPI and 1–2 taxane chemotherapy regimens were randomized 2:1 to receive 177 Lu-PSMA-617 (7.4 GBq Q6W, 4–6 cycles) + SoC (which included ARPIs) vs SoC alone. In this secondary analysis, we assessed baseline characteristics, OS, rPFS, prostate-specific antigen (PSA) response rate, duration of PSA response, PSA-PFS, and safety among patients in the intervention arm who were treated with vs without concomitant ARPIs. Results: In total, 289 patients were treated with concomitant ARPIs and 262 patients were not (N=551). Imbalances between the groups were observed in some baseline characteristics: patients treated with concomitant ARPIs were younger, had lower ECOG performance scores, lower mean PSA and lactate dehydrogenase levels, and fewer prior taxane chemotherapy regimens. Baseline mean standardized [ 68 Ga]Ga-PSMA-11 uptake values and mean hemoglobin levels were well-balanced. A statistically significant difference in median OS was observed in patients treated with concomitant ARPIs vs those without (17.8 vs 12.4 mo; HR, 0.72; 95% CI, 0.58–0.89; nominal P=0.001). No statistically significant between-group differences were observed for rPFS, PSA response rate, duration of PSA response or PSA-PFS. The proportion of adverse events reported was similar in patients with or without concurrent ARPI, except for the number of adverse events leading to interruption of best supportive care/SoC, which was higher in patients treated with concurrent ARPIs. Conclusions: OS was significantly different in patients treated with concomitant ARPIs vs those without, while other efficacy endpoints were not. No new safety signals were observed for 177 Lu-PSMA-617 with concomitant ARPI. These findings may be confounded by varied exposure to ARPIs, or differing patient characteristics; patients who received concomitant ARPIs may represent a more favorable treatment population than those who did not. These findings should be considered as hypothesis-generating, and a multivariate analysis has been planned to ascertain the influence of these potential biases. Clinical trial information: NCT03511664 .

e16260 Background: Therapeutic inhibition of constitutive signaling mediated by mutated KRAS in PDAC remains a challenge except for modest success reported with KRAS G12C inhibition. A combinatorial strategy utilizing simultaneous MEK and autophagy inhibition holds therapeutic promise based on mechanism of action and preclinical data. We described characteristics and outcomes of patients (pts) treated with MEK-inh and HCQ at our institution. Methods: Ten KRAS-mutated advanced PDAC pts were treated with trametinib-HCQ (n = 9) or cobimetinib-HCQ (n = 1) off label due to lack of standard treatment options or toxicity concerns with cytotoxic systemic therapy. Trametinib dose was 2 mg once daily orally, Cobimetinib dose was 20 mg BID orally for 3/4 weeks cycles. HCQ was started at 200 mg BID and up-titrated weekly to 600 mg BID. Description of baseline and treatment (tx) characteristics, safety and efficacy is provided. Results: Median age at diagnosis was 61.3 years, and 7 pts were female. The number of prior lines of tx were 0/1/2/3/4 in 3/2/1/2/2 pts, respectively. KRAS mutations were: G12R/G12D/G12V/Q61H in 6/2/1/1 pts. Median overall survival was 6.6 months (m) in all pts, and 6.6/1.7 m in KRAS G12R/other KRAS (p = 0.31). Median progression-free survival was 5.7/6.2/1.5 m in all/ KRAS G12R/other KRAS (p = 0.16). Among 8 pts with evaluable response, 1 (12%) had partial response ( KRAS G12R) and 4 (50%) stable disease (3/4 KRAS G12R) as best response with disease control rate of 63%/80%/33% in total/ KRAS G12R/other KRAS (p = 0.29). Toxicity data are summarized in table 1. Conclusions: MEK-inh-HCQ demonstrated modest efficacy and manageable toxicities among KRAS G12R PDAC pts. Unlike G12D and G12V mutations in the KRAS gene, G12R is defective of conductive interactions for both PI3Ka and NF1. This ultimately results in a weakened signal being shunted through MAPK cascade and provides a unique opportunity where MEK inh can ablate signaling without the alternate pathways and WT-RAS isoforms compensating. Furthermore, as activation of PI3Ka is known to suppress autophagy, its lack of activation by KRAS G12R further sensitizes cells to HCQ. The combination therapy MEK-inh-HCQ is therefore mechanistically-rationale and warrants the further investigation of KRAS G12R as an actionable biomarker.[Table: see text]

Background: Readmission rates are a widely accepted quality indicator. Our objective was to study characteristics of readmissions at 30 and 180 days after Transcatheter Aortic Valve Replacement (TAVR). Methods: Patients undergoing TAVR between 2016 and 2017 in the U.S. Nationwide Readmission Database were evaluated for the rates, causes, predictors, and mortality of readmission at 30 and multiple readmission within 180 days after index discharge. Results: This analysis included 89601 hospitalizations; 13% were readmitted within 30 days and 8.7% were readmitted multiple times within 180 days. Most important predictors of readmissions, were Length of stay >5 days during index hospitalization (hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.47-1.71 at 30 days & HR 1.72; 95% CI 1.58-1.87 at 180 days), > 4 Charlson comorbidities (HR 1.27; 95% CI, 1.19-1.34 at 30 days & HR, 1.54; 95% CI, 1.44-1.65 at 180 days), discharge to skilled nursing facility (HR, 1.34; 95% CI, 1.24-1.44 at 30 days & HR, 1.49; 95% CI, 1.36-1.65 ), atrial fibrillation (HR, 1.25; 95% CI, 1.18-1.32 at 30 days & HR, 1.35; 95% CI, 1.26-1.45 at 180 days), Transapical TAVR approach (HR, 1.21; 95% CI, 1.04-1.42 & HR, 1.20; 95% CI, 1.01-1.43 at 180 days), and acute kidney injury (HR, 1.22; 95% CI, 1.12-1.32 at 30 days & HR, 1.1; 95% CI, 1.01-1.21 at 180 days)(Figure 1 A,B). 67% patients were readmitted at least 1 time within 180 days, 22% were readmitted 2 times within 180days and 11% were readmitted more than 3 times within 180 days. Readmissions were because of noncardiac causes in 67.8% of cases and because of cardiac causes in 32.2% of cases. Conclusion: The study demonstrates that baseline comorbidities alongside non-cardiac causes contributed significantly to readmissions after TAVR at both 30 days and 180 days. The results help to target the susceptible patients in both short as well as long term and to provide evidence-based interventions to reduce the risk and financial burden associated with readmissions.