Treatment Failure-free Survival Research Articles

Abiraterone Acetate Versus Enzalutamide Against Chemo-Naïve Castration-Resistant Prostate Cancer With Full-Dose Induction.

Purpose We recently released the multi-institutional real-world analysis about the difference in survival outcomes between abiraterone acetate and enzalutamide against chemo-naïve castration-resistant prostate cancer (CRPC) in a first-line setting. Although reduced dose induction cases were included in that analysis, induction dose reduction might correlate with reduced efficacy. In this study, we analyzed full-dose induction subgroups from our overall cohort and investigated the true difference in efficacy between these agents. Methods A total of 220 chemotherapy-naïve CRPC cases treated with full-dose induction of first-line androgen receptor signaling inhibitor (ARSI) were analyzed. Outcome measures were prostate-specific antigen (PSA) response, PSA progression-free survival (PSA-PFS), treatment failure-free survival (TFF), cancer-specific survival (CSS), and overall survival (OS). Results Abiraterone acetateand enzalutamide were administered to 58 and 162 patients, respectively. The median PSA response rate (-65.4% (A) and -81.5% (E), p = 0.0252), PSA decline ≥ 90% (22.4% (A) and 37.0% (E), p = 0.0478), PSA-PFS (median four months (A) and seven months (E), p = 0.00833), TFF (median six months (A) and 15 months (E), p<0.0001), CSS (median 45 months (A) and not reached (E), p < 0.0001), and OS (median 34 months (A) and 80 months (E), p<0.001) were significantly better in the E group. Conclusion This study showed that PSA response, PSA-PFS, TTF, CSS, and OS were better with first-line enzalutamide administration. Direct inhibition of androgen receptor signaling by enzalutamide is associated with better clinical outcomes in the full-dose induction cohort.

Comparative patient-reported tolerability (PRT): A multiplicity-controlled analysis of LIBRETTO-531, a randomized controlled trial (RCT) in medullary thyroid cancer (MTC).

11111 Background: In cancers with longer natural histories, progression free survival (PFS) alone may not adequately capture the impact of treatment side effects (SE) and may, therefore, be complemented by robust measures of patient-reported tolerability (PRT) to quantify overall SE burden. Here, we pioneer the use of a novel, scalable, quantitative PRT metric as a key secondary endpoint to support the regulatory review and inform clinical decision-making of selpercatinib use in LIBRETTO-531 (NCT04211337), an RCT that demonstrated the PFS benefit (HR=0.28) of selpercatinib over vandetanib/cabozantinib (control) in RET-mutant MTC. Methods: We first assessed PRT using the single Functional Assessment of Cancer Therapy (FACT) item GP5, asking patients to rate “bothered by treatment side effects” from 0 to 4. Patients who reported “3=quite a bit” or “4=very much” on GP5 were classified as “high SE bother,” a validated meaningful cutoff for treatment SE burden. In a second pre-specified step, PRT was defined as the proportion of time on treatment (PTOT) with “high SE bother” and was compared between selpercatinib vs. control arms in the tolerability evaluable population. PRT was tested at a 1-sided significance level of 0.025, conditional on achieving statistical significance for PFS and treatment failure-free survival by BICR. To complement PRT, other patient-reported outcomes including health-related quality of life (HRQoL, using EORTC QLQ-C30) and symptomatic adverse events (AEs; using PRO-CTCAE) were evaluated. We calculated the PTOT that patients reported clinically meaningful impairment of HRQoL (using pre-specified cutoff scores) and highly symptomatic AEs (scores of 3 or 4). Results: Patients on selpercatinib (n=161) had a significantly better PRT (lower PTOT with high SE bother) than control (n=81) (8% vs. 24%, p&lt;.0001). Sensitivity analyses using different cutoffs for high SE bother showed consistent results (p&lt;.0001). On QLQ-C30, patients on selpercatinib reported significantly less PTOT with HRQoL impairment across physical (36% vs. 52%), role (2% vs. 11%), cognitive (4% vs. 8%), emotional (6% vs. 11%), and social (2% vs. 8%) functions (all p&lt;0.01) vs. control. On PRO-CTCAE, patients on selpercatinib reported significantly less PTOT with diarrhea (5% vs. 38%), fatigue (6% vs. 21%), taste change (3% vs. 15%), decreased appetite (2% vs. 15%), hand/foot syndrome (2% vs. 9%) (all p&lt;.001) vs. control. Conclusions: Through the incorporation of a novel, single question and quantifiable metric that measured time on treatment under high SE bother into the LIBRETTO-531 study, we demonstrated superior PRT and improved PFS for selpercatinib in patients with RET-mutant MTC versus vandetanib/cabozantinib. This simplified PRT metric deserves further adoption as a quantitative endpoint to complement PFS in future RCTs.

Identification of genomic drivers for the therapeutic response of Cabozantinib in patients with metastatic renal cell carcinoma

PurposeCabozantinib (CAB) as monotherapy or in combination with immune checkpoint inhibitors is used for systemic treatment of metastatic renal cell carcinoma (mRCC). However, little is known about predictors of treatment response to CAB. For this reason, known genomic drivers were examined to identify potential predictors of treatment response with CAB.MethodsTwenty mRCC patients receiving monotherapy (≥ first-line) with CAB were prospectively included. DNA was extracted from archived primary tumors or metastatic tissue. Targeted DNA sequencing was performed using a gene panel including 328 genes (QIAseq Targeted DNA V3 Panel, Qiagen). The variant evaluation was performed using Varsome. The endpoints were treatment-failure-free-survival (TFFS) to CAB.Results26% of patients received systemic RCC treatment as the primary option. Six patients were treated with CAB in first-line (1L) and 12 patients in ≥ 2L. The median follow-up after initiation of systemic treatment was 26.7 months (mo). The PBRM1 (7 alleles), SETD2 (7 alleles), VHL (11 alleles), and CHEK2 (14 alleles) genes were most frequently altered. The median time to TFFS was 10.5 mo (95% confidence interval (CI) 6.2–14.7 mo). There was a longer treatment response to CAB in patients with alterations of the SETD2 gene (SETD2 alteration median TFFS not reached vs. no SETD2 alterations 8.4 mo (95% CI 5.2–11.6 mo); p = 0.024).ConclusionPathogenic variant genes may indicate treatment response to systemic therapy in mRCC. Patients with alterations of the SETD2 gene show longer responses to CAB treatment.

P1038 Does combination immunomodulator therapy impact real-world biologic effectiveness in Inflammatory Bowel Diseases?A propensity score analysis in patients treated with anti-TNF and non-anti-TNF biologics in the UK IBD BioResource

Abstract Background Randomised controlled trials have demonstrated that the combination of infliximab and azathioprine is superior to either drug as monotherapy both in patients with Crohn’s Disease (CD) and ulcerative colitis (UC). Data on the combination of other biological agents -including other anti-TNFs, vedolizumab and ustekinumab- and immunomodulators (IMMs) is lacking or shows conflicting results. Given the risks of combination therapy, physicians are often hesitant on whether to combine IMMs with biologic therapies. Methods We measured the effectivenessof biologic therapies [infliximab (IFX), adalimumab (ADA), golimumab (GLM), vedolizumab (VDZ) and ustekinumab (UST)] in patients with UC and CD with and without IMM use enrolled in the UK Inflammatory Bowel Disease (IBD) BioResource over long durations of followup.Demographic, disease, treatment and outcome data were retrieved. Inverse probability of treatment weighting (IPTW) was used to balance groups of those receiving vs those not receiving IMM using a propensity score-weighting approach accounting for baseline patient or disease related clinical characteristics. Effectiveness of treatment was based on persistence free of treatment discontinuation or treatment failure. Failure was defined as occurring if any of the following occurred: (a) clinician-recorded treatment failure (b) start of treatment with a different advanced therapy (c) occurrence of resectional or defunctioning bowel surgery. We compared Kaplan Meier curves for treatment failure-free survival after IPTW and used a log rank test for differences between the groups. Results In UC, we included 2479 patients receiving IFX (1173 on IMM), 1117 ADA (401 on IMM), 188 GLM (77 on IMM) and 1256 VDZ (392 on IMM). In CD, we included 5956 patients receiving IFX (3062 on IMM), 4524 ADA (1898 on IMM), 1067 VDZ (340 on IMM) and 627 UST (198 on IMM).As expected, combination IMM therapy was associated with increased drug effectiveness for IFX in both UC and CD. Combination IMM therapy was also associated with increased effectiveness of ADA in CD. For all other drugs, there was no significant benefit for combination IMM. Hazard ratios(HRs) for the effect of IMM of each drug effectiveness in UC and CD are summarised (Figure 1). Conclusion We confirm prior results indicated that IFX effectiveness is improved by concomitant use of an IMM in both UC and CD.In contrast to RCT data but in accordance to other robust real-world studies, we find evidence that for ADA in CD concomitant IMM can increase drug effectiveness. We find no evidence of benefit for concomitant IMM for other biologics in UC or CD.

Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer

BackgroundSelpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET-mutant medullary thyroid cancer in a phase 1–2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear.MethodsWe conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician’s choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure–free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety.ResultsA total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure–free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure–free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively.ConclusionsSelpercatinib treatment resulted in superior progression-free survival and treatment failure–free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.)

External validation of biochemical recurrence definition to predict oncologic outcomes following focal therapy for localized prostate cancer using high intensity focused ultrasound.

This is an external validation of several biochemical recurrence definitions based on prostate specific antigen criteria (PSA). The purpose is to predict the need of additional treatment and failure after focal therapy using high intensity focused ultrasound (HIFU) for localized prostate cancer (PCa). A total of 343 consecutive patients who underwent HIFU with Ablatherm® and Focal One® devices between June 2001 and November 2020 were identified. Treatment failure was defined as clinically significant PCa on postoperative biopsy, the need for salvage radical or systematic treatment, metastasis, or PCa-related death. The biochemical recurrence definitions tested were PSA nadir, time to PSA nadir, percentage of PSA reduction, Huber et al. criteria defined as PSA nadir + 1 ng/mL at 12 months or PSA nadir + 1.5 ng/mL at 24-36 months. Multivariable Cox regression analysis and decision-curve analysis were used to validate and compare criteria. Kaplan-Meier analysis was used to assess criteria associated with the highest accuracy. One hundred seventy-eight patients met the inclusion criteria and were analyzed. Overall, 61 (34%) and 41 (23%) patients had an additional treatment and failure with a median follow-up of 52 months. At multivariable analysis, model including Huber et al. criteria exhibited the highest Harrell's C-index for the prediction of the need of additional treatment (hazard ratio [HR]: 10, p < 0.001, c-index: 84%) and treatment failure (HR: 9.1, p < 0.001, c-index: 82%) as well as higher net benefit. The 60-months need of additional treatment and treatment failure-free survival were 89% and 98% compared to 26% and 49%, respectively, when stratified according to Huber et al. criteria (Log-rank test, p < 0.001). Similar results were found after excluding patient with non-clinically significant PCa at initial biopsy. We report an external validation of biochemical recurrence definitions predicting the need of additional treatment and failure after focal therapy using HIFU for localized PCa. Huber et al. criteria were identified as the most accurate and could be used to guide clinicians toward further evaluation and salvage treatments.

Multidrug chemotherapy, whole-brain radiation and cytarabine therapy for primary central nervous system lymphoma in elderly patients with dose modification based on geriatric assessment: study protocol for a phase II, multicentre, non-randomised study

IntroductionMultidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central nervous system lymphoma (PCNSL); however, prospective data regarding its use...

Staphylococcus lugdunensis prosthetic joint infection: A multicentric cohort study

ObjectivesTo describe Staphylococcus lugdunensis prosthetic joint infection (PJI) management and outcome. MethodsAdults with proven S. lugdunensis PJI were included in a multicentric retrospective cohort. Determinants for failure were assessed by logistic regression and treatment failure-free survival curve analysis (Kaplan-Meier). ResultsOne hundred and eleven patients were included (median age 72.4 [IQR, 62.7–79.4] years), with a knee (n = 71, 64.0%) or hip (n = 39, 35.1%) PJI considered as chronic in 77 (69.4%) cases. Surgical management consisted in debridement, antibiotic with implant retention (DAIR; n = 60, 54.1%), two-stage (n = 28, 25.2%) or one-stage (n = 15, 13.5%) exchange. Total duration of antimicrobial therapy was 13.1 (IQR, 11.8–16.9) weeks. After a median follow-up of 99.9 (IQR, 53.9–178.1) weeks, 22 (19.8%) S. lugdunensis-related treatment failures were observed. Independent determinants for outcome were diabetes (OR, 3.741; p = 0.036), sinus tract (OR, 3.846; p = 0.032), DAIR (OR, 3.749; p = 0.039) and rifampin-based regimen (OR, 0.319; p = 0.043). Twenty-four (40.0%) of the 60 DAIR-treated patients experienced treatment failure, with hip location (OR, 3.273; p = 0.048), delay from prosthesis implantation (OR, 1.012 per month; p = 0.019), pre-surgical CRP level >115 mg/L (OR, 4.800; p = 0.039) and mobile component exchange (OR, 0.302; p = 0.069) constituting additional determinants of outcome. ConclusionsStaphylococcus lugdunensis PJI are difficult-to-treat infections, with pivotal roles of an optimal surgical management.

Comparative survival analysis of platinum-based adjuvant chemotherapy for early-stage squamous cell carcinoma and adenocarcinoma of the lung.

Background and PurposeAlthough cytotoxic platinum‐based adjuvant chemotherapy (pACT) has been recommended for patients with completely resected early‐stage (ES) non–small‐cell lung cancer (ES‐NSCLC), therapeutic regimens for NSCLC have evolved in the past two decades. The study was aimed to examine the effectiveness of postoperative pACT for resected ES‐NSCLC patients with squamous cell carcinoma (SCC) or adenocarcinoma (ADC) according to real‐world data.Methods and PatientsInverse probability treatment weighting (IPTW) was used to adjust baseline characteristics between the group receiving pACT and those not receiving any treatment (observation, OBS) within 3 months after curative surgery. Cox regression models were used to compare overall survival (OS) and treatment failure‐free survival (TFS) between the groups.ResultsOf 31,208 patients with ES‐NSCLC, 4700 undergoing complete tumor resection were eligible, with a mean follow‐up period of 4.5 years. The pACT (n = 2347) and OBS (n = 2353) groups were well‐balanced after IPTW. The median OS differed between the pACT and OBS groups (77.2 vs. 75.5 months, adjusted hazard ratio [aHR] = 0.87, 95% confidence interval [CI] = 0.79–0.95, p = 0.003), and the 5‐year survival rates were 58.2% and 55.3%, respectively (p < 0.001). In the SCC group, pACT was superior to OBS in OS (75.0 vs. 57.4 months, aHR = 0.74, 95% CI = 0.62–0.88, p = 0.001) and TFS (32.7 vs. 21.8 months, aHR = 0.74, 95% CI = 0.63–0.86, p < 0.001). Both OS and TFS did not differ between two groups in those with ADC.ConclusionReal‐world data indicated that pACT confers a survival benefit for resected ES‐NSCLC patients with SCC but not ADC, which needs to be verified by a large sample of randomized controlled studies.

Hydroxychloroquine versus tacrolimus for the treatment of persistently active systemic lupus erythematosus.

We aimed to reveal the effectiveness of hydroxychloroquine (HCQ) compared with tacrolimus (TAC), an immunosuppressive agent, in patients with systemic lupus erythematosus (SLE) with persistent activity on standard treatment. We retrospectively compared the efficacy and safety of the treatment between 18 patients receiving HCQ and 27 patients receiving TAC. None of the patients were in the lupus low disease activity state (LLDAS) at the beginning of this study. The efficacy end points were the cumulative incidence of LLDAS attainment without additional immunosuppressive agents, drug continuation rate, and treatment failure-free survival. The safety end point was the frequency of adverse events. Eight (44.4%) patients in the HCQ group and 10 (37.0%) patients in the TAC group achieved LLDAS during the follow-up period; thus, the cumulative incidences of LLDAS attainment of the two treatments were nearly identical. The drug continuation and treatment failure-free survival rates were also not different between the two groups. The frequency of adverse events showed no clear differences between the two groups. The efficacy and safety of an add-on treatment with HCQ are similar to those with TAC. Patients with persistently active SLE can benefit from HCQ in efforts to achieve at least low disease activity.

Ruxolinitib As Salvage Therapy for Chronic Graft-Versus-Host Disease

Background:Chronic graft-versus-host disease (cGVHD) remains a common and potentially life-threatening complication after allogenic hematopoietic stem cell transplantation (HCT). Systemic corticosteroids are first-line therapy, however, they are often associated with inadequate responses and multiple side effects. There has been no single standard therapy for refractory cGVHD. Recently, ruxolitinib, a selective JAK1/2 inhibitor, has been suggested to have efficacy as salvage therapy in cGVHD. However, data are limited to a multi-center retrospective survey of 41 patients (Zeiser et al. Leukemia. 2015; 29(10):2062-8). Herein, we present a single-institution's experience with ruxolitinib as salvage therapy for management of refractory cGVHD.Methods:In this single-center, IRB-approved, retrospective analysis, the charts of 47 patients who received ruxolitinib as salvage therapy for cGVHD from March 2016 through December 2016 were reviewed. Clinical data were collected and analyzed at start of ruxolitinib treatment, 3 months-post, and 6 months-post to identify changes in prednisone dose, patient perceived improvement, physician perceived improvement, and incidence of adverse events including hospitalizations, documented infections, cytopenias, relapse, and death. In addition, we assessed for treatment failure-free survival (FFS) from the time of ruxolitinib to any of the following events: initiation of new cGVHD therapy, relapsed disease, patient death, or discontinuation of ruxolitinib.Results:The cohort consisted of 47 patients (median age = 51; range = 21 - 91; 21 females and 26 males) who received fully ablative (n=26) or reduced-intensity conditioning (n=18) followed by an allogeneic HCT from matched related donor (n=15), unrelated donor (n=13), or other donor sources (cord or haplo-identical donors: n=16) for their hematologic disorders. The median time from HCT to ruxolitinib initiation was 40.5 months (range: 3.8 to 267.2). Of the 47 patients in this cohort, 38 patients (80.9%) had sclerotic chronic graft versus host disease.The average dose of prednisone in evaluable patients was 11.1 mg/day (95% CI 6.9 - 15.3 mg/day) at time of ruxolitinib initiation, which decreased to 7.7 mg/day (95% CI 4.1 - 11.4 mg/day, p=0.043 by paired signed rank test, 30% reduction) at 3 months, and 5.6 mg/day (95% CI 3.2 - 8.0, p<0.001, 49% reduction) after 6 months of ruxolitinib therapy. There were 12 patients (36%) and 14 patients (42%) who experienced prednisone dose reduction at 3 & 6 months, respectively. Patient-reported subjective improvement was observed in 22 of 41 evaluable patients (53.7%) and 23 of 37 evaluable patients (62.2%) at 3 and 6 months, respectively. Physicians rated subjective improvement in 29 patients (70.7%) at 3 months and 25 patients (67.6%) at 6 months. Infections were documented in 25 patients (56.8%), of which 6 (12.8%) were considered life-threatening. Two patients (4.2%) with CMV viremia with no end-organ disease were identified. Significant cytopenias requiring ruxolitinib dose reduction or discontinuation were observed in 3 patients (7.0%). During the study period of 6 months, 18 patients (40.9%) required hospitalization at least once, and 6 patients (12.8%) died within first 6 months of ruxolitinib use. Treatment failure-free survival at 6 months was 68.1% (95%CI; 52.7% to 79.4%) with the failure events including death (n=6), relapse (n=2), addition of new therapy (n=2), and discontinuation of ruxolitinib for any reason other than resolution of cGVHD symptoms (n=6) (Figure 1).Conclusion:Ruxolitinib is associated with prednisone reduction after 3 and 6 months, self-/physician-reported improvements, and favorable FFS at 6 months in patients with steroid-refractory chronic GVHD. Prospective randomized trials are warranted to further define its therapeutic benefits and risks of cytopenia/infectious complications. [Display omitted] DisclosuresSalhotra:Kadmon: Consultancy.

Characteristics and probability of survival for patients with advanced melanoma who live five or more years after initial treatment with immune checkpoint blockade (ICB).

9534 Background: A subset of melanoma patients treated with ICB (ipilimumab [ipi], nivolumab [nivo], pembrolizumab [pembro] or nivo+ipi) will experience durable responses. While five-year survival rates have been reported for patients treated with ICB on clinical trials, little is known about the clinical characteristics, survival past five years, and patterns of late relapse of long-term survivors. Methods: We retrospectively reviewed all patients treated at Memorial Sloan Kettering for unresectable stage III/IV melanoma who survived at least five years following their first dose of ICB (N = 151). Demographics, disease characteristics, and nature of progression were examined. Overall survival (OS) was calculated from 5 years post-ICB. Time to Treatment failure (TTF) was calculated conditionally from 5 years out until next therapy, progression, or death. Results: Of the 151 long-term survivors, median age at first ICB treatment was 62 years (range 22-83), with 101 (66.9%) male and 50 (33.1%) female patients. Stage at first ICB treatment was unresectable stage III (26, 17.2%), M1a (21,13.9%), M1b (39, 25.8%), M1c (52, 34.4%), M1d (13, 8.6%). Melanoma subtype was cutaneous (122, 80.8%), unknown primary (24, 15.9%), mucosal (3, 2%), and acral (2, 1.3%). First ICB was ipi (108, 71.5%), PD-1 (nivo or pembro) (5, 3.3%), and nivo+ipi (37, 24.5%). The best overall response to first ICB was CR (76, 50.3%), PR (27, 17.9%), SD (16, 10.6%) and PD (32, 21.2%). Of the patients who progressed after initial ICB, 38 received subsequent systemic treatment as follows: PD-(L)1 in 20 (53%), BRAF ± MEK in 9 (23.7%), ipi in 7 (18.4%), and chemotherapy in 2 (5.3%). Median duration of follow-up among survivors (N = 138) was 93 months (range 60-192). From 5 years post-ICB, 85% (95% CI: 73-92%) survived an additional 5 years. In those who made it to 5 years without treatment failure (N = 72), the probability of remaining failure-free was 92% (95% CI: 86-99%) at 7 years. Of the 151 patients, only 4 patients (2.6%) experienced disease progression after 5 years. Three patients had radiographic or pathologic disease progression in the lymph nodes and one in the subcutaneous tissue. No patients progressed in the lungs, visceral organs, or CNS after 5 years. At time of analysis, 13 (8.6%) patients died after 5 years post ICB, none died of progressive melanoma. 6 patients died of unknown causes, 2 died of other causes, and 5 died of other non-melanoma cancer-related causes. Conclusions: Patients who survive five years after their initial immunotherapy have excellent overall survival and treatment failure-free survival. Given the anxiety surrounding survivorship and late progression, long-term survivors should be reassured of their excellent prognosis. These data suggest that aggressive follow-up schedules and imaging of melanoma patients after 5 years of survival may not be required.

Clinical Outcomes of Platinum-ineligible Patients with Advanced Urothelial Carcinoma Treated With First-line PD1/L1 Inhibitors

PD1/L1 inhibitors are approved by FDA as first-line therapy for patients with advanced urothelial carcinoma (aUC) who are cisplatin-ineligible with high tumor PD-L1 expression or are platinum-ineligible regardless of PD-L1 expression. However, the outcomes when employing PD1/L1 inhibitors for platinum-ineligible patients are unclear. This retrospective analysis evaluates the clinical outcomes of first-line PD1/L1 inhibitors in patients with aUC deemed to be platinum-ineligible. Data were retrospectively collected from 8 academic institutions. The following criteria were used to define platinum ineligibility: creatinine clearance (CrCl) < 30 mL/min; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 3; CrCl 30 to 59 mL/min and ECOG PS 2; elderly and/or comorbidities. Patient characteristics, responses and treatment-related toxicities were identified. Survival curves were estimated by the Kaplan-Meier method. A Cox regression analysis was conducted to explore the association of baseline variables with response and survival. A total of 79 platinum-ineligible patients with aUC were eligible. Patients were treated with atezolizumab (51.9%), pembrolizumab (35.5%), nivolumab (8.9%), or durvalumab (3.8%). The objective response rate was 27.9%. The median overall survival was 45 weeks (95% confidence interval [CI], 32-80), and the median treatment failure-free survival was 16 weeks (95% CI, 9-18). Treatment-related toxicity of any grade and grade ≥ 3 was seen in 41.8% and 31.7% of patients, respectively. Anemia and liver metastasis were associated with worse survival. The efficacy of first-line PD1/L1 inhibitors for platinum-ineligible patients with aUC in the real world appears comparable to those reported in trials of unselected cisplatin-ineligible patients, whereas grade ≥ 3 toxicities appear more common. Further validation is required including data based on PD-L1 status and other biomarkers. Platinum-ineligible patients with aUC warrant evaluation of novel, safe, and effective agents.

Salvage High-Intensity Focused Ultrasound for Local Recurrence in the Prostatic Bed after Prostatectomy and Adjuvant or Salvage Radiotherapy: Preliminary Results.

We sought to report the preliminary results of salvage high-intensity focused ultrasound for locally recurrent prostate cancer in the prostatic bed after radical prostatectomy and adjuvant or salvage radiotherapy. We retrospectively analyzed a single-center cohort of men treated with salvage high-intensity focused ultrasound for locally recurrent prostate cancer after radical prostatectomy and adjuvant or salvage radiotherapy. All patients had a combination of choline positron emission tomography, multiparametric magnetic resonance imaging, and transrectal biopsies to confirm the local recurrence. Treatment failure was defined as persistent or recurrent prostate cancer in the prostatic bed and/or metastasis and/or introduction of systemic treatment. Progression was defined as metastasis and/or introduction of systemic treatment. Complications (Clavien-Dindo classification) and continence (Ingelman-Sundberg score) were evaluated. Kaplan-Meier analysis estimated oncological outcomes. Between July 2009 and November 2018, 22 patients were included; the median followup was 2.32 years. At 3 years, treatment failure-free survival rate was estimated to be 49.7% and progression-free survival rate 60.4%. Prostate specific antigen nadir ≤0.2 ng/ml was reached in 50% of the patients. A nadir of ≤0.2 ng/ml was significantly associated with better treatment failure-free and progression-free survival probabilities (p=0.003 and p=0.037, respectively). Grade III complications occurred in 6 patients (27.3%). Onset of grade II-III incontinence was significantly more frequent in cases of perianastomotic (36.4%) compared to retrovesical recurrence (0%; p=0.027). Salvage high-intensity focused ultrasound for locally recurrent prostate cancer after radical prostatectomy and salvage radiotherapy showed encouraging oncological results despite significant morbidity. The perianastomotic recurrence was linked to a higher risk of incontinence.

Temporal Arteritis Revealing Antineutrophil Cytoplasmic Antibody-Associated Vasculitides: A Case-Control Study.

Temporal arteritis (TA) is a typical manifestation of giant cell arteritis (GCA). Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are rarely revealed by TA manifestations, leading to a risk of misdiagnosis of GCA and inappropriate treatments. This study was undertaken to describe the clinical, biologic, and histologic presentations and outcomes in cases of TA revealing AAV (TA-AAV) compared to controls with classic GCA. In this retrospective case-control study, the characteristics of patients with TA-AAV were compared to those of control subjects with classic GCA. Log-rank test, with hazard ratios (HRs) and 95% confidence intervals (95% CIs), was used to assess the risk of treatment failure. Fifty patients with TA-AAV (median age 70 years) were included. Thirty-three patients (66%) presented with atypical symptoms of GCA (ear, nose, and throat involvement in 32% of patients, and renal, pulmonary, and neurologic involvement in 26%, 20%, and 16% of patients, respectively). Blood samples were screened for ANCAs at the time of disease onset in 33 patients, and results were positive in 88%, leading to a diagnosis of early TA-AAV in 20 patients. The diagnosis of AAV was delayed a median interval of 15 months in 30 patients. Compared to controls with GCA, patients with TA-AAV were younger (median age 70 years versus 74 years), were more frequently men (48% versus 30%), and had high frequencies of atypical manifestations and higher C-reactive protein levels (median 10.8 mg/dl versus 7.0 mg/dl). In patients with TA-AAV, temporal artery biopsy (TAB) showed fibrinoid necrosis and small branch vasculitis in 23% of patients each, whereas neither of these characteristics was evident in controls with GCA. Treatment failure-free survival was comparable between early TA-AAV cases and GCA controls, whereas those with delayed TA-AAV had a significantly higher risk of treatment failure compared to controls (HR 3.85, 95% CI 1.97-7.51; P < 0.0001). TA-AAV should be considered diagnostically in cases of atypical manifestations of GCA, refractoriness to glucocorticoid treatment, or early relapse. Analysis of TAB specimens for the detection of small branch vasculitis and/or fibrinoid necrosis could be useful. Detection of ANCAs should be performed in cases of suspected GCA with atypical clinical features and/or evidence of temporal artery abnormalities on TAB.

68Ga-PSMA-PET/CT-based radiosurgery and stereotactic body radiotherapy for oligometastatic prostate cancer.

Androgen deprivation therapy (ADT) remains the standard therapy for patients with oligometastatic prostate cancer (OMPC). Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT)-based stereotactic body radiotherapy (SBRT) is emerging as an alternative option to postpone starting ADT and its associated side effects including the development of drug resistance. The aim of this study was to determine progression free-survival (PFS) and treatment failure free-survival (TFFS) after PSMA-PET/CT-based SBRT in OMPC patients. The efficacy and safety of single fraction radiosurgery (SFRS) and ADT delay were investigated. Patients with ≤5 metastases from OMPC, with/without ADT treated with PSMA-PET/CT-based SBRT were retrospectively analyzed. PFS and TFFS were primary endpoints. Secondary endpoints were local control (LC), overall survival (OS) and ADT-free survival (ADTFS). Fifty patients with a total of 75 metastases detected by PSMA-PET/CT were analyzed. At the time of SBRT, 70% of patients were castration-sensitive. Overall, 80% of metastases were treated with SFRS (median dose 20 Gy, range: 16-25). After median follow-up of 34 months (range: 5-70) median PFS and TFFS were 12 months (range: 2-63) and 14 months (range: 2-70), respectively. Thirty-two (64%) patients had repeat oligometastatic disease. Twenty-four (48%) patients with progression underwent second SBRT course. Two-year LC after SFRS was 96%. Grade 1 and 2 toxicity occurred in 3 (6%) and 1 (2%) patients, respectively. ADTFS and OS rates at 2-years were 60.5% and 100%, respectively. In multivariate analysis, TFFS significantly improved in patients with time to first metastasis (TTM) >36 months (p = 0.01) and PSA before SBRT ≤1 ng/ml (p = 0.03). For patients with OMPC, SBRT might be used as an alternative to ADT. This way, the start/escalation of palliative ADT and its side effects can be deferred. Metastases treated with PSMA-PET/CT-based SFRS reached excellent LC with minimal toxicity. Low PSA levels and longer TTM predict elongated TFFS.

Impact of sickle cell disease on presentation and progression of paediatric HIV: a retrospective cohort study.

HIV and sickle cell disease (SCD) are significant causes of morbidity and mortality in sub-Saharan Africa. Given their separate roles in immune dysregulation, our objective was to characterise the impact that SCD has on the presentation and progression of paediatric HIV. The study was a retrospective cohort study (study period 2004-2018). Cases of HIV+and SCD-afflicted patients (HIV+/SCD+) were obtained via electronic chart review from a paediatric HIV clinic in Kampala, Uganda and matched 1:3 with HIV+controls without SCD (HIV+/SCD-). Thirty-five HIV+/SCD+subjects and 95 HIV+/SCD- controls were analysed (39% female (51/130), age 3.6years (SD3.9)). At baseline, WHO clinical stage (64% total cohort Stage III/IV) and nutritional status (9.4% severe acute malnutrition) were similar for both groups, whereas HIV+/SCD+had higher though non-significant baseline CD4 count (1036 (SD713) vs 849 (SD638) cells/microlitre, P=0.20, two-tailed t-test). There were 19 deaths, 6 (17%) HIV+/SCD+and 13 (14%) HIV+/SCD-, with unadjusted/adjusted models showing no significant difference. Nutritional progression and clinical stage progression showed no significant differences between groups. Kaplan-Meier analysis showed a slower rate of treatment failures in the HIV+/SCD+cohort (P=0.11, log-rank survival test). Trajectory analysis showed that in the time period analysed, the HIV+/SCD+cohort showed a more rapid rise and higher total CD4 count (P=0.012, regression analysis). The study suggests that SCD does not adversely affect the progression of HIV in patients on ART. Further, HIV+/SCD+achieved higher CD4 counts and fewer HIV treatment failures, suggesting physiological effects due to SCD might mitigate HIV progression.

MP35-01 INTERNAL URETHROTOMY AS PRIMARY TREATMENT FOR UNTREATED BULBAR URETHRAL STRICTURES

INTRODUCTION AND OBJECTIVE: Direct visual internal urethrotomy (DVIU) represents the most common surgical procedure for urethral strictures’ repair. Nevertheless, since the selection of the patients, follow up criteria, and assessment of success and failure are not homogeneous, the evaluation of short and long-term outcomes after DVIU appear challenging. The aim of this retrospective study is to investigate the outcomes and identify the predictors of failure for DVIU as primary treatment for untreated bulbar urethral strictures, performing a multivariable analysis of the results of DVIU in a homogeneous series of patients who underwent a strict follow up after surgery. METHODS: A retrospective descriptive analysis on a cohort of patients who DVIU in a referral center for reconstructive urethral surgery was performed. Patients who underwent DVIU for untreated bulbar urethral strictures with a 12 months’ follow-up were included. The primary outcome was treatment failure, defined as any postoperative instrumentation. All patients underwent preoperative evaluation using urine culture, uroflowmetry, post-void residual (PVR), retrograde urethrogram, voiding cystourethrogram, and urethral ultrasonography. Follow-up visits were scheduled every 4 months in the first year and every 6 months later including urine culture, uroflowmetry and PVR. Statistical analyses consisted of Kaplan-Meyer plots to depict treatment-failure free survival and univariate and multivariable Cox regression analysis to test the association between predictors and treatment failure. RESULTS: 136 patients were included. The median stricture length was 2 cm. Median follow-up was 55 months. At 5-years follow-up failure-free survival rate was 57%. At univariate analysis, presence of diabetes, non-idiopathic etiology, stricture length of 3-4 cm, and pre-operative maximum flow were significantly associated with treatment failure (p value <0.00001). These predictors were included at multivariable analysis, where pre-operative maximum flow was the only significant predictor of treatment failure. Patients were stratified into three groups based on pre-operative maximum flow: ≤5ml/s, 5-8 ml/s, ≥8 ml/s. Failure-free survival at 5 years after surgery was significantly different in the three groups: 31% vs. 53% vs. 83% (p<0.00001). Similarly, stratifying according to stricture length (1-2 cm vs. 2-3 cm vs. 3-4 cm), a significantly different treatment failure-free survival was observed at 5 years (71% vs. 51% vs. 39%; p<0.00001). CONCLUSIONS: The failure of internal urethrotomy for untreated bulbar urethral strictures depends on pre-operative maximum flow at uroflowmetry. Patients with pre-operative maximum flow>8ml/s have a high rate of success, and patients with maximum flow<5 ml/s have low chances of success. The success rates of DVIU as primary treatment in patients with stricture lengths of 1-2 cm compared to longer strictures was statistically significant, however the use of DVIU for untreated bulbar urethral stricture should be suggested only in selected cases. Source of Funding: None

MP09-18 MISSENSE POLYMORPHISM IN SRD5A2 IN COMBINATION WITH HSD3B1 VARIATION IS ASSOCIATED WITH OUTCOME OF CASTRATION-RESISTANT PROSTATE CANCER PATIENTS TREATED WITH ABIRATERONE

INTRODUCTION AND OBJECTIVE: Missense polymorphism in HSD3B1, encoding 3β-hydroxysteroid dehydrogenase-1, was associated with outcome after abiraterone treatment. However, the impact of missense polymorphism in SRD5A2 encoding 5α-reductase type 2 has not been reported. In this study, we investigated the significance of missense polymorphism in SRD5A2 gene and in combination with HSD3B1 variation in prostate cancer patients treated with abiraterone. METHODS: A total of 99 Japanese male castration-resistant prostate cancer patients treated with abiraterone between 2014 and 2018 were included. Genomic DNA was obtained from whole blood samples, and genotyping on SRD5A2 (rs523349, V89L) was performed by PCR-based technique. The association of HSD3B1 and SRD5A2 genotypes with clinicopathological parameters and oncological outcome, including treatment failure-free survival and overall survival, was examined. RESULTS: Among the 99 patients, 32 (32.3%), 49 (49.5%), and 18 patients (18.2%) carried GG, GC, and CC alleles in SRD5A2, respectively. CC allele was associated with lower risk of treatment failure (hazard ratio, 0.43; 95% confidence interval, 0.20–0.87; P = 0.017) on multivariate analyses, compared with GG/GC alleles (Fig. A). In the combination model using HSD3B1 and SRD5A2 polymorphisms, compared with the combination of AA in HSD3B1 and GG/GC in SRD5A2, other combinations were associated with lower risk of treatment failure (hazard ratio, 0.34; 95% confidence interval, 0.17–0.62; P = 0.0003) on multivariate analyses (Fig. B). CONCLUSIONS: This study showed that SRD5A2 genetic variation was associated with the risk of treatment failure in abiraterone. Combinational use of genetic variation in HSD3B1 with SRD5A2 genetic variation augmented the ability of prognostic stratification.Source of Funding: JSPS KAKENHI grant (17K11145)

Genetic 3\u2032UTR variations and clinical factors significantly contribute to survival prediction and clinical response in breast cancer patients

The study describes a relationship between the 3′UTR variants, clinicopathological parameters and response to chemotherapy. We analyzed 33 germline polymorphisms in 3′UTRs of ADME genes in 305 breast cancer women treated with FAC regime. Clinical endpoints of this study were: overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS) and overall response defined as treatment failure-free survival (TFFS). The shortened OS was connected with the presence of NR1/2 rs3732359 AA, SLC22A16 rs7756222 CC, as well as SLC22A16 rs9487402 allele G and clinical factors belonging to TNM classification: tumor size >1 cm, nodal involvement and presence of metastases. PFS was related to two polymorphisms PGR rs1824125 GG, PGR rs12224560 CC and SLC22A16 rs7756222 CC as well as preexisting metastases. The RFS was shortened due to the DPYD rs291593 CC, AKR1C3 rs3209896 AG and negative expression of PGR. The presence of ALDH5A1 rs1054899 allele A, lack of pre-chemotherapy surgery and negative status of PGR correlated with worse treatment response. The germline variants commonly present in the population are important factors determining the response to treatment. We observed the effect of the accumulation of genetic and clinical factors on poor survival prognosis and overall treatment response.