Citations

4023 Background: Metastatic pancreatic cancer (mPC) remains a deadly disease with very limited treatment options. FFX is a standard first-line therapy for mPC with a median overall survival (mOS) of 11.1 months. CPI-613 is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic cycle preferentially within the mitochondria of cancer cells. In a phase I study, CPI-613+mFFX was safe and exhibited promising signal of efficacy. Methods: A global, randomized phase 3 trial was conducted across 73 sites to investigate the efficacy and safety of CPI-613 in combination with mFFX compared to standard dose FFX in treatment-naïve patients with mPC. Treatment was administered in 2-weekly cycles until progression or intolerable toxicity. In the experimental arm, CPI-613 at 500 mg/m2 was given intravenously on days 1 and 3. The doses of irinotecan, oxaliplatin, and 5-fluorouracil in the experimental arm were 65 mg/m2, 140 mg/m2, and 2,400 mg/2, respectively. Primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics, patient reported outcomes and safety. Results: 528 patients were randomly assigned (266 in test and 262 in control arm). There were 362 deaths, with a mOS of 11.1 months for CPI-613+mFFX vs. 11.7 months for FFX [hazard ratio (HR), 0.95; 95% CI, 0.77 to 1.18; P = 0.655]; mPFS was 7.8 months vs. 8.0 months respectively [HR, 0.99; 95% CI, 0.76 to 1.29; P = 0.94]; ORR was 39% in the test arm vs. 34% in the control arm [ORR ratio, 1.23 (95% CI, 0.86 to 1.75)]. Grade ≥ 3 treatment-emergent adverse events with ≥ 10% frequency in CPI-613 plus mFFX vs. FFX arm were diarrhea (11.2% vs. 19.6%), hypokalemia (13.1% vs. 14.9%), anemia (13.9% vs. 13.6%), neutropenia (11.2% vs. 14.0%), thrombocytopenia (11.6% vs. 13.6%) and fatigue (10.8% vs. 11.5%). Conclusions: The addition of CPI-613 to mFFX failed to show significant improvements of ORR, PFS or OS. The mFFX in the test arm that had the lowest prospectively tested doses of FFX was without compromise on PFS or OS and may be considered as a reference for future FFX administration. Clinical trial information: NCT03504423.

3067 Background: The KEYNOTE-177 trial demonstrated pembrolizumab’s superiority over first-line chemotherapy in patients with MSI-H/dMMR mCRC. However, in a subgroup analysis, patients with KRAS or NRAS mutations did not show the same favorable PFS benefit with PD-1 blockade therapy (HR 1,19; CI 0.68-2,07). The impact of RAS mutations on the immunologic characteristics of the TME of MSI-H/dMMR CRC has not been well characterized. Methods: A retrospective review of deidentified records of patients with MSI-H/dMMR CRC tumors was conducted using next-generation sequencing data (Tempus |xT assay, DNA-seq of 595-648 genes at 500x coverage, and full transcriptome RNA-seq). MSI-H determined by assessment of 239 loci by NGS. Several immune markers were assessed, including tumor mutational burden (TMB), neoantigen tumor burden (NTB, ScanNeo), PD-L1 expression, immune infiltration, and canonical immune pathways (82 geneset signatures). Results: A total of 463 MSI-H/dMMR CRCs were analyzed, of which 110 (24%) tumors harbored RAS mutations ( RASmut) [ KRAS: 93%, NRAS 6% and HRAS 1%}, while 353 were RAS-wild-type ( RASWT). Compared to MSI-H/dMMR RASWT, MSI-H/dMMR RASmut tumors were more frequently identified in males (53% vs. 38%; P= 0.005), and younger patients (median age: 57 yrs vs. 71 yrs, P< 0.001). Although there were no significant differences in median TMB (40 mut/MB for both, p = 0.9) or frequency of TMB-high status (≥10 mut/MB) between the two groups, RASmuttumors tended to have a lower tumor NTB (16 vs. 12 neoAg/Mb, P <0.001) and lower % CD8 T cell but higher % CD4 T cell infiltration (P < 0.05). Significant differences were observed in genomic alterations co-occurring with RASmut compared to RASWT (e.g., MLH1 (23% vs. 8.8%, P < 0.001), MSH6 (36% vs. 24%, P = 0.017), APC (60% vs. 20%, P< 0.001), ARID1A (54% vs 30%, P< 0.001), PIK3CA (36% vs 19%, P< 0.001), and TP53 (32% vs. 19%, P = 0.014). Pathway enrichment analysis identified 14 differentially expressed pathways among RASmut tumors. Four pathways showed significant upregulation, including Hedgehog, Wnt, TGFβ, and cancer stem cell pathways. Ten pathways of interest showed significant downregulation among RASmut tumors. The majority (9/10) were immune-related, including cytokine signaling [ JAK-STAT, TGFβ, TH1], innate immune [ NK cells], and adaptive immune events (CD8 T cell, Tregs)]. Conclusions: MSI-H/dMMR CRCs harboring RASmut exhibited overall upregulated WNT/SHH pathway activity, coupled with reduced NTB, cytokine signaling, and innate and adaptive immune events. TGFβ is pleiotropic, and different members were associated with variable modulation. These data suggest that MSI-H/dMMR CRCs harboring RAS mutations are less immunogenic and appeared to contain a TME that is less sensitive to immune checkpoint blockade than MSI-H/dMMR RAS wt CRCs.

3066 Background: The BRAFV600E mutation is associated with the hypermethylator phenotype CIMP, which can also lead to the MSI-H phenotype. BRAFV600E mutation and MSI-H/dMMR status seem to be biologically intertwined; however, the impact of coexisting BRAFV600E mutations on the TME and immunometabolomic features of MSI-H/dMMR CRC tumors is not well characterized. Methods: A retrospective review of deidentified records of patients with MSI-H/dMMR CRC tumors was conducted using next-generation sequencing data (Tempus |xT assay: DNA-seq of 595-648 genes at 500x coverage, and full transcriptome RNA-seq). Several immune markers of tumor immunogenicity in BRAF wild-type ( BRAFwt) vs. V600E-mutated (BRAFV600E) tumors were assessed, including tumor mutational burden (TMB), neoantigen tumor burden (NTB, ScanNeo), PD-L1 expression, immune infiltration, and canonical immuno-metabolomic pathways (82 geneset signatures). Results: A total of 459 MSI-H/dMMR CRC tumors were analyzed, of which 123 (27%) tumors harbored BRAFV600Emutations, and 336 (73%) were BRAFwt. MSI-H/dMMR BRAFV600E tumors were more frequently identified in females (69% vs. 55%; P= 0.01), non-Hispanic or non-Latino (100% vs. 73%; P =0.001), and older patients (median age: 76 yrs vs. 62 yrs; P< 0.001). Compared to BRAFWT, BRAFV600E tumors exhibited significantly higher TMB (Median: 49 mut/MB vs. 36 mut/MB; P < 0.001) and were more frequently associated with TMB-High status (> 10 mut/MB; 100% vs. 95%; P = 0.008); however, no significant differences were observed with tumor NTB, immune score, or T cell infiltration (CD4 or CD8). NK cell infiltration was higher in the BRAFV600Ecohort (< 0.001). When compared to BRAFWT tumors , BRAFV600E tumors harbored a greater frequency of mutations in MSH6(42% vs. 20%), B2M (33% vs. 16%), BRCA2 (31% vs. 12%), ATM (23% vs. 12%), and TP53 (30% vs. 19%) but a lower frequency of MSH2 (3.3% vs. 11%), all P< 0.05. Pathway enrichment analysis identified 10 significantly altered signaling pathways, most of which related to stromal/immune cell signaling and metabolism. Five were upregulated among BRAFV600E tumors: glycerophospholipid, galactose, cyclin-dependent cell signaling; Nucleotide, and TH1 inflammation. Five pathways were downregulated (Wnt, Notch, TH17 inflammation, amino sugar, and cancer stem cell signaling). Conclusions: MSI-H/dMMR BRAFV600E CRCs undergo broad metabolic reprogramming (e.g., glycerophospholipidgalactose, nucleotide). A rise in lipid metabolism, particularly with NK inflammation, suggests that BRAFV600Emutated tumors may be associated with a non-classical immune component. BRAFV600E and BRAFwt CRCs exhibited similar NTB and T cell infiltration, suggesting that both are likely to benefit from immune checkpoint inhibitors.

AbstractAchalasia is rare in the pediatric population and should prompt clinicians to consider genetic disorders associated with this condition. While AAA syndrome (also known as Allgrove or Triple A syndrome) is commonly considered, GMPPA‐congenital disorder of glycosylation (CDG) should also be in the differential diagnosis. We report a 9‐month‐old female born to nonconsanguineous parents with achalasia and alacrima found to have two novel compound heterozygous variants in the GMPPA gene associated with GMPPA‐CDG. This rare disorder is commonly associated with developmental delay and intellectual disability. We discuss management of this disorder including the importance of confirming a genetic diagnosis and summarize reported cases.

Abstract Introduction Transnasal access to the anterior skull base provides a minimally invasive approach for sellar and parasellar masses compared with its open counterparts. The unique microbiome of the sinonasal mucosa provides distinct challenges not encountered with other cranial approaches. The use of antibiotics in these cases has not been standardized, and data remain scarce regarding infectious outcomes. Methods We conducted a multicenter retrospective analysis of shared quality data points for the endoscopic endonasal approach (EEA) for pituitary adenomas, along with other sellar and parasellar region masses that were included by participating institutions. Patient and operative characteristics, perioperative and postoperative antibiotic regimens and their durations, intraoperative and postoperative cerebrospinal fluid leak, and onset of postoperative meningitis and sinusitis were compared. Results Fifteen institutions participated and provided 6 consecutive months' worth of case data. Five hundred ninety-three cases were included in the study, of which 564 were pituitary adenomectomies. The incidences of postoperative meningitis and sinusitis were low (0.67 and 2.87% for all pathologies, respectively; 0.35% meningitis for pituitary adenomas) and did not correlate with any specific antibiotic regimen. Immunocompromised status posed an increased odds of meningitis in pituitary adenomectomies (28.6, 95% confidence interval [1.72–474.4]). Conclusions The results show no clear benefit to postoperative antimicrobial use in EEA, with further larger studies needed.

PURPOSE American Society of Radiation Oncology (ASTRO) has developed a guideline on appropriate radiation therapy for brain metastases. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS “Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline” 2 was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations. RESULTS The ASCO Endorsement Panel determined that the recommendations from the ASTRO guideline, published May 6, 2022, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorses “Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline.” 2 RECOMMENDATIONS Within the guideline, stereotactic radiosurgery (SRS) is recommended for patients with Eastern Cooperative Oncology Group performance status of 0-2 and up to four intact brain metastases, and conditionally recommended for patients with up to 10 intact brain metastases. The guideline provides detailed dosing and fractionation recommendations on the basis of the size of the metastases. For patients with resected brain metastases, radiation therapy (SRS or whole-brain radiation therapy [WBRT]) is recommended to improve intracranial disease control; if there are limited additional brain metastases, SRS is recommended over WBRT. For patients with favorable prognosis and brain metastases ineligible for surgery and/or SRS, WBRT is recommended with hippocampal avoidance where possible and the addition of memantine is recommended. For patients with brain metastases, limiting the single-fraction V 12Gy to brain tissue to ≤ 10 cm 3 is conditionally recommended. Additional information is available at www.asco.org/neurooncology-guidelines .

ABSTRACT Introduction Despite an increasing number of publications on Peyronie's disease (PD), evidence-based clinical decision making remains challenging due to the small number of well-designed clinical trials. The quality of available PD literature has not been assessed to date. Objective We sought to evaluate the quality of the methodology and reporting of systematic reviews and meta-analyses in PD literature Methods Study protocol registration was performed on the Open Science Framework platform. In January 2021, a systematic electronic search of the Medline/PubMed, Embase, Ovid, Scopus, Joanne Briggs Institute and Cochrane databases was performed. Search terms included “Peyronie's disease” and “systematic review OR meta-analysis OR meta analysis”. Eligibility criteria were relevance to Peyronie's disease and specification of “systematic review” or “meta-analysis” in the title or abstract. A database was created to summarize the relevant methodological and reporting criteria for each article. The outcomes included review type, authorship, journal, publication date, “A MeaSurement Tool to Assess systematic Reviews” (AMSTAR-2) score and “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) score. Risk of bias was assessed using the ROBIS tool. Data were tabulated and reported as means with standard deviation, median with interquartile range (IQR) and t-testing as appropriate. Strength of association between variables was calculated using the Pearson correlation coefficient. Statistical analyses were performed on RStudio (version 1.4.1106). Results From 1974 to 2021, 340 articles were identified. After review 23 full length articles were included. Seventeen were systematic reviews, 4 meta-analyses and 2 were combined. Twenty-one (87.5%) articles were published after the year 2009 when the PRISMA guidelines were published. There was median 53.8% (IQR 38.2%) adherence to AMSTAR-2 criteria and 66.7% (IQR 38.9%) adherence to PRISMA criteria. The overall AMSTAR confidence rating was Critically Low in 15/23 studies, indicating more than one critical flaw. Correlation analysis revealed very high positive association between AMSTAR 2 and PRISMA adherence (+0.97). ROBIS revealed “High” concern regarding methods used to collect data and appraise 17/23 studies (73.9%), and “High” concern regarding synthesis and findings in 14/23 studies (60.9%). Conclusions Transparent reporting of methodology and findings in SRs and MAs is crucial to maintaining research integrity and allowing for accurate interpretation of results. Despite an increasing number of publications in PD, many of these studies fail to meet accepted methodological criteria for reporting. More high quality randomized controlled trials in PD are necessary; while systematic reviews and meta-analyses should focus on these high-quality studies with uniform use of accepted reporting guidelines. Disclosure No

ABSTRACT Introduction Penile prosthesis (PP) implantation with concurrent straightening maneuvers is the gold standard surgical therapy for men with Peyronie's Disease (PD) and concurrent medication-refractory ED. Satisfaction rates exceed 80-90% in modern series. PD is characterized by other bothersome effects on penile morphology (i.e. penile shortening) that also negatively impact patient satisfaction with PP. We hypothesized that men with both PD+ED would report lower overall satisfaction with PP implantation compared to those with ED alone. Objective To compare patient outcomes in a cohort of patients undergoing PP implantation for ED with and without concurrent PD. Methods We identified all patients who underwent PP implantation by a single surgeon between May 2012 and August 2019 (n=354). A retrospective chart review was performed to evaluate pertinent clinical demographics and surgical outcomes. A survey was mailed to all patients in July 2019. This included validated ED questionnaires (IIEF, EDITS, and QOLSP) and clinician-derived questions to evaluate subjective outcomes. Survey results were compared between those patients with and without a history of PD, using two-sample student t- and chi-squared tests (p-value &lt; 0.05 considered significant). Results 79 patients completed the survey (response rate 22%), including 38 (48%) with PD+ED. Mean survey follow-up duration was 45.5 (SD 19.5) months. There was no significant difference in patient demographics amongst those patients who did and did not respond to the survey. Amongst survey respondents, the mean preoperative IIEF-EF score was significantly higher for patients with PD+ED (10.2; SD 9.1) compared to those with ED alone (3.9; SD 5.0, p=0.003). Respondents with a history of both PD+ED were also less likely to have previously used oral therapy and intracavernosal injection to treat ED prior to PP implantation (p&lt;0.009). For those respondents with PD+ED, mean preoperative curvature was 59O (SD 43). Adjunctive straightening maneuvers at the time of PP implantation included manual modeling (87%), plication (5%), and incision/grafting (50%). Overall, device infection occurred in 4/79 patients (5%), and mechanical malfunction occurred in 3/79 (4%). 87% of all survey respondents felt their ED was “very much” or “much” improved. 80% stated they would recommend PP to a friend. 60% reported postoperative penile length loss, but only 35% were “dissatisfied” with current length and only 20% were dissatisfied with penile girth. In those with PD+ED, 91% were satisfied with the degree of penile straightening. There was no significant difference in patient-reported outcomes pertaining to length, girth, and overall satisfaction between those with and without PD. The mean follow-up IIEF-EF was 27.4 (SD 5.7), mean EDITS was 18 (SD 8), and mean QOLSP was 55 (SD 15). Once again, there was no significant difference in these outcomes based on the presence of PD. Conclusions PP results in high rates of patient satisfaction. The presence of concurrent PD, even amongst those requiring adjunctive maneuvers, does not appear to significantly impact patient outcomes. While there are inherent limitations to a survey-based study including reporter bias, these results support the use of PP and concurrent straightening as an excellent treatment option for men with PD and ED. Disclosure Yes, this is sponsored by industry/sponsor: This project was funded by an investigator-initiated grant from Coloplast Corporation. Clarification: Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast Corporation (Dr. Laurence Levine - consultant); Boston Scientific (Dr. Laurence Levine - Consultant)

Diffuse large B-cell lymphoma (DLBCL) is the most common form of aggressive non-Hodgkin lymphoma. Approximately 40% of patients with DLBCL will experience disease relapse or will be refractory to first line chemoimmunotherapy, necessitating second-line salvage therapy. This has historically consisted of platinum-based chemotherapy regimens followed by autologous hematopoietic stem cell transplantation with curative intent for transplant-eligible patients or palliative chemotherapy for transplant-ineligible patients. In recent years there have been several new therapeutic agents approved for the treatment of relapsed/refractory DLBCL, thereby expanding the therapeutic landscape. These agents include polatuzumab vedotin, tafasitamab, loncastuximab tesirine, selinexor, and anti-CD19 chimeric antigen receptor T-cell therapies such as axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. This review summarizes the pharmacology, efficacy, safety, dosing, and administration of new agents recently approved for the treatment of relapsed/refractory DLBCL.

PURPOSE Orteronel (TAK-700) is a nonsteroidal 17,20-lyase inhibitor suppressing androgen synthesis. We evaluated the clinical benefit of orteronel when added to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. METHODS In this open-label randomized phase III study, patients with metastatic hormone-sensitive prostate cancer were randomly assigned 1:1 to ADT with orteronel (300 mg oral twice daily; experimental arm) or ADT with bicalutamide (50 mg oral once daily; control arm). The primary objective was the comparison of overall survival (OS), targeting a 33% improvement in median survival. A stratified log-rank test with a one-sided P ≤ .022 would indicate statistical significance. Secondary end points were progression-free survival (PFS), prostate-specific antigen (PSA) level at 7 months (≤ 0.2 v 0.2 to ≤ 4 v > 4 ng/mL), and adverse event profile. RESULTS Among 1,279 patients included in the analysis, 638 were randomly assigned to the ADT plus orteronel arm and 641 to the control arm. The median age was 68 years; 49% had extensive disease. After a median follow-up of 4.9 years, there was a significant improvement in PFS (median 47.6 v 23.0 months, hazard ratio 0.58; 95% CI, 0.51 to 0.67; P < .0001) and PSA response at 7 months ( P < .0001), but not in OS (median 81.1 v 70.2 months, hazard ratio 0.86; 95% CI, 0.72 to 1.02; P = .040, one-sided). More grade 3/4 adverse events occurred in the experimental versus the control arms (43% v 14%). Postprotocol life-prolonging therapy was received by 77.4% of patients in the control arm and 61.3% of patients in the orteronel arm. CONCLUSION The study did not meet the primary end point of improved OS with orteronel. The lack of correlation of PFS and PSA response with OS raises concerns over assumption of their consistent surrogacy for OS in the context of extensive postprotocol therapy in this setting.