Updated Outcomes Research Articles

Updated clinical outcomes from ULI-EAP-100, an intermediate expanded access program for ulixertinib (BVD-523).

e15101 Background: Ulixertinib is a first-in-class selective small molecule inhibitor of ERK1/2 with demonstrated clinical efficacy in patients with solid tumors harboring MAPK pathway alterations in BRAF and NRAS. Emerging clinical data suggest improved efficacy for certain patient populations when MEK/ERK inhibitors are combined with inhibitors of autophagy (hydroxychloroquine), CDK4/6 (palbociclib), or EGFR/BRAF (cetuximab/encorafenib). Methods: ULI-EAP-100 (NCT04566393) is an ongoing intermediate expanded access protocol (EAP) that offers ulixertinib to US patients with advanced solid tumors harboring MAPK pathway alterations including but not limited to KRAS, BRAF, NRAS, MEK1/2, and ERK1/2, who have exhausted or not tolerated standard-of-care. Combinations with approved agents are permitted at the discretion of the treating physician and approval. Clinical data is collected and structured in a 21 CFR Part 11-compliant database according to XCELSIOR (NCT03793088), a real-world observational registry. Results: As of February 1st, 2022, 48 patients (pts) across 17 sites have been treated with ulixertinib under ULI-EAP-100 including pts with colorectal cancer (CRC) (21), melanoma (8), pancreatic ductal adenocarcinoma (PDAC) (6), lung cancer (5), cholangiocarcinoma (4), glioblastoma (2), and appendiceal cancer (2). Qualifying alterations were mutations in KRAS (21 pts), BRAF (13), NRAS (3), MAP2K1 (1), multiple genes (7), and overexpression of MAPK1 (1). Regimens included ulixertinib monotherapy (28 pts), ulixertinib + hydroxychloroquine (12), ulixertinib + encorafenib + EGFRi (cetuximab, panitumumab) (5), ulixertinib + palbociclib (2), and ulixertinib + encorafenib + atezolizumab (1). Thirty-nine (39) pts have discontinued ulixertinib for reasons including progression (25), AEs (9), and patient choice including hospice (5). Most common AEs (any grade/relatedness) were acneiform rash (29%), fatigue (25%), diarrhea (19%), abdominal pain (15%), and anorexia (15%). Grade 3/4 SAEs occurred in 15 pts (31%). Nine pts (19%) expired while on protocol, all attributed to disease progression. Four pts attained clinical benefit including BRAF V600E PDAC and glioblastoma pts on monotherapy for 413 and 128 days, respectively. A BRAF D594G melanoma pt’s tumor rapidly shrunk with monotherapy permitting surgery and rendering pt with no evidence of disease and a BRAF V600E CRC pt experienced a complete response following ulixertinib + encorafenib + cetuximab combination therapy. Conclusions: ULI-EAP-100 is a unique EAP permitting monotherapy and personalized combination regimens at treating physicians’ discretion. Safety of ulixertinib in this program is consistent with previous experience and all grade 5 AEs were attributed to disease progression. Multiple patients who exhausted prior therapies gained significant clinical benefit from ulixertinib under ULI-EAP-100. Clinical trial information: NCT04566393.

Two-year update from KEYNOTE-799: Pembrolizumab plus concurrent chemoradiation therapy (cCRT) for unresectable, locally advanced, stage III NSCLC.

8508 Background: Primary analysis (database cutoff, Oct 28, 2020) of the global KEYNOTE-799 study (NCT03631784) in patients (pts) with unresectable, locally advanced stage III NSCLC, showed that pembrolizumab (pembro; anti–PD-1) plus cCRT resulted in an ORR of 70.5% in cohort A (n = 112; squamous and nonsquamous) and 70.6% in cohort B (n = 102; nonsquamous only) and grade ≥3 pneumonitis in 9 (8.0%) and 7 (6.9%) pts, respectively. We present updated outcomes with 1 y of additional follow-up. Methods: In this nonrandomized, phase 2 study, eligible pts were aged ≥18 y with previously untreated, unresectable, pathologically confirmed, stage IIIA-C NSCLC with measurable disease per RECIST v1.1. Pts in cohort A (squamous and nonsquamous) received carboplatin AUC 6 plus paclitaxel 200 mg/m2 and pembro 200 mg for one 3-wk cycle, followed by carboplatin AUC 2 plus paclitaxel 45 mg/m2 QW for 6 wks plus 2 cycles of pembro 200 mg Q3W plus standard thoracic radiotherapy (TRT). Pts in cohort B (nonsquamous) received 3 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and pembro 200 mg Q3W plus standard TRT in cycles 2 and 3. All pts received 14 additional cycles of pembro 200 mg Q3W. Primary endpoints were ORR per RECIST v1.1 by blinded independent central review (BICR) and the incidence of grade ≥3 pneumonitis (per NCI CTCAE v4.0). Results: Of 216 pts enrolled in this study, 112 in cohort A and 102 in cohort B received treatment. Median (range) time from first dose to database cutoff (Oct 18, 2021) was 30.2 (25.3–35.5) mo in cohort A and 25.4 (14.5–35.2) mo in cohort B. ORR (95% CI) was 71.4% (62.1%–79.6%) in cohort A and 75.5% (66.0%–83.5%) in cohort B. Median duration of response (DOR) and OS were not reached (NR) in both cohorts; median PFS was 30.6 mo in cohort A, and NR in cohort B (Table). ORR was 66.7% in pts with PD-L1 TPS <1% and 77.3% in pts with PD-L1 TPS ≥1% in cohort A and 78.6% and 72.5%, respectively, in cohort B. ORR was similar by histology (squamous, 72.0%; nonsquamous, 74.1%). Grade ≥3 pneumonitis occurred in 16 pts (7.5%) overall; 9 pts (8.0%) in cohort A and 7 (6.9%) in cohort B. Treatment-related grade ≥3 AEs occurred in 64.3% and 51.0% of pts in cohort A and B, respectively. Conclusions: With the accrual of additional responses after >2 y of follow-up, pembro plus cCRT continues to demonstrate robust and durable responses, regardless of PD-L1 TPS and tumor histology, promising survival outcome and manageable safety in pts with previously untreated, locally advanced stage III NSCLC. Clinical trial information: NCT03631784. [Table: see text]

Cabozantinib (C) plus atezolizumab (A) or C alone in patients (pts) with advanced non–small cell lung cancer (aNSCLC) previously treated with an immune checkpoint inhibitor (ICI): Results from Cohorts 7 and 20 of the COSMIC-021 study.

9005 Background: C, a multitargeted receptor tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment that may enhance ICI activity. COSMIC-021 (NCT03170960) is a multicenter phase 1b study evaluating C + A in advanced solid tumors. In COSMIC-021, C + A demonstrated encouraging clinical activity in the cohort of pts with aNSCLC previously treated with ICIs (cohort 7 [C7]) (Neal. ASCO 2020. Abstr 9610). Updated outcomes of C + A in expanded C7 and outcomes for C alone in exploratory cohort 20 (C20) are presented. Methods: Pts with stage IV nonsquamous NSCLC without mutations in EGFR, ALK, ROS1, or BRAF V600E who progressed on one prior ICI and ≤2 prior lines of systemic anticancer therapy but no prior VEGFR TKI were eligible. Cohorts were not accrued contemporaneously. Pts received C 40 mg PO QD plus A 1200 mg IV Q3W (C7) or C alone 60 mg PO QD (C20). Primary endpoint was objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). CT/MRI scans were performed Q6W for the first year and Q12W thereafter. Results: A total of 81 and 31 pts received C + A and C, respectively; baseline characteristics were as follows: median age, 67 y, 70 y; male, 57%, 58%; ECOG PS 1, 64%, 71%; liver metastasis, 21%, 23%; refractory to prior ICI (progressive disease [PD] as best response), 32%, 45%; median number of prior systemic therapies, 3 and 3. As of Nov 30, 2021, median follow-up (range) (mo) was 24.7 (10.7, 42.8) and 21.5 (17.3, 27.6) for C + A and C, respectively, with 6 (7%) and 1 (3%) on study treatment. Clinical activity was observed for C + A and C alone (Table). Most common treatment-related adverse events (TRAEs) of any grade for C + A and C, respectively, included diarrhea (40%, 42%), nausea (22%, 45%), decreased appetite (25%, 26%), vomiting (14%, 23%), and fatigue (28%, 19%); grade 3/4 TRAEs occurred in 44% and 52% and one grade 5 TRAE occurred in each cohort (pneumonitis [C + A] and gastric ulcer hemorrhage [C]). Conclusions: C + A and C demonstrated encouraging clinical activity with manageable toxicity in pts with aNSCLC previously treated with ICIs. A phase 3 trial (CONTACT-01; NCT04471428) of C + A vs docetaxel is ongoing in NSCLC previously treated with an ICI and platinum-containing chemotherapy. Clinical trial information: NCT03170960. [Table: see text]

Two-year follow-up of KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult patients (Pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) in ZUMA-3.

7010 Background: Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the US to treat adult R/R B-ALL based on the ZUMA-3 study. The overall complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) was 71% (95% CI, 57-82) after 16.4 mo median follow-up (N = 55; Shah et al. Lancet 2021). Here, we report updated outcomes with longer follow-up in these pts and in a larger pooled analysis of Phase (Ph) 1 and 2 pts who received the pivotal dose of KTE-X19. Methods: Eligible adults (≥18 years) had R/R B-ALL and received a single infusion of KTE-X19 at the pivotal dose (1×106 CAR T cells/kg) following leukapheresis and conditioning chemotherapy. The primary endpoint was CR/CRi rate by central review. Results: As of 23 July 2021, median follow-up was 26.8 mo (range, 20.7-32.6) for treated Ph 2 pts (N = 55). The CR/CRi rate per central review was 71% (95% CI, 57-82; 56% CR; 15% CRi). Eleven pts (20%; 8 CR and 2 CRi) proceeded to subsequent allogeneic stem cell transplant (alloSCT). Median duration of remission (DOR) censored at subsequent alloSCT was 14.6 mo (9.4-not estimable [NE]); not censored: 18.6 mo (9.6-NE); 6/39 responders (15%) had ongoing responses at data cutoff. Median (95% CI) relapse-free survival (RFS) was 11.6 mo (2.7-20.5) censored at subsequent alloSCT and 11.7 mo (2.8-20.5) not censored at subsequent alloSCT; 18-mo RFS rates (95% CI) were 35% (20.5-50.6) and 42% (28.0-55.0), respectively. Median (95% CI) overall survival (OS) was 25.4 mo (16.2-NE) among all KTE-X19-treated pts and not reached (25.4-NE) in pts with CR (n = 31). For Ph 1/2 pts (N = 78) who received the pivotal KTE-X19 dose (median follow-up: 29.7 mo; range 20.7-58.3), the CR/CRi rate by independent review was 73% (95% CI, 62-82). Medians (95% CI) for DOR, RFS, and OS were 18.6 mo (9.6-NE), 11.7 mo (6.1-20.5), and 25.4 mo (16.2-NE), respectively. A subgroup analysis revealed that in pts aged 18-39 (n = 36), 40-59 (n = 27), and ≥60 (n = 15) years, the CR/CRi rates (95% CI) were 69% (52-84), 70% (50-86), and 87% (60-98); 24-mo OS rates (95% CI) were 48% (30-64), 54% (33-71), and 57% (28-78), respectively. In pts with pre-KTE-X19 infusion marrow blast percentages > 25 to ≤50 (n = 12), > 50 to ≤75 (n = 14), and > 75 to 100 (n = 30), CR/CRi rates (95% CI) were 83% (52-98), 86% (57-98), and 57% (37-75); 24-mo OS rates (95% CI) were 58% (27-80), 55% (26-77) and 37% (19-55), respectively. There were no new safety signals; the proportion of treated Ph 2 pts with Gr ≥3 treatment emergent adverse events was unchanged since prior data cutoff. One pt had an ongoing neurologic event of Gr 1 finger numbness. Conclusions: With longer follow-up and an expanded data set by independent review, outcomes remain durable in adults with R/R B-ALL, most of whom were heavily pretreated, with median OS not yet reached in pts with CR. Long-term safety was favorable. Clinical trial information: NCT02614066.

Three-year follow-up of outcomes with KTE-X19 in patients with relapsed/refractory mantle cell lymphoma in ZUMA-2.

7518 Background: Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL). In ZUMA-2, a 93% objective response rate (ORR; 67% complete response [CR] rate) was reported with KTE-X19 in pts with R/R MCL (median follow-up: 12.3 mo; 60 efficacy-evaluable pts; Wang et al. N Engl J Med. 2020). Here, we present updated outcomes with 2 years of additional follow-up. Methods: Adult pts (≥18 years) with R/R MCL underwent leukapheresis and conditioning chemotherapy followed by a single infusion of KTE-X19. Minimal residual disease (MRD) was an exploratory endpoint (sensitivity 10-5) evaluated in peripheral blood using next-generation sequencing. Updated results are reported for all 68 treated pts. Results: After 35.6 mo median follow-up, the ORR (CR + partial response) was 91% (95% CI, 81.8-96.7), with a 68% CR rate (95% CI, 55.2-78.5). The median duration of response (DOR) was 28.2 mo (95% CI, 13.5-47.1), with 25 of 68 treated pts (37%) still in ongoing response (all CR) at data cutoff. Late relapse > 24 mo post-infusion was infrequent (n = 3). The medians for progression-free survival (PFS) and overall survival (OS) were 25.8 mo (95% CI, 9.6-47.6) and 46.6 mo (95% CI, 24.9-not estimable), respectively. MRD was analyzed in 29 pts total; 24 of 29 were MRD-negative at mo 1, and 15 of 19 with available data were MRD-negative at mo 6. At data cutoff, the medians for DOR, PFS, and OS in the 15 MRD-negative pts were all not reached, vs 6.1, 7.1, and 27.0 mo, in the 4 MRD-positive pts, respectively. MRD-negative status at mo 1, 3, and 6 was associated with durable response, with 55%, 71%, and 69% of MRD-negative pts at those timepoints remaining in ongoing CR at data cutoff. Circulating tumor DNA analysis of MRD at mo 3 and 6 was predictive of relapse (AUC 0.80 and 0.75, respectively). No new safety signals were observed. Only 3% of treatment-emergent adverse events (AEs) of interest occurred since the primary report. The most frequent Grade ≥3 AE was neutropenia (1 [1%] Grade 3; 7 [10%] Grade 4). Two pts had KTE-X19-related Grade 3 serious infections: pneumonia and upper respiratory tract infection (n = 1); influenza (n = 1). There were no new cytokine release syndrome AEs and 1 new serious neurologic AE of Grade 3 encephalopathy (13.0 mo post-infusion) that was considered not related to study treatment. Three new Grade 5 AEs occurred, none of which were considered related to study treatment: Salmonella bacteremia (24.9 mo post-infusion), myelodysplastic syndrome (25.2 mo post-infusion), and acute myeloid leukemia (37.5 mo post-infusion). Conclusions: These data represent the longest follow-up of CAR T-cell therapy in pts with MCL to date and suggest that KTE-X19 induces durable long-term responses with manageable safety and low late relapse potential in R/R MCL. Clinical trial information: NCT02601313.

Pediatric acute liver failure: Reexamining key clinical features, current management, and research prospects.

This review aims to synthesize the most updated research, outcomes, and trends in the field of pediatric liver transplantation (LT), specifically focusing on children who have suffered from acute liver failure. Pediatric acute liver failure is a dynamic, life-threatening condition that can either self-resolve or lead to death. LT is a lifesaving intervention. With the introduction of technical variant grafts and recent immunosuppression modifications, overall patient survival, graft survival, and waitlist mortality have improved. Furthermore, recent advances in the knowledge of immunologic mediators of acute liver failure offer the possibility of more detailed understanding of the pathophysiology and new areas for research. Given the success of living donor LT for pediatric patients with acute liver failure, this option should continue to be actively considered as an alternative treatment option for patients who are listed for transplantation and are managed at a multidisciplinary tertiary care transplant center.

Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab

AbstractThe MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia [CLL]; ClinicalTrials.gov identifier #NCT02005471) reported superior progression-free survival (PFS) and overall survival (OS) with venetoclax-rituximab (VenR) vs bendamustine-rituximab (BR) in relapsed/refractory (R/R) CLL. Patients were randomized to 2 years of VenR (n = 194; rituximab for the first 6 months) or 6 months of BR (n = 195). Although undetectable minimal residual disease (uMRD) was achieved more often with VenR, the long-term implications of uMRD with this fixed-duration, chemotherapy-free regimen have not been explored. We report MRD kinetics and updated outcomes with 5 years' follow-up. Survival benefits with VenR vs BR were sustained (median PFS [95% confidence interval]: 53.6 [48.4, 57.0] vs 17.0 [15.5, 21.7] months, respectively, P < .0001; 5-year OS [95% confidence interval]: 82.1% [76.4, 87.8] vs 62.2% [54.8, 69.6], P < .0001). VenR was superior to BR, regardless of cytogenetic category. VenR-treated patients with uMRD at end of treatment (EOT; n = 83) had superior OS vs those with high-MRD+ (n = 12): 3-year post-EOT survival rates were 95.3% vs 72.9% (P = .039). In those with uMRD at EOT, median time to MRD conversion was 19.4 months. Of 47 patients with documented MRD conversion, 19 developed progressive disease (PD); median time from conversion to PD was 25.2 months. A population-based logistic growth model indicated slower MRD median doubling time post-EOT with VenR (93 days) vs BR (53 days; P = 1.2 × 10−7). No new safety signals were identified. Sustained survival, uMRD benefits, and durable responses support 2-year fixed-duration VenR treatment in R/R CLL.

Tivozanib (T) as first-line (1L) treatment of metastatic renal cell carcinoma (mRCC): A real-world outcome review in North-West of England (NWE), UK.

335 Background: The TIVO-1 study demonstrated improved PFS in mRCC patients (pts) undergoing 1L treatment with T compared with sorafenib. We previously presented outcomes of our experience of T in 4 cancer centres in NWE. Here we present updated outcomes with longer follow-up (FU). Methods: mRCC pts commencing 1L T March 2017- May 2019 were identified. Outcomes of interest included overall response rate (ORR), survival (OS, PFS) and toxicity. Data cut off for this update was 30/11/2020. Results: 113 pts were identified with characteristics as in the table. Median FU was 25.9 mo (18.3-44.7mo), 18% pts remain on treatment at data cut-off. 88.5% commenced T at full dose, of which 67% maintained dose intensity. 11.5% commenced T with dose reduction due to prior TKI toxicities or comorbidities. Median number of cycles was 7 (1-33). In terms of efficacy, ORR was 29% (CR 0%, PR29%, SD39%, PD26%, NE 6%) and median PFS was 9.0 months (95% C.I. 6.0-12.1mo). Median PFS by IMDC risk group was: F= 23.0 months (95% C.I. 7.6-38.4mo); I= 10.0 months (95% C.I. 6.3-13.7mo); P= 3.0 months (95% C.I. 1.5.- 4.5mo), p value&lt;0.0001. Median OS was 25.0 months (95% C.I. 15.4-34.6mo). Median OS by IMDC risk group was: F= NR with 72% alive at data cut-off; I= 26.0 months (95% C.I. 17.9-34.1mo); P= 7.0 months (95% C.I. 4.4-9.6mo), p value&lt;0.0001. Adverse events (AEs) of any grade occurred in 77% (≥G3 13%) including fatigue 42% (≥G3 0%), diarrhoea 19% (≥G3 &lt; 1%), mucositis 24% ( ≥G3 2%), anorexia 12% (≥G3 &lt; 1%); and hypertension 7% (≥G3 2%). Notable ≥G3 events included abnormal liver function 3%; vascular events 2% and seizure &lt; 1%. 18% of patients discontinued treatment due to toxicity with no treatment-related deaths. Conclusions: Our real world experience of 1L T suggests comparable activity with randomized data and other TKIs, particularly in F and I IMDC risk groups. The low incidence of serious AEs makes it an attractive option if unsuitable for combination therapies. [Table: see text]

Abstract P4-11-08: Impact of ovarian stimulation for fertility preservation in young women with breast cancer: Updated survival and pregnancy outcomes

Abstract Background: Chemotherapy (CTx) and hormone therapy may impair fertility in women with breast cancer (BC) by direct gonadotoxicity or delayed childbearing. Inconsistent data regarding the safety and efficacy of ovarian stimulation for fertility preservation (FP) in BC may limit clinician referral and patient uptake of FP. We previously examined the effect of FP on BC recurrence and herein present updated survival and pregnancy outcomes in relation to FP from an expanded BC cohort. Methods: Women aged ≤ 40 years diagnosed with stage I-III BC between 2007-2018 referred to one of six cancer centres and to a reproductive endocrinologist in British Columbia, Canada were identified from a central database. Clinicopathologic, treatment and outcome characteristics were compared using uni/multivariate Cox and logistic regression analyses for survival and pregnancy outcomes, respectively, for patients who did and did not undergo FP prior to systemic cancer treatment. Results: 158 patients were identified. Sixty-four (41%) had lymph node involvement, 119 (75%) had ER-positive and 39 (25%) had HER2-positive BC. The 72 (46%) patients who underwent FP were more likely to be younger (mean age 33 vs 34 y, p=0.030), ECOG 0 (p=0.013), have CTx (p&amp;lt;0.001) and GnRH agonist during CTx (p=0.010) compared to patients with no FP. Tumor stage, ER/HER2/BRCA-positivity, BMI, radiation and number of existing children were not associated with decision to pursue FP (p&amp;gt;0.05). After a median follow-up of 4.7 years, BC recurrence occurred in 15 (17%) non-FP patients and 9 (13%) FP patients (Table 1). FP did not affect overall survival by univariate (HR 0.9; 95% CI 0.7-1.3) or multivariate analysis controlling for age, BMI, ECOG/ER/HER2 status, tumor stage and receipt of CTx or radiation (HR 1.0, 95% CI 0.7-1.4). Post-diagnosis, 22 (31%) FP patients and 11 (13%) non-FP patients had ≥ 1 pregnancy (Table 2). The use of assisted reproductive technology (ART) was similar in both groups. Patients who had FP were 2.8 times more likely (p=0.013) to conceive at least once. The results remained significant on multivariate analysis controlling for age, BMI, ECOG status and baseline parity (p=0.030). Non-FP patients had a 31% higher miscarriage rate than those who did (p=0.26). Conclusions: FP was not associated with an increased risk of locoregional recurrence, distant recurrence or death over a follow-up period of 3-11 years, supporting its safety in young women with BC. Despite more often receiving CTx, patients who underwent FP were significantly more likely to conceive after BC than those who did not, even when accounting for differences in patient profiles. This may relate to greater use of GnRH agonists during CTx, known to protect ovarian function, and stronger desires for future childbearing in patients who pursued FP. Although there was similar use of ART in both groups, the higher pregnancy rate and more successful reproductive outcomes in FP patients support the value and promotion of pre-oncologic treatment FP in young BC patients early in their disease trajectory, to enhance survivorship family planning. Table 1.Survival outcomes of patients.CharacteristicNo FP (n=86)FP (n=72)p-valueRecurred [n (%)]0.85Locoregional6 (7)4 (6)Distant9 (10)5 (7)Deceased [n (%)]8 (9)4 (6)0.38 Table 2.Characteristics of first pregnancies in patients conceiving after diagnosis.CharacteristicNo FP (n=11)FP (n=21)p-valuePregnancy outcome [n (%)]0.26Completed3 (27)11 (52)Miscarriage7 (64)7 (33)Ongoing1 (9)3 (14)Pregnancy interval from diagnosis [n (%)]0.29≤ 2 y04 (19)2-5 y8 (73)13 (62)&amp;gt; 5 y3 (27)4 (19)Type of conception [n (%)]0.52Natural9 (82)15 (71)Assisted2 (18)6 (29) Citation Format: Megan E Tesch, Ying Wang, Chloe Lim, Ying Hui Xu, Shaina Lee, Kirstin Perdrizet, Dan Yokom, Ellen Warner, Jeffrey Roberts, Caroline Lohrisch. Impact of ovarian stimulation for fertility preservation in young women with breast cancer: Updated survival and pregnancy outcomes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-08.

First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743

In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs). With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61-0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation. With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.

Can Latin America AML effectiveness impact corruption prevention?

PurposeThe purpose of this paper is to analyze the effectiveness of the Financial Action Task Force (FATF’s) recommendations in Latin America in the fight against Money Laundering (ML) through the Immediate Outcomes 4 (Preventive Measures) and 6 (Financial Intelligence) and the relationship between anti-money laundering (AML) effectiveness and anti-corruption measures.Design/methodology/approachThrough quantitative and quality methods measure the performance of the Immediate Outcomes’ levels in compliance with the established FATF’ standards; The objective is to analyze progress in the prevention and identification of ML.FindingsThe authors discuss the relationship between AML effectiveness and anti-corruption measures starting with the analysis of the best-ranked country in these indicators (IO4 and IO6).Research limitations/implicationsMutual evaluations require a long process, which is why the authors do not have all the updated data for all the Latin American countries; only the updated Immediate Outcomes data up to September 16, 2021, are taken. This paper is part of the Research Project “The impacts of corruption in the Western Hemisphere and regional responses.”Originality/valueThrough a multidisciplinary analysis, the Immediate Results evaluation model is prioritized to measure the effectiveness of the methods applied in Latin America through the IO4 and IO6. The model that presents the best effectiveness is selected and the successes that this country is applying over its peers are analyzed. From this analysis, a quantitative and qualitative analysis can be appreciated.

The Northwestern University Novel Urology Residency Curriculum: Updated Outcomes from a 13-Year Experience with Flexible Residency Training and Electives.

We evaluated educational outcomes and satisfaction following institution of a novel, flexible and urology-driven resident curriculum. A new urology resident curriculum was instituted at Northwestern University in 2006. Rotation schedules and resident electives were recorded annually. Operative case logs and American Urological Association In-Service Examination scores were collected prospectively. Residents and faculty rated satisfaction with the residency program on a 5-point Likert scale from "poor" to "outstanding." Differences in cases logged, In-Service Examination scores and satisfaction ratings under the new and prior curricula were compared. Curriculum changes included full 5-year urology oversight of the residency curriculum by the program director, 8 months of urology rotations in the first postgraduate year and 2 months of general surgery during the second postgraduate year. General surgery rotations were modified annually based on educational rationale and feedback. Cases logged per resident and In-Service Examination scores were comparable between old and new curricula groups. All residents matriculating under the new curriculum took and passed their written boards. The percentage of faculty and residents describing the program as "outstanding" increased from 50% in 2004‒2005 to 82% in 2017‒2018. Program satisfaction increased significantly when comparing the first and last 6 years (percent rating "outstanding": 56.1±2.1% vs 71.6±10.0%, p=0.028). After 13 years with the novel curriculum, resident case numbers and In-Service Examination scores remained similar while faculty/resident satisfaction increased. Direct control of general surgery rotations enabled adjustments based on educational rationale. These results demonstrate that a urology-directed and flexible residency program can be instituted without compromising learner outcomes.

Updated Outcomes during the Pandemic: Relationship between CD34and CD3 Cell Doses, One-Year Graft-Versus-Relapse-Free-Survival, Graft-Versus-Host Disease, and Overall Survival in Haploidentical Hematopoietic Stem Cell Transplantation Using Post Transplant Cytoxan: A Single Center Experience

Background:Haploidentical hematopoietic cell transplantation (haplo-HCT) has emerged as a popular alternative to traditional HLA-matched hematopoietic cell transplant. The major advancement of haplo-HCT has increased donor availability to many patients in need, therefore investigating the factors that may affect outcomes is necessary to improve overall survival and reduce transplant-related mortality. Data regarding optimal dose of CD34 cells, CD3 cells and CD34/CD3 ratio used during haplo-HCT to ensure favorable outcomes with post-transplant cyclophosphamide (PTCy) is lacking. Previously we have reported improved outcomes using CD34 cells limited to 7x10^6 cells/kg or less. In this report we are presenting an updated analysis including outcomes related to CD34/CD3 ratio used during haplo-HCT.Methods:We retrospectively analyzed adult patients at USC Norris Cancer Hospital who received haplo-HCT from 2014 to 2020. The primary endpoint assessed was 1-year GVHD-free/relapse-free survival (GRFS). Secondary endpoints included overall survival (OS), 1-year transplant related mortality (TRM) and incidence of acute and chronic GVHD. Kaplan Meier survival curves and log-rank tests were used to evaluate 1-year GRFS and OS with CD34 cell dose ≥ 7x10^6 cells/kg and < 7x10^6 cells/kg; CD3 cell dose < 2.5x10^8 cells/kg and ≥ 2.5x10^8 cells/kg; and CD34/CD3 ratio <2, 2-3, >3-5 and >5.Results:103 adult haplo-HCT recipients were reviewed with 55.3% male and 44.7% female. The age range was 21-71 years old (median = 51), and a majority of patients were Hispanic (62%). The most common underlying hematologic disorders included AML (40.8%), ALL (34.1%), and MDS/MPN (13.6 %). 41.7% patients with leukemia were in CR1, 55% were CR2/CR3 and 78% were MRD negative by flow cytometry prior to transplant. 73% received myeloablative conditioning and 83.5% received peripheral blood stem cells.Median CD34 dose, CD3 dose and CD34/CD3 ratio were 6.1 x10^6cells/kg, 2.27 x10^8 cells/kg and 3.2 respectively. Median time to recovery of neutrophil, platelets, and lymphocyte was 17, 24, and 124 days respectively. Incidence of 1-year GRFS was 43.7%. 1-year TRM was 13.6% and rate of aGVHD and cGVHD was 42.7% (n = 44) and 35.9% (n = 37) respectively.There was no difference in 1-year GRFS and OS when multiple dose levels of CD34 cells and CD3 cells were compared. Although when dichotomized, a CD34 cell dose of ≥ 7x10^6 cells/kg compared to < 7x10^6 cells/kg showed higher dose had significant improvement in 1- year overall survival (p-value=0.01) but no statistical difference in 1 year GRFS (p value=0.24).CD3 cell dose < 2.5 x 10^8 cells/kg trended towards worse 1-Year GRFS compared to ≥ 2.5 x 10^8 cells/kg (43.9% compared to 58.6%; p-value 0.075), similarly CD3 dose of < 2.5x10^8 cells/kg showed a lower 1-year OS compared to > 2.5x10^8 cells/kg but was not statistically significant (78.7% compared to 89.4%; p-value 0.092). 1-year GRFS and OS did not show statistical difference at CD34:CD3 ratios of < 2, 2-3, 3-5 and > 5, although on cox regression analysis the HR for 1-year GRFS was 2.92 (95% CI 1.21-7.05) in patients with CD34:CD3 > 5 as compared to reference of < 2 (p-value 0.017). Multivariate regression also showed CD3 cell doses of 2-3x10^8 cells/kg and >3 x 10^8 cells/kg were associated with worse 1-year GRFS with HR of 0.43 and 0.40 and p-value of 0.041 and 0.048 respectively when compared to reference of < 1x10^8 CD3 cells/kg.Discussion:Our results demonstrate 43.7% survived 1 year compared with reports of 24-35%. The OS was significantly better in the CD34 dose > 7x10^6 cells/kg. CD3 <2.5x10^8 cells/kg showed a trend towards lower 1-year GRFS and OS, which was not statistically significant. On multivariate analysis CD3 dose of > 2x10^8 cells/kg was associated with inferior 1-year GRFS. Conversely, higher CD34/CD3 ratio >5 was associated with increased 1-year GRFS. Thus, our findings indicate that along with improvement in OS by using >7x10^6 CD34 cells/kg, lower CD 3 cell dose <2x10^8 cells/kg and higher CD34/CD3 ratio > 5 can improve 1-year GRFS in patients receiving haplo-HCT. [Display omitted] DisclosuresChaudhary: Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy ; Athelas: Consultancy, Current holder of stock options in a privately-held company; Oncotartis: Consultancy; Pancella: Consultancy; Moderna: Current equity holder in publicly-traded company; Celldex: Current equity holder in publicly-traded company; TCR2: Current equity holder in publicly-traded company; Allogene: Current equity holder in publicly-traded company. Yaghmour: Jazz: Consultancy, Honoraria; Astellas: Consultancy; Takeda: Consultancy; Incyte: Consultancy.

Phase II Trial of Ten-Day Decitabine with Venetoclax (DEC10-VEN) in Acute Myeloid Leukemia: Updated Outcomes in Genomic Subgroups

Phase II Trial of Ten-Day Decitabine with Venetoclax (DEC10-VEN) in Acute Myeloid Leukemia: Updated Outcomes in Genomic Subgroups

An Australasian Leukemia Lymphoma Group (ALLG) Phase 2 Study to Investigate Novel Triplets to Extend Remission with Venetoclax in Elderly (INTERVENE) Acute Myeloid Leukemia

An Australasian Leukemia Lymphoma Group (ALLG) Phase 2 Study to Investigate Novel Triplets to Extend Remission with Venetoclax in Elderly (INTERVENE) Acute Myeloid Leukemia

A Phase 1 First-in-Human Study of Tnb-383B, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

A Phase 1 First-in-Human Study of Tnb-383B, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

Updated Analysis Confirms Sustained Poor Prognosis of COVID-19 in Patients with Lymphoma in Latin America: A Cohort of 160 Patients from Gell

Updated analysis confirms sustained poor prognosis of COVID-19 in patients with lymphoma in Latin America: A cohort of 160 patients from GELL.Introduction: Ongoing SARS-COV-2 pandemic has impacted the management of cancer patients worldwide. Several reports have demonstrated inferior outcomes of patients with hematological malignancies, including higher rates of intensive care unit admission, need for mechanical ventilation and death. The impact of COVID-19 is profound in resource-restricted countries, including Latin America. Most cohorts reported have not included patients from Latin America, and there is paucity of data of the outcome of cancer patients with COVID-19 in low- and middle-income countries. Grupo de Estudio De Linfoproliferativos En Latino-America (GELL )is a collaborative network of hematological centers in 13 countries in Latin America. We report updated outcomes of lymphoma patients diagnosed with COVID-19 in Latin America.Methods: We conducted a retrospective study including patients with a diagnosis of lymphoma and COVID-19 infection. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma were excluded from the analysis We defined active disease as follow: (1) patients with detectable disease either prior to initiating therapy or upon relapse, and/or (2) patients undergoing active cancer treatment. The primary outcome was overall survival at 100 days. Survival curves were estimated using the Kaplan Meier method. Uni and multivariable analysis were carried out with Cox model.Results: A total of 160 patients were available for analysis. Median age was 60 years old. Hypertension was the most common comorbidity (33%). Most patients had aggressive lymphomas (62%), including 43% of patients with diffuse large B-Cell lymphoma (DLBCL). Follicular lymphomas were observed in 13% of patients and Hodgkin lymphoma in 12.5% of patients. With a median follow-up of 37 days, the 100-day OS was 64% (95CI 56-74%, fig. 1). In univariate analysis, age (HR 1.03, p=0.0025), hypertension (HR 2.01, p=0.017), >1 number of prior lines (HR 2.78, p=0.011), patients currently on treatment (HR 1.83, p=0.043), ferritin >2000 ng/mL (HR 4.74 p=0.00047) were associated with inferior OS. In multivariate analysis, age (HR 1.03, p=0.0026) and patients currently on treatment (HR 1.82, p=0.04) had inferior OS. There was a trend towards inferior outcomes in patients receiving monoclonal antibodies in univariate analysis (HR 1.82, p=0.081) but not in multivariable analysis (HR=1.29, p=0.48). Use of steroids was not statistically related to mortality (HR 1.79, p=0.074). Finally, contrary to other cohorts, no improvement in OS was observed in patients diagnosed later on the pandemic (fig. 2).Conclusion: In this large cohort of Latin American patients with lymphoma malignancies, our updated analysis showed a maintained dismal prognosis with COVID-19 infection. With a median follow up of 37 days, the 100-day OS was 64%. Older age and ongoing active cancer treatment were significantly associated with mortality. The use of monoclonal antibodies and systemic corticosteroids were not statistically associated to poor survival. Current efforts are focused on improving immunization in the Latin American population. There is an unmet need for improving survival in patients with hematologic malignancies and COVID-19 infection. [Display omitted] DisclosuresPerini: Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau. Otero: ASTRA ZENECA: Current Employment. Abello: Dr Reddy's: Research Funding; Amgen: Honoraria; Janssen: Honoraria. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

TCT-57 Updated Clinical and Procedural Outcomes in TAVR for Bicuspid Versus Tricuspid Aortic Valve Stenosis

TCT-57 Updated Clinical and Procedural Outcomes in TAVR for Bicuspid Versus Tricuspid Aortic Valve Stenosis

Chronic thoracoabdominal aortic dissection: endovascular options to obliterate the false lumen.

Persistent false lumen patency in chronic thoracoabdominal aortic dissections after thoracic endovascular aortic repair (TEVAR) contributes to negative aortic remodeling. We have previously described the evolution of various endovascular techniques to treat persistent false lumen perfusion including false lumen embolization. Objectives of this study are to describe endovascular techniques to obliterate the false lumen and present updated outcomes in a recent series of patients undergoing false lumen embolization for chronic aortic dissection. From January 2018 to May 2021, 17 patients with chronic dissection underwent false lumen embolization with coils, iliac plugs, and nitinol plugs. This was often in conjunction with or following TEVAR and balloon fracture fenestration. Mean follow-up 354±324 days. After false lumen embolization there was no mortality, stroke, spinal cord ischemia, or visceral and limb ischemia. No patients required dialysis, though 1 (5.9%) did experience acute kidney injury. There was 1 (5.9%) patient that required endovascular re-intervention on the thoracoabdominal aorta. No patients underwent subsequent open surgical repair. TEVAR with adjunctive false lumen embolization and balloon fracture fenestration are techniques to obliterate retrograde flow into the false lumen of chronic thoracoabdominal aortic dissections in appropriately selected patients.

Integration of EGFR Inhibition With Radiation-Based Multimodality Treatment in Stage III EGFR Mutant NSCLC

<h3>Purpose/Objective(s)</h3> Patients with stage III epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) treated with concurrent chemoradiation therapy (CRT) may not benefit from consolidation immune checkpoint inhibitors, and adjuvant EGFR tyrosine kinase inhibitor (TKI) treatment with osimertinib is now approved for stage IB-IIIA. Whether and how to integrate TKI into the treatment of unresectable or borderline resectable stage III disease is unclear. <h3>Materials/Methods</h3> Patients with stage III (AJCC 7th ed.) EGFR mutant NSCLC amenable to CRT ± surgery were enrolled onto an IRB-approved Phase II trial (clinicaltrials.gov registered) and received induction afatinib 40 mg QD x 2 months, either definitive or neoadjuvant CRT with cisplatin/pemetrexed, surgery if appropriate, and 2 years of adjuvant afatinib provided there was no primary progression during the induction phase. The trial was closed for slow accrual. The primary endpoint of objective response rate after induction TKI and early survival outcomes have been previously reported. This is a secondary analysis of recurrences and updated outcomes. <h3>Results</h3> Seventeen patients completed induction TKI and CRT ± surgery between 2012 and 2020. There were 74% females. Median age was 56 years (range, 34-75 years). Neoadjuvant and definitive median radiation doses were 54 Gy (range, 45-66 Gy) and 66.6 Gy (range, 63-72 Gy). Ten patients with biopsy confirmed N2 (n = 9) or N3 (n = 1) disease underwent surgery which showed a mediastinal sterilization rate of 60%. Adjuvant TKI was initiated in 14 patients including 1 case of off-protocol erlotinib. Three patients aborted TKI, 7 completed 2 years of TKI, 2 remained on TKI at last follow-up while 2 switched to other treatments after recurrence. Notably, of the 7 patients completing 2 years of TKI, 6 recurred after a median interval of only 3 months (range, 1-55 months) from the completion date. In total there were 11 recurrences. The dominant pattern of recurrence was distant with just 1 isolated local failure in a patient treated with definitive CRT. Five of 11 recurrences were CNS-only, all of which occurred after completion of adjuvant TKI at a median interval of 4 months. Four of these patients had intracranial disease control at last follow-up. No grade 3+ radiation treatment related toxic events were observed. With a median follow-up of 43.3 months for patients alive, median progression-free survival (PFS) and overall survival (OS) times were 32 months and not reached, respectively. 3-year PFS and OS rates were 31% (95% CI, 6-56%) and 69% (43-94%), respectively. <h3>Conclusion</h3> This trial highlights the efficacy of aggressive local therapy and the potential promise of TKI treatment for stage III EGFR mutant NSCLC though interpretations are limited by small sample size. One particular risk for patients was CNS-only recurrence suggesting that better CNS directed treatments and CNS surveillance strategies should be studied to increase cure rates in this unique, genotype-defined NSCLC population.