Final Efficacy Analysis Research Articles

A phase II, two-stage study of avelumab and axitinib among patients with mismatch repair proficient recurrent or persistent endometrial cancer: Final efficacy analysis and correlative studies

A phase II, two-stage study of avelumab and axitinib among patients with mismatch repair proficient recurrent or persistent endometrial cancer: Final efficacy analysis and correlative studies

A multivalent RSV vaccine based on the modified vaccinia Ankara vector shows moderate protection against disease caused by RSV in older adults in a phase 3 clinical study

Respiratory syncytial virus (RSV) causes a significant disease burden in older adults. The live recombinant vaccine based on a nonreplicating modified vaccinia Ankara (MVA-BN) poxvirus, MVA-BN-RSV, encoding for multiple proteins of RSV subtypes A and B, was assessed for efficacy against respiratory disease caused by RSV.Adults aged ≥60 years, with or without underlying chronic conditions, were enrolled and randomized in a 1:1 ratio to receive a single dose of vaccine or placebo and were followed for disease caused by RSV infection during the 2022–2023 season. The 2 primary endpoints were RSV-associated lower respiratory tract disease (LRTD) with ≥3 and ≥ 2 symptoms; acute respiratory disease (ARD) was a key secondary endpoint. The humoral RSV-specific immune response was assessed at baseline and 14 days post-vaccination. Safety was evaluated by collection of solicited adverse events (AEs) and unsolicited AEs for 7 and 28 days post-vaccination respectively, and SAEs for the entire study period.In total, 18,348 participants were included in the final efficacy and safety analyses. Vaccine efficacy was 42.9 % (95 % CI: −16.1; 71.9) against RSV-associated LRTD with ≥3 symptoms, 59.0 % (95 % CI: 34.7; 74.3) against LRTD with ≥2 symptoms, and 48.8 % (95 % CI: 25.8; 64.7) against ARD. The primary objective was not met for LRTD with ≥3 symptoms since the lower bound of the 95 % CI was below 20 %, the prespecified success criterion. The vaccine-elicited immune response showed mean fold-increases of 1.7 for RSV A and B neutralizing antibodies and 2.9 and 4.3 for RSV-specific IgG and IgA, respectively. The vaccine displayed mild to moderate reactogenicity, and no safety concerns were identified.MVA-BN-RSV induced suboptimal protection against RSV-associated LRTD, likely due to suboptimal neutralizing antibody response. The vaccine had an acceptable safety profile and confirmed immunogenicity, overall showing promise for MVA-BN-vectored constructs targeting other diseases.Trial Registration:Clinicaltrials.gov Identifier NCT05238025 (Registered February 14, 2022).

Ravulizumab in Atypical Hemolytic Uremic Syndrome: Final Analysis of Efficacy and Safety Outcomes in Two Phase 3 Trials

Ravulizumab in Atypical Hemolytic Uremic Syndrome: Final Analysis of Efficacy and Safety Outcomes in Two Phase 3 Trials

1965MO Phase II study of futibatinib plus pembrolizumab in patients (pts) with advanced/metastatic urothelial carcinoma (mUC): Final analysis of efficacy and safety

1965MO Phase II study of futibatinib plus pembrolizumab in patients (pts) with advanced/metastatic urothelial carcinoma (mUC): Final analysis of efficacy and safety

GABA Analogue HSK16149 in Chinese Patients With Diabetic Peripheral Neuropathic Pain

Many patients with diabetic peripheral neuropathic pain (DPNP) experience inadequate relief, despite best available medical treatments. There are no approved and effective therapies for patients with DPNP in China. To evaluate the efficacy and safety of capsules containing γ-aminobutyric acid (GABA) analogue HSK16149 in the treatment of Chinese patients with DPNP. This phase 2 to 3 adaptive randomized clinical trial was multicenter, double blind, and placebo and pregabalin controlled. The trial started on December 10, 2020, and concluded on July 8, 2022. In stage 1, various doses of HSK16149 were evaluated to determine safety and efficacy for stage 2. The second stage then validated the efficacy and safety of the recommended dose. In stage 1, enrolled patients (n = 363) were randomized 1:1:1:1:1:1 to 4 HSK16149 doses (40, 80, 120, or 160 mg/d), pregabalin (300 mg/d), or placebo. In stage 2, patients (n = 362) were randomized 1:1:1 to receive HSK16149, 40 or 80 mg/d, or placebo. The final efficacy and safety analysis pooled data from patients receiving the same treatment. The primary efficacy end point in stage 1 was the change from baseline in average daily pain score (ADPS) at week 5. The primary efficacy end point in stage 2 was the change from baseline in ADPS at week 13. When the final statistical analysis was performed, the P values calculated from the independent data of each phase were combined using the weighted inverse normal method to make statistical inferences. Of 725 randomized patients in the full-analysis set (393 men [54.2%]; mean [SD] age, 58.80 [9.53] years; 700 [96.6%] of Han Chinese ethnicity), 177 received placebo; 178, HSK16149, 40 mg/d; 179, HSK16149, 80 mg/d; 66, HSK16149, 120 mg/d; 63, HSK16149, 160 mg/d; and 62, pregabalin, 300 mg/d. A total of 644 patients (88.8%) completed the study. The 40- and 80-mg/d doses of HSK16149 were recommended in stage 2. At week 13, the ADPS mean (SD) change from baseline was -2.24 (1.55) for the 40-mg/d and -2.16 (1.79) for 80-mg/d groups and -1.23 (1.68) for the placebo group, showing statistical significance for both HSK16149 doses vs placebo (both P < .001). In a safety set (n = 726), 545 patients (75.1%) had adverse events, which were generally mild to moderate, with dizziness and somnolence being the most common. Forty- and eighty-mg/d doses of HSK16149 were recommended for treating patients with DPNP in China. The efficacy of HSK16149 capsules was superior to placebo in all groups for relieving DPNP and appeared well tolerated. ClinicalTrials.gov Identifier: NCT04647773.

Beneficial effects of saw palmetto (Serenoa repens) fruit extract on the urinary symptoms of healthy Japanese adults with possible lower urinary tract symptoms: A randomized, double-blind, placebo-controlled study.

Saw palmetto extract (SPE) is the most commonly used supplement for the treatment of lower urinary tract symptoms (LUTS), but most evidence is for those with LUTS, and little data is verifying its effectiveness for those who do not have the disease but are troubled by symptoms. The purpose of this study was to examine the effect of SPE on the improvement of urinary frequency problems that present stress due to urinary urgency in daily life, among healthy Japanese adults aged ≥50 years who are not diagnosed with benign prostatic hyperplasia or overactive bladder. They were randomly assigned to the SPE group or placebo group (34 participants per group) using a computerized random number generator. Each participant was instructed to take one capsule containing SPE (320 mg) or placebo every day for 12 weeks. Subjective symptoms were assessed using the overactive bladder questionnaire, and the score of symptom bother by frequent urination during the daytime hours was set as the primary outcome. The other outcomes were subjective urinary symptoms and urinary frequencies. The final efficacy analysis dataset was per protocol set, and 33 participants in each group were analyzed. After SPE intervention for 12 weeks, the score of symptom bother by frequent urination during the daytime hours was significantly improved and the daytime frequency of urination assessed using the urinary log was significantly decreased. The consumption of SPE improved urinary frequency-related quality of life such as bother of urinary symptoms in healthy Japanese adults (UMIN000045334).

Efficacy and safety of erdafitinib in pediatric patients with advanced solid tumors and FGFR alterations in the phase 2 RAGNAR trial.

10002 Background: Erdafitinib is an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved in the US for adult patients (pts) with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations, as determined by an FDA-approved companion diagnostic test, whose disease has progressed on or after ≥1 line of prior systemic therapy. Primary analysis of the RAGNAR study Broad Panel Cohort demonstrated tumor agnostic efficacy in pts with solid tumors harboring predefined FGFR mutations or fusions (Pant 2023). Here we report on Final Analysis of efficacy and safety results from the Pediatric Cohort of the RAGNAR study. Methods: Pediatric pts ≥6 years with advanced solid tumors and any FGFR mutation, fusion, or tandem duplication received oral erdafitinib. Starting doses were 8 mg, 5 mg, and 3 mg daily for ages &gt; 15 years, 12 to &lt; 15 years, and 6 to &lt; 12 years, respectively, in 21-day cycles with possible individualized up-titration based on serum phosphate and adverse events (AEs). The primary endpoint was objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 or Response Assessment in Neuro-Oncology [RANO]) by independent review committee (IRC). Secondary endpoints included ORR by investigator, duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Results: 11 pts (median age 13 years; range, 6-16; 64% female) received erdafitinib. Median follow-up was 9.7 months at data cutoff. Histologies included low-grade glioma (LGG-6 pts); high-grade glioma (HGG-3 pts); soft tissue sarcoma (1 pt), and temporal neurocytoma (TNEURO-1 pt). 7, 1, and 3 pts had FGFR1, FGFR2, and FGFR3 alterations, respectively. 6, 4, and 1 pts had FGFR fusions, mutations, and tandem duplication, respectively. Pts had a median of 1 prior line of systemic treatment; 6 (55%) had prior radiotherapy. At data cutoff, 1 of 3 pts (33%) with HGG and an FGFR1-TACC1 fusion achieved a partial response based on investigator assessment with a response duration of 19.8 months. Investigator-assessed objective responses were not observed in the other tumor types. DCR and CBR were 100% in pts with LGG and 67% in pts with HGG. Most common treatment-emergent adverse events (TEAEs) included hyperphosphatemia (64%), diarrhea (64%), pain in extremity (45%), alanine transaminase increased (36%), nausea (36%), and onycholysis (27%). No central serous retinopathy events occurred; related serious adverse events (SAEs) occurred in 4 (36%) pts, including 1 SAE of epiphysiolysis; there were no related TEAEs leading to death. Conclusions: In this small pediatric population comprising primarily refractory HGG and LGG with any FGFR alteration, erdafitinib demonstrated limited objective responses but promising disease control with acceptable safety. Clinical trial information: NCT04083976 .

Acalabrutinib, venetoclax, and obinutuzumab in relapsed/refractory CLL: final efficacy and ctDNA analysis of the CLL2-BAAG trial

AbstractThe phase 2 CLL2-BAAG trial tested the measurable residual disease (MRD)–guided triple combination of acalabrutinib, venetoclax, and obinutuzumab after optional bendamustine debulking in 45 patients with relapsed/refractory chronic lymphocytic leukemia (CLL). MRD was measured by flow cytometry (FCM; undetectable MRD <10–4) in peripheral blood (PB) and circulating tumor DNA (ctDNA) using digital droplet polymerase chain reaction of variable-diversity-joining (VDJ) rearrangements and CLL-related mutations in plasma. The median number of previous treatments was 1 (range, 1-4); 18 patients (40%) had received a Bruton tyrosine kinase inhibitor (BTKi) and/or venetoclax before inclusion, 14 of 44 (31.8%) had TP53 aberrations, and 34 (75.6%) had unmutated immunoglobulin heavy-chain variable region genes. With a median observation time of 36.3 months and all patients off-treatment for a median of 21.9 months, uMRD <10–4 in PB was achieved in 42 of the 45 patients (93.3%) at any time point, including 17 of 18 (94.4%) previously exposed to venetoclax/BTKi and 13 of 14 (92.9%) with TP53 aberrations. The estimated 3-year progression-free and overall survival rates were 85.0% and 93.8%, respectively. Overall, 585 paired FCM/ctDNA samples were analyzed and 18 MRD recurrences (5 with and 13 without clinical progression) occurred after the end of treatment. Twelve samples were first detected by ctDNA, 3 by FCM, and 3 synchronously. In conclusion, time-limited MRD-guided acalabrutinib, venetoclax, and obinutuzumab achieved deep remissions in almost all patients with relapsed/refractory CLL. The addition of ctDNA-based analyses to FCM MRD assessment seems to improve early detection of relapses. This trial was registered at www.clinicaltrials.gov as #NCT03787264.

Brentuximab Vedotin Plus Ibrutinib in Relapsed and Refractory Hodgkin Lymphoma

IntroductionBrentuximab vedotin (BV) is an antibody-drug conjugate that delivers monomethyl auristatin E (MMAE) to CD30+ cells and is safe and effective in relapsed/refractory (r/r) Hodgkin lymphoma (HL). Although most patients respond to BV, only a minority will obtain a complete response (CR), and almost all patients eventually progress.Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor highly active in multiple subtypes of non-Hodgkin lymphoma; limited data exist regarding its use in HL. It irreversibly inhibits interleukin-2-inducible kinase (ITK) with Th1 based immune responses. As we previously observed preclinical synergy between ibrutinib and BV, we hypothesized ibrutinib may enhance the antitumor activity of BV in HL. We designed and conducted a phase II trial of ibrutinib plus BV in patients with R/R HL, and herein report the final primary analysis of safety and efficacy. MethodsThis was a multicenter phase II trial with a lead-in cohort in patients with r/r HL. Eligibility criteria included age ≥ 15 years with r/r HL after at least one prior line of therapy. Treatment consisted of 1.8 mg/kg BV intravenously every 3 weeks and ibrutinib 560 mg PO daily (420 mg PO daily in the lead-in cohort). Prior BV was allowed if patients were not refractory. The primary endpoint was the CR rate according to Lugano 2014. Secondary endpoints included toxicities, overall response rate (ORR), and duration of response (DOR). ResultsThe 39 patients were enrolled onto the study, of which 67% were male; the median age was 33 (range: 17-71). 38% had extranodal disease at baseline, 51% had advanced stage disease, 51% were refractory to the prior therapy, and 21% had prior BV. Of 36 patients who were evaluable for response, the CR rate was 33% and ORR 64%; median DOR was 25.5 months. Thirteen patients proceeded to autologous transplant and 3 patients proceeded to allogeneic transplant for consolidation after response. The most common adverse events were nausea (67%), peripheral neuropathy (62%), diarrhea (59%), fatigue (46%), thrombocytopenia (46%), headache (41%), rash (41%), elevated ALT (38%), anemia (36%), vomiting (36%), abdominal pain (33%), fever (33%), and hypertension (33%). Six patients experienced unacceptable toxicity, defined as Gr 3/4 non-hematologic toxicity or non-resolving Gr 3/4 hematologic toxicity including one patient who died of multiorgan failure from suspected COVID-19 infection during cycle 1. DiscussionThe combination of BV and ibrutinib was active in r/r HL; however, given significant toxicity, it cannot be recommended for future development.

Efficacy outcomes and biomarker analysis from phase II trial of escalating doses of neoadjuvant atezolizumab in patients with muscle-invasive urothelial carcinoma ineligible for cisplatin-based chemotherapy.

602 Background: There are no current standard of care options for patients (pts) with muscle-invasive bladder cancer (MIBC) ineligible for cisplatin-based chemotherapy (cisplatin). This trial investigated the safety and efficacy of escalating doses of neoadjuvant atezolizumab (ATZ) prior to radical cystectomy (RC) (NCT02451423). Methods: This single-arm, single institution, phase II trial investigated treatment with 1 (n=6), 2 (n=6) or 3 (n=11) cycles of ATZ (1200 mg IV every 3 weeks) in pts with MIBC. Key inclusion criteria were urothelial carcinoma of the bladder (T2-T4a,N0-1,M0), cisplatin-ineligibility, and eligibility for RC. High-risk pts (&gt;pT2 or LN+ at RC) could receive adjuvant ATZ for up to 16 total cycles. Primary efficacy endpoint was pathologic complete response (pCR; pT0/Ta/TisN0). Secondary endpoints included rate of pathologic downstaging (≤T1N0), 2-year recurrence-free survival (RFS), overall survival (OS), and biomarker assessments of pre and post-treatment biopsies. Pts had RC between 7/2016 and 6/2021. The censor date for survival outcomes was 9/10/2023, representing the final efficacy analysis. Results: A total of 23 pts received ATZ; 1 pt was excluded from efficacy analyses due to lack of confirmed MIBC (≥T2). Among 22 included pts, median age was 70, 74% were men, 83% Caucasian; reasons for cisplatin-ineligibility were renal impairment (37%), hearing loss (27%) or neuropathy (9%); remainder declined cisplatin (27%). At enrollment, cT2/T3/T4 rates were 77%, 14%, and 9%, while 9% were cLN+. All pts completed intended treatment and had RC in the defined timeframe (&gt;3 weeks from last and &lt;12 weeks from first treatment). pCR at RC was 14% (3/22), occurring in pts receiving 1 and 2 cycles of ATZ. Pathologic downstaging (≤pT1N0) was achieved in 23% (5/22), occurring at all three dose levels. Adjuvant ATZ was given to 8 pts. Another 4 pts received off-study adjuvant therapy with cisplatin (3) or nivolumab (1). After median follow-up of 51.4 months from RC, mRFS and mOS were Not Reached. Two-year RFS and OS were 77% and 90%. In 13 pts with available paired pre and post treatment samples, there was significant increase in T-cell % following ATZ (Wilcoxon signed rank test, p&lt;0.05), driven by increase in % and density of CD8+ T-cells (p&lt;0.05). All T-cell populations were significantly more abundant in tumor than in adjacent normal tissue post-treatment but not pre-treatment (CD3+,CD3+CD8+, CD3+CD4+, p&lt;0.001 for all; CD4+FOXP3+, p=0.01). Conclusions: Neoadjuvant ATZ results in durable long-term survival rates in cisplatin-ineligible pts with MIBC. These data are comparable to previously reported trials with immunotherapy based regimens, despite a lower pCR rate. Changes suggestive of T-cell migration into the tumor microenvironment were observed following ATZ treatment. Clinical trial information: NCT02451423 .

COVID-19 Pandemic and IBS. Results of the All-Russian Observational Non-interventional Program to Study the Effectiveness of the Drug Kolofort® in Real Clinical Practice in Patients with Irritable Bowel Syndrome After a New Coronavirus Infection (VESNA)

Aim: to study the effectiveness and safety of using the drug Kolofort® in outpatients with irritable bowel syndrome (IBS) after a new coronavirus infection.Materials and methods. An observational non-interventional program was conducted in patients with exacerbation of IBS symptoms after a new coronavirus infection. One hundred forty-one patients took part in the study. The final efficacy analysis included data from 127 study participants. All patients complained of increased/appearing gastrointestinal symptoms that appeared within 1–6 months after the infection (all patients had a history of COVID-19 infection). To assess the presence and severity of symptoms of the disease, the “7 × 7” questionnaire was used before the start of treatment and three months after the start of treatment.Results. At the stage of inclusion in the program, the average total score on the “7 × 7” questionnaire was 17.36, which corresponded to a moderately severe disorder. During the treatment period, the average total score decreased to 6.14, which corresponded to borderline disorder. In addition, significant improvement was observed for each symptom separately. After three months of therapy, doctors rated the overall impression of the treatment on a 5-point Likert scale from “very effective” to “ineffective”. The average score was 4.24. In addition, no serious adverse events were identified while taking the drug.Conclusion. In real clinical practice, the drug Kolofort® demonstrated high clinical efficacy in the treatment of patients with IBS after COVID-19 infection.

Phase II Study Assessing Safety and Preliminary Efficacy of High Dose Intravenous Ascorbic Acid in Patients with TET2 Mutant Clonal Cytopenias

Background: Clonal cytopenia(s) of undetermined significance ( CCUS) is defined as persistent cytopenias arising in the context of myeloid neoplasm ( MN)-associated somatic mutations ( MT) in hematopoietic stem cells. Patients ( PTs) with TET2MT CCUS have a high probability of progression to MN. To date, no FDA-approved therapies exist for CCUS, and PTs often have similar cytopenias/transfusion needs as those with myelodysplastic syndromes ( MDS). TET2 is an ascorbic acid (AA)-dependent dioxygenase that catalyzes the conversion of 5-methylcytosine ( 5mC) to 5-hydroxymethylcytosine ( 5hmC), providing rationale to study high-dose IV (HI)-AA in TET2MT CCUS. Here we report the final results of this pilot trial. Methods: This is an investigator-initiated, single-institutional, phase II trial assessing the safety and efficacy of HI-AA in PTs with TET2MT CCUS (NCT03418038). PTs≥ 18 years with ≥1 TET2MT with or without additional somatic MTs, without prior treatment, and with any of the following laboratory criteria: (1) hemoglobin ( Hb) ≤10g/dL, (2) absolute neutrophil count ( ANC) ≤1(10^9/L), (3) platelet count ( PLT)≤100 (10^9/L) were eligible. HI-AA (1g/kg, maximum 100g) was given 3 times weekly for 12 weeks. The primary endpoint was hematologic response rates determined by MDS IWG 2018 criteria at week 20. (Platzbecker Blood 2018) and reported as hematologic improvement ( HI)- erythropoietic ( HI-E), platelets ( HI-P), neutrophils ( HI-N). Secondary endpoints include safety and adverse events ( AEs), graded by NCI-CTCAE v4.03. Correlative studies include changes in TET2MT variant allele fraction ( VAF), in vitro colony formation and differentiation, global and sequence-specific DNA methylation/hydroxymethylation, and quantitative 5hmC estimated by IHC in bone marrow biopsy specimens. Results: Ten patients were enrolled, with a median age of 71.4 (range: 65, 79) years, 8 (80%) males. The median number of mutations was 3, with 9 (90%) having co-mutations. All PTs but one [-Y] had normal karyotype. Baseline Hb levels were normal in all but one who was red blood transfusion dependent. Five (50%) PTs were thrombocytopenic, and 5 (50%) PTs had ANC&amp;lt;1 (10^9/L). ( Table). HI-AA was well tolerated with the most common AEs being infusion-related polyuria (40%) and polydipsia (40%, 3 Grade 1, 1 Grade 2). One (10%) PT had constipation and headaches (both Grade 1), and 1 (10%) experienced dyspepsia. No treatment-related Grade 3 or 4 AEs' or deaths were reported. The median follow-up duration was 16.8 months (range: 9.4, 24.1). Overall, no PTs met the criteria for HI. There were no significant differences with regards to median Hb, PLT, and ANC values at baseline, week 20, and 1-year (median Hb: 13.3, 12.5, and 12.7 g/dL, p=0.93; PLT: 97 vs. 120 vs. 92.5X10^9/L, p&amp;gt;0.99, and ANC: 0.9 vs. 1.2 vs. 1.3X10^9/L, p=0.99). By CTCAE grading criteria for cytopenias, 3 (30%) PTs had an improvement in severity of cytopenias, while 2 had worsening. One (10%) PT had an improvement in PLT (baseline vs. week 20: 62 vs 192X10^9/L) but was morphologically deemed to meet criteria for CMML-1 at week 20. Four (40%) PTs met criteria for disease progression (PT_4, 7,8,10); CMML-1- 2 and MDS-2. The median time to progression was 5 months (95% CI: 4.9, unreached). Two PTs had mutational clonal evolution, with 1 (PT_8) acquiring a RUNX1 (VAF: 20%) and 1 (PT_9) acquiring 2 CBL mutations (both VAF:4%) at one-year follow-up. There were no significant differences regarding the clinical characteristics or the TET2 variants between PTs who had stable disease vs. progression. There were no significant differences in TET2 VAF at baseline, week 20, and 1-year (median: 39% vs. 43% vs. 42%, p=0.54). We profiled changes in 5-mC and 5-hmC (Ilumina EpicArray) in PTs pre- and post-IV AA treatment and did not observe global changes. However, we were able to highlight site-specific changes in differentially methylated regions, largely resulting in hypomethylation at enhancer sites and affecting actively transcribed states in PTs with an improvement in cytopenia(s) severity by CTACE criteria ( Figure). Conclusion: We report the final safety and efficacy analysis of HI-AA in PTs with TET2 MT CCUS. The trial data suggest that HI-AA is safe and well tolerated. Although there were no significant responses by IWG MDS criteria, alleviation in severity of cytopenias in a subset of PTs (n=3) along with correlative epigenetic changes in enhancer regions, needs further exploration.

Final Results of a Multicenter Pilot Study Evaluating Brentuximab Vedotin with Cyclophosphamide, Doxorubicin, Etoposide, and Prednisone (BV-CHEP) for the Treatment of Aggressive Adult T-Cell Leukemia/Lymphoma

Introduction: Aggressive adult T-cell leukemia/lymphoma (ATLL) is a type of non-Hodgkin lymphoma that is often fatal. ATLL is exceedingly rare in the United States (US), with most cases occurring in emigrants from human T-lymphotropic virus type 1 (HTLV-1) endemic regions. Studies focusing on ATLL in the US are sparse, and have shown poor response rates; because of this, there is no standard of care treatment approach. Brentuximab vedotin (BV) is a CD30 targeting antibody-drug conjugate that is effective in treating many types of lymphoma, including CD30+ peripheral T-cell lymphomas. Studies have shown efficacy even in lymphomas with very low CD30 expression. We developed a prospective, multicenter pilot study evaluating BV in combination with cyclophosphamide, doxorubicin, etoposide, and prednisone (BV-CHEP) for the treatment of ATLL. We report the final safety and efficacy analysis below. Methods: Adult patients (pts) from 5 centers were enrolled from October 2017 through June 2022. Newly diagnosed ATLL pts were eligible, including the acute, lymphomatous and chronic unfavorable subtypes. Pts did not have to express CD30 to be enrolled; pts were considered CD30+ if there was &amp;gt;1% expression. Frontline consolidation with allogeneic stem cell transplant (alloSCT) was permitted at any time after 2 cycles of BV-CHEP. Transplant-ineligible pts completed a total of 6 cycles of BV-CHEP and those who expressed CD30 were eligible for BV maintenance. Pts could receive prephase steroids and/or 1 cycle of CHOP-equivalent chemotherapy prior to enrollment. Prior antiviral therapy was allowed. Pts were treated with standard dosing every 21 days: BV 1.8 mg/kg on day 1, cyclophosphamide 750 mg/m2 on day 1, doxorubicin 50 mg/m2 on day 1, etoposide 100 mg/m2 days 1-3, and prednisone 100mg days 1-5. All pts received GCSF support. The primary endpoint was CR by PET-CT (and peripheral blood for leukemic types) after at least 2 cycles of therapy per adapted Lugano and ATLL criteria. Secondary endpoints were safety, overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: 16 pts were enrolled and evaluable for the safety and efficacy analysis. All pts were HTLV-1 positive. Seven of 16 were the acute type, 8 were lymphomatous, and 1 was chronic unfavorable. Seven of 16 (43.75%) expressed CD30. The median age was 56 (range 34 to 69) and 12 of 16 (75%) were female. 14 of 16 pts identified as Black, 1 identified as Asian, and 1 was other. Countries of origin included: Antigua and Barbuda N=1, Colombia N=1, Haiti N=7, Jamaica N=2, Japan N=1, Liberia N=1, and the US N=3. All pts were advanced stage (12 of 16 stage IV; 4 stage III). Four had positive cerebrospinal fluid at baseline, which cleared with intrathecal (IT) treatments, and 10 were given IT prophylaxis. Nine pts had an ATL-PI score &amp;gt;3 (56.25%) with a median score of 3 (range 2-4). No subjects received prior antiretroviral therapy. 12 of 16 pts completed at least 4 cycles of treatment (median 4.5 cycles; range 2 to 6). Ten of 16 pts achieved a CR (62.5%) and 4 pts achieved a PR (ORR of 87.5%) after &amp;gt;2 cycles of BV-CHEP. The median duration of follow-up was 47.2 mo. The median PFS (mPFS) was 7.11 mo (3.93 to NR) and the median OS (mOS) was 12.2 mo (9.29 to NR) (Fig.1). Of pts who achieved a CR, the mPFS was 11.07 mo and the mOS was 15.7 mo. There was no significant difference in PFS or OS by CD30 status or by ATLL subtype. One pt received 3 cycles of maintenance BV. 5 pts received alloSCT consolidation and there was an OS benefit for this group ( p=0.007; Fig.2). Grade 3 or higher toxicities included neutropenia (N=13), anemia (N=11), thrombocytopenia (N=9), febrile neutropenia (N=7), mucositis (N=6), colitis (N=3), infections (N=3; COVID19, thrush, clostridium difficile), hyponatremia (N=3), and vomiting (N=2). Nine of 16 patients had peripheral neuropathy (all grade 1/2). There were 11 pt deaths, 9 of which were disease-related and 2 were due to shock (hypovolemic and septic) off-treatment. No patients had to come off study due to toxicity and there were no treatment-related deaths. Conclusions: In this final analysis, BV-CHEP was safe and effective for the treatment of aggressive ATLL. High ORR and CR rates were achieved regardless of CD30 status, and compare favorably to prior clinical trials. AlloSCT had an OS benefit with 4 of 5 pts achieving long-term remission. Toxicity was manageable and cytopenias were expected. Peripheral neuropathy was common, but low-grade.

Brentuximab Vedotin in Combination with Nivolumab in CD30+ Malignancies Refractory to Brentuximab Vedotin

Introduction Brentuximab vedotin (BV), in combination with multi-agent chemotherapy, is considered a standard of care for newly diagnosed CD30+ lymphomas. Despite high reported efficacy, some patients fail to respond to initial BV exposure and many more eventually progress despite ongoing BV therapy. In addition to direct cytotoxicity, BV may also induce immunogenic cell death (Gardai, et al. Cancer Res 2015) and foster a reduction of regulatory T-cells (Herrera, et al. Blood 2018) that may synergize with immune checkpoint inhibitors. To date, the high response rates reported with BV and anti-PD-1 combinations have been limited to patients naïve to both of these agents (Advani, et al. Blood 2021). To address the more clinically relevant scenario of prior BV +/- anti-PD-1 exposure, we designed a study to evaluate the combination of BV and nivolumab in patients with CD30+ lymphoma refractory to prior BV, including those with prior anti-PD-1 therapy. We report the final safety, efficacy and correlative analysis of BV in combination with nivolumab in R/R CD30+ lymphomas refractory to BV. Methods We conducted an open-label trial (NCT01703949) involving patients 18 years and older with CD30+ lymphomas refractory to BV therapy. Refractoriness was defined as lack of disease response or progression within 6 months following a minimum of 2 cycles of BV. BV was given at 1.8 mg/kg in combination with nivolumab at 3 mg/kg every 3 weeks for 4 cycles. The primary endpoint was overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival, overall survival, time to next treatment, safety and tolerability and immune response biomarkers. Results As of July 27, 2023, 19 patients have enrolled and 17 have initiated therapy (Table 1). Fourteen patients had classical Hodgkin lymphoma (cHL), 2 had ALK-negative anaplastic large cell lymphoma (ALK- ALCL) and 3 had CD30+ mycosis fungoides (MF). Median age was 35 (range 27-71) years and the median number of prior regimens was 5 (range 1-9), including a median of 6 prior cycles of BV (range 2-19). All patients had BV-refractory disease including 16 (84%) who were non-responsive to and 3 (16%) who relapsed within 6 months of BV. Five (26%) patients with cHL received prior anti-PD-1 therapy and 4 (21%) had anti-PD-1 refractory disease. Median time from last BV and anti-PD-1 therapy to study treatment was 5.2 and 1.1 months, respectively. Eight (42%) patients had prior autologous stem cell transplant. Of response evaluable patients, the ORR and CR rate was 44% and 6% after 2 cycles and 44% and 19% after 4 cycles of therapy. Of patients who were refractory to prior BV and anti-PD-1 therapy, 1 (25%) and 1 (25%) achieved a PR and CR, respectively. ORR and CR rate was 43% and 14% for patients with cHL, 100% and 50% for patients with ALK- ALCL, and 100% and 100% for patients with MF, respectively. At completion of study, 1 patient with cHL, 1 with MF and 2 with cHL continued BV with nivolumab, BV monotherapy and nivolumab monotherapy, respectively. Median time to progression and next therapy was 4.5 (range 1.8-45.6) and 5.0 (range 1.8-45.6) months, respectively. Of the 3 patients who achieved a CR after 4 cycles of therapy, 2 (67%) continued treatment (1 with BV and nivolumab and 1 with BV monotherapy), and 1 (33%) has been on surveillance for 45.6 months with no evidence of relapse. At a median follow-up of 21.7 (range 0.5-60.4) months, 15 (79%) patients are alive with 3 in CR. Eleven (58%) and 8 (42%) patients reported no and grade 1 peripheral neuropathy (PN) at baseline, respectively. At end of treatment, 12 (63%) and 1 (5%) patients reported grade 1 and 2 PN, respectively. No patients experienced grade ≥3 PN, transaminitis, infections or infusion reactions. One (5%) patient had a 1-week dose delay due to grade 1 ALT/AST elevation. Two (11%) deaths were noted on study; one patient developed respiratory failure secondary to pneumonitis and influenza and another patient experienced cardiac arrest due to benzodiazepine withdrawal. Correlative PD-1 levels drawn at baseline and at the end of treatment did not correlate with response. Conclusions Despite the presence of BV-refractory disease, 4 cycles of BV and nivolumab is tolerable and associated with encouraging efficacy in patients with heavily treated CD30+ lymphoma. This treatment option may have increasing relevance as more patients receive BV or anti-PD-1 therapy as part of initial treatment.

Ruxolitinib in Patients With Chronic Graft-Versus-Host Disease: 3-Year Final Analysis of Efficacy and Safety From the Phase III REACH3 Study

Introduction: Corticosteroids (CS) are the standard first-line treatment for patients (pts) with chronic graft-versus-host disease (cGvHD), but pts can be unresponsive or become refractory to or dependent on CS (SR/D).Ruxolitinib (RUX), a JAK1/2 inhibitor, is approved for the treatment of pts ≥12 years of age with SR/D-cGVHD, based on the primary outcomes from the randomized, phase III REACH3 (NCT03112603) study, which demonstrated the superior efficacy of RUX vs best available treatment (BAT) in pts with SR/D-cGVHD. Here, we present the final, long-term efficacy and safety outcomes from REACH3. Methods: Pts ≥12 years of age with moderate or severe SR/D-cGVHD were randomized 1:1 to receive either RUX 10 mg twice daily (BID) or investigator-selected BAT and followed for 3 years, till discontinuation or death. The primary analysis was conducted at week 24 (Cycle 7 Day 1 [C7D1]) in randomized pts, then pts entered the extension period (C7-39) in which they continued treatment, switched from BAT to RUX (crossover cohort), or discontinued treatment and entered long-term survival follow-up (FU). Failure-free survival (FFS; key secondary endpoint), duration of response (DOR), overall survival (OS), non-relapse mortality (NRM), malignancy relapse (MR), and safety were analyzed at 3 years (week 156; final data cut off 15 Dec 2022). Overall response rate (ORR) and best overall response (BOR) during the crossover treatment period were analyzed for pts who switched from BAT to RUX on or after C7D1. Results: Of 329 pts randomized, 53 completed the treatment period and 276 discontinued, 115 entered survival FU (RUX: 73/165; BAT:42/164); 70 pts crossed over from BAT to RUX of which 16 completed the crossover treatment period and 24 entered survival FU. Median FFS was longer in the RUX vs BAT arms (38.4 vs 5.7 months; hazard ratio [HR]=0.361, 95% confidence interval [CI]: 0.268, 0.485) with 12-month FFS probabilities of 64.0% (95% CI: 56.1, 70.8) and 28.8% (95% CI: 21.8, 36.1), respectively. Median OS was not reached and there was no difference in risk of death between the arms (HR=0.851, 95% CI: 0.544, 1.331) [Table 1]. Median DOR was 6.4 months (95% CI: 4.9, 11.4) in the BAT arm but was not reached for the RUX arm; notably, the probability of maintaining DOR at 3 years was higher in RUX (59.6%; 95% CI: 50.4, 67.6) vs BAT (26.7%; 95% CI: 18.5, 35.5). NRM event rates were similar between the arms (RUX: 29/165; BAT 34/164), and MR events were similar and low in both arms (13/156 and 11/160, RUX and BAT respectively) up to 3 years. The ORR at week 24 after crossover from BAT to RUX was 50.0% (95% CI: 37.8, 62.2), including complete response (CR) in 4 (5.7%) pts and partial response (PR) in 31 (44.3%) pts. The BOR during crossover was 81.4% (95% CI: 70.3, 89.7), including CR of 7.1% and PR of 74.3%; disease progression only occurred in 1 pt. Almost all pts treated during the main treatment period (RUX: 100%; BAT: 93.7%) experienced ≥1 adverse event (AE) and, in general, AE rates were higher in the RUX vs BAT arms [Table 2], likely due to prolonged FU and exposure to RUX (median exposure to treatment of 52.9 weeks vs. 24.1 weeks for RUX and BAT, respectively).Anemia was the most common AE (RUX: 33.9%; BAT: 15.8%) and grade ≥3 AE for RUX (17.6% vs BAT 9.5%, respectively); grade ≥3 neutropenia, thrombocytopenia, alanine aminotransferase increase, and gamma-glutamyltransferase increase were also ≥5% higher for RUX than BAT. Anemia (24.2%; grade ≥3, 10.3%) and thrombocytopenia (3.8%) were the most common RUX and BAT treatment-related AEs, respectively. Infections, excluding tuberculosis, were the most common AE of special interest (77.6% vs. 68.4%; grade ≥3, 31.5% and 26.6%, for RUX and BAT, respectively). On-treatment deaths were mainly due to cGvHD (n/N, RUX: 10/18; BAT 6/12). Conclusions: After 3 years of treatment in REACH3, the longer FFS and higher DOR with RUX vs BAT indicated that cGVHD was more in control with RUX treatment. Notably, efficacy was demonstrated in pts who switched from BAT to RUX with an ORR similar to that in pts randomized to RUX. RUX was well tolerated with no unexpected toxicities and safety that was consistent with earlier studies. Overall, the long-term control of cGVHD and tolerability of RUX was demonstrated for pts ≥12 years of age with SR/D-cGvHD.

Construction and Evaluation of Clinical Prediction Model for Immunotherapy-related Adverse Events and Clinical Benefit in Cancer Patients Receiving Immune Checkpoint Inhibitors Based on Serum Cytokine Levels.

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of cancer therapy. This study aimed to develop novel risk classifiers to predict the risk of immune-related adverse events (irAEs) and the probability of clinical benefits. Patients with cancer who received ICIs from the First Affiliated Hospital of Xi 'an Jiaotong University from November 2020 to October 2022 were recruited and followed up. Logistic regression analyses were performed to identify independent predictive factors for irAEs and clinical response. Two nomograms were developed to predict the irAEs and clinical responses of these individuals, with a receiver operating characteristic curve to assess their predictive ability. Decision curve analysis was performed to estimate the clinical utility of the nomogram. This study included 583 patients with cancer. Among them, 111 (19.0%) developed irAEs. Duration of treatment (DOT)>3 cycles, hepatic-metastases, IL2>2.225pg/mL, and IL8>7.39pg/mL were correlated with higher irAEs risk. A total of 347 patients were included in the final efficacy analysis, with an overall clinical benefit rate of 39.7%. DOT>3 cycles, nonhepatic-metastases, and irAEs and IL8>7.39pg/mL were independent predictive factors of clinical benefit. Ultimately, 2 nomograms were successfully established to predict the probability of irAEs and their clinical benefits. Ultimately, 2 nomograms were successfully established to predict the probability of irAEs and clinical benefits. The receiver operating characteristic curves yielded acceptable nomogram performance. Calibration curves and decision curve analysis supported the hypothesis that nomograms could provide more significant net clinical benefits to these patients. Specific baseline plasma cytokines were closely correlated with irAEs and clinical responses in these individuals.

Interim results of a phase II trial of first line retifanlimab (R) plus gemcitabine and docetaxel (GD) in patients (pts) with advanced soft tissue sarcoma (STS).

11518 Background: GD is an alternative to doxorubicin in the front line setting in advanced STS. In the Phase I portion of this study, the PD-1 antibody R, plus GD, was generally well tolerated. We hypothesized that R+GD would be more effective than historical controls treated with GD alone. Methods: This is an ongoing open-label single-center study of R+GD in pts with treatment-naïve unresectable or metastatic high-grade STS. G (900 mg/m2) is administered on days 1 and 8 and D (75 mg/m2) on day 8, in 21-day cycles. R (375 mg flat dose) is administered on day 1 starting in cycle 2 and continued as monotherapy ‘maintenance’ after completion of 6 cycles of GD. Up to fifty pts can accrue into five histology-specific cohorts of 10 pts each. The primary endpoint is to estimate the progression-free survival (PFS) rate at 24 weeks. Secondary endpoints included safety, best overall response rate (RR) by RECIST 1.1, disease control rate (DCR), and duration of response (DOR). Subgroup analyses to evaluate all endpoints within each histology-specific cohort are preplanned. An early stopping rule for excessive toxicity will halt accrual if a prespecified severe adverse event rate is surpassed. Results: As of January 11, 2023, 43 pts were enrolled and treated with R+GD. The leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma (MFS), dedifferentiated liposarcoma (DDLPS), and other STS cohorts (n = 10 pts each) were fully accrued. Three of 10 angiosarcoma (AS) pts were enrolled. Median age was 59.5 (range 21 – 81) and 27 (63%) were male. Two DDLPS patients were not yet evaluable for response. Of 41 evaluable pts, the best overall RR was 22% (95% confidence interval [CI]) 11 – 38). Confirmed responses were seen in UPS/MFS (n = 4), LMS (2), AS (2), and follicular dendritic cell sarcoma (1). Three pts (LMS, ossifying fibromyxoid tumor, AS) had an unconfirmed PR, for a best RR of 29% (95% CI 16 – 46). Median PFS was 32.7 weeks (95% CI 26.4 – not estimable [NE]) and median DOR was 24 weeks (95% CI 15 – NE). Safety was evaluated in all 43 pts and the early stopping rule was not triggered. Eighteen (42%) pts had at least one Grade (Gr) 3 or 4 treatment-related adverse event (TRAE). The most common ( &gt; 5%) were anemia (16%), neutropenia (9%), febrile neutropenia (7%), lung infection (7%), and leukopenia (7%). Seven pts (16%) had pneumonitis: one Gr 1, four Gr 2, and two Gr 3. Six pts (14%) stopped treatment due to toxicity, including five with pneumonitis. Conclusions: The median PFS of R+GD appears promising compared to historical controls, although the primary endpoint analysis is pending completion of accrual. There was a higher incidence of pneumonitis with the combination compared to GD alone. Future studies of this combination will need to carefully consider the benefits and risks after the final efficacy and safety analyses are performed. Clinical trial information: NCT04577014 .

Abstract OT3-09-01: Clinical Trial of Alpelisib and Tucatinib in Patients with PIK3CA-Mutant HER2-Positive Metastatic Breast Cancer

Abstract Phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in resistance to the drugs targeting human epidermal growth factor receptor 2 (HER2). Activating mutations in the gene encoding alpha catalytic subunit of PI3K (PIK3CA) are present in approximately 30% of HER2+ tumors. PIK3CA mutations are linked to drug resistance and decreased survival in patients with HER2+ breast cancer. To overcome this resistance mechanism, we designed a phase IB/II clinical trial to evaluate the combination of HER2 small molecule inhibitor tucatinib with PI3K inhibitor alpelisib in patients with HER2+ metastatic breast cancer (NCT05230810). This multicenter clinical trial is conducted through the Academic Breast Cancer Consortium (ABRCC), with the University of Colorado Cancer Center as the lead site. Target enrollment: 40 patients. This is a run-in phase IB/roll-over phase II study. Phase IB will follow Time-to-Event Bayesian Optimal Interval design and enroll from 9 to 19 patients to find the maximum tolerated doses (MTDs) of tucatinib and alpelisib. From 21 to 31 patients will be enrolled in phase II part, for a total of 40 patients in the final efficacy analysis. Main inclusion criteria: 1. Women and men ≥ 18 years old 2. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 3. Presence of activating PIK3CA mutation in the tumor 4. Patients with HR-/HER2+ or HR+/HER2+ breast cancer may enroll; ovarian suppression is mandatory for premenopausal patients with HR+/HER2+ disease 5. HR+/HER2+ patients should be agreeable to concomitant treatment with fulvestrant 6. Prior treatment with at least two FDA-approved HER2-targeted agents 7. Measurable or evaluable disease. Bone only disease is allowed. 8. Subjects with untreated central nervous system (CNS) metastases not needing immediate local therapy, and subjects with previously treated stable or progressive brain metastases may enroll, provided that there is no indication for immediate re-treatment. For patients with treated CNS metastases: time from treatment of CNS disease until the first dose of study drugs should be as follows: WBRT ≥ 21 days, surgical resection ≥ 14 days, SRS ≥ 7 days. 9. Adequate organ and marrow function Main exclusion criteria: 1. Contraindications to undergo contrast brain MRI 2. Leptomeningeal disease 3. Poorly controlled seizures 4. Diabetes mellitus type I, or uncontrolled diabetes mellitus type II 5. Acute pancreatitis within 1 year of screening, or history of chronic pancreatitis 6. History of severe cutaneous hypersensitivity reactions 7. Toxicities of prior cancer therapies that have not resolved to grade 1 or less, except peripheral neuropathy, which must have resolved to grade 2 or less, and alopecia 8. Previous treatment with EGFR or HER2 tyrosine kinase inhibitors, or PI3K/mTOR/AKT inhibitors. 9. Systemic anti-cancer therapy, palliative radiation to extracranial sites, or surgery within 2 weeks of the first dose of study drugs 10. Active bacterial, fungal, or viral infections, hepatitis B, C, or HIV 11. Clinically significant cardio-vascular disease Primary objectives: • Phase IB: safety and tolerability of combination therapy • Phase II: efficacy by progression free survival Exploratory assessment of biomarkers will be performed in the liquid biopsy samples. Study contact: Elena Shagisultanova, MD, PhD, elena.shagisultanova@cuanschutz.edu Citation Format: Elena Shagisultanova, Kari B. Wisinski, Chelsea D. Gawryletz, Farrah M. Datko, Diana Medgyesy, Jennifer R. Diamond, Virginia F. Borges, Peter Kabos. Clinical Trial of Alpelisib and Tucatinib in Patients with PIK3CA-Mutant HER2-Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-09-01.

Abstract PD18-03: Final analysis of the Phase III PEONY trial: long-term efficacy and safety of neoadjuvant–adjuvant pertuzumab or placebo, plus trastuzumab and docetaxel, in patients with HER2-positive early or locally advanced breast cancer

Abstract BACKGROUND In the Phase II NeoSphere study (NCT00545688), dual HER2 blockade with pertuzumab (P) + trastuzumab (H), + docetaxel (D) significantly increased pathologic complete response (pCR) vs. H+D in the neoadjuvant setting for HER2-positive early breast cancer (EBC), locally advanced (LA) BC, or inflammatory BC, with supportive progression- and disease-free survival (DFS) data. Consistently, the randomized, multicenter, double-blind, placebo (Pla)-controlled Phase III PEONY trial (NCT02586025) significantly improved total pCR (tpCR; primary endpoint) with P+H+D vs. H+D in an Asian population, and safety data were in-line with the known P safety profile. We present the final analysis of long-term efficacy (at 3 and 5 years) and safety from the study. METHODS Patients had centrally confirmed HER2-positive EBC (T2–3, N0–1) or LABC (T2–3, N2 or N3; T4, any N) and were randomized 2:1 to four neoadjuvant P+H+D or Pla+H+D cycles every 3 weeks. P: 840 mg loading/420 mg maintenance doses (or Pla); H: 8 mg/kg loading/6 mg/kg maintenance; D: 75 mg/m2. Patients then received three fluorouracil, epirubicin, and cyclophosphamide cycles, followed by 13 of P+H or Pla+H in the adjuvant setting for up to 1 year. Long-term outcomes (event-free survival [EFS], DFS, overall survival [OS]; all secondary endpoints) were assessed by Kaplan–Meier methods, Cox proportional hazards models, and a two-sided log-rank test (stratified by disease category and hormone receptor status). RESULTS Data cut-off was Mar 14, 2022, and 329 patients were randomized; 219 to P; 110, to Pla. Safety populations were 218 and 110 patients, respectively. Baseline characteristics were well balanced. Most patients received the full HER2-targeted cycles. Median follow-up was 62.9 months. Long-term efficacy data are shown in the table. During the overall treatment period, 70.6% of patients in the P+H+D arm and 68.2% in the Pla+H+D arm experienced grade ≥3 adverse events (AEs); the most common (in ≥5% of patients in either arm) being neutropenia (59.2% vs. 55.5%), leukopenia (34.4% vs. 34.5%), and febrile neutropenia (5.0% vs. 3.6%). Of the most common any-grade AEs (in ≥30% of patients in either arm), diarrhea was more common in the P+H+D arm (40.8% vs. 17.3% in the Pla+H+D arm). Serious AEs were reported in 17.0% and 13.6% of patients, respectively. No primary cardiac events (heart failure [New York Heart Association grade III or IV] or significant decline of left ventricular ejection fraction) or secondary cardiac events occurred during any study periods. CONCLUSIONS Long-term efficacy endpoints (EFS, DFS, and OS) were supportive of the primary endpoint results (tpCR) and suggested a clinically meaningful improvement with P+H vs. Pla+H when administered before and after surgery for one year of anti-HER2- therapy. Safety data were in-line with the known P safety profile and generally comparable between arms, with the exception of diarrhea. PEONY adds to the totality of data showing the benefit of the P+H+D regimen in HER2-positive EBC. Table 1: Long-term efficacy data Citation Format: Zhi-Ming Shao, Da Pang, Hongjian Yang, Wei Li, Shusen Wang, Shude Cui, Ning Liao, Yong-Sheng Wang, Chuan Wang, Yuan-Ching Chang, Hwei-Chung Wang, Seok Yun Kang, Jae Hong Seo, Kunwei Shen, Suphawat Laohawiriyakamol, Zefei Jiang, Liang Huang, Haiyan Wang, François Lamour, Grace Song, Eleonora Restuccia. Final analysis of the Phase III PEONY trial: long-term efficacy and safety of neoadjuvant–adjuvant pertuzumab or placebo, plus trastuzumab and docetaxel, in patients with HER2-positive early or locally advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-03.

Final Efficacy and Cost Analysis of a Fish Skin Graft vs Standard of Care in the Management of Chronic Diabetic Foot Ulcers: A Prospective, Multicenter, Randomized Controlled Clinical Trial

Introduction. DFUs remain a cause of significant morbidity. Objective. This is the third of 3 planned articles reporting on a prospective, multicenter, randomized controlled trial evaluating the use of omega-3–rich acellular FSG compared with CAT in the management of DFUs. Materials and Methods. A total of 102 patients with a DFU (n = 51 FSG, n = 51 CAT) participated in the trial as ITT candidates, with 77 of those patients included in the PP analysis (n = 43 FSG, n = 34 CAT). Six months after treatment, patients with healed ulcers were followed up for ulcer recurrence. A cost analysis model was applied in both treatment groups. Results. The proportion of closed wounds at 12 weeks was compared, as were the secondary outcomes of healing rate and mean PAR. Diabetic foot wounds treated with FSG were significantly more likely to achieve closure than those managed with CAT (ITT: 56.9% vs 31.4%; P =.0163). The mean PAR at 12 weeks was 86.3% for FSG vs 64.0% for CAT (P =.0282). Conclusions. Treatment of DFUs with FSG resulted in significantly more wounds healed and an annualized cost savings of $2818 compared with CAT.