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PURPOSE The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes—both pathologic and time-to-event survival end points—particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor–positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.

Objective Myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) can be monophasic or relapsing, with early relapse being a feature. However, the relevance of early relapse on longer‐term relapse risk is unknown. Here, we investigate whether early relapses increase longer‐term relapse risk in patients with MOGAD. Methods A retrospective analysis of 289 adult‐ and pediatric‐onset patients with MOGAD followed for at least 2 years in 6 specialized referral centers. “Early relapses” were defined as attacks within the first 12 months from onset, with “very early relapses” defined within 30 to 90 days from onset and “delayed early relapses” defined within 90 to 365 days. “Long‐term relapses” were defined as relapses beyond 12 months. Cox regression modeling and Kaplan–Meier survival analysis were used to estimate the long‐term relapse risk and rate. Results Sixty‐seven patients (23.2%) had early relapses with a median number of 1 event. Univariate analysis revealed an elevated risk for long‐term relapses if any “early relapses” were present (hazard ratio [HR] = 2.11, p < 0.001), whether occurring during the first 3 months (HR = 2.70, p < 0.001) or the remaining 9 months (HR = 1.88, p = 0.001), with similar results yielded in the multivariate analysis. In children with onset below aged 12 years, only delayed early relapses were associated with an increased risk of long‐term relapses (HR = 2.64, p = 0.026). Interpretation The presence of very early relapses and delayed early relapses within 12 months of onset in patients with MOGAD increases the risk of long‐term relapsing disease, whereas a relapse within 90 days appears not to indicate a chronic inflammatory process in young pediatric‐onset disease. ANN NEUROL 2023;94:508–517

ImportanceCombination therapy with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i: palbociclib, ribociclib, abemaciclib) and endocrine therapy (ET) has been a major advance for the treatment of hormone receptor–positive (HR+), ERBB2 (formerly HER2)–negative (ERBB2−) advanced or metastatic breast cancer.ObservationsRandomized phase 3 studies demonstrated that the addition of CDK4/6i reduced the hazard risk of disease progression by approximately half compared with hormonal monotherapy (an aromatase inhibitor, tamoxifen, or fulvestrant) in the first-line (1L) and/or second-line (2L) setting. Hence, the US Food and Drug Administration and European Medicines Agency approved 3 CDK4/6i, in both 1L and 2L settings. However, differences among the CDK4/6i regarding mechanisms of action, adverse effect profiles, and overall survival (OS) are emerging. Both abemaciclib and ribociclib have demonstrated efficacy in high-risk HR+ early breast cancer. While ET with or without CDK4/6i is accepted as standard treatment for persons with advanced HR+ ERBB2− metastatic breast cancer, several key issues remain. First, why are there discordances in OS in the metastatic setting and efficacy differences in the adjuvant setting? Additionally, apart from HR status, there are few biomarkers predictive of response to CDK4/6i plus ET, and these are not used routinely. Despite the clear OS advantage noted in the 1L and 2L metastatic setting with some CDK4/6i, a subset of patients with highly endocrine-sensitive disease do well with ET alone. Therefore, an unanswered question is whether some patients can postpone CDK4/6i until the 2L setting, particularly if financial toxicity is a concern. Finally, given the lack of endocrine responsiveness following progression on some CDK4/6i, strategies to optimally sequence treatment are needed.Conclusions and RelevanceFuture research should focus on defining the role of each CDK4/6i in HR+ breast cancer and developing a biomarker-directed integration of these agents.

PURPOSEThere are numerous barriers to enrollment in oncology biomarker-driven studies.METHODSThe ELAINE 2 study (ClinicalTrials.gov identifier: NCT04432454 ) is an open-label phase 2 study of lasofoxifene combined with abemaciclib in patients with advanced or metastatic estrogen receptor–positive/human epidermal growth factor receptor 2–negative breast cancer with an ESR1 mutation. ELAINE 2 opened clinical sites by using a Traditional approach, which activated a site before patient identification, and the Tempus TIME Trial network, which opened a site only after identifying an eligible patient. This manuscript presents the operational metrics comparing the Traditional and TIME Trial site data.RESULTSThe study enrolled patients over 34 weeks and 16 sites (six Traditional and 10 TIME Trial) participated. Duration for full clinical trial agreement execution for Traditional sites and TIME Trial sites averaged 200.5 (range, 142-257) and 7.6 days (range, 2-14), respectively. Institutional review board approval time for Traditional sites and TIME Trial sites was 27.5 (range, 12-71) and 3.0 days (range, 1-12), respectively. Duration from study activation to first consent was 33.3 (range, 18-58) and 8.8 days (range, 1-35) for Traditional and TIME Trial sites, respectively. The first patient on study was at a TIME Trial site 115 days before a Traditional site and the first seven patients enrolled were at TIME Trial sites. Traditional sites consented 23 and enrolled 16 patients, while TIME Trial sites consented 16 and enrolled 13. The trial enrolled 29 patients in 8.5 months with the anticipated enrollment duration being 12-18 months.CONCLUSIONThe TIME Trial network opened earlier and enrolled the first study patients. These results demonstrate that the Just-in-TIME model, along with a Traditional model, can improve enrollment in biomarker-driven studies.

TPS1115 Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients progress during maintenance therapy with T + P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in patients with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T + P as maintenance therapy for HER2+ MBC. Approximately 650 patients will be enrolled. Eligible patients will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Patients will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T + P once every 21 days. Patients with hormone receptor-positive disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), PFS by Blinded Independent Central Review (BICR), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, Canada, Brazil, APAC and EU countries with additional sites planned. Clinical trial information: NCT05132582 .

1057 Background: Endocrine therapy (ET), particularly aromatase inhibitors (AIs), for estrogen receptor (ER)-positive breast cancer can lead to acquired ESR1 mutations ( mESR1) driving endocrine resistance and tumor progression. Treatments for mBC with mESR1 are limited, especially after progression on ET/cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) combinations. In ELAINE 2, LAS, a next-generation ET (breast ER antagonist) plus Abema had a median progression-free survival (PFS) of ~13 mos, objective response rate (ORR) of 33%, and 24-wk clinical benefit rate (CBR) of 62% with a favorable safety profile in patients with resistant mESR1 mBC (Damodaran S, et al. J Clin Oncol. 2022;40:16 suppl 1022). Here, we report ELAINE 2 data with longer patient follow up (Jan 31, 2023). Methods: In this open-label, phase 2, single-arm study, 29 women with mESR1, ER+/HER2- mBC that progressed on prior ET took oral LAS 5 mg/day and Abema 150 mg BID until disease progression/toxicity. The primary endpoint was safety/tolerability; secondary included PFS, CBR, and ORR. Data were summarized descriptively with no formal hypothesis testing. Results: Patients (median age 60 yrs) had received a median of 2 prior therapy lines for mBC; all but one had prior CDK4/6i exposure and 14 (48%) had prior chemotherapy for mBC. LAS/Abema was well tolerated with primarily grade 1/2 treatment-emergent adverse events (most commonly diarrhea, nausea, fatigue, and vomiting). One treatment withdrawal occurred due to grade 2 diarrhea. No deaths occurred. LAS dose was not reduced; Abema dose was reduced to 100 mg BID in 6 (21%) patients. Median PFS was 56.0 wks (~13 mos) and CBR 65.5% (95% CI, 47.3‒80.1). Median overall survival was not estimable. In 18 patients with measurable lesions, ORR was 55.6% (95% CI, 33.7‒75.4), with median time to response of 5.7 mos and median duration of response of 6.4 mos. Seventy-six percent, 56%, and 39% of patients were progression free at 6, 12, and 18 mos, respectively. Three (10%) patients had scan-identified venous thromboembolic events, with one symptomatic pulmonary embolism and one symptomatic deep vein thrombosis. In 26 patients with evaluable baseline and wk 4 ctDNA, ESR1 mutant allele fraction decreased from baseline to wk 4 in 81% of patients and was not detected in 54%. Conclusions: With longer ELAINE 2 follow up, LAS/Abema continues to be well tolerated with clinically meaningful efficacy in women with mESR1, ER+/HER2- mBC that had progressed on ET and CDK4/6is. Decreases in mESR1 ctDNA suggest effective target engagement of LAS. The PFS (median ~13 mos) and ORR (56%) with LAS/Abema are promising and a confirmatory phase 3 study (ELAINE 3) will begin in 2023. If ELAINE 2 results are confirmed, the combination of LAS and Abema would address a critical unmet need, providing a practice changing option for treating mESR1 breast cancer. Clinical trial information: NCT04432454 .

Recent 2022 SARS-CoV-2 Omicron variants, have acquired resistance to most neutralizing anti-Spike monoclonal antibodies authorized, and the BQ.1.* sublineages are notably resistant to all authorized monoclonal antibodies. Polyclonal antibodies from individuals both vaccinated and recently recovered from Omicron COVID-19 (VaxCCP) could retain new Omicron neutralizing activity. Here we reviewed BQ.1.* virus neutralization data from 920 individual patient samples from 43 separate cohorts defined by boosted vaccinations (Vax) with or without recent Omicron COVID-19, as well as infection without vaccination (CCP) to determine level of BQ.1.* neutralizing antibodies and percent of plasma samples with neutralizing activity. More than 90 % of the plasma samples from individuals in the recently (within 6 months) boosted VaxCCP study cohorts neutralized BQ.1.1, and BF.7 with 100 % neutralization of WA-1, BA.4/5, BA.4.6 and BA.2.75. The geometric mean of the geometric mean 50 % neutralizing titres (GM (GMT 50 ) were 314, 78 and 204 for BQ.1.1, XBB.1 and BF.7, respectively. Compared to VaxCCP, plasma sampled from COVID-19 naïve subjects who also recently (within 6 months) received at least a third vaccine dose had about half of the GM (GMT 50 ) for all viral variants. Boosted VaxCCP characterized by either recent vaccine dose or infection event within 6 months represents a robust, variant-resilient, neutralizing antibody source against the new Omicron BQ.1.1, XBB.1 and BF.7 variants.