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PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+HER2–) patients from five IO arms. METHODS A total of 204 HR+HER2– (MammaPrint high-risk) patients from five IO arms (anti–PD-1, anti–PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti–PD-1/toll-like receptor 9 dual-IO combination, and anti–PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint– (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2– patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint–, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint–. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5). CONCLUSION Using an accurate selection strategy, HR+HER2– patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2– patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Abstract Neurofibrillary tangles are dynamic neuropathologic hallmarks of Alzheimer’s disease with a hypothesized lifespan morphologically-defined by three maturity levels: pretangles, mature tangles, and ghost tangles. To better understand the progression of tangle pathophysiology, we characterized tangle maturity level predilection of 15 tau antibodies recognizing a broad range of linear, phosphorylation, conformational, and truncation epitopes in the hippocampus of 24 postmortem brains. We developed the tangle maturity scoring system to semi-quantitatively evaluate each tangle maturity level. Based on proportions of tangle maturity levels, we classified antibodies as “early” (mostly pretangles and mature tangles), “middling” (mature tangles with pretangles and ghost tangles), and “advanced” (mostly ghost tangles and mature tangles) tangle maturity markers. To summarize tangle maturity predilection, we developed the tangle maturity scale to integrate individual tangle maturity scores. Correlations showed stronger relationships between tangle maturity scale and subsector thickness for more advanced tangle maturity markers in CA1 and subiculum, whereas Braak tangle stage remained consistently correlated throughout markers of the tangle lifespan. To aid in scoring hippocampi, we used machine learning to recognize tangle maturity levels, which performed comparably to a domain expert and showed similar relationships by Spearman correlation. Pattern recognition software was used to assess tangle and neuritic tau burden separately, which generally correlated with Braak stage and neuronal counts. However, tangle-derived tau burden more consistently correlated with hippocampal subsector thickness. In conclusion, we developed manual and automated scoring systems to evaluate tangle maturity levels, demonstrating early 4R, phosphorylated, and oligomeric tau accumulation preceding more advanced 3R and truncated tau. Our study provides supportive evidence of disease-relevant ordering of tau posttranslational modifications in the brain, which may have implications for theragnostic development. These findings underscore the promise of computerized quantitative analyses (i.e., pathomics) for high-throughput feature extraction from whole-slide images to enhance our understanding of microscopically observed morphologic changes.

Barriers to incorporating pharmacogenetics into routine clinical practice in the United States are well documented. Initial surveys by the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2009 and 2010 identified barriers across four key domains that have hindered the widespread adoption of clinical pharmacogenetic testing. These are presented verbatim as: (i) absence of a definition of the processes required to interpret genotype information and to translate genetic information into clinical actions; (ii) need for recommended drug/gene pairs to implement clinically now; (iii) clinician resistance to consider pharmacogenetic information at the bedside; and (iv) concerns about test costs and reimbursement. Over time, many of these challenges have been overcome, and clinical pharmacogenetic testing has subsequently reached broader implementation. Despite this progress, several barriers remain that block further adoption. This narrative review used authors' expertise and experience to identify and describe current barriers to pharmacogenetic implementation across seven domains in the United States: equity and inclusion; guidelines and supporting evidence; regulatory agency oversight; payer coverage and insurance; availability of quality pharmacogenetic tests; electronic health records; and provider and patient education. Within each domain, it revisits past successes and challenges and explores remaining barriers. We also propose solutions to address ongoing challenges across these domains, including further expansion of recommendations beyond pharmacogenetic‐specific guidelines, standards for designing clinical decision support tools, and broader pharmacogenetics education. Addressing these remaining obstacles directs work to enable broader adoption of clinical pharmacogenetic implementation to ultimately improve patient outcomes.

LBA3500 Background: BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating first-line (1L) encorafenib + cetuximab (EC) ± chemotherapy (chemo) vs standard of care (SOC; chemo ± bevacizumab) in BRAF V600E-mutant metastatic colorectal cancer (mCRC). The study previously met one of its dual primary endpoints (EPs) demonstrating clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR) by blinded independent central review (BICR) in the ORR subset. These results were the basis for the FDA accelerated approval of EC+mFOLFOX6 for BRAF V600E-mutant mCRC, including in the 1L, under Project Frontrunner. Here, we report the primary analysis of progression-free survival (PFS) by BICR, updated interim analysis of OS, updated safety, and other analyses. Methods: Eligible patients (pts) with untreated BRAF V600E-mutant mCRC were randomized 1:1:1 to receive EC, EC+mFOLFOX6, or SOC; EC arm enrollment was closed after a protocol amendment. Dual primary EPs: ORR and PFS by BICR (EC+mFOLFOX6 vs SOC); key secondary EP: OS (EC+mFOLFOX6 vs SOC). Results: 637 pts were randomized to EC, EC+mFOLFOX6, or SOC. Baseline demographics and disease characteristics were generally balanced between arms. EC+mFOLFOX6 (data cutoff: Jan 6, 2025) demonstrated a clinically meaningful and statistically significant PFS improvement vs SOC, meeting the other dual primary EP; HR=0.53 (95% CI 0.407, 0.677; P<0.0001); median PFS 12.8 vs 7.1 mo. OS was clinically meaningful and statistically significant vs SOC; HR=0.49 (95% CI 0.375, 0.632; P<0.0001); median OS 30.3 vs 15.1 mo. Median PFS and OS in the EC arm were 6.8 and 19.5 mo. These data and response data for all randomized pts are shown in the table. Serious treatment-emergent adverse events occurred in 30%, 46%, and 39% of pts in the safety analysis set. Safety was consistent with that known for each agent. Conclusions: BREAKWATER demonstrated clinically meaningful and statistically significant PFS and OS improvements with EC+mFOLFOX6 vs SOC and manageable toxicities. EC+mFOLFOX6 is potentially practice changing as the new SOC. Clinical trial information: NCT04607421 . ECn=158 EC+mFOLFOX6n=236 SOCn=243 EC+mFOLFOX6vs SOCHR (95% CI)P-value a Median PFS b , mo (95% CI) 6.8(5.7, 8.3) 12.8(11.2, 15.9) 7.1(6.8, 8.5) 0.53 (0.407, 0.677) <0.0001 Median OS, mo (95% CI) 19.5(17.6, 22.5) 30.3(21.7, NE) 15.1(13.7, 17.7) 0.49 (0.375, 0.632)<0.0001 ORR, b % (95% CI) 45.6(38.0, 53.3) 65.7(59.4, 71.4) 37.4(31.6, 43.7) Median DOR b , mo (95% CI) c 7.0 (4.2, 11.6) 13.9 (10.9, 18.5) 10.8 (7.6, 13.4) DOR b ≥6 mo, n (%) c 29 (40.3) 110 (71.0) 38 (41.8) DOR b ≥12 mo, n (%) c 15 (20.8) 54 (34.8) 16 (17.6) Median time to response, b wk (range) c 6.6(4.3-86.4) 7.0(5.1-103.6) 7.3 (5.4-48.0) a 1-sided stratified log rank test. b By BICR. c Responders: n=72, n=155, and n=91. DOR, duration of response.

Crohn's disease (CD) is an idiopathic inflammatory disorder of unknown etiology with genetic, immunologic, and environmental influences. The incidence of CD has steadily increased over the past several decades. The diagnosis and treatment of patients with CD has evolved since the last practice guideline was published. These guidelines represent the official practice recommendations of the American College of Gastroenterology and were developed under the auspices of the Practice Parameters Committee for the management of adult patients with CD. These guidelines are established for clinical practice with the intent of suggesting preferable approaches to medical problems as established by interpretation and collation of scientifically valid research, derived from extensive review of published literature. When exercising clinical judgment, health care providers should incorporate this guideline along with patient's needs, desires, and their values to care for patients fully and appropriately with CD. Shared decision-making with the patient is advocated. This guideline is intended to be flexible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are inflexible and rarely violated. To evaluate the level of evidence and strength of recommendations, we used the Grading of Recommendations Assessment, Development, and Evaluation system. The Committee reviews guidelines in depth, with participation from experienced clinicians and others in related fields. The final recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientific developments later.

8644 Background: RET fusions are targetable oncogenic drivers in 1-2% of non-small cell lung cancers (NSCLC). ARROW (NCT03037385) study results (final data lock May 20, 2024) supported the US FDA approval of pralsetinib, a highly potent, oral, selective RET inhibitor for metastatic RET -altered NSCLC. Here, we present final study results. Methods: ARROW was a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 included patients with RET -fusion-positive NSCLC who received 400 mg pralsetinib once daily (QD). Initially, treatment-naïve patients were not candidates for platinum-based therapy and presented with several unfavorable prognostic factors; this requirement was removed by protocol amendment in July 2019. Primary objectives were overall response rate (ORR, per RECIST v1.1) and safety. Progression-free survival (PFS) and overall survival (OS) are reported in the full efficacy population; the measurable disease population (MDP) was the primary analysis population for ORR and duration of response (DOR). Results: 281 patients with RET -fusion-positive NSCLC received pralsetinib 400 mg QD, with a median duration of treatment of 14.95 months (mos). Median age was 60 years; 46% were male. In the MDP (n=259), ORR was 70.3% (95% confidence intervals [CI]: 64.3, 75.8) and median DOR was 19.1 mos (95% CI: 14.5, 27.9; Table). In the efficacy population (N=281), median OS was 44.3 mos (95% CI: 30.9, 53.1) with median follow up of 47.6 mos (95% CI: 44.8, 49.2), and median PFS was 13.1 mos (95% CI: 11.4, 16.8). ORR (Table) and median PFS were markedly higher in the US (25.9 mos, n=64) vs. Asia (12.6 mos, n=122) or Europe (12.9 mos, n=95). In the safety population, 95% of patients experienced treatment-related adverse events (TRAEs); 66% experienced ≥grade 3. Common TRAEs included increased AST (n=128 [46%]), anemia (n=121 [43%]), increased ALT (n=98 [35%]), and hypertension (n=77 [27%]). 3 patients died due to TRAEs (pneumonia, n=2; interstitial lung disease and rhabdomyolysis, n=1 each). No new safety signals were identified with this update. Conclusions: Pralsetinib produced clinically meaningful and durable responses in patients with RET -fusion-positive NSCLC (regardless of prior therapies) with a manageable safety profile, confirming with this longer follow up previously published results. Clinical trial information: NCT03037385 . All MDP(n=259) Prior Platinum (n=130) Treatment-naive(n=106) ORR, % (95% CI) Overall 70.3(64.3, 75.8) 63.1(54.2, 71.4) 78.3(69.2, 85.7) US (n=58)77.6(64.7, 87.5) (n=31)64.5(45.4, 80.8) (n=19)100(82.4, 100) Europe (n=89)65.2(54.3, 75) (n=36)63.9(46.2, 79.2) (n=43)65.1(49.1, 79) Asia (n=112)70.5(61.2, 78.8) (n=63)61.9(48.8, 73.9) (n=44)81.8(67.3, 91.8) Median DOR, mos (95% CI) a (n=182)19.1(14.5, 27.9) (n=82)31.8(15.1, 40.4) (n=83)13.4(9.4, 21.7) Median DOR follow up, mos (95% CI) 46.8(42.3, 50.2) 50.3(46.9, 56.8) 42.3(37.4, 44.2) a Per FDA censoring rule.

8618 Background: Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate comprising the mAb telisotuzumab and the microtubule polymerization inhibitor monomethyl auristatin E. In the phase 2 LUMINOSITY trial (NCT03539536), Teliso-V monotherapy 1.9 mg/kg showed durable responses and a generally manageable safety profile in patients (pts) with c-Met protein–overexpressing (OE) non-squamous (NSQ) EGFR -wildtype (WT) non-small cell lung cancer (NSCLC). Herein we present an analysis of efficacy outcomes according to prior platinum or prior platinum and immune checkpoint inhibitor (ICI)-based therapies. Methods: Pts (≥18 years) with locally advanced/metastatic c-Met protein–OE NSQ EGFR -WT NSCLC who had ≤2 prior lines of therapy, including ≤1 line of chemotherapy, were treated with 1.9 mg/kg Teliso-V Q2W. c-Met protein overexpression (by immunohistochemistry clinical trial assay for MET [SP44] [Roche]) was defined as ≥25% tumor cells with 3+ staining intensity (high: ≥50% 3+; intermediate [int]: 25 to <50% 3+). The primary endpoint was overall response rate (ORR) by independent central review per RECIST v1.1. Results: As of 21 Feb 2024, 172 pts received ≥1 dose of Teliso-V and 168 pts were included in efficacy analyses (c-Met high, n=84; c-Met int, n=84). In the c-Met OE total population, 97.6% of pts received prior platinum and 78.6% received prior platinum + ICI. Efficacy data for pts with prior platinum and platinum + ICI therapies are shown in the Table. Among the 172 dosed pts, the most common any-grade treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (31%), peripheral edema (16%), and fatigue (14%). The most common grade ≥3 TRAE was peripheral sensory neuropathy (7%). Conclusions: This analysis demonstrated that Teliso-V elicited durable responses in pts with c-Met protein–OE NSQ EGFR -WT NSCLC regardless of whether they had received prior platinum or platinum + ICI therapies; the efficacy outcomes in these subgroups were consistent with those in the overall pt population. Clinical trial information: NCT03539536 . Platinum Platinum + ICI Overall ORR, a n/N (%) [95% CI] c-Met OE total c-Met high c-Met int 48/164 (29.3) [22.4, 36.9]28/81 (34.6) [24.3, 46.0]20/83 (24.1) [15.4, 34.7] 38/132 (28.8) [21.2, 37.3]22/67 (32.8) [21.8, 45.4]16/65 (24.6) [14.8, 36.9] 49/168 (29.2) [22.4, 36.7]29/84 (34.5) [24.5, 45.7]20/84 (23.8) [15.2, 34.3] Median DOR, a mo [95% CI] c-Met OE total c-Met high c-Met int 7.2 [5.5, 11.3]9.0 [3.8, 12.0]7.2 [4.7, 11.5] 7.2 [5.5, 11.0]9.0 [3.8, 11.3]7.2 [5.3, 11.5] 7.2 [5.5, 11.0]7.2 [4.2, 12.0]7.2 [4.7, 11.5] a Per independent central review. DOR, duration of response.

8513 Background: The MET pathway is a known mediator of EGFR-TKI resistance and represents a therapeutic vulnerability to select MET-TKIs. Savo is an oral, highly selective MET-TKI that, when combined with osi, has the potential to overcome MET-driven resistance after progressive disease (PD) on osi. The Phase 2 SAVANNAH study has demonstrated clinically meaningful activity with the combination of savo + osi in patients (pts) with EGFR-mutated (EGFRm) advanced NSCLC and MET overexpression/amplification (NCT03778229). Isolating the efficacy of savo in the use of savo + osi is a key question for this combination. Methods: A subset of SAVANNAH included eligible pts who had EGFRm advanced NSCLC with MET overexpression (IHC 3+ intensity in ≥90% of tumor cells [IHC3+/≥90%]) and/or amplification (≥10 MET gene copies by FISH [FISH10+]) after PD on first-line (1L) osi; asymptomatic stable brain metastases (treated/untreated) were allowed. Pts were randomized 2:1 (double-blind) to savo 300 mg BID + osi 80 mg QD, or savo 300 mg BID + PBO (stratified by investigator [INV] assessed baseline [BL] brain metastases [yes/no]), until INV-assessed PD per RECIST 1.1. Brain imaging occurred at BL and PD; pts with brain metastases were re-imaged at each tumor assessment to PD. Endpoints included objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) by BICR and INV; CNS PFS, and presence/absence of CNS lesions at PD by BICR. Results: Overall, 73 pts were randomized (savo + osi n=48; savo + PBO n=25). At BL, median age: 67 vs 65 years, female: 73% vs 64%, White: 73% vs 52% in the savo + osi and savo + PBO arms, respectively. Efficacy outcomes (ORR, DoR, and PFS) were higher with savo + osi than savo + PBO (Table). CNS PFS events by CNS BICR occurred in 5/14 (36% savo + osi) and 2/4 pts (50% savo + PBO). In pts without BL brain metastases, none of the 13 pts (savo + osi) with RECIST PD by BICR had a new CNS lesion; 6/11 pts in the savo + PBO arm developed a new CNS lesion. Conclusions: In EGFRm advanced NSCLC with MET IHC3+/≥90% and/or FISH10+ status after PD on 1L osi, efficacy of savo 300 mg BID + osi was numerically greater than savo + PBO and showed promising CNS activity. To date, this is one of the largest randomized data sets presented evaluating an oral MET-TKI in EGFRm NSCLC. Efficacy findings from SAVANNAH suggest that targeting both EGFR and MET is key and support further investigation of savo + osi and CNS activity in the Phase 3 SAFFRON study. Clinical trial information: NCT03778229 . Assessment Savo + osi (n=48) Savo + placebo (n=25) ORR, % (95% CI) BICR 58 (43, 72) 16 (5, 36) INV 54 (39, 69) 24 (9, 45) DoR, mo, median (95% CI) BICR 11.8 (6.0, NC) 4.5 (2.6, NC) INV 8.0 (4.9, 11.7) 4.2 (2.6, NC) PFS, mo, median (95% CI) BICR 8.3 (5.8, 15.1) 3.6 (1.4, 5.7) INV 7.6 (5.6, 11.0) 2.7 (1.4, 4.1) BICR, blinded independent central review; CI, confidence interval; mo, months; NC, not calculable.