Citations

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.

Abstract Background: Savo is an oral, potent and highly selective MET-TKI. In the Phase 2 SAVANNAH study (NCT03778229), savo + osi had a high rate of durable responses in pts with EGFRm advanced NSCLC and high MET OverExp and/or Amp levels. Early clearance of plasma EGFRm may predict outcomes. We report an exploratory analysis of plasma EGFRm clearance and its association with MET tissue biomarker status, ORR and PFS. Methods: Pts with EGFRm advanced NSCLC and MET OverExp and/or Amp with PD on 1L+ osi received savo 300 mg QD, 300 mg BID or 600 mg QD + osi 80 mg QD. MET OverExp/Amp was centrally confirmed (by IHC [Roche], 3+ intensity in ≥50% of tumor cells [MET IHC3+/≥50%]; by FISH [Abbott Molecular], MET gene copy number ≥5 or MET:CEP7 ratio ≥2 [FISH5+], or at higher thresholds of MET IHC3+/≥90% or FISH10+). Baseline (BL) and Wk 3 plasma EGFRm (Ex19del/L858R) were analyzed by ddPCR (Biodesix) as an estimate of tumor burden. MET Amp was not monitored in ctDNA due to low detection sensitivity. Clearance was defined as undetected EGFRm ctDNA at Wk 3, when detected at BL. PFS was investigator-assessed (RECIST 1.1). DCO: Aug 23, 2024. Results: Of 344 pts with evaluable BL ctDNA, 259 (75%) had detected EGFRm ctDNA. Of these, 225 had evaluable ctDNA at Wk 3 (82 [36%] had EGFRm clearance at Wk 3). Confirmed ORR was higher in pts with EGFRm Wk 3 clearance (56/82; 68%) vs non-clearance (38/143; 27%). PFS was longer in pts with vs without EGFRm clearance at Wk 3 (Table). Across all pts evaluable for ctDNA at Wk 3, clearance rates were higher in pts with vs without high MET (69/162 [43%] vs 13/63 [21%]; odds ratio [95% CI] 0.35 [0.16, 0.72]). Similar results were seen in the savo 300 mg QD + osi subgroup. Conclusions: In SAVANNAH, among pts with detected EGFRm ctDNA at BL, clearance at Wk 3 was associated with improved ORR and PFS. Plasma EGFRm clearance at Wk 3 is enriched in pts with MET IHC3+/≥90% or FISH10+ status, consistent with improved efficacy in this biomarker subgroup. Citation Format: Jonathan W. Riess, Filippo de Marinis, Benjamin Levy, Tae Min Kim, Laura Bonanno, Quincy Chu, Marcello Tiseo, Adrian Sacher, Silvia Novello, Christina Baik, Lyudmila Bazhenova, Jacques Cadranel, Giulio Metro, Cheng-Ta Yang, Tsung-Ying Yang, Gee-Chen Chang, Konstantinos Leventakos, Lorenzo Livi, James Chih-Hsin Yang, Lecia V. Sequist, John Argue, Wanning Xu, Aleksandra Markovets, Ryan Hartmaier, Myung-Ju Ahn. SAVANNAH: Clearance of plasma EGFRm in patients with EGFRm MET-overexpressed (OverExp) and/or -amplified (Amp) NSCLC post-osimertinib (osi) treated with savolitinib (savo) + osi [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB416.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P < .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P < .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P < .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

Abstract We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe coronavirus disease 2019 (COVID-19). We combine our latest data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting.

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

37 Background: While parenchymal hepatic metastases were previously considered a contraindication to cytoreductive surgery(CRS) and heated intraperitoneal chemotherapy(HIPEC), liver resection(LR) is increasingly performed concomitantly with CRS/HIPEC. As this practice continues to expand, identification of preoperative factors associated with poor outcomes is paramount. Methods: Patients from the US HIPEC Collaborative(2000-2017) with invasive appendiceal or colorectal adenocarcinoma undergoing primary, curative intent CRS/HIPEC with CC0-1 resection were included. LR was defined as a formal parenchymal resection. Primary endpoints were postoperative complications and overall survival(OS). Results: 658 patients were included. Average age was 54 years and 45% were male; 83 (15%) underwent liver resection of colorectal (58%) or invasive appendiceal (42%) metastases. Liver resection patients had more complications (81 vs 60%; p = 0.001), greater number of complications (2.3 vs 1.5; p < 0.001), and required more reoperations (22 vs 11%; p = 0.007) and readmissions (39 vs 25%; p = 0.014) than non-liver resection patients. Liver resection patients had decreased OS (2-year OS 62% vs 79%, p < 0.001), which persisted on multivariable Cox regression when accounting for PCI and histology type. Preoperative factors associated with decreased OS on multivariable analysis in patients undergoing liver resection included age < 60 years (HR:3.61), colorectal histology (HR:3.84), and multiple liver tumors (HR:3.45) (all p < 0.05). When assigning one point for each factor, there was an incremental decrease in 2-yr survival as the risk score increased from 0 to 3 (0: 100%; 1: 91%; 2: 58%; 3: 0%; p < 0.001). Conclusions: As concurrent liver resection with CRS/HIPEC has become more common, we created a simple risk score to stratify patients considered for CRS/HIPEC with liver resection. These data aid in striking the balance between an increased perioperative complication profile with the potential for improvement in overall survival.

AbstractIntroductionEmerging medical technology has allowed for monitoring of heart rhythm abnormalities using smartphone compatible devices. The safety and utility of such devices have not been established in patients with cardiac implantable electronic devices (CIEDs). We sought to assess the safety and compatibility of the Food and Drug Administration‐approved AliveCor Kardia device in patients with CIEDs.Methods and ResultsWe prospectively recruited patients with CIED for a Kardia recording during their routine device interrogation. A recording was obtained in paced and nonpaced states. Adverse clinical events were noted at the time of recording. Electrograms (EGMs) from the cardiac device were obtained at the time of recording to assess for any electromagnetic interference (EMI) introduced by Kardia. Recordings were analyzed for quality and given a score of 3 (interpretable rhythm, no noise), 2 (interpretable rhythm, significant noise) or 1 (uninterpretable). A total of 251 patients were recruited (59% with a pacemaker and 41% with ICD). There were no adverse clinical events noted at the time of recording and no changes to CIED settings. Review of all EGMs revealed no EMI introduced by Kardia. Recordings were correctly interpreted in 90% of paced recordings (183 had a score of 3, 43 of 2, and 25 of 1) and 94.7% of nonpaced recordings (147 of 3, 15 of 2, and 9 of 1).ConclusionThe AliveCor Kardia device has an excellent safety profile when used in conjunction with most CIEDs. The quality of recordings was preserved in this population. The device, therefore, can be considered for heart rhythm monitoring in patients with CIEDs.

AbstractBackgroundLeadless cardiac pacing (LCP) has emerged as a new modality for permanent pacing. We sought to describe comparative outcomes between LCP and transvenous pacemakers.MethodsPatients receiving LCP (Micra [Medtronic, Minneapolis, MN, USA] and Nanostim [St. Jude Medical/Abbott Laboratories, Chicago, IL, USA]) between 2014 and 2017 at the Mayo Clinic Heart Rhythm Enterprise practice (Rochester, MN, USA; Jacksonville, FL, USA; and Scottsdale, AZ, USA) were identified. We identified 1:1 age‐ and sex‐matched controls receiving single‐chamber transvenous ventricular pacemakers (TVP). Statistical analyses were performed with JMP 13.0.0 (SAS, Institute Cary, NC, USA).ResultsNinety patients underwent LCP implantation (73 Micra and 17 Nanostim) with a median follow‐up duration of 62 (interquartile range 28‐169) days. Both groups had 100% successful device implant rates. There were no differences in procedure‐related major (0% vs 1%) or minor complications (8% vs 3%) in the LCP versus TVP groups (P > 0.05). Excluding Nanostim patients, there was a lower rate of device‐related revision or extraction in the Micra versus TVP groups (0% vs 5%, P = 0.028). Device endocarditis was more common in the TVP group (0% vs 3%, P = 0.04). Estimated longevity was greater for the LCP group (median 12.0 vs 10.0 years, P < 0.0001). An increase in severity of tricuspid valve regurgitation (TR) by ≥2 grades occurred in none of the LCP patients, and in 19% of the TVP patients (P = 0.017).ConclusionThere are no significant differences in procedural complications among patients receiving LCP versus TVP. The Micra group had lower rates of device‐related revision/extraction compared to the TVP group. Patients with leadless pacemaker were less likely to develop endocarditis or worsening TR.