Early Surrogate Research Articles

Strong association between reduction of late-stage cancers and reduction of cancer-specific mortality in meta-regression of randomized screening trials across multiple cancer types.

Late-stage cancer incidence has been proposed as an early surrogate for mortality in randomized controlled trials (RCTs) of cancer screening; however, its validity has not been systematically evaluated across screening RCTs of different cancers. We conducted a meta-regression analysis of cancer screening RCTs that reported both late-stage cancer incidence and cancer mortality. Based on a systematic literature review, we included 33 RCTs of screening programs targeting seven cancer types, including lung (n = 12), colorectal (n = 8), breast (n = 5), and prostate (n = 4), among others. We regressed the relative reduction of cancer mortality on the relative reduction of late-stage cancer incidence, inversely weighted for each RCT by the variance of estimated mortality reduction. Across cancer types, the relative reduction of late-stage cancer incidence was linearly associated with the relative reduction of cancer mortality. Specifically, we observed this association for lung (R2 = 0.79 and 0.996 in three recent large trials), breast (R2 = 0.94), prostate (R2 = 0.98), and colorectal cancer (R2 = 0.75 for stage III/IV cancers and 0.93 for stage IV cancers). Trials with a 20% or greater reduction in late-stage cancers were more likely to achieve a significant reduction in cancer mortality. Our results also showed that no reduction of late-stage cancer incidence was associated with no or minimal reduction in cancer mortality. Meta-regression of historical screening RCTs showed a strong linear association between reductions in late-stage cancer incidence and cancer mortality.

Abstract A077: The utility of surgical minimal residual disease after frontline treatment for prognostic and investigational opportunities in advanced ovarian cancer

Abstract Cure rates for patients with advanced stage ovarian cancer have not changed significantly over the last four decades likely due to inability to eradicate residual cancer cells after frontline therapy. Identifying clinically undetectable minimal residual disease (MRD) after frontline therapy by second look laparoscopy (SLL) has potential to a) uncover mechanisms of chemoresistance and tumor dormancy, b) identify MRD-specific therapeutic targets, and c) allow for earlier intervention with investigational therapies. The objective of this study is to describe the initial safety and feasibility of SLL and illustrate clinical and pathological correlates. Methods: This IRB-approved observational, single-center study includes patients with epithelial high-grade ovarian cancer with complete CA-125 and radiologic response after frontline treatment (combination of surgery and platinum-taxane chemotherapy) who underwent SLL from 4/2017-6/2023. Patients were subsequently offered standard of care or investigational maintenance therapy options based on homologous recombination deficiency (HRD) and MRD status. Summary statistics described the study population, chi-square tests compared categorical variables, and progression free survival (PFS) based on MRD status was estimated using Kaplan-Meier method and compared using log rank test. Results: 70 patients underwent SLL with a median of 8.5 biopsies (range 3-16). The majority of patients had stage III-IV disease (90%), and high-grade serous histology (90%). Approximately half (51.4%) of patients underwent neoadjuvant chemotherapy (NACT) with interval tumor reductive surgery (TRS). MRD was present in 32 patients (45.7%), and the presence of MRD was associated with a worse PFS (HR 3.0, 95% CI 1.5-5.8; 12.5 vs. 24.8 months; p=0.001). MRD was more frequent among NACT recipients compared to those who underwent primary TRS (63% vs 26%, P=0.002), those with HRD negative tumors (58% vs 24%, P=0.025), and those with R1 versus R0 resections (71% vs 39%, P=0.024). Of patients with MRD, 22 patients (71%) received bevacizumab until progression as part of a clinical trial (NCT02884648), 3 (10%) received bevacizumab off trial, 5 (16%) received a PARP inhibitor (all HRD positive), and 1 received other therapy. There were two (2.9%) intraoperative complications (both enterotomies) requiring conversion to laparotomy. Conclusions: SLL is feasible, overall safe, and detected MRD in 46% of ovarian cancer patients who were in radiologic and CA-125 remission after frontline therapy. PFS was significantly shorter for patients with residual disease, despite those patients all receiving additional therapy. Knowledge of MRD status in this patient population enables interventional, observational, and translational opportunities, as well as personalized prognostic counseling. MRD rate may also have utility as an early surrogate for efficacy in trials evaluating novel frontline investigational therapies. Future studies will compare the performance of circulating tumor DNA (ctDNA) versus surgical MRD. Citation Format: Anne Knisely, Roni Nitecki, J. Alejandro Rauh-Hain, R. Tyler Hillman, Jolyn S. Taylor, Lois M. Ramondetta, Michaela O. Grinsfelder, Lauren P. Cobb, David M. Boruta, Gwyn Richardson, Pamela T. Soliman, Aaron Shafer, Shannon N. Westin, Nicole D. Fleming, Travis T. Sims, Anil K. Sood, Pedro T. Ramirez, Karen H. Lu, Amir A. Jazaeri. The utility of surgical minimal residual disease after frontline treatment for prognostic and investigational opportunities in advanced ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A077.

Objective response rate and progression-free survival as surrogates for overall survival treatment effect: A meta-analysis across diverse tumour groups and contemporary therapies

BackgroundOverall survival (OS) results from randomized control trials (RCT) provide the strongest evidence for efficacy of anti-cancer treatments but can take a considerable amount of time to mature. Progression free survival (PFS) and objective response rate (ORR) are used as an early surrogate of OS treatment effect however their validity remains unclear. Our study aims to comprehensively evaluate ORR and PFS as surrogates for OS treatment effect across tumor groups and treatment types. Material and MethodsPhase 3 RCTs in solid malignancies that reported OS/PFS and ORR published between 1st of January 2010 and 30th of June 2022 were evaluated. The relationship of surrogate endpoints and OS treatment effect was assessed via weighted linear regression. The coefficient of determination (R2) quantified the fit of the regression model. Results675 phase 3 RCT comprising of 350 112 patients were analysed. ORR (R2 of 0.10) and PFS (R2 of 0.38) were poor surrogate markers of OS treatment effect. The strength of surrogacy differed within treatment and tumour groups. PFS had the highest R2 for chemotherapy (0.56) and lowest for targeted therapy (0.40). PFS had the highest level of surrogacy for melanoma (R2 = 0.72) and pancreatic cancer (R2 = 0.70) compared to other tumour groups. Importantly ORR and PFS were also poorly correlated to each other (R2 = 0.33). ConclusionsORR and PFS were poor trial-level surrogate markers of OS. The surrogacy performance of ORR and PFS differed by treatment and malignancy sub-type.

1485P Systemic inflammatory index dynamics at 6 weeks as an early surrogate for clinical benefit in patients with NSCLC and PD-L1≥50% expression treated with pembrolizumab: Data from the real-life practice

1485P Systemic inflammatory index dynamics at 6 weeks as an early surrogate for clinical benefit in patients with NSCLC and PD-L1≥50% expression treated with pembrolizumab: Data from the real-life practice

Time to deterioration of patient-reported outcomes as a surrogate of overall survival: a meta-analysis.

Overall survival is the optimal marker of treatment efficacy in randomized clinical trials (RCTs) but can take considerable time to mature. Progression-free survival (PFS) has served as an early surrogate of overall survival but is imperfect. Time to deterioration in quality of life (QOL) measures could be a surrogate for overall survival. Phase 3 RCTs in solid malignancies that reported overall survival, PFS, and time to deterioration in QOL or physical function published between January 1, 2010, and June 30, 2022, were evaluated. Weighted regression analysis was used to assess the relationship between PFS, time to deterioration in QOL, and time to deterioration in physical function with overall survival. The coefficient of determination (R2) was used to quantify surrogacy. In total, 138 phase 3 RCTs were included. Of these, 47 trials evaluated immune checkpoint inhibitors and 91 investigated non-immune checkpoint inhibitor agents. Time to deterioration in QOL (137 RCTs) and time to deterioration in physical function (75 RCTs) performed similarly to PFS as surrogates for overall survival (R2 = 0.18 vs R2 = 0.19 and R2 = 0.10 vs R2 = 0.09, respectively). For immune checkpoint inhibitor studies, time to deterioration in physical function had a higher association with overall survival than with PFS (R2 = 0.38 vs R2 = 0.19), and PFS and time to deterioration in physical function did not correlate with each other (R2 = 0). When time to deterioration in physical function and PFS are used together, the coefficient of determination increased (R2 = 0.57). Time to deterioration in physical function appears to be an overall survival surrogate measure of particular importance for immune checkpoint inhibitor treatment efficacy. The combination of time to deterioration in physical function with PFS may enable better prediction of overall survival treatment benefit in RCTs of immune checkpoint inhibitors than either PFS or time to deterioration in physical function alone.

The neoadjuvant rectal score and a novel magnetic resonance imaging based neoadjuvant rectal score are stage independent predictors of long-term outcome in locally advanced rectal cancer.

Neoadjuvant rectal (NAR) score is an early surrogate for longer-term outcomes in rectal cancer undergoing radiotherapy and resection. In an era of increasing organ preservation, resection specimens are not always available to calculate the NAR score. Post-treatment magnetic resonance imaging (MRI) re-staging of regression is subjective, limiting reproducibility. We explored the potential for a novel MRI-based NAR score (mrNAR) adapted from the NAR formula. Locally advanced rectal cancer patients undergoing neoadjuvant therapy (nCRT) and surgery were retrospectively identified between 2008 and 2020 in a single cancer network. mrNAR was calculated by adapting the NAR formula, replacing pathological (p) stages with post-nCRT MR stages (ymr). Cox regression assessed relationships between clinicopathological characteristics, NAR and mrNAR with overall survival (OS) and recurrence-free survival (RFS). In total, 381 NAR and 177 mrNAR scores were calculated. On univariate analysis NAR related to OS (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.33-3.14, p = 0.001) and RFS (HR 2.52, 95% CI 1.77-3.59, p = 0.001). NAR 3-year OS <8 was 95.3%, 8-16 was 88.6% and >16 was 80%. mrNAR related to OS (HR 2.96, 95% CI 1.38-6.34, p = 0.005) and RFS (HR 2.99, 95% CI 1.49-6.00, p = 0.002). 3-year OS for mrNAR <8 was 96.2%, 8-16 was 92.4% and >16 was 78%. On multivariate analysis, mrNAR was a stage-independent predictor of OS and RFS. mrNAR corresponded to NAR score category in only 15% (positive predictive value 0.23) and 47.5% (positive predictive value 0.48) of cases for categories <8 and >16, respectively. Neoadjuvant rectal score is validated as a surrogate end-point for long-term outcomes. mrNAR categories do not correlate with NAR but have stage-independent prognostic value. mrNAR may represent a novel surrogate end-point for future neoadjuvant treatments that focus on organ preservation.

Utility of surgically documented minimal residual disease as a therapeutic target and early surrogate of frontline treatment outcomes in ovarian cancer.

5549 Background: Cure rates for patients with advanced stage ovarian cancer have not changed over the last four decades likely due to inability to eradicate residual cancer cells after frontline therapy. Identifying clinically undetectable minimal residual disease (MRD) after frontline therapy by second look laparoscopy (SLL) has potential to a) uncover mechanisms of chemoresistance, b) identify MRD-specific therapeutic targets, and c) allow for earlier intervention with investigational therapies. The objective of this study is to describe the initial safety and feasibility of SLL and illustrate clinical pathologic correlates. Methods: This IRB-approved observational, single-center study includes patients with epithelial high-grade ovarian cancer with complete CA-125 and radiologic response after frontline treatment who underwent SLL from 4/2017-12/2022. Patients were subsequently offered standard of care or investigational maintenance therapy options based on homologous recombination deficiency (HRD) and MRD status. Summary statistics described the study population, chi-square tests compared categorical variables, and progression free survival (PFS) based on MRD status was estimated using Kaplan-Meier method and compared using log rank test. Results: 64 patients underwent SLL with a median of 8 biopsies (range 1-16). The majority of patients had stage III-IV disease (89%), and high-grade serous histology (89%). Approximately half (52%) of patients underwent neoadjuvant chemotherapy (NACT) with interval tumor reductive surgery (TRS). MRD was present in 28 patients (44%), and the presence of MRD was associated with a worse PFS (HR 3.1, 95% CI 1.5-6.3; 9.2 vs 24.6 months; P=0.002). MRD was more frequent among NACT recipients compared to those who underwent primary TRS (61% vs 26%, P=0.005), those with HRD negative tumors (63% vs 22%, P=0.003), and those with R1 versus R0 resections (71% vs 35%, P=0.012). Of patients with MRD, 20 patients (71%) received bevacizumab until progression as part of a clinical trial (NCT02884648), 3 (11%) received bevacizumab off trial, 4 (14%) received a PARP inhibitor (all HRD positive) and 1 received other therapy. There was one (1.6%) intraoperative complication requiring conversion to laparotomy. Conclusions: SLL is feasible, overall safe, and detected MRD in 44% of ovarian cancer patients who were in radiologic and CA-125 remission after frontline therapy. MRD rates were higher in patients who received NACT and HRD negative patients, and PFS was significantly longer in patients without residual disease. MRD rate by SLL may have utility as an early surrogate for efficacy in trials evaluating novel frontline investigational therapies. Knowledge of MRD status in this patient population enables interventional, observational, and translational investigations, as well as personalized prognostic counseling.

Quantitative evaluation of very early cartilage damage in experimental osteoarthritis using scanning electron microscopy

ObjectiveTo describe parametric changes observed using scanning electron microscopy (SEM) in very early stages in posttraumatic osteoarthritis (OA) models in mice.MethodsMice (5/group) had their knees subjected to anterior cruciate ligament transection (ACLT), ACLT plus meniscectomy (MNCT) or sham surgery, sacrificed after 3, 7 or 14 days, had the articular cartilage evaluated under optical microscopy using Osteoarthritis Research Society International (OARSI) parameters as well as cartilage thickness, roughness, and a damage index using SEM.ResultsAlterations of the cartilage under optical microscopy were not significantly relevant among groups. SEM analysis revealed reduction of femoral and tibial cartilage thickness in ACLT and MNCT groups at 7 and 14 days, with increased cartilage roughness in MNCT group as early as 3 days postsurgery, being sustained up to 14 days. Articular damage index was significantly higher at 14 days post surgery in ACLT and MNCT vs control groups.ConclusionThis is the first demonstration of very early quantitative changes in the cartilage of mice subjected to posttraumatic experimental OA using SEM, revealing increased roughness and thickness as early as 3 days post surgery. These changes may be used as early surrogates for later joint damage in experimental OA.

Early surrogates of outcome after thrombectomy in posterior circulation stroke.

Early surrogates for functional outcome in anterior circulation stroke have been described with the National Institute of Health Stroke Scale (NIHSS) at 24 h being reported as the most accurate metric. We compare discriminatory power of established definitions of early neurological improvement (ENI) and NIHSS scores at admission and 24 h to predict functional outcome at 90 days after thrombectomy in posterior circulation stroke (PCS). All patients enrolled in the German Stroke Registry (June 2015-December 2019) with PCS and at least vertebral or basilar artery occlusions were included. NIHSS admission, 24 h and ENI definitions (improvement of 8/10 NIHSS points or 0/1 NIHSS points at 24 h) were compared for predicting functional outcome at 90 days. Favourable and good outcome were defined as modified Rankin Scale (mRS) 0-2 and 0-3. Multivariable logistic regression analysis was conducted to identify factors impairing predictive power. Three hundred and eighty-seven patients were included. NIHSS 24 h had the highest discriminative power with receiver operator characteristics area under the curve of 0.87 (95% confidence interval: 0.83; 0.90) for good and 0.89 (0.85; 0.92) for favourable outcome; optimal cut-off values were ≤9 and ≤5. Higher age (odds ratio=1.10 [1.05; 1.16]), adverse events during treatment (9.46 [1.52; 72.5]) and until discharge (18.34 [2.33; 172]) and high NIHSS scores at 24 h (1.29 [1.10; 1.53]) were independent predictors for turning the outcome prognosis from good (mRS ≤3) to poor (mRS ≥4). NIHSS 24 h ≤9 points serves best as surrogate for good functional outcome after thrombectomy in PCS. Advanced age, severe neurological symptoms at admission and adverse events decrease its predictive value.

Total Neoadjuvant Therapy for Rectal Cancer in the CAO/ARO/AIO-12 Randomized Phase 2 Trial: Early Surrogate Endpoints Revisited.

Simple SummaryMultimodal treatment of rectal cancer is undergoing dynamic change. In phase II/III multimodal rectal cancer trials, long-term survival remains the most objective endpoint for reporting treatment efficacy, but long follow-up is required, and there is a risk that the study results will lose scientific significance over time. To address these limitations, early surrogate endpoints are increasingly used to identify treatment efficacy at an earlier timepoint. We here report the prognostic role of pCR (pathological complete response), TRG (tumor regression grade) and NAR score (neoadjuvant rectal score) for DFS (disease-free survival) in the CAO/ARO/AIO-12 trial. Surrogate markers were significant prognostic factors for DFS, but the higher pCR rate und improved TRG in trial Arm B did not lead to improved survival compared to Arm A. Therefore, early surrogate marker correlated with clinical outcome in the CAO/ARO/AIO-12 trial, but the early differences in pCR and TRG did not translate into a survival benefit.Background: Early efficacy outcome measures in rectal cancer after total neoadjuvant treatment are increasingly investigated. We examined the prognostic role of pathological complete response (pCR), tumor regression grading (TRG) and neoadjuvant rectal (NAR) score for disease-free survival (DFS) in patients with rectal carcinoma treated within the CAO/ARO/AIO-12 randomized phase 2 trial. Methods: Distribution of pCR, TRG and NAR score was analyzed using the Pearson’s chi-squared test. Univariable analyses were performed using the log-rank test, stratified by treatment arm. Discrimination ability of non-pCR for DFS was assessed by analyzing the ROC curve as a function of time. Results: Of the 311 patients enrolled, 306 patients were evaluable (Arm A:156, Arm B:150). After a median follow-up of 43 months, the 3-year DFS was 73% in both groups (HR, 0.95, 95% CI, 0.63–1.45, p = 0.82). pCR tended to be higher in Arm B (17% vs. 25%, p = 0.086). In both treatment arms, pCR, TRG and NAR were significant prognostic factors for DFS, whereas survival in subgroups defined by pCR, TRG or NAR did not significantly differ between the treatment arms. The discrimination ability of non-pCR for DFS remained constant over time (C-Index 0.58) but was slightly better in Arm B (0.61 vs. 0.56). Conclusion: Although pCR, TRG and NAR were strong prognostic factors for DFS in the CAO/ARO/AIO-12 trial, their value in selecting one TNT approach over another could not be confirmed. Hence, the conclusion of a long-term survival benefit of one treatment arm based on early surrogate endpoints should be stated with caution.

Effect of 3-Dimensional, Virtual Reality Models for Surgical Planning of Robotic Prostatectomy on Trifecta Outcomes: A Randomized Clinical Trial.

Planning complex operations such as robotic-assisted radical prostatectomy requires surgeons to review 2-dimensional magnetic resonance imaging (MRI) cross-sectional images to understand 3-dimensional (3D), patient-specific anatomy. We sought to determine surgical outcomes for robotic-assisted radical prostatectomy when surgeons reviewed 3D, virtual reality (VR) models for operative planning. A multicenter, randomized, single-blind clinical trial was conducted from January 2019 to December 2020. Patients undergoing robotic-assisted laparoscopic radical prostatectomy were prospectively enrolled and randomized to either a control group undergoing usual preoperative planning with prostate biopsy results and MRI only or to an intervention group where MRI and biopsy results were supplemented with a 3D VR model. The primary outcome measure was margin status, and secondary outcomes were oncologic control, sexual function and urinary function. Ninety-two patients were analyzed, with trends toward lower positive margin rates (33% vs 25%) in the intervention group, no significant difference in functional outcomes and no difference in traditional operative metrics (p >0.05). Detectable postoperative prostate specific antigen was significantly lower in the intervention group (31% vs 9%, p=0.036). In 32% of intervention cases, the surgeons modified their operative plan based on the model. When this subset was compared to the control group, there was a strong trend toward increased bilateral nerve sparing (78% vs 92%), and a significantly lower rate of postoperative detectable prostate specific antigen in the intervention subset (31% vs 0%, p=0.038). This randomized clinical trial demonstrated patients whose surgical planning involved 3D VR models have better oncologic outcomes while maintaining functional outcomes.

Assessment of Irreversible Tissue Injury in Extensive Ischemic Stroke-Potential of Quantitative Cerebral Perfusion.

Computed tomography perfusion (CTP) is used as a tool to select ischemic stroke patients for endovascular treatment (EVT) and is currently investigated in the setting of extensive stroke with low Alberta Stroke Program Early CT scores (ASPECTS). The purpose of this study was to perform a comprehensive quantitative analysis of cerebral blood flow within the ischemic lesion compared to threshold-derived core lesion volumes. We hypothesized that the degree of cerebral blood volume (CBV) reduction within the ischemic lesion is predictive of irreversible tissue injury and functional outcome in patients with low ASPECTS. Ischemic stroke patients with an ASPECTS ≤ 5 who received multimodal CT on admission and underwent thrombectomy were analyzed. The ischemic lesion on CTP was identified, and CTP-derived parameters were measured as absolute means within the lesion and relative to the physiological perfusion measured in a contralateral region of interest. The degree of irreversible tissue injury was assessed using quantitative net water uptake (NWU). Functional endpoint was good outcome defined as modified Rankin Scale (mRS) scores 0-3 at day 90. One hundred eleven patients were included. The median core lesion volume was 71ml (IQR: 25-107), and the median quantitative NWU was 9.5% (IQR: 6-13). Relative CBV (rCBV) reduction and ASPECTS at baseline were independently associated with NWU in multivariable linear regression analysis (ß: 12.4, 95%CI: 6.0-18.9, p < 0.0001) and (ß: - 0.78, 95% CI: - 1.53 to - 0.02; p = 0.045), respectively. Furthermore, rCBV was significantly associated with good outcome in patients with core volumes > 50ml (OR: 0.16, 95% CI: 0.05-0.49, p = 0.001). Our study shows that rCBV reduction serves as an early surrogate for increase of NWU as a marker of irreversible tissue injury and lesion progression. Thus, the analysis of rCBV reduction within ischemic lesions may add another dimension to acute stroke triage in addition to core volumes or ASPECTS as indicators of the infarct extent and viability.

Abstract CT547: Neoadjuvant and adjuvant capmatinib in resectable non-small cell lung cancer with MET exon 14 skipping mutation or high MET amplification: GEOMETRY-N trial

Abstract Background: Neoadjuvant therapy is the earliest opportunity to eliminate micrometastatic disease. Emerging data suggest that neoadjuvant therapy in non-small cell lung cancer (NSCLC) can elicit major pathological responses (MPRs) that translate into prolonged survival outcomes, serving as an early surrogate for efficacy. Adjuvant therapy can improve overall and disease-free survival (DFS) in patients with completely resected NSCLC. DFS observed with osimertinib in patients with early-stage EGFR-mutated tumors supports evaluation of other tyrosine kinase inhibitors (TKIs) in the neoadjuvant and adjuvant settings. In early-stage NSCLC, MET exon 14 skipping mutation (METex14) and de novo MET amplification (METamp) are estimated to occur in up to 2.8% and 1.7% of patients, respectively. Capmatinib, a selective MET TKI, is FDA approved for patients with metastatic METex14 NSCLC. It was studied in GEOMETRY mono-1 in patients with advanced/metastatic NSCLC with METex14 or METamp. In 2 treatment-naive METex14 cohorts, overall response rate (ORR) was 68% and 66%. In a treatment-naive high-level METamp cohort, ORR was 40%. Capmatinib had a tolerable safety profile; most adverse events were reversible with dose adjustments. Based on the response rates and safety profile observed in treatment-naive patients with advanced/metastatic MET-dysregulated NSCLC, GEOMETRY-N (NCT04926831), a Phase II, 2-cohort, 2-stage study, is evaluating the efficacy and safety of neoadjuvant and adjuvant capmatinib therapy in improving the MPR rate and outcomes in patients with METex14 or high-level METamp NSCLC. Methods: Adults with resectable, histologically confirmed NSCLC stage IB-IIIA, N2 and select IIIB (T3N2 or T4N2) with either METex14 (cohort A) or high-level METamp (gene copy number ≥10; cohort B) are eligible. METex14 must be determined by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab. METamp must be determined by fluorescence in situ hybridization at a CLIA-certified lab or by FoundationOne CDx next-generation sequencing. Prior systemic anticancer therapy is prohibited. Patients will receive capmatinib 400 mg twice daily for 8 weeks before surgical resection, followed by 3 years of adjuvant capmatinib. In the 2-stage design, stage 1 will enroll 9 patients per cohort, with MPR evaluated in each cohort after 9 patients have completed neoadjuvant therapy; stage 2, enrolling 10 more patients in a cohort, will proceed only if ≥1 of 9 participants has an MPR. About 42 patients will be enrolled, with 19 evaluable patients per cohort. The primary endpoint is MPR rate (local assessment). Secondary endpoints are complete pathological response rate (central and local review), ORR (local assessment), DFS, and safety. Following treatment, there will be a 2-year survival follow-up. The expected first patient first visit is December 30, 2021. Citation Format: Jay M. Lee, Mark M. Awad, Teddy Saliba, Nydia Caro, Hiya Banerjee, Karen Kelly. Neoadjuvant and adjuvant capmatinib in resectable non-small cell lung cancer with MET exon 14 skipping mutation or high MET amplification: GEOMETRY-N trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT547.

Neoadjuvant and adjuvant capmatinib in resectable non–small cell lung cancer with MET exon 14 skipping mutation or high MET amplification: GEOMETRY-N trial.

TPS8590 Background: Neoadjuvant therapy is the earliest opportunity to eliminate micrometastatic disease. Emerging data suggest that neoadjuvant therapy in non-small cell lung cancer (NSCLC) can elicit major pathological responses (MPRs) that translate into prolonged survival outcomes, serving as an early surrogate for efficacy. Adjuvant therapy can improve overall and disease-free survival (DFS) in patients with completely resected NSCLC. DFS observed with osimertinib in patients with early-stage EGFR-mutated tumors supports evaluation of other tyrosine kinase inhibitors (TKIs) in the neoadjuvant and adjuvant settings. In early-stage NSCLC, MET exon 14 skipping mutation ( METex14) and de novo MET amplification ( METamp) are estimated to occur in up to 2.8% and 1.7% of patients, respectively. Capmatinib, a selective MET TKI, is FDA approved for patients with metastatic METex14 NSCLC. It was studied in GEOMETRY mono-1 in patients with advanced/metastatic NSCLC with METex14 or METamp. In 2 treatment-naive METex14 cohorts, overall response rate (ORR) was 68% and 66%. In a treatment-naive high-level METamp cohort, ORR was 40%. Capmatinib had a tolerable safety profile; most adverse events were reversible with dose adjustments. Based on the ORRs and safety profile observed in treatment-naive patients with advanced/metastatic MET-dysregulated NSCLC, GEOMETRY-N (NCT04926831), a Phase II, 2-cohort, 2-stage study, is evaluating the efficacy and safety of neoadjuvant and adjuvant capmatinib therapy in improving the MPR rate and outcomes in patients with METex14 or high-level METamp NSCLC. Methods: Adults with resectable, histologically confirmed NSCLC stage IB-IIIA, N2 and select IIIB (T3N2 or T4N2) with either METex14 (cohort A) or high-level METamp (gene copy number ≥10; cohort B) are eligible. METex14 must be determined by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab. METamp must be determined by fluorescence in situ hybridization at a CLIA-certified lab or by FoundationOne CDx next-generation sequencing. Prior systemic anticancer therapy is prohibited. Patients will receive capmatinib 400 mg twice daily for 8 weeks before surgical resection, followed by 3 years of adjuvant capmatinib. In the 2-stage design, stage 1 will enroll 9 patients per cohort, with MPR evaluated in each cohort after 9 patients have completed neoadjuvant therapy; stage 2, enrolling 10 more patients in a cohort, will proceed only if ≥1 of 9 participants has an MPR. About 42 patients will be enrolled, with 19 evaluable patients per cohort. Primary endpoint is MPR rate (local assessment). Secondary endpoints are complete pathological response rate (central and local review), ORR (local assessment), DFS, and safety. Following treatment, there will be a 2-year survival follow-up. Enrollment has started; expected first patient first visit: March 31, 2022. Clinical trial information: NCT04926831.

Treatment Efficacy Score—continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials

Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab+ olaparib arm (n= 72) and corresponding controls (n= 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n= 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Abstract P2-07-12: Triple negative breast cancer subtypes and early dynamics of the 27-gene IO score predict pCR in the NeoTRIPaPDL1 trial

Abstract Background A post-hoc of NeoTRIP trial showed that 27-gene IO score assessed on baseline samples is predictive of increased pathological complete response (pCR) with the addition of atezolizumab to carboplatin/nab-paclitaxel, whereas the LAR subtype has the lowest rate of pCR with and without atezolizumab (Bianchini G ESMO 2021). We evaluated 27-gene IO score and TNBC subtypes on biopsies collected during treatment, assessed biomarker dynamics, and studied the association with pCR. Methods In NeoTRIP, patients randomly received 8 cycles of nab-paclitaxel/carbo alone (CT) or with atezolizumab (CT/A). 258 patients were evaluable for pCR (Per-Protocol Population). We assessed IO score as binary and continuous variable, and the five 101-gene TNBC types (BL1, BL2, LAR, M, and MSL; Ring et al 2016) by RNA-seq on biopsies at baseline and day 1 of second treatment cycle (d1c2) (n: baseline 242/258, 94%; d2c2 161/258, 62%; paired 152/258, 59%). Forty-four paired samples were excluded due to lack of tumor cells at d1c2. PD-L1 (Ventana SP142) and sTILs data were available. We evaluated the association with pCR of biomarkers assessed at d1c2 and their dynamics from baseline. Results Frequency of TNBC types at d1c2 showed minor differences between arms (p = 0.055). TNBC type frequencies were 22.9% BL1, 11.4% BL2, 22.9% LAR, 21.4% M, and 21.4% MSL in the CT/A arm and 43.8% BL1, 6.2% BL2, 11.2% LAR, 21.2% M, and 17.5% MSL in the CT arm. Individual TNBC type changes from baseline to d1c2 were observed, but overall, it was not significant. Frequency of IO positive score at d1c2 was similar in CT and CT/A arm (p = 0.75). Only in CT/A, an increase from baseline to d1c2 was observed (30.9% to 49.3%, p = 0.04).Overall, TNBC types at d1c2 were predictive of pCR (p = 0.00002). Compared to BL1, LAR and M were associated with lower pCR rate in CT (OR = 0.09, 95% CI = 0.01-0.83, p = 0.034 for LAR; OR = 0.16, 95% CI = 0.04-0.66, p = 0.011 for M) and CT/A arm (OR = 0.05, 95% CI = 0.01-0.49, p = 0.010 for LAR; OR = 0.28, 95% CI = 0.06-1.28, p = 0.102). pCR rate in LAR was 11.1% and 6.2% in CT and CT/A arm, respectively. TNBC types were predictive of pCR independently of PD-L1 and sTILs.Continuous IO score at d1c2 was predictive of pCR in both CT/A (p = 0.004) and CT arms (p = 0.009). The binary IO score was significantly associated to higher pCR rate in CT/A arm only (OR = 5.42, 95% CI = 1.95-15.07, p = 0.001). A strong predictive value of the highest quartile of IO score compared to the lowest was observed in CT/A (OR = 14.73, 95% CI = 2.97-73.21, p = 0.001) and CT (OR = 4.38, 95% CI = 1.21-15.81, p = 0.024) arms. pCR rates for the highest and lowest quartiles were 72.2% vs 15.0% in CT/A and 65.2% vs 30.0% in CT arm. In CT/A binary IO score at d1c2 retained significance after adjustment for baseline PD-L1 and sTILs (p = 0.036).Combining baseline and d1c2 IO score, only d1c2 assessment was informative in CT arm. In CT/A arm, both biomarkers were informative, with assessment at d1c2 being more informative than baseline IO score when continuous scores were considered. Baseline binary IO score (OR = 25.0, 95% CI = 3.31-188.9, p = 0.002) and ΔIO score (d1c2-baseline) (OR = 11.3, 95% CI = 1.07-120.1, p = 0.044) retained significance. The combination of baseline and d1c2 binary IO score defined four groups with different likelihood of pCR: 73.7% vs 15.2% in positive/positive and negative/negative groups, respectively (OR = 15.68, 95% CI = 3.88-63.32, p = 0.0001). Conclusions Dynamic of IO score early on treatment was linked to likelihood of pCR independently of baseline biomarkers and may be an early surrogate of treatment benefit especially in atezolizumab arm. LAR and M are associated with lower pCR rate, suggesting that different therapeutic strategies may be beneficial. Combining baseline and on-treatment biomarkers can be more informative than baseline only of the complex tumor/immune co-evolution dynamic and of clinical outcome. Citation Format: Matteo Dugo, Chiun-Sheng Huang, Daniel Egle, Begoña Bermejo, Claudio Zamagni, Robert S. Seitz, Tyler J. Nielsen, Marc Thill, Antonio Anton, Stefania Russo, Eva Maria Ciruelos, Brock L. Schweitzer, Douglas T. Ross, Barbara Galbardi, Richard Greil, Vladimir Semiglazov, Balázs Gyorffy, Marco Colleoni, Catherine Kelly, Gabriella Mariani, Lucia Del Mastro, Pinuccia Valagussa, Giuseppe Viale, Maurizio Callari, Luca Gianni, Giampaolo Bianchini. Triple negative breast cancer subtypes and early dynamics of the 27-gene IO score predict pCR in the NeoTRIPaPDL1 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-12.

Abstract LBA046: Neoadjuvant and Adjuvant Capmatinib in Resectable Non-Small Cell Lung Cancer With MET Exon 14 Skipping Mutation or High MET Amplification: GEOMETRY-N Trial

Abstract Background: Neoadjuvant therapy is the earliest opportunity to eliminate micrometastatic disease. Emerging data suggest that neoadjuvant therapy in non-small cell lung cancer (NSCLC) can elicit major pathological responses (MPRs) that translate into prolonged survival outcomes, serving as an early surrogate for efficacy. Adjuvant therapy is well known to improve overall and disease-free survival (DFS) in patients with completely resected NSCLC. DFS observed with osimertinib in patients with early-stage EGFR-mutated tumors supports evaluation of other tyrosine kinase inhibitors (TKIs) in the neoadjuvant and adjuvant settings. In early-stage NSCLC, MET exon 14 skipping mutation (METex14) and de novo MET amplification (METamp) are estimated to occur in up to 2.8% and 1.7% of patients, respectively. Capmatinib, a selective MET TKI, is FDA approved for patients with metastatic METex14 NSCLC. It was studied in GEOMETRY mono-1 in patients with advanced/metastatic NSCLC with either METex14 or METamp. In two treatment-naive METex14 cohorts, overall response rate (ORR) was 68% and 66%. In a treatment-naive high-level METamp cohort, ORR was 40%. Capmatinib had a tolerable safety profile; most adverse events were reversible with dose adjustments. Based on the response rates and the safety profile observed in GEOMETRY mono-1 in treatment-naive patients with advanced/metastatic MET-dysregulated NSCLC, GEOMETRY-N (NCT04926831) a Phase II, two-cohort, two-stage study is evaluating the efficacy and safety of neoadjuvant and adjuvant capmatinib therapy in improving the MPR rate and outcomes beyond those achieved with surgery, chemotherapy, and radiation in patients with METex14 or high-level METamp NSCLC. Methods: Adult patients with resectable, histologically confirmed NSCLC stage IB-IIIA, N2 and select IIIB (T3N2 or T4N2) with either METex14 irrespective of MET gene copy number (GCN) (cohort A) or high-level METamp with GCN ≥10 (cohort B) are eligible. METex14 must be determined by a Clinical Laboratory Improvement Amendments (CLIA)-certified lab. METamp must be determined by fluorescent in situ hybridization at a CLIA-certified lab or by FoundationOne CDx next-generation sequencing. Prior systemic anticancer therapy is prohibited. Patients will receive capmatinib 400 mg twice daily for 8 weeks prior to surgical resection, followed by 3 years of adjuvant capmatinib. In the two-stage design, stage 1 will enroll 9 patients in each cohort, with MPR evaluated in each cohort after 9 patients have completed neoadjuvant therapy; stage 2, enrolling 10 more patients in a cohort, will proceed only if ≥1 of 9 participants has an MPR. About 42 patients will be enrolled, with 19 evaluable patients per cohort. The primary endpoint is MPR rate based on local investigator assessment. Secondary endpoints are complete pathological response rate (central and local investigator review), ORR (local investigator assessment), DFS, and safety. Following treatment, there will be a 2-year survival follow-up. The expected first patient first visit is September 30, 2021. Citation Format: Karen Kelly, Mark M. Awad, Teddy Saliba, Nydia Caro, Beth Inserra, Hiya Banerjee, Jay M. Lee. Neoadjuvant and Adjuvant Capmatinib in Resectable Non-Small Cell Lung Cancer With MET Exon 14 Skipping Mutation or High MET Amplification: GEOMETRY-N Trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA046.

Sarcopenia as a Predictor of Survival in Patients with Pancreatic Adenocarcinoma After Pancreatectomy.

To determine whether sarcopenia can potentially predict worse survival after resection of pancreatic ductal adenocarcinoma. Sarcopenia is correlated with poor outcomes in hepatopancreatobiliary malignancies, but the relationship of both its qualitative and quantitative features with patient survival after pancreatectomy has not been investigated in a western population. Preoperative cross-sectional computed tomography scans of consecutive patients who underwent pancreatectomy in 2005-2017 were evaluated for skeletal muscle index (SMI), intramuscular adipose tissue content (IMAC), and visceral-to-subcutaneous adipose tissue area ratio (VSR). Sex-specific categorical cut-offs were determined. Findings were correlated with outcome. The study included 111 patients, 47% of whom were female, with a median age of 67 years (range: 35-87 years), and median body mass index of 23kg/m2 (range: 16-40kg/m2); 77% had a Whipple procedure and 66% received adjuvant chemotherapy. Low SMI correlated with poor overall survival (OS) (P = 0.007), disease-specific survival (DSS) (P = 0.006), and recurrence-free survival (RFS) (P = 0.01). High IMAC correlated with poor OS (P = 0.04). Patients with high IMAC tended to have a shorter DSS (P = 0.09), with no correlation with RFS (P = 0.6). VSR was not associated with survival. Multivariable analysis yielded an independent association of low SMI with OS (HR = 1.7, 95%CI: 1.1-2.8, P = 0.02), DSS (HR = 1.8, 95%CI:1.03-3.2, P = 0.04), and RFS (HR = 1.8, 95%CI: 1.1-2.8, P = 0.01), and of high IMAC with OS (HR = 1.9, 95%CI: 1.1-3.1, P = 0.01). Both qualitative and quantitative measures of skeletal muscle were independently associated with impaired survival in patients with resectable PDAC. Sarcopenia might serve as an early radiographic surrogate of aggressive tumor behavior, with potential implications for clinical decision-making and future study.

Acute phase segmental radial strain correlates with recovery and late gadolinium extent in ST-elevation myocardial infarction (STEMI): analysis of the abciximab intracoronary versus intravenously drug application in STEMI substudy.

The role of regional strain evaluation in patients with acute reperfused ST-elevation myocardial infarction (STEMI) is not well determined. The objective of this study was the description of regional strain characteristics in the acute and chronic phase of myocardial infarction and its correlation with symptom-to-balloon time and final extent of myocardial scar assessed by cardiac magnetic resonance imaging. The study cohort has been derived from the randomized controlled Abciximab Intracoronary versus Intravenously Drug Application in STEMI (AIDA STEMI) trial enrolled at the University of Ulm. All patients received comprehensive cardiac magnetic resonance imaging examinations in the acute phase and 6 months later. There was a significant improvement of all global deformation indices over time (global longitudinal strain: -13.1%±5.1% to -15.5%±5.8%, P=0.001; global circumferential strain: -14.4%±3.7% to -16.8%±3.6%, P<0.0001; global radial strain: 28.1%±8.7% to 31.9%±9.2%, P=0.0002). Mean radial strain of ischemic segments significantly improved (16.6%±10.8% to 23.7%±12.8%, P<0.0001), while mean radial strain of remote segments remained unchanged (40.2%±9.4% to 39.4%±9.4%, P=0.570). There was a significant correlation between acute phase radial strain of ischemic segments and either symptom-to-balloon time (P=0.013), as well as extent of late gadolinium enhancement at follow-up (P<0.0001). Using a cut-off of ≤27%, acute phase radial strain predicted infarction of the corresponding segment with high sensitivity and specificity (74.4% and 69.0% respectively, P<0.001). Segmental radial strain in the acute phase of infarction showed a significant correlation to either symptom-to-balloon-time and the extent of late gadolinium enhancement at follow-up, thus potentially serving as early surrogate for left ventricular remodeling and outcome in STEMI.

Early clinical surrogates for outcome prediction after stroke thrombectomy in daily clinical practice

Background and purposeTo investigate early clinical surrogates for long-term independency of patients treated with thrombectomy for large vessel occlusion stroke in daily clinical routine.MethodsAll patients with anterior circulation stroke enrolled...