Surrogate Endpoint For Survival Research Articles

Abstract 3638: Pathologic endpoints as surrogates for survival endpoints in neoadjuvant immunotherapy clinical trials for non-small cell lung cancer

Abstract Background: The use of neoadjuvant immunotherapy alone or in combination has rapidly evolved in the last 5 years. There is significant debate as to whether pathologic complete response (pCR) or major pathologic response (MPR) can be considered a surrogate endpoint for survival. We therefore performed a systematic review and meta-analysis to evaluate the surrogacy of pCR and MPR for event free survival (EFS) in neoadjuvant clinical trials for early-stage NSCLC. Methods: We performed a systematic literature search on PubMed and reviewed abstracts of the most relevant international conferences until June 2023. Relevant information relative to response rates, Odds Ratios (ORs) of response, 2-years EFS rates and Hazard ratios (HRs) were retrieved from all eligible clinical trials and the association were analyzed. To evaluate patients level surrogacy the association between response rate and 2-year EFS was evaluated. In trials presenting EFS rates by achievement of pCR and MPR a forest plot with random effect model was also produced. For trial level surrogacy, ORs for pCR and MPR and HRs for EFS were retrieved and analyzed using a linear regression model weighted by sample size. R2 and linear regression slope were used respectively to estimate the proportion of variation in EFS effect explained by pCR effect and the magnitude of change in EFS effect as a function of the magnitude of change in pCR effect. The R2 with 95% CI were calculated by bootstrapping approach. Results: Seven RCTs were identified for a total of 2940 patients. At patient level, the R2 of pCR and MPR with 2-years EFS were 0.82 (0.66-0.94) and 0.81 (0.63-0.93), respectively, with slopes of 0.96 (0.68-1.19) and 0.64 (0.45-0.85), respectively. At trial level, R2 for association of OR for response and HR for EFS was 0.58 (0.00-0.97) and 0.61 (0.00-0.97) for pCR and MPR, respectively. Conclusions: While we were able to show a strong correlation between pCR and EFS, trial level surrogacy was not proven. The lack of surrogacy can be related to the high heterogeneity among clinical trials and the still scarce number of data available. More research to reduce the heterogeneity (e.g., pathological evaluation, surgery, and staging harmonization) must be done to introduce pCR as a primary measure to predict EFS. Citation Format: Robert B. Cameron, Jacobi B. Hines, Alessandra Esposito, Christine Bestvina, Marina C. Garassino, Valter Torri, Rajat Thawani. Pathologic endpoints as surrogates for survival endpoints in neoadjuvant immunotherapy clinical trials for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3638.

Evaluation of Major Pathologic Response and Pathologic Complete Response as Surrogate End Points for Survival in Randomized Controlled Trials of Neoadjuvant Immune Checkpoint Blockade in Resectable in NSCLC

IntroductionControversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC. MethodsA search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were analyzed using a linear regression model weighted by sample size. The regression coefficient and R2 with 95% confidence interval were calculated by the bootstrapping approach. ResultsSeven randomized clinical trials were identified for a total of 2385 patients. At the patient level, the R2 of pCR and MPR with 2-year EFS were 0.82 (0.66–0.94) and 0.81 (0.63–0.93), respectively. The OR of 2-year EFS rates by response status was 0.12 (0.07–0.19) and 0.11 (0.05–0.22), respectively. For the 2-year OS, the R2 of pCR and MPR were 0.55 (0.09–0.98) and 0.52 (0.10–0.96), respectively. At the trial level, the R2 for the association of OR for response and HR for EFS was 0.58 (0.00–0.97) and 0.61 (0.00–0.97), respectively. ConclusionsOur analyses reveal a robust correlation between pCR and MPR with 2-year EFS but not OS. Trial-level surrogacy was moderate but imprecise. More mature follow-up and data to assess the impact of study crossover are needed.

Comparison of different criteria for estimating major pathological response in resectable non-small cell lung cancer treated with neoadjuvant chemoimmunotherapy

BackgroundMajor pathological response (MPR) is proposed as a surrogate endpoint for survival in non-small cell lung cancer (NSCLC) after neoadjuvant chemoimmunotherapy. However, the criteria for estimating MPR differ between the recommendations of the International Association for the Study of Lung Cancer (IASLC) and the immune-related pathologic response criterion (irPRC). IASLC's criteria focus solely on evaluating the primary tumor, while irPRC's criteria encompass both the primary tumor and lymph node metastasis. Our objective is to compare the prognostic value of different criteria for estimating MPR. MethodsWe conducted a retrospective study on a cohort of 235 patients with NSCLC after neoadjuvant chemoimmunotherapy. The survival endpoint was event-free survival (EFS). The MPR status of each patient was evaluated using both IASLC's criteria and irPRC's criteria. The prognostic value was compared using the Area Under Curve (AUC). ResultsThe MPR rates were 63.4 % (149/235) and 57.4 % (135/235) according to IASLC's and irPRC's criteria, respectively. Inconsistent cases, characterized by MPR status according to IASLC's criteria but non-MPR status according to irPRC's criteria, constituted 6.0 % (14/235) of the overall cohort and 15.2 % (14/92) of patients with pretreatment N positive disease. Interestingly, all inconsistent patients showed no recurrence during the study period. Although both MPR statuses according to IASLC (p = 0.00039) and irPRC (p = 0.0094) were associated with improved EFS, IASLC's criteria (AUC = 0.65) were superior to irPRC's criteria (AUC = 0.62) with a higher AUC value. ConclusionIASLC's criteria for estimating MPR were superior to irPRC's criteria in predicting EFS for NSCLC after neoadjuvant chemoimmunotherapy.

Surrogate end points for survival in patients with advanced hepatocellular carcinoma treated with immune checkpoint inhibitors.

Aim: The authors investigated surrogacy of radiology-based end points for clinical trials investigating immune checkpoint inhibitors in advanced hepatocellular carcinoma. Methods: Data were collected from electronic databases reporting median overall survival (OS), median progression-free survival (PFS) and objective response rate (ORR). Weighted Pearson correlation coefficients and 95% confidence intervals (CIs) were calculated. Results: 26 clinical trials (41 treatment arms, 5144 patients) were included. ORR (coefficient: 0.71; 95% CI: 0.52-0.84) and PFS (coefficient: 0.63; 95% CI: 0.21-0.92) were positively correlated with OS. Sensitivity analyses suggested liver function, line of therapy and study phase did not greatly impact results. The COSMIC-312 study negatively impacted the overall weighted correlation. Conclusion: ORR and PFS are positively correlated with OS in patients with advanced hepatocellular carcinoma.

MRD Monitoring by Multiparametric Flow Cytometry in AML: Is It Time to Incorporate Immune Parameters?

Simple SummaryMeasurable residual disease (MRD) is emerging as an important prognostic and predictive biomarker in acute myeloid leukemia (AML). However, its use is currently hampered by the disparity and lack of harmonization between the available MRD methodologies. In addition, the current assessment of MRD in AML focuses only on the quantification of the residual leukemic burden, without addressing the parallel alterations of the antineoplastic immune response that can critically affect the course and outcome of AML, often despite MRD persistence. Incorporating parameters of immune competence provides more consistency with the biological concept of MRD and may lead to higher accuracy. Multiparameter flow cytometry (MFC) is a highly efficacious and sensitive technology for the thorough and synchronous investigation of the kinetics of both antitumor immunity and the leukemic clone. MFC-based MRD provides the platform for the development of a composite leukemia- and immune-based biomarker which can outcompete the current MRD assessment.Acute myeloid leukemia (AML) is a heterogeneous group of clonal myeloid disorders characterized by intrinsic molecular variability. Pretreatment cytogenetic and mutational profiles only partially inform prognosis in AML, whereas relapse is driven by residual leukemic clones and mere morphological evaluation is insensitive for relapse prediction. Measurable residual disease (MRD), an independent post-diagnostic prognosticator, has recently been introduced by the European Leukemia Net as a new outcome definition. However, MRD techniques are not yet standardized, thus precluding its use as a surrogate endpoint for survival in clinical trials and MRD-guided strategies in real-life clinical practice. AML resistance and relapse involve a complex interplay between clonal and immune cells, which facilitates the evasion of the leukemic clone and which is not taken into account when merely quantifying the residual leukemia. Multiparameter flow cytometry (MFC) offers the possibility of capturing an overall picture of the above interactions at the single cell level and can simultaneously assess the competence of anticancer immune response and the levels of residual clonal cells. In this review, we focus on the current status of MFC-based MRD in diverse AML treatment settings and introduce a novel perspective of combined immune and leukemia cell profiling for MRD assessment in AML.

Multimodal prediction of response to neoadjuvant nivolumab and chemotherapy for surgically resectable stage IIIA non–small cell lung cancer.

8542 Background: The NADIM trial (NCT03081689), led by the Spanish Lung Cancer Group, assessed the antitumor activity and safety of neoadjuvant chemoimmunotherapy for resectable stage IIIA NSCLC. Patients received neoadjuvant nivolumab and paclitaxel-carboplatin for three cycles before surgical resection, followed by one year of adjuvant nivolumab. At 24 months, progression-free survival (PFS) was 77%, suggesting that neoadjuvant chemoimmunotherapy represents a promising option in this setting. Pathological complete response (pCR) could potentially be used as an important surrogate endpoint for survival. We present here a re-analysis of the NADIM cohort aiming to develop a machine learning algorithm to predict the pCR status based on multimodal baseline data. Methods: We combined baseline clinical data (e.g., age, smoking status), biological data (e.g., tumor histology, mutations), radiology reports and radiomics analysis of the baseline CT scan in a multimodal analysis. While 46 patients were enrolled in the NADIM trial, only 28 had a complete set of data available for this retrospective study. For each patient, tumors were segmented on the baseline CT-scan in 3D by a Deep Learning algorithm. Radiomics features were extracted following the IBSI standards and combined with the other data modalities. A filter-based variable selection method was applied before training several machine learning algorithms. The optimization criterion was the Area Under the ROC Curve (AUC). Due to the small size of the cohort, a leave-one-out cross-validation approach was used to properly estimate the model performance. For a sub-cohort of 20 patients for which data have been collected longitudinally during the neoadjuvant treatment, an additional Delta-radiomics model was used to predict the pCR status. Results: An XGBoost algorithm with a linear base learner displayed an AUC of 0.69, a precision of 75%, a sensitivity of 83% and a specificity of 50%. Features with highest weight in the algorithm were a mix of radiological, radiomics, biological and clinical features (including the neutrophils to lymphocytes ratio, mutations and histology) highlighting the importance of a truly multimodal analysis. Indeed, withdrawing a specific data modality (e.g., radiomics or biological features), led to a decrease of ̃15% of the AUC. Inclusion of the Delta-radiomics analysis on the data collected longitudinally prior to surgery led to an improved AUC of 0.76 in that patient sub-cohort. Conclusions: This study is, to our knowledge, the first to offer a multimodal analysis of the response to neoadjuvant treatment for surgically resectable stage IIIA NSCLC and is a proof of concept that a machine learning algorithm can be used to predict the pCR in this context. These preliminary results are being confirmed in the ongoing NADIM II trial. Clinical trial information: NCT03838159.

Meta-analysis of surrogate endpoints for survival in patients with unresectable hepatocellular carcinoma treated with immune checkpoint inhibitor-based regimens.

483 Background: Overall survival (OS) remains the gold standard for demonstrating clinical benefit in advanced hepatocellular carcinoma (HCC). While surrogate radiology-based endpoints for OS, such as progression-free survival (PFS) and objective response rate (ORR) are commonly used in the field of oncology, they remain controversial in the setting of HCC where antiangiogenic agents were the mainstay of treatment until recently. Immune checkpoint inhibitors (CPIs) as monotherapy or in combination have shifted the treatment paradigm in HCC. We investigated the surrogacy of radiology-based endpoints from CPI clinical trials in advanced HCC. Methods: Study level data were collected for disclosures published in EMBASE, PubMed, Clinicaltrials.gov and conference abstracts. Keywords used included (abbreviated here): immune CPIs, advanced or metastatic HCC and ORR, PFS and OS. Key inclusion criteria included: Phase I, II and III trial data, and patients with advanced or metastatic HCC who received CPI monotherapy or in a combination regimen. The endpoints investigated were median OS (mOS), median PFS (mPFS) and ORR (RECIST v1.1). A weighted Pearson correlation coefficient, with weights corresponding to the number of patients in the different treatment arms of the trials, was calculated between ORR/mOS, ORR/mPFS and mPFS/mOS in all arms, arms that included only patients with Child-Pugh A liver function, and arms in the first-line therapy setting. 95% confidence intervals (CIs) based on the empirical bootstrap re-sampling method are also reported. Results: Eighteen clinical trials (8 randomized trials and 10 multi-cohort trials) published between 2017 and 2021, including 3,246 patients across 32 treatment arms, were selected for inclusion in this meta-analysis. Ten trials included CPI monotherapy arms, 5 trials included CPI + TKI arms, 4 trials included CPI + anti-angiogenic monoclonal antibody arms, and 2 trials included CPI + CPI arms. There was 1 CPI + chemotherapy arm and 1 CPI + CPI + TKI arm in separate trials. Weighted Pearson correlation coefficients and corresponding 95% CIs are presented in the table. Conclusions: Our analysis suggests ORR/mOS, ORR/mPFS, and mPFS/mOS are positively correlated, with ORR/mPFS more strongly correlated compared to the other pairs, in patients with advanced HCC who were treated with CPI-based regimens. [Table: see text]

Evaluation of Pathologic Response in Lymph Nodes of Patients With Lung Cancer Receiving Neoadjuvant Chemotherapy

IntroductionMajor pathologic response (MPR), defined as residual viable tumor of less than or equal to 10%, currently serves as a surrogate end point for survival for patients with resectable NSCLC after neoadjuvant chemotherapy. However, the significance of pathologic response in lymph nodes harboring metastatic tumors in such patients remains uncertain. Therefore, we studied the effect of neoadjuvant chemotherapy on resected positive lymph nodes and determined if the degree of pathologic response in the lymph nodes alone (LN-MPR) or in combination with that of the primary tumor (PT-MPR) was able to predict the outcome. MethodsA total of 75 patients with NSCLC who underwent neoadjuvant chemotherapy and completed surgical resection were included in this study. Tissue specimens were retrospectively evaluated by two pathologists blinded to the patients’ treatments and outcomes. Specimens were reviewed for the degree of pathologic response in the primary tumor and in any involved lymph nodes. The prognostic performance of LN-MPR alone or in combination with PT-MPR with respect to overall survival (OS) was evaluated using the Kaplan-Meier method and Cox regression model. ResultsLN-MPR was significantly predictive of long-term OS after neoadjuvant chemotherapy. A combination of PT-MPR with LN-MPR was significantly associated with outcome and allowed stratification of patients into three prognostic groups (p = 0.001). ConclusionsLN-MPR in isolation is a reliable predictor of OS in patients with NSCLC receiving neoadjuvant chemotherapy. A combination of LN-MPR with PT-MPR seems to correlate well with the outcome and can be used to predict prognosis in this patient population.

Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival

Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence. Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years. At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P= 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n= 17, 100%). For those who did not achieve pCR (n= 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5). Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

Pathological Complete Response in Locally Advanced Breast Cancer after Neoadjuvant Chemotherapy: Survival Outcome and Its Relevance as a Surrogate End Point.

Background Pathological complete response (pCR) to neoadjuvant chemotherapy has emerged as a reliable surrogate marker for improved survival in breast cancer (BC), but its role as a surrogate end point is still controversial. Aims and Objectives The aim of the study is to investigate the clinical course of BC patients with pCR and to evaluate the relevance of pCR as a surrogate end point for survival. Materials and Methods This was a single-institution retrospective analysis done at Amrita Institute of Medical Sciences. Records of BC patients from 2004 to 2014 were analyzed. Disease-free survival (DFS) and overall survival (OS) were compared using the Kaplan–Meier method and log-rank test, respectively. pCR and survival association were evaluated using regression analysis ( R 2 ). Results Of 224 patients included in the study pCR rate was 15.2%. The median duration of follow-up was 61 months (range: 3–151 months). DFS (73.4 vs. 46.1%, p = 0.032) and OS (82.5 vs. 56.4%, p = 0.022) of pCR cohort was significantly higher than non-pCR cohort. Recurrence rate was significantly lower in the pCR cohort at: All distant sites ( p = 0.01 3), visceral sites ( p = 0.007), both bone and visceral sites ( p = 0.007), and nodal sites ( p = 0.007). There was no difference in the bone-only recurrence ( p = 0.3 15). Death rate was significantly lower in pCR cohort ( p = 0.007). The R2 value for pCR as a surrogate for DFS and OS was 0.006 and 0.004, respectively. Conclusion pCR is a favorable prognostic factor associated with improved survival. However, there is no association between pCR and survival.

Agreement on Major Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemotherapy

IntroductionWe have suggested that major pathologic response (MPR) could serve as a surrogate endpoint for survival and provide rapid means of comparing different neoadjuvant treatment regimens. Here, we confirm that MPR is predictive of long-term overall survival (OS) in patients with non–small-cell lung cancer (NSCLC) who underwent neoadjuvant chemotherapy and surgical resection, to assess agreement on MPR between 2 observers, and to determine the minimum number of slides needed to obtain an accurate determination of MPR. Patients and MethodsWe identified 151 patients with NSCLC who had been treated with neoadjuvant chemotherapy followed by complete surgical resection from 2008 to 2012. Tissue specimens were retrospectively evaluated by 2 pathologists who had been blinded to patients’ treatment and outcome. We assessed the relationships between MPR and OS, the levels of agreement between the pathologists, and determined the number of slides needed to obtain an accurate determination of MPR. ResultsOur results reveal that MPR examined by either observer 1 (experienced) or by observer 2 (trained) was significantly predictive of long-term OS after neoadjuvant chemotherapy. MPR was associated with long-term OS in patients with NSCLC undergoing neoadjuvant chemotherapy on multivariable analysis (hazard ratio 2.68; P = .01). The levels of agreement between 2 pathologists were high after direct in-person training by one pathologist or the other (R2 = 0.994). Our data suggest that at least 3 slides should be read to accurately determine MPR. ConclusionsMPR is significantly predictive of long-term OS in neoadjuvant chemotherapy–treated patients with NSCLC. MPR may serve as a surrogate endpoint for evaluating novel chemotherapies and immunotherapy response in biomarker-driven translational clinical trials.

Abstract P5-01-04: Personalized monitoring of circulating tumor DNA during neoadjuvant therapy in high-risk early stage breast cancer reflects response and risk of metastatic recurrence

Abstract Background: The detection of circulating tumor DNA (ctDNA) during neoadjuvant therapy (NAT) may serve as an early indicator of emerging resistance and disease progression. In this study, we analyzed ctDNA from high-risk early breast cancer patients who received NAT and definitive surgery in the I-SPY 2 TRIAL (NCT01042379). We hypothesized that ctDNA can serve as a biomarker of response and survival in this setting. Methods: ctDNA analysis was performed on 291 plasma samples from 84 high-risk stage II and III breast cancer patients randomized either to an investigational agent MK-2206, an AKT inhibitor, in combination with paclitaxel followed by doxorubicin and cyclophosphamide (AC) (n=52)—or standard-of-care (paclitaxel followed by AC) (n=32). HER2+ patients also received trastuzumab. Serial plasma was collected at pretreatment (T0), at 3 weeks after initiation of paclitaxel treatment (T1), between paclitaxel and AC regimens (T2), and after NAT prior to surgery (T3). A personalized ctDNA test was designed to detect a set of 16 patient-specific somatic variants, initially identified from whole exome sequencing of pretreatment tumor, then tested in plasma samples. Regions containing the somatic variants were amplified from cell-free DNA using specific polymerase chain reaction primers. Amplified products were subjected to ultra-deep sequencing (mean: 94,000x) to detect somatic variants. Association between ctDNA and clinicopathologic variables was assessed using Fisher’s exact test. Association of ctDNA with response and survival was analyzed using logistic and Cox regressions, respectively. The survival endpoint of the study was distant disease-free survival. The median follow-up was 4.8 years. Results: At pretreatment (T0), 61 of the 84 (73%) patients had detectable ctDNA. Pretreatment (T0) ctDNA positivity and levels (mean mutant molecules per mL of plasma) were significantly associated with increased tumor burden (clinical T stage T3/T4), more aggressive tumor biology (higher Mammaprint scores) and subtype (HER2+ and Triple negative). CtDNA detection during NAT decreased over time (T0- 73%; T1- 35%; T2- 14%; T3- 9%). Of the 84 patients, 23 (27%) achieved pCR and all were ctDNA-negative after NAT (T3), while all 6 patients who had detectable ctDNA at T3 did not achieve pCR. Patients who cleared ctDNA early at T1 (n=27, 48% pCR rate) had significantly increased probability of achieving a pathologic complete response (pCR) compared to those who remained ctDNA-positive (n=29, 17% pCR rate; Odds ratio=4.33, Likelihood ratio p=0.012). Patients who were ctDNA-positive at T3 (n=6) had significantly increased risk of metastatic recurrence (HR 14.7; 95% CI 1.6-131.5) compared to those who achieved pCR and were ctDNA-negative (n=17). The risk of metastatic recurrence in patients who cleared ctDNA during NAT was not significantly different from those who were negative at T0 and remained negative by T3 (hazard ratio, HR: 2.1, 95% CI: 0.22-20.2). Interestingly, patients who were ctDNA-negative (n=37) but failed to achieve pCR had similar risk of metastatic recurrence with those who achieved pCR (HR 1.4; 95% CI 0.15-13.5). Conclusions: Early clearance of ctDNA during NAT was significantly associated with increased likelihood of achieving pCR. Residual ctDNA after NAT was a significant predictor of metastatic recurrence, while clearance of ctDNA at any point during NAT was associated with improved outcomes. Taken together, personalized monitoring of ctDNA during NAT may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival. Validation studies in a larger cohort are warranted. Citation Format: Mark Jesus M Magbanua, Lamorna Brown-Swigart, Gillian Hirst, Christina Yau, Denise Wolf, Hsin-Ta Wu, Antony Tin, Svetlana Shchegrova, Himanshu Sethi, Raheleh Salari, Alexey Aleshin, Maggie Louie, Bernhard Zimmermann, Angela DeMichele, Minetta Liu, Amy Delson, Amy Jo Chien, Smita Asare, Laura Esserman, I-SPY 2 TRIAL Consortium, Laura van't Veer. Personalized monitoring of circulating tumor DNA during neoadjuvant therapy in high-risk early stage breast cancer reflects response and risk of metastatic recurrence [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-04.

Abstract P3-07-13: Neoadjuvant composite score as a prognostic marker in early and locally advanced triple negative breast cancer

Abstract Aim Triple negative subtype (TNBC) is an aggressive breast cancer with inferior survival. Pathological CR (pCR) is a good surrogate endpoint for survival among patients receiving neoadjuvant chemotherapy (NACT). We attempted to validate the composite score(CPS) (Jaccqueline et al, J Clin Oncol 26:246-252) combining clinical and pathological variables among TNBC patients receiving NACT at our center. Methodology Data of patients with TNBC who underwent NACT between January 2014 to July 2017 was retrospectively analysed. The composite CPS score included cTN stage and y pTN stage, and ranged from 0 to 4. This was calculated using an online software (http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=bcnt). The scores obtained from the calculator was used to develop a risk grouping into low risk (0,1) and High risk (2,3,4). Overall survival (OS)and disease free survival (DFS) were calculated using the Kaplan-Meier method and differences was examined using the log rank test. Results Seventy-eight patients with TNBC [median age: 45 (24-75)] had received NACT (anthracyclines and taxanes). Early and locally advanced breast cancer constituted 17 (21.8 %) and 61 (78.2%) respectively and 22 (28.2 %) achieved pCR. After a median follow up of 28 months (5-62), 3-yr DFS and OS were 59% and 82% respectively for the entire population. The 3-yr DFS in low (n=18) and high risk (n=60) patients was 85.7% and 51.4% respectively (p=0.032). The 3-yr OS in the low and high risk was 93% and 79% respectively(p=0.28, NS). Conclusion Our study supports the use of the composite clinical pathological score (CPS) as a prognostic marker in patients with non-metastatic triple negative breast cancer. The risk stratification developed may help identify patients who may require additional adjuvant therapy. Citation Format: Biswajit Dubashi, Smita Kayal, Kirankumar Matta, Divya bala Thumaty, Nisha Yadav, D Kadambari, Pampa ch Toi, K Gunaseelan, Prasanth Ganesan. Neoadjuvant composite score as a prognostic marker in early and locally advanced triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-13.

Validation of neoadjuvant rectal cancer(NAR) score as a surrogate endpoint for disease free survival in Chinese FOWARC study.

e15162 Background: NAR score is considered as a surrogate endpoint for survival in patients with locally advanced rectal cancer who received neoadjuvant treatment. Here we validate it in Chinese FOWARC study, especially in the chemotherapy alone arm. Methods: NAR score is calculated based on cT, ypT, ypN as reported for patients who received surgery in FOWARC study. NAR score is correlated to DFS with COX regression and Kaplan-Meier analysis. Results: 451 patients had surgery, 147 in FU-RT group, 152 in FOLFOX-RT arm and 152 in FOLFOX arm. NAR score is a significant prognostic factor in COX regression (P=0.000, HR 1.034, 95% CI 1.024-1.045) and in FOLFOX alone group (p=0.001, HR 1.030, 95% CI 1.013-1.047). When NAR score is quartile to <5, 5-10, 10-15,>15, the survival of patients is listed below, and similar to pathological staging. Conclusions: NAR score can be used as a surrogate endpoint for disease free survival Chinese patients. But it is not superior to pathological stage, especially in patients who received chemotherapy alone. [Table: see text]

Assessment of circulating tumor cell number as a transitional surrogate endpoint for survival in phase II trials for metastatic castration-resistant prostate cancer.

143 Background: Short-term measures of response that reflect clinical benefit are a critical unmet need for clinical trials for mCRPC. Using data from 5 randomized mCRPC trials, we showed that a response endpoint (RE) based on a change in CTC number using the FDA cleared CellSearch® (Menarini) platform from any, (≥ 1, CTC any) to 0 (CTC0) per 7.5 ml of blood was associated strongly with overall survival (OS). Here we explored whether different CTC and PSA REs could serve as “transitional surrogates” defined as a biomarker validated in phase 2 but not in phase 3 trials for overall survival (OS), using the baseline and week 13 prostate-specific antigen (PSA) level and CTC counts. Methods: Four 13-week REs were studied: (i) PSA50 (≥ 50% PSA decline from baseline), (ii) CTC0 (≥ 1 CTC/7.5 ml of blood at baseline and 0 CTCs at week 13), (iii) both PSA50 and CTC0, and (iv) either PSA50 or CTC0. The relative effectiveness of these REs as transitional surrogates for OS was evaluated at the patient level by discrimination, the separation between responder and non-responder survival curves, and at the trial level using explained variation, the accuracy in predicting k-month survival in a trial with the response proportion. Results: A total of 6081 pts were enrolled of whom 5660 (93%) survived until week 13 and among these patients 3080 (54%) had a baseline CTC count ≥ 1 and baseline PSA ≥ 5 ng/ml. At the patient level, separation between responder and non-responder survival curves over time was greater using CTC0 than PSA50 (average difference in survival probability 0.35 vs. 0.29, respectively). At the trial level, explained variation in survival over time was also greater for CTC0 than PSA50 (average R-squared 0.67 vs. 0.58, respectively). CTC/PSA combination REs did not improve on CTC0 at either level. Conclusions: The CTC0 RE provides stronger discrimination than PSA50 at the patient level and greater observed explained variation at the trial level. The results suggest that for the individual patient, a decrease in CTCs to zero at week 13 is a stronger indicator of longer term OS than the more widely used PSA50 and serves as a reasonably likely surrogate for OS in clinical trials.

Association of Sustained Response Duration With Survival After Conventional Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma

Defining early reliable surrogate end points for survival in patients with hepatocellular carcinoma (HCC) after conventional transarterial chemoembolization (cTACE) is of great value. To evaluate the association between sustained response duration (SRD) and overall survival (OS) after cTACE for intermediate HCC. This multicenter cohort study enrolled 2403 consecutive patients in China with naive intermediate HCC between June 1, 2000, and December 31, 2008, as the primary cohort, and 331 consecutive patients with intermediate naive HCC between January 1, 2011, to June 30, 2012, as the validation cohort. All patients received cTACE as an initial treatment. Initial response and best response were defined as the radiological response after first cTACE or best radiological response after 2 or more sessions of cTACE, respectively. Responders were those who experienced complete response or partial response. Sustained response duration was defined as the time between the date when complete response, partial response, or stable disease was achieved and the date progressive disease occurred after cTACE. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors. Information about patients in the study was collected from January 1, 2018, to March 31, 2018, and analysis of these data was performed in April 2018. Overall survival. A total of 2734 total patients (2499 of 2734 [91.4%] male; median [range] age, 56.5 [18-75] years) were included in the analysis. In the primary cohort, SRD of 6 months or more was found to have the strongest association with 5-year OS after cTACE among different durations of sustained response. Patients with SRD of 6 months or more (387 of 430 male; median [range] age, 57 [18-75] years) had the longest median (range) OS (67.7 [64.8-72.1] months), followed by initial responders (760 of 874 male; median [range] age, 56 [18-75] years; median [range] OS, 55.8 [55.0-57.7] months) and best responders (939 of 1032 male; median [range] age, 57 [18-75] years; median [range] OS, 53.2 [52.2-54.6] months). Response duration of 6 months or more was found to be an independent prognostic factor for OS (hazard ratio, 0.145; 95% CI, 0.124-0.170; P < .001). The significance of SRD as a factor associated with OS was confirmed in the validation cohort. Sustained response duration of 6 months or more was associated with OS and may serve as an early surrogate end point after cTACE for intermediate HCC.

639P - Volume reduction rate of the primary tumor of esophageal squamous cell carcinoma after neoadjuvant chemotherapy: Could this measurement be a surrogate end point for survival before surgery?

639P - Volume reduction rate of the primary tumor of esophageal squamous cell carcinoma after neoadjuvant chemotherapy: Could this measurement be a surrogate end point for survival before surgery?

Abstract 4959: CP-506, a next generation hypoxia-activated prodrug, as promising novel anti-cancer therapeutic

Abstract Hypoxia is a characteristic of many solid tumors and is defined as a low level or absence of oxygen due to an insufficient vascularization of the tumor or a transient blockage of blood vessels. Hypoxia activates a survival response within the tumor cells driving cancer progression and is associated with poor prognosis. Hypoxia-activated prodrugs (HAPs) are anti-neoplastic agents that can solely be activated in hypoxic areas allowing the targeted delivery of cytotoxic compounds in the hypoxic tumor niches. Convert Pharmaceuticals is developing CP-506, a novel generation of HAP presenting a strong bystander effect. A key step in the activation of CP-506 is its conversion by one-electron reductases to an oxygen-sensing intermediate. Under normoxic conditions, the intermediate is rapidly re-oxidized to the pro-drug. However, under severe hypoxic conditions, further reduction steps lead to the generation of the active cytotoxic metabolite, CP-506M. In an in vitro cytotoxicity assay, CP-506 significantly inhibited the viability of several tumor cell lines specifically under anoxic conditions. In spheroid models, CP-506 demonstrates a strong bystander effect i.e. the ability of the active metabolite to locally diffuse beyond the hypoxic core and induce tumor cell death. CP-506 was administered intraperitoneally at a dose of 600 mg/kg once a day for 5 consecutive days and showed a significant inhibition of tumor growth in four tumor xenograft models (triple negative breast cancer, lung and pancreatic cancers). In all tumor models, CP-506 treatment significantly increased the survival of treated mice assessed by the time to reach four times the start volume as a surrogate endpoint for survival. Different dosing regimens for CP-506 were investigated and all demonstrated a significant tumor growth inhibition compared to the vehicle group. The most profound anti-tumor effect was observed for the repeated cycles of daily consecutive administrations. Finally, no cumulative toxicity was observed for any of the repeated dosing schedules as indicated by bodyweight change. The successful development of CP-506 will require combination with treatments targeting well-oxygenated cells and the careful selection of patients predicted to benefit from a HAP treatment. To this end, we are currently identifying key parameters (presence of tumor hypoxia, expression of reductases and DNA repair capacity) in the activation of CP-506 to define predictive gene signatures in liquid biopsies enabling patient selection. Our current pre-clinical data strongly suggest that CP-506 is a potent, highly selective HAP with a favorable pharmacokinetic profile and the addition of predictive gene signatures or imaging biomarkers for patient selection holds great promise for the treatment of cancer. Citation Format: sophie thiolloy, Sofie Deschoemaeker, Nicolas Ongenae, Julie Gilissen, Ludwig Dubois, Ala Yaromina, Amir Ashoorzadeh, Jeff Smaill, Adam Patterson, Philippe Lambin, Arne Heyerick. CP-506, a next generation hypoxia-activated prodrug, as promising novel anti-cancer therapeutic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4959.

Optimal surrogate endpoint of survival for gastric cancer patients undergoing neoadjuvant chemotherapy.

141 Background: Surrogate endpoint of survival for gastric cancer patients undergoing neoadjuvant chemotherapy (NAC) has not been established yet. To determine the most optimal surrogate endpoint, we compared the validity of outcomes according to the endoscopic or histological response criteria and other histological factors in gastric cancer patients who underwent NAC. Methods: The target population in this study was 77 gastric cancer patients who underwent NAC followed by curative gastrectomy between January 2010 and December 2016. In histological response criteria, if necrosis or disappearance of the tumor was present in more than 2/3 of the primary lesion, the case was diagnosed as a histological responder. Hazard ratio (HR) for RFS in responders according to each factor was estimated, and survival curves were compared between responders and non-responders using log-rank test. Results: The number of patients in each regimen was as follows: docetaxel/cisplatin/S-1, 40; docetaxel/oxaliplatin/S-1, 16; cisplatin/S-1, 15; S-1/oxaliplatin, 4; docetaxel/S-1, 2. The endoscopic and histological response rates were 73% (56/77) and 16% (12/77), respectively. The proportions of patients with ypT0-1 and ypN0 were 17% (13/77) and 23% (18/77), respectively. HRs were 0.761 (log-rank p = 0.43) in the endoscopic response criteria, 0.879 (log-rank p = 0.77) in the histological response criteria, 0.703 (log-rank p = 0.46) in ypT0-1, and 0.121 (log-rank p = 0.001) in ypN0, respectively. Three-year RFS rates in ypN status were ypN0/1/2/3 = 93%/48%/43%/14%. Conclusions: Pathological ypN status was the most optimal surrogate endpoint of RFS for gastric cancer patients undergoing NAC. Patients with ypN0 would be expected for long relapse-free survival.

Objective response rate is a possible surrogate endpoint for survival in patients with advanced, recurrent ovarian cancer

ObjectiveEvaluate literature to assess response rate as a surrogate endpoint of survival in ovarian cancer (OC). MethodsSystematic review consistent with PRISMA criteria, identified randomized, controlled trials reporting overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in recurrent OC. MEDLINE® and Embase® searches (year 2000–March 23, 2015) were augmented by bibliographic screening. Proposed surrogate measures (independent variables) were ORR and disease control rate. True clinical outcomes (dependent variables) were median OS and PFS. Analyses were performed on unweighted and weighted data using correlation analysis, linear regression, and surrogate threshold effect (STE). Smaller STE indicates greater predictive precision with magnitude of STE dependent on variance of prediction. ResultsThirty-nine studies were included for review, representing 9223 platinum-sensitive and resistant patients. Objective response rate (r=0.82; P<0.001) was a better predictor than disease control rate (r=0.58; P<0.001) and strongly correlated with PFS (r=0.85; P<0.0001). Weighted-regression analysis demonstrated that for each 10% increase in ORR, PFS increased by 1.20months and OS by 2.83months. Regression analysis of treatment effects (odds ratio of response, hazard ratio of survival) suggests that a 10% increase in odds ratio of ORR would result in 2.5% reduction in the hazard ratio of OS. Based on weighted data, STE indicated that an ORR of ≥1% is needed to achieve nonzero OS benefit. ConclusionThis systematic review supports ORR as a possible surrogate clinical trial endpoint for OS in recurrent OC with at least second-line therapy.