Citations

Abstract Background: Overall survival (OS) remains the definitive primary efficacy endpoint to evaluate previously untreated acute myeloid leukemia (AML) therapies, but it requires prolonged follow-up. An earlier endpoint assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate event-free survival (EFS) as a surrogate endpoint for OS in untreated AML. Methods: Individual patient data were analyzed from 2,475 patients (pts) from 4 multicenter, randomized controlled phase III trials of active treatment in previously untreated AML using anthracycline and cytarabine induction chemotherapy as the concurrent control (CALGB 10201, n=506, enrollment period 2003-2006, age 60-88 years (y); CALGB 10603, n=717, enrollment period 2008-2015, age 18-60 y, FLT3-mutated pts only; SWOG 0106, n=595, enrollment period 2004-2009, age 18-60 y; ECOG-ACRIN 1900, n=657, enrollment period 2002-2008, age 17-60 y). Individual patient-level surrogacy examines the association between the individual patients' EFS and OS time after adjusting for treatment effect, and was assessed using the copula bivariate survival model (Kendall's tau). Trial-level surrogacy measures how precisely the treatment effect on OS can be predicted on the basis of observed treatment effect on EFS, and was evaluated using both linear regression (R2WLS) weighted by trial size and Copula bivariate (R2Copula) models. Pre-specified criteria for surrogacy required either R2WLS or R2Copula ≥0.80, neither below 0.7, with either lower bound 95% Confidence Interval (CI) >0.60. Sensitivity analyses were conducted using different EFS definitions (Table 1). Results: With a median follow-up of 50.2 months for the 896 patients still alive, the median OS and EFS across all four trials were 20.9 months (95% CI: 19.0-22.7) and 5.6 months (95% CI: 4.5-6.4), respectively. Trial-level surrogacy for EFS was strong (R2WLS=0.79; R2Copula=0.89), indicating a high correlation of treatment effect between EFS and OS. At the individual patient-level, however, EFS showed weak association with OS (tau= 0.52), compared to the strength of trial-level surrogacy. The discrepancy between patient-level EFS and OS was greatest among patients who did not achieve a CR, followed by those who achieved a CR but relapsed (Figure 1). Sensitivity analysis on alternative EFS definitions showed that the trial-level surrogacy was similar, but individual patient-level surrogacy varied across different EFS definitions (Table 1). This is consistent with what we previously reported (ASH 2016): EFS estimates differed considerably based on the definition of induction failure (IF) in a single arm setting, but this had minimal impact on the estimation of the treatment effect using EFS in randomized trials. In addition, when considering only relapse and death as events (definition 4), both individual patient- and trial-level correlations were high. Conclusions: Correlation between EFS and OS was impacted by patients not achieving CR during induction. Despite the lack of patient-level correlation, a strong correlation between hazard ratios for treatment effects was observed between EFS and OS on the trial level. Hence, it remains debatable whether EFS represents a clinical benefit in itself for patient with untreated AML considering the strong correlation in treatment effects. Further validation is needed due to the small number of trials included and the heterogeneity across trials. Acknowledgment: We gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf, SWOG S0106 Study Chair. Support: U10CA180821, U10CA180882, U10CA180794, U10CA180820, U10CA180888; Clinicaltrials.gov Identifiers: NCT00085124 (10201), NCT00651261 (10603), NCT01253070 (11001), NCT00085709 (SWOG S0106), and NCT00049517 (ECOG-ACRIN E1900) Disclosures Uy: Curis: Consultancy; GlycoMimetics: Consultancy. Larson:Pfizer: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding.

Abstract Background: Potent inhibitors of BCR-ABL1have improved remission results and altered post-remission therapy for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Dasatinib plus dexamethasone followed by hematopoietic cell transplantation (HCT) promises high response rates, reduced toxicity, and durable remissions. Methods: We conducted a Phase II trial at 17 U.S. centers with the primary objective being to estimate the 3-year overall survival and disease-free survival of patients with Ph+ ALL treated with dasatinib and dexamethasone for remission induction and intensification, central nervous system (CNS) prophylaxis, consolidation with reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or etoposide and cytarabine, and dasatinib-based maintenance. Eligible patients had untreated Ph+ ALL, were ≥18 years old, and had normal cardiac function. Induction (Course I) used dasatinib 140 mg oral daily and dexamethasone 10 mg/m2/day oral or intravenous (IV) days 1-7. For patients with ≤20% blasts in the Course I, Day 15 bone marrow biopsy, intensification (course II) continued daily dasatinib with another 7 days of dexamethasone. Those with >20% lymphoblasts also received vincristine (VCR) and daunorubicin (DNR). Patients (n=3) not in CR/CRi after Course II received a second induction (Course III) with dasatinib, cyclophosphamide, VCR, DNR, and dexamethasone. After Course II or III, CNS prophylaxis (Course IV) consisted of IV VCR and IV, oral, and intrathecal methotrexate (MTX). Dasatinib was restarted at serum [MTX] <0.05 microM. Course V consisted of HCT or chemotherapy. Patients aged 18-70 years with an HLA-matched donor underwent RIC allogeneic HCT; otherwise they underwent autologous HCT. Allogeneic HCT conditioning used fludarabine 30 mg/m2/day IV day -7 through -3, alemtuzumab 20 mg/day IV day -7 through -3, and melphalan 140 mg/m2 once on day -2. GVHD prophylaxis with tacrolimus began day -2. Patients undergoing autologous HCT received etoposide 10 mg/kg/day (age >65 years, 5 mg/kg/day) continuous IV for 4 days and cytarabine 2 g/m2 (age >65 years, 1 g/m2) IV every 12 hours for 8 doses (EA) then G-CSF for mobilization. Autologous HCT conditioning used melphalan 100 mg/m2/day on days -2 and -1. Patients >70 years or unable to undergo HCT received EA alone. Dasatinib maintenance (Course VI) began on day 30 of Course V and continued for 12 months and until 2 consecutively negative bone marrow BCR-ABL1RT-PCR assays 3 months apart or until relapse. Dasatinib levels were measured on day 15 of induction. Results: Sixty-six patients enrolled from 12/15/2010 to 11/14/2014; 65 received dasatinib and are evaluable. Median age was 60 years (22-87); 49% were male. Median presenting WBC count was 23.1 x 103/ul (0.3-453.6). No deaths occurred during induction or intensification. CR or CRi occurred 31 patients (48%) by Day 15 of induction and in 62 patients overall (95%; CR 86%). Median dasatinib levels in serum and CSF on Day 15 of induction were 30.3 ng/mL (<3-308) and 0.29 ng/mL (<0.2-1.37), respectively suggesting approximately 1% of plasma dasatinib penetrates into the CSF, less than the unbound fraction (6%). Fifty-four patients started Course IV, 38 Course V, and 37 Course VI. Fourteen patients continue on protocol therapy. Of 38 patients receiving Course V, 22 had allogeneic HCT, 6 had autologous HCT, and 10 had EA chemotherapy. Median age of allogeneic HCT recipients was 61 years (31-69). Robust autologous stem cell mobilization was observed [median CD34+ cell count, 90 x 106/kg (31-166, n=6)]. Dasatinib maintenance was feasible after allogeneic HCT, autologous HCT, and chemotherapy alone with no missed doses in 59%, 83%, and 63% of cycles, respectively. Ten patients have relapsed with one isolated CNS relapse. No relapses have occurred after allogeneic HCT with 3 relapses after autologous HCT and one after Course V EA alone. Median follow up for survivors is 22.8 months (longest, 51 months). There have been 23 deaths: 5 treatment-related (4 after allogeneic HCT, 1 after course V EA), 16 disease-related and 2 unrelated. Conclusions: Dasatinib with dexamethasone yields CR rates comparable to those reported with tyrosine kinase inhibitors combined with conventional chemotherapy. Post-remission therapy with reduced-intensity allogeneic HCT, autologous HCT, or chemotherapy followed by dasatinib maintenance is feasible. Survival follow up is maturing. Disclosures Stock: Sigma-Tau: Honoraria, Research Funding; Royalties for a chapter in Up to Date: Patents & Royalties; ADC Therapeutics: Honoraria; Amgen: Honoraria; Gilead Sciences: Honoraria. Beumer:Bristol-Myers Squibb: Research Funding. Stone:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Sunesis Pharmaceuticals: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Jansen: Consultancy; Merck: Consultancy; ONO: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy. Larson:Bristol-Myers Squibb: Consultancy; Astellas: Consultancy, Research Funding.

Abstract Background: Event free survival (EFS) is often used as an endpoint in AML clinical trials. EFS-based endpoints are controversial due to the lack of a consistent definition for the timing of complete remission (CR), and consideration of hematopoietic cell transplantation (HCT). Here, we examined the impact of the timing of achievement of CR and censoring for HCT in the estimation of the EFS, and assessed its robustness as an endpoint in AML. Methods: All prospective trials since 2003 using anthracycline and cytarabine chemotherapy for newly diagnosed patients (pts) with AML conducted through the Alliance for Clinical Trials in Oncology, and whose primary endpoint data has been reported, were included (5 trials total). Trial 1 - randomized phase III study in older AML pts (n=504, median age 69, 61% male); trial 2 - single-arm phase II study in older FLT3-mutated AML pts (n=54, median age 67, 56% male); trial 3 - randomized phase III study in younger AML pts (n=546, median age 48, 55% male); trial 4 - randomized phase III study in younger FLT3-mutated AML pts (n=717, median age 48, 45% male); and trial 5 - single arm phase II study in core-binding factor AML pts with no restriction on age (n=61, median age 51, 51% male). Induction failure was defined as one of: no CR by 60 days (Definition 1), no CR by the end of all protocol induction courses (Definition 2), or no CR by the end of all protocol treatment (Definition 3). CR was defined as <5% blasts in a cellular marrow with recovery of >1000 neutrophils/ul (>1500 neutrophils/ul for trial 1), >100,000 platelets/ul, and no red cell transfusion requirement. EFS was defined as the time from randomization / registration to the first evidence of induction failure using each of the 3 methods above, relapse, or death from any cause. Patients last known to be alive without relapse were censored at the date of last contact. Including the 3 induction failure definitions and consideration of censoring or no censoring for HCT, the Kaplan Meier estimates of EFS were computed for the six different definitions of EFS. Results: The number of deaths was respectively 464, 38, 307, 357, and 13 across the 5 trials, with a median follow-up of 99.7, 28.2, 60.1, 58.2, and 33.5 months on the alive patients, respectively. Not considering HCT, in trial 1, the median EFS ranged from 2.0 to 4.3 months (115% difference); in trial 2, the median EFS ranged from 6.9 to 8.3 months (20% difference); in trial 3, the median EFS ranged from 9.8 to11.2 months (14% difference); and in trial 4, the median EFS ranged from 5.5 to 9.7 months (76% difference). The median EFS was not achieved in trial 5; however the 1-year EFS estimates ranged from 78 to 83% (6% difference). Consistently across all trials, as expected, the EFS estimate using the 60-day induction failure yielded the shortest estimates, whereas the end-of-treatment induction failure yielded the longest estimates. Results were similar both with and without censoring at the time of HCT as the event of interest occurred prior to transplantation in most cases. Conclusions: Although relapse and death are firm endpoints, the determination of failure to achieve CR is not consistent across studies. While there is minimal impact of censoring at HCT on EFS estimates, the median EFS estimates differed considerably based on the timing of CR used to define induction failure, with the magnitude of difference being large enough in most cases (observed range: 14% to >100%) to lead to incorrect conclusions about efficacy in a single arm trial if the trial definition was not consistent with the definition used for the historical control. The timing of CR should be carefully examined in the historical control data used to guide the design of the next trial. Table. Table. Disclosures Uy: Glycomimetics: Consultancy; Boehringer Ingelheim: Consultancy. Stone:Celator: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy.

Background: Anaplastic thyroid cancer (ATC) has poor prognosis with median overall survival (OS) of ∼6 months. We previously reported high PD-1/PDL-1 staining in ATC, raising the possibility of the productive application of the immunotherapeutic pembrolizumab. However, having found pembrolizumab to anecdotally have limited single-agent activity in ATC, we sought to alternatively define whether pembrolizumab might synergistically combine with chemoradiotherapy as initial ATC therapy. Methods: An investigator-initiated therapeutic phase 2 trial of pembrolizumab, 200 mg intravenously (IV) every 3 weeks, combined with chemoradiotherapy (docetaxel/doxorubicin, 20 mg/m 2 each IV weekly plus volumetric modulated arc therapy) was initiated as frontline therapy (with or without surgery) in ATC to assess efficacy and toxicities. Six-month OS was selected as the primary endpoint using a Simon's optimal design with interim analysis (targeting accrual of 25 patients; Cohort A: prior resection, Cohort B: no resection). Based on a prior patient cohort-treated similarly, but without pembrolizumab, the design was such that, if 6-month true survival is 75%, the probability of declaring the approach worthy of further pursuit would be 91%. Results: Three patients were enrolled, two with rapidly enlarging unresectable neck masses. Early tumor responses were favorable in all three, and all three satisfactorily completed: intended radiotherapy, preceding and radiotherapy-concurrent pembrolizumab, and concurrent chemoradiotherapy. However, all three patients died <6 months following therapy initiation—one from pulmonary metastases and two from otherwise unexpected fatal pulmonary complications occurring subsequent to chemoradiotherapy completion—prompting study closure. Conclusions: Although initially tolerated and effective in terms of locoregional disease control, disappointing survival outcomes compared with historical controls raise uncertainty that the piloted approach merits further pursuit in ATC.

Abstract Event-free survival (EFS) is controversial as an end point for speeding approvals in newly diagnosed acute myeloid leukemia (AML). We aimed to examine the robustness of EFS, specifically timing of complete remission (CR) in defining induction failure and impact of hematopoietic cell transplantation (HCT). The study included 1884 untreated AML patients enrolled across 5 trials conducted through Alliance for Clinical Trials in Oncology using anthracycline and cytarabine induction chemotherapy. EFS was defined as time from randomization/registration to induction failure, relapse, or death. Three definitions of induction failure were evaluated: failure to achieve CR by 60 days after randomization/registration, failure to achieve CR by the end of all protocol-defined induction courses, and failure to achieve CR by the end of all protocol-defined treatment. We considered either censoring or no censoring at time of non–protocol-mandated HCT. Although relapse and death are firm end points, the determination of induction failure was not consistent across studies. There was minimal impact of censoring at HCT on EFS estimates; however, median EFS estimates differed considerably based on the timing of CR in defining induction failure, with the magnitude of difference being large enough in most cases to lead to incorrect conclusions about efficacy in a single-arm trial, if the trial definition was not consistent with the definition used for the historical control. Timing of CR should be carefully examined in the historical control data used to guide the design of single-arm trials using EFS as the primary end point. Trials were registered at www.clinicaltrials.gov as #NCT00085124, #NCT00416598, # NCT00651261, #NCT01238211, and #NCT01253070.

3502 Background: DFS with 3 years median follow-up (3yDFS) was validated as a surrogate for OS with 5 years median follow-up (5yOS) in adjuvant chemotherapy CC trials prior. Recent data showed improved survival after recurrence and OS, over time, in pts who received adjuvant FOLFOX. Hence, re-evaluation of the association between DFS and OS, as well as the optimal follow-up of OS to aid its utility in future adjuvant trials is needed. Methods: Individual patient data from 8 randomized adjuvant studies conducted from 1998-2009 were included; 3 trials tested anti-VEGF or anti-EGFR agents. Trial-level surrogacy examining the correlation of treatment effect estimates (i.e. hazard ratios) of 3yDFS and 5y to 8yOS was evaluated using both linear regression (R2WLS) and Copula bivariate (R2Copula) models. For the R2, a value closer to 1 indicates a stronger correlation. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% Confidence Interval (CI) > 0.60. The rank correlation coefficient (ρ) quantified the individual-level surrogacy. Results: Total of 18,886 pts were analyzed, with median age 60, 54% male, 83% stage III, 59% > 12 nodes examined. Median follow-up for survival ranged from 5 to 10 years across trials. Trial level correlation between 3yDFS and OS remained strong (R2WLS ≥0.74; R2Copula ≥ 0.89) and increased as the median follow-up of OS extended longer (see table). Analyses limited to stage III pts and/or trials tested biologics showed consistent results. Conclusions: 3yDFS remains a validated surrogate endpoint for 5yOS in adjuvant trials in CC pts per prespecified criteria. The correlation was strengthened with more than 6 years of follow-up for OS. [Table: see text]

3101 Background: PDO is a promising translational tool that recapitulates the biology and drug response of donor cancer patient. However, an unmet need is to have PDO drug-screening data available for treatment decision making in clinic. We conducted a pilot study to determine whether PDO testing results will be available at critical treatment decision points in metastatic GI cancer patients. Methods: Metastatic GI cancer patients undergoing core-needle biopsy were eligible. Tumor cells isolated from ≤4 fresh biopsy tissues were grown in a Matrigel-based culture. PDO response to anti-cancer drugs were evaluated; and when available, correlated with donors’ clinical response to the same agent(s). PDO response was defined as IC50 < 0.1 × published Cmax of the drug clinically; stable as IC50 between 0.1 to 10 × Cmax. Radiographic response was per RECIST criteria. Results: We enrolled 27 refractory metastatic GI cancer patients (9 colorectal [CRC], 9 pancreas, and 9 biliary tract). Median lines of therapy were 4, 2, and 2; the success rate of organoid establishment was 89%, 44%, and 55%, respectively. The median time from biopsy to availability of drug-testing data was 64 days (range: 24 to 93 days). The median time from biopsy to next CT re-staging in donors was 64 days. The established PDOs shared histological and genomic features with donor clinical tissue. PDO and clinical responses to the same agent(s) were correlated in 2 CRC donors including (1) BRAFV600E-mutated PDO responded to vemurafenib + panitumumab, as did the donor who had partial response (PDO drug-testing data were available 55 days post-biopsy, 23 days prior to restaging scan); (2) KRAS/FGF-dual amplified PDO had stable disease status to regorafenib, as did the biopsied lesion from the donor (73 days post-biopsy, 5 days post-scan). Conclusions: We showed the feasibility of completing PDO drug sensitivity testing in metastatic GI cancer patients within a short time that could impact clinical decision making, particularly in CRC. PDO drug response showed correlation with clinical response. With further refinement, PDO can be a powerful tool for personalizing cancer therapy in metastatic GI cancer patients.

Abstract Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.

728 Background: Adjuvant FOLFOX therapy for stage II patients remains controversial, and selection criteria are imprecise. We examined the trend of disease-free survival (DFS: time to recurrence or death, whichever occurs first); time to recurrence (TTR: time to recurrence, censored at death without recurrence); survival after recurrence (SAR); and overall survival (OS) of pts treated with FOLFOX over a ten-year period. Methods: Outcomes of pts with stage II colon cancer enrolled in 6 adjuvant trials receiving FOLFOX alone were analyzed. Pt enrollment period was dichotomized as old (1998 – 2003) vs. new era (2004 – 2009) based on the FDA approval date of bevacizumab. 3/5yr event-free rates were estimated using adjusted Kaplan-Meier methods. Outcomes were compared between the two eras by multivariate Cox model. To control for potential confounding effects, all analyses were adjusted for age, gender, performance score, T stage, number of lymph nodes (LNs) examined, tumor side, and histologic grade. Results: In total, 1,122 pts with stage II were identified; 71% and 29% were treated in the old and new era, respectively. Pts enrolled in the new era were significantly younger and more likely to have higher tumor-grade and right-sided tumors compared to old era. More pts in the new era (71%) had ≥12 LNs examined compared to the old era (53%). After adjusting for potential confounding effects, no difference in DFS, TTR, SAR or OS between old and new eras was found (Table). Although median SAR increased from 13.6 to 26 months over time, this was not statistically significant, likely due to lack of power. An increased TTR over time (HRadj. 0.41, padj.= 0.002) was observed in pts with ≥12 LNs examined (3-yr TTR: 92% in old era vs. 96% in new era), but not pts with <12 LNs examined (pinteraction = 0.04). Conclusions: In stage II colon cancer pts who received adjuvant FOLFOX, no significant increase of DFS or OS was observed over time. However TTR was longer only in pts with ≥12 LNs examined. [Table: see text]