Citations

612 Background: mCRC is a heterogeneous disease leading to possible disparate responses among lesions in a single pt. This study assesses the heterogeneity of lesion responses and evaluates the prognostic value of LBR12 and its mortality risk discrimination beyond RECIST responses. Methods: Pts with ≥ 2 lesions and no new lesions at 12 weeks (wks) were eligible. For each pt, after 12 wks of Rx, each lesion was categorized as progressive disease (L-PD: ≥20% increase in the longest diameter [LD]), partial response (L-PR: ≥30% decrease in LD), or stable disease (L-SD: neither L-PD nor L-PR). LBR12 was defined, per patient, by the combination of lesion responses: homogeneous LBR12 (L-PD, L-SD, L-PR only) and heterogeneous LBR12 (mixture of L-PD/L-SD, L-PD/L-PR, L-SD/L-PR). LBR12 and overall survival (OS) were correlated using stratified multivariate Cox models after adjusting for age, gender, and ECOG PS. Results: Among 9,092 mCRCs (Rx: chemo alone 44%; chemo + VEGF inhibitor [VEGFi] 42%; chemo + EGFR inhibitor [EGFRi] 10%) from 16 1st-line studies. Median OS: 2.2 years. Per RECIST at 12 wks, CR 0%; PR 36.1%; SD 60.9%; PD 3.0%. Responses in 52% were heterogeneous (Table). VEGFi and EGFRi treated pts had the highest rate of L-SD/L-PR (45%) and L-PR only (22%) status, respectively. Median OS increased monotonically across pts with more L-PRs and fewer L-PDs (Table). Pts with L-SD/L-PR status, among which 51% had SD per RECIST, had longer OS than those with L-SD only status (HRadj.= .81, padj.< .0001), but shorter OS than those with L-PR only status (HRadj.= 1.46, padj.< .0001). Pts with L-PD/L-SD status, among which 71% were SD per RECIST, had shorter OS than those with L-SD only status (HRadj.= 2.22, padj.< .0001). These associations were consistent across treatment regimens. Conclusions: The lesion-based response captures the heterogeneity of within pt lesion responses and provides refinement in predicting outcome beyond RECIST response at 12 wks. [Table: see text]

Abstract Purpose: Colorectal cancers with deficient DNA mismatch repair (dMMR) are presumed to uniformly have dense lymphocytic infiltration that underlies their favorable prognosis and is critical to their responsiveness to immunotherapy, as compared with MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors. Experimental Design: CD3+ and CD8+ T-cell densities were quantified at the invasive margin (IM) and tumor core (CT) in 561 stage III colon cancers (dMMR, n = 278; pMMR, n = 283) from a phase III adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis. Results: Although CD3+ and CD8+ T-cell densities in the tumor microenvironment were higher in dMMR versus pMMR tumors overall, intertumoral heterogeneity in densities between tumors was significantly higher by 30% to 88% among dMMR versus pMMR cancers (P &lt; 0.0001 for all four T-cell subtypes [CD3+IM, CD3+CT, CD8+IM, CD8+CT]). A substantial proportion of dMMR tumors (26% to 35% depending on the T-cell subtype) exhibited T-cell densities as low as that in the bottom half of pMMR tumors. All four T-cell subtypes were prognostic in dMMR with CD3+IM being the most strongly prognostic. Low (vs. high) CD3+IM was independently associated with poorer OS among dMMR (HR, 4.76; 95% confidence interval, 1.43–15.87; P = 0.0019) and pMMR tumors (P = 0.0103). Conclusions: Tumor-infiltrating T-cell densities exhibited greater intertumoral heterogeneity among dMMR than pMMR colon cancers, with CD3+IM providing robust stratification of both dMMR and pMMR tumors for prognosis. Potentially, lower T-cell densities among dMMR tumors may contribute to immunotherapy resistance.

Purpose The US National Cancer Institute (NCI) Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed to enable patient reporting of symptomatic adverse events in oncology clinical research. This study was designed to assess the feasibility and resource requirements associated with implementing PRO-CTCAE in a multicenter trial. Methods Patients with locally advanced rectal cancer enrolled in the National Cancer Institute–sponsored North Central Cancer Treatment Group (Alliance) Preoperative Radiation or Selective Preoperative Radiation and Evaluation before Chemotherapy and Total Mesorectal Excision trial were asked to self-report 30 PRO-CTCAE items weekly from home during preoperative therapy, and every 6 months after surgery, via either the Web or an automated telephone system. If participants did not self-report within 3 days, a central coordinator called them to complete the items. Compliance was defined as the proportion of participants who completed PRO-CTCAE assessments at expected time points. Results The prespecified PRO-CTCAE analysis was conducted after the 500th patient completed the 6-month follow-up (median age, 56 years; 33% female; 12% nonwhite; 43% high school education or less; 5% Spanish speaking), across 165 sites. PRO-CTCAE was reported by participants at 4,491 of 4,882 expected preoperative time points (92.0% compliance), of which 3,771 (77.2%) were self-reported by participants and 720 (14.7%) were collected via central coordinator backup. Compliance at 6-month post-treatment follow-up was 333 of 468 (71.2%), with 122 (26.1%) via backup. Site research associates spent a median of 15 minutes on PRO-CTCAE work for each patient visit. Work by a central coordinator required a 50% time commitment. Conclusion Home-based reporting of PRO-CTCAE in a multicenter trial is feasible, with high patient compliance and low site administrative requirements. PRO-CTCAE data capture is improved through centralized backup calls.

TPS4135 Background: Gastric cancer is a prevalent and morbid illness for which new treatment strategies are needed. Peri-operative therapy is a standard approach that is associated with only a 15% improvement in overall survival. Early FDG-PET scanning, performed prior to cycle 2, can distinguish patients (pts) responding to chemotherapy from those who are not. FDG-PET non-responding pts have poorer survival. This study addresses the question of salvage therapy in pts who are PET non-responders. Specifically, does salvage chemotherapy with docetaxel /irinotecan improve pt survival in FDG-PET-nonresponding pts with locally advanced gastric cancer. Methods: This is a multicenter, cooperative group, NCI supported, randomized phase II study of salvage chemotherapy + surgery versus surgery and post-operative chemoradiotherapy in pts who are FDG-PET non-responders (defined as a decrease in SUVmaxof the primary tumor of less than 35%). A total of 176 pts with locally advanced, resectable gastric cancer who were FDG-PET non-responders to cycle 1 of platinum/capecitabine based chemotherapy will be randomized in a 1:1 manner to receive either (Arm A) surgery followed by fluoropyrimidine-sensitized radiotherapy (4500 cGy), or (Arm B) salvage chemotherapy with docetaxel / irinotecan (DI) for 2 cycles followed by standard resection and 3 cycles DI post-operatively. DI is administered as D 30 mg/m2, I 50 mg/m2 given on D1, D8 of a 21 day cycle. 416 pts will be screened to yield 162 non-responders (81 FDG-PET non-responders per treatment group). With expected 120 events, the study will have 80% power to detect a hazard ratio of 0.625 for improved survival at the one-sided significant level of 0.15. Pts will be required to provide tissue at the time of resection, as well as whole blood prior to resection for correlative studies associated with platinum sensitivity, FDG avidity, and prognostic markers. This study is available through all cooperative groups (SWOG, ACRIN/ECOG, Alliance, and NRG) and the National Clinical Trials Network. Enrollment began in November 2015. Support: U10CA180821, U10CA180882; Clinical Trial Information: NCT02485834 .

TPS4151 Background: Borderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo. In a pilot study, Alliance for Clinical Trials in Oncology Trial A021101, the median survival of patients who received chemotherapy and radiation prior to anticipated pancreatectomy was 22 months, and an R0 resection was achieved in 64% of operations. However, the individual contributions of preoperative chemotherapy and radiation therapy are poorly defined.This study, Alliance for Clinical Oncology Trial A021501, will help define a standard preoperative treatment regimen for borderline resectable pancreatic cancer and position the superior arm for further evaluation in future phase III trials. Methods: In this recently activated randomized phase II trial, 134 patients with a biopsy-confirmed pancreatic ductal adenocarcinoma that meets centrally-reviewed radiographic criteria for borderline resectable disease are randomized to receive either 8 cycles of modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 for 4 cycles) or to 7 cycles of modified FOLFIRINOX followed by stereotactic body radiation therapy (33-40 Gy in 5 fractions). Patients without evidence of disease progression following preoperative therapy undergo pancreatectomy and subsequently receive 4 cycles of postoperative modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 for 4 cycles). The primary endpoint is the 18-month overall survival rate of patients enrolled into each of the two treatment arms. An interim analysis of the R0 resection rate within each arm will be conducted to assess treatment futility after accrual of 30 patients. Secondary endpoints include rates of margin-negative resection and event-free survival. The trial is activated nationwide and eligible to be opened for accrual at any National Clinical Trials Network cooperative group member site. Clinical trial information: NCT02839343.

TPS3630 Background: In metastatic colorectal cancer with deficient DNA mismatch repair (MMR), anti-PD-1 antibody monotherapy produced high tumor response rates and extended progression-free survival compared to lack of benefit for proficient MMR tumors (Le, M, et al, NEJM 2016). We propose a phase III randomized trial to determine if the addition of the anti-PD-L1 antibody, atezolizumab (Genentech™), to adjuvant FOLFOX can improve patient disease-free survival (DFS) vs FOLFOX alone in patients with stage III colon cancers with dMMR or microsatellite instability (MSI). By blocking the PD-1/PD-L1 interaction, atezolizumab may activate T cells, thereby, restoring their ability to detect and attack tumor cells. Limited data suggest that FOLFOX may increase intratumoral cytotoxic CD8+ T cells that may serve as ‘immune priming.’ Methods: Patients with curatively resected stage III colon carcinomas with evidence of dMMR or MSI will be randomized to modified FOLFOX6 for 6 months (12 cycles) alone or combined with atezolizumab (840 mg IV q2 wk) continued as monotherapy for an additional 6 months (total duration of 12 months). Patients will be stratified by T, N stage and tumor sidedness. Local testing for MSI or MMR proteins is allowed. Atezolizumab must begin by/with cycle 2. The targeted accrual goal of 700 patients provides 90% power to detect an effect size expressed as hazard ratio of 0.6 for the primary endpoint DFS at two-sided alpha of 0.05. Interim analyses are planned at 50% and 75% of events. Secondary endpoints include overall survival, treatment tolerability, and quality of life. This study will be conducted by the Alliance for Clinical Trials in Oncology. The protocol has been approved by NCI CTEP and is expected to be activated in mid 2017. Clinical trial information: NCT02912559.