Fiskum, Jack

LBA7564 Background: Patients with r/r B-NHL have a dismal prognosis. DIAL (Dual Immunomodulation in Aggressive Lymphoma) was a multi-center randomized phase II study testing the efficacy of nivolumab (PD-1 inhibitor) plus varlilumab (CD27 agonist) in this population. Methods: Patients were randomized (1:1) to nivolumab (240 mg IV every 2 weeks for 4 months, 480 mg IV monthly thereafter; group 1) alone or combined with varlilumab (3 mg/kg IV monthly; group 2). Cross-over (group 1 to 2) was allowed for progression. Primary endpoint was overall response (ORR) per LYRIC criteria. A sample size of 48 patients per arm would provide 80% power to detect increase in ORR from 25% to 45% using a one-sided test (p = 0.15). Pre-specified interim analysis occurred after half of the patients completed first radiologic assessment. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Exploratory endpoints included tumor genomic assessment and immune profiling of blood and tumor. Results: 53 patients were enrolled (27 in group 1; 26 in group 2). Interim analysis included 24 patients from each arm. Mean age was 65.2 years, 34 (70.8%) were male, and 36 (75%) received prior CAR-T cell therapy. Baseline characteristics were balanced between arms. Grade ≥ 3 AEs were observed in 8 (33.3%) and 7 (30.4%) of patients in groups 1 and 2, respectively. Common AEs (> 5%) of any grade included fatigue, lymphopenia, diarrhea, rash. There were no treatment-associated deaths. Toxicity profile was similar between arms. Table summarizes efficacy outcomes. ORR was achieved in 6 patients (12.5%), not statistically different between arms; 4 responses were complete. Seven patients crossed over (1 responded after crossing). Median OS (8.6 vs 7.3 months; p = 0.39) and PFS (2.7 vs 1.4 months; p = 0.06) were similar between arms. Subgroup analysis of patients with prior CAR-T cell therapy showed similar ORR (5/36; 14%), not statistically different between arms. Correlative analysis results will be presented at conference. The trial met futility criterion on interim analysis and enrollment ceased based on pre-specified stopping rule. Conclusions: Dual immunomodulatory therapy did not enhance anti-tumor activity in patients with aggressive B-NHL compared to nivolumab alone. Response rates were low and consistent with previous data using PD-1 inhibitors in this population. Prior therapy with CAR-T cell does not seem to sensitize patients to PD-1 blockade. Toxicity profile was acceptable and dual therapy did not increase the rate of AEs. Clinical trial information: NCT03038672. [Table: see text]

101 Background: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (20-49 years, named early-onset CRC, eoCRC) has been increasing. eoCRC patients with metastatic disease are treated with the same standard regimens as late-onset CRC (loCRC, age ≥ 50 years) although detailed response data for eoCRC are largely missing. Methods: Individual patient data on 7,604 subjects with metastatic eoCRC from 11 first line randomized bevacizumab studies between 2000 and 2012 in the ARCAD advanced colorectal cancer database were pooled. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were summarized by age groups. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables. Results: Female eoCRC are more commonly seen compared to loCRC (46.8% vs. 38.7%, p<0.0001). Patients with eoCRC (n=1,289) were significantly more likely to have had prior metastasectomy (17.5% vs. 13.5%, p=0.043) and lung metastatic disease (67% vs. 59.8%, p<0.001), but less likely to have distant lymph node metastatic disease (58.8 vs. 62.9%, p=0.036) or KRAS mutation (29.2% vs. 34.4%, p=0.042) compared to those with loCRC (n=6,315). eoCRC and loCRC patients had similar distributions according to PS, primary tumor sidedness, prior primary tumor resection, liver involvement, peritoneal involvement, number of metastatic sites, NRAS and BRAF. Age of disease onset was not a statistically significant prognostic factor for PFS in univariate and multivariate analysis (seen in table). Bevacizumab in addition to chemo improved PFS in eoCRC population (9.9 vs. 6.8 months, HR = 0.66, p<0.001), which was similar to the findings in loCRC population (9.4 vs. 7.3 months, HR= 0.73, p<0.001, interaction p=0.54). By multivariate analysis, a greater improvement in PFS was noted for the addition of bevacizumab in eoCRC relative to LoCRC patients (HR = 0.62 vs. HR = 0.82). Conclusions: Treatment naive eoCRC patients with metastatic disease derive similar benefit from bevacizumab relative to their average age counterparts.[Table: see text]

80 Background: Higher baseline body mass index is associated with improved survival in metastatic CRC (mCRC). Whether weight gain or loss after mCRC diagnosis is associated with survival remains largely unknown. Methods: We analyzed individual patient data from 3504 patients with previously untreated mCRC enrolled in five phase III randomized trials (AVF2017g, AVF2192g, CRYSTAL, N9741, OPUS) conducted between 2000 and 2006. Weight measurements were prospectively collected at 3 months after diagnosis and then up to 5 years. Patients were categorized into three groups based on the percent weight change at 3 months: stable weight or gain, weight loss up to 5% of baseline weight, and ≥5% weight loss of baseline weight. Cox models were used to assess the prognostic associations of weight change at 3 months with overall survival (OS) and progression-free survival (PFS), adjusting for baseline BMI, age, sex, performance score, chemotherapy backbone (oxaliplatin vs. irinotecan), and biologics type (cetuximab vs. bevacizumab). Sub-analyses included Cox models adjusted for additional clinical-pathological factors (primary tumor sidedness [right colon vs. left colon-rectum], and BRAF status; N=1,511). Results: Median percent weight change at 3 months was -0.5% (IQR -4.0 to+1.6%). OS was better in patients with weight stability or gain than in those with weight loss (up to 5% or ≥5%; (Table). Results were consistent for PFS for patients with ≥5% weight loss of baseline weight, as well as for sub-analyses. Conclusions: Patients losing weight during the first 3 months of systemic therapy for metastatic colorectal cancer have significantly shorter overall survival than those with stable or increasing weight. Degree of weight loss is proportional to the observed increased risk of death and remains evident among underweight, normal weight and obese individuals. Further studies examining possible usefulness of on-treatment early weight loss as a novel intermediary end-point are needed.[Table: see text]

Abstract Background Colon cancer (CC) incidence in young adults (age 20-49 years), termed early-onset CC (EO-CC), is increasing. Methods Individual patient data on 35 713 subjects with stage III colon cancer from 25 randomized studies in the Adjuvant Colon Cancer ENdpoint database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and outcome data were summarized by age group. Overall survival, disease-free survival, time to recurrence, and survival after recurrence were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for sex, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness, and molecular markers. All statistical tests were 2-sided. Results Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III EO-CC had similar sex, race, performance status, risk group, tumor sidedness, and T stage compared with patients with late-onset CC (age 50 years and older). EO-CC patients were less likely to be overweight (30.2% vs 36.2%) and more commonly had 12 or more lymph nodes resected (69.5% vs 58.7%). EO-CC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%) and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher rate of Lynch syndrome in EO-CC. Patients with EO-CC had statistically significantly better overall survival (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.74 to 0.89; P &lt; .001), disease-free survival (HR = 0.91, 95% CI = 0.84 to 0.98; P = .01), and survival after recurrence (HR = 0.88, 95% CI = 0.80 to 0.97; P = .008) in the analysis without molecular markers; however, age at onset of CC lost its prognostic value when outcome was adjusted for molecular markers. Conclusion Tumor biology was found to be a more important prognostic factor than age of onset among stage III colon cancer patients in the Adjuvant Colon Cancer ENdpoint database.

Abstract Background First-line therapeutic strategies for patients with BRAFV600E-mutated (BRAFmt) metastatic colorectal cancer (mCRC) mainly rely on subgroup analyses from randomized controlled trials (RCTs). We aimed to assess the prognostic and predictive impact of BRAFmt on the efficacy of targeted therapies with first-line chemotherapy. Methods Individual patient data from first-line RCTs with BRAF and KRAS status data in the ARCAD database were pooled. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier and Cox models. Outcomes were compared between treatment groups that were concurrently randomly assigned whenever possible. Results A total of 6391 patients from 10 RCTs were included: 573 BRAFmt (9.0%), 2059 KRASmt (32.2%), and 3759 double wild type (58.8%). BRAFmt mCRC patients experienced statistically significantly poorer OS than those with KRASmt (adjusted hazard ratio [HRadj] = 1.46, 95% confidence interval [CI] = 1.30 to 1.64) and patients with double wild-type tumors (HRadj = 2.14, 95% CI = 1.94 to 2.36). Anti-EGFR agents did not improve progression-free survival or OS of BRAFmt mCRC patients, based on 4 RCTs testing chemotherapy with or without anti-epidermal growth factor receptor (anti-EGFR) (HRadj = 0.96, 95% CI = 0.71 to 1.30; and HRadj = 0.85, 95% CI = 0.66 to 1.14, respectively). Conclusions Our data suggest that the addition of anti-EGFR agents to chemotherapy is ineffective as first-line treatment for BRAFmt mCRC patients.

PURPOSE: In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain. MATERIALS AND METHODS: Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors. RESULTS: MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses. CONCLUSION: Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.

4090 Background: EGFR mAbs have become incorporated into clinical practice for the management of mCRC over the last decade. KRAS and NRAS mutations are used as predictive biomarkers and BRAF V600E mutations are associated with an adverse prognosis. The observed TE within biomarker subpopulations has varied between studies. Methods: IPD from randomized trials with head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or BSC) in mCRC, across all lines of therapy (first, second and later), were pooled. Biomarker subpopulations are defined in the table. Overall survival (OS) and progression-free survival (PFS) were compared between groups by Cox model, stratified by studies and adjusted by age, gender, and performance status. TEs were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). Within each biomarker subgroup, EGFR mAb efficacy was explored according to multiple exploratory factors, including line of therapy, type of backbone chemo, gender, sidedness and site of metastasis. Interaction tests were performed. P-values < 0.01 were considered statistically significant to account for multiple comparisons. Results: 5729 pts from 8 studies with data available for ≥ 1 biomarker were analysed. PFS benefits (median 9.2 mos in EGFR mAbs, 8.0 mos in no EGFR mAbs) were confirmed in triple-WT pts, but not for OS (refer to table). No OS/PFS benefits were observed for pts with any of the MT tumors. Exploratory analyses showed a potential detrimental TE of EGFR mAbs in KRAS MT mCRC with liver metastasis (OS: HRadj 1.22, p = .003, pinteraction .0056; PFS: HRadj 1.24, p = .0009, pinteraction .0008). These results were confirmed within the subgroup of pts with all 3 biomarkers available. Conclusions: This is the largest IPD analysis to explore the predictive value of RAS/BRAF biomarkers in mCRC. Our findings demonstrate that there is no evidence of efficacy of EGFR mAbs in KRAS, BRAF and/or NRAS MT mCRC. EGFR mAbs might have a detrimental effect in KRAS MT mCRC with liver metastases. [Table: see text]