FOLFOX4 Arm Research Articles

Inflammatory stress determines the need for chemotherapy in patients with HER2-positive esophagogastric adenocarcinoma receiving targeted and immunotherapy.

Anti-PD-1, trastuzumab, and chemotherapy are used in the treatment of patients with advanced HER2-positive esophagogastric adenocarcinoma (EGA), but long-term survival remains limited. Herein, we report extended follow-up data from the INTEGA trial (NCT03409848), which investigated the efficacy of the anti-PD-1 nivolumab, trastuzumab, and FOLFOX chemotherapy (FOLFOX arm) in comparison to a chemotherapy-free regimen involving nivolumab, trastuzumab, and the anti-CTLA-4 ipilimumab (Ipi arm) in the first-line setting for advanced disease. The 12-month overall survival (OS) showed no statistical difference between the arms, with 57% OS (95% CI: 41%-71%) in the Ipi arm and 70% OS (95% CI: 54%-82%) in the FOLFOX arm. Crossing of the survival curves indicated a potential long-term benefit for some patients within the Ipi arm, but early progressors in the Ipi arm underlined the need for biomarker-guided strategies to optimize treatment selection. To this end, metabolomic and cytokine analysis demonstrated elevated levels of normetanephrine, cortisol, and interleukin 6 (IL-6) in immunotherapy-unresponsive patients in the Ipi arm, suggesting a role for systemic inflammatory stress in modulating antitumor immune responses. Patients with this signature also showed an increased neutrophil-to-lymphocyte ratio (NLR) that persisted in the Ipi arm, but not in the FOLFOX arm, and strongly correlated with survival. Furthermore, a low NLR characterized patients benefiting from immune- and targeted therapy without the need for additional chemotherapy. This data suggests that patient selection based on inflammatory stress-driven immune changes could help to customize first-line treatment in patients with advanced HER2-positive EGA to potentially improve long-term survival.

The NEO-RT trial: A phase 3 randomized trial of neoadjuvant chemotherapy, excision and observation versus chemoradiotherapy for early rectal cancer, CCTG CO.32.

TPS3646 Background: There is significant interest in organ-sparing management of rectal cancer. Data from the National Cancer Database suggest that in 2020 only 20% of US patients with stage I rectal cancer are managed non-operatively. The phase II CCTG CO.28/NEO trial previously reported high rates of tumor downstaging, organ preservation and excellent rectal function among patients with T1-T3abN0 rectal adenocarcinoma treated with 3 months of FOLFOX/CAPOX followed by Transanal Endoscopic Surgery (TES). The phase III CO.32/NEO-RT trial (NCT06205485) will compare two organ sparing strategies for patients with stage I rectal cancer. Methods: Eligible patients with clinical stage T1/2 N0 adenocarcinoma with preserved mismatch repair (MMR) will be randomized 1:1 to ARM A, 3 months of FOLFOX or CAPOX versus ARM B, chemoradiation (54 Gy) followed by tumor restaging within 16 weeks of start of therapy. Patients with histological high grade, mucinous or deficient MMR and those that can be treated with tumor excision alone are excluded. The primary endpoint is tumor downstaging to clinical Complete Response (cCR) by pelvic MRI, endoscopy and digital rectal exam. Subsequent TES is recommended for all patients with tumor response and may be done within 24 weeks of treatment begin, followed by 5 years (y) of observation with serial MRI (q6m x 2y then annually) and endoscopy (q4m x 2y, then q6m during year 3, then annually). The co-primary endpoint is Quality Of Life (QOL) measured by the Low Anterior Resection Score (LARS). In a non-inferiority comparison between treatment arms, if the cCR is assumed to be 45% in ARM B and if there is no true difference between ARMS A and B, then 250 patients are required to be 80% sure that the upper limit of a one-sided 90% confidence interval will exclude a difference in favor of chemoradiation of more than 14%. Results: The approved CCTG CO.32 trial is expected to open February, 2024 at Canadian CCTG and US Alliance, ECOG-ACRIN, NRG, and SWOG NCTN sites with an estimated accrual duration of 4 years. Conclusions: The results of this study will have a major impact on the treatment of patients with stage I rectal cancer. Both arms offer the potential of organ preservation and results will inform whether induction chemotherapy is non-inferior to ChemoRT and compare patient QOL and functional outcomes. Clinical trial information: NCT06205485 .

Final survival results of ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in previously untreated HER2 positive esophago gastric adenocarcinoma: The randomized AIO INTEGA trial.

4026 Background: In metastatic esophagogastric adenocarcinoma (EGA), the addition of PD-1 inhibitors (i) to chemotherapy has improved the outcome in selected patient populations. The randomized INTEGA trial investigated trastuzumab and PD-1i with FOLFOX or CTLA-4i in 1st line treatment of advanced HER2+ EGA. Methods: Patients with previously untreated, metastatic HER2+ (local IHC3+ or 2+/ISH+) EGA, and adequate organ function were randomized to trastuzumab and nivolumab (1mg/kg Q3W x4 /240mg Q2W for up to 12 months) in combination with ipilimumab (3mg/kg x4 Q3W; Ipi arm) or mFOLFOX6 (FOLFOX arm) accompanied by a large translational program. The primary endpoint was the 12month overall survival (OS) rate. The trial was registered at ClinicalTrials.gov, NCT03409848. Results: Between March 2018 and May 2020, 97 patients were enrolled and 88 randomized across 21 German sites with the following baseline characteristics: female/male 18/70, median age 60.5 (range 41-80), ECOG 0/1 54/34, GEJ/stomach 66/22. Central post hoc biomarker analysis on 82 evaluable patients showed PD-L1 CPS≥1/≥5 in 59/46 patients and confirmed HER2 (central IHC3+ or 2+/ISH+) positivity in 77 patients. The observed OS rate at 12 months was 70% (95% confidence interval (CI) 54-81%) in the FOLFOX arm, and 57% (95% CI 41-71%) in the Ipi arm. The progression free survival was 10.7 and 3.2 months, and the overall response rate was 53.5% and 34% in the FOLFOX and the Ipi arm, respectively. Although these data are in favor of the FOLFOX arm, the overall survival curves crossed with increased follow-up (median follow-up of 18.8 months) and thus the final median OS was 22.1 and 23.3 months, numerically favoring the Ipi arm. According to the centrally assessed CPS the OS was: 22.1 and 32.2 months in the CPS<5 group, and 22.7 and 12.6 months in the CPS≥5 group for the FOLFOX and the Ipi arm, respectively. Notably, the median tumor burden calculated as the sum of target lesions was numerically lowest in the Ipi arm with higher than median OS. Conclusions: In contrast to limited short term efficacy of the Ipi arm as reflected by the lower PFS, the Ipi arm showed favorable OS, that was inversely correlated to the CPS status. Further analysis of baseline clinical and molecular data to better identify the subgroup of patients benefitting the most of trastuzumab/nivolumab/ipilimumab will be presented at the meeting. Clinical trial information: NCT03409848 . [Table: see text]

A randomized phase II trial of hepatic arterial infusion of oxaliplatin plus raltitrexed versus oxaliplatin plus 5-fluorouracil for unresectable colorectal cancer liver metastases.

BackgroundThe purpose was to compare the efficacy and safety of hepatic arterial infusion (HAI) of oxaliplatin plus raltitrexed (TOMOX) to those of oxaliplatin plus 5-fluorouracil (FOLFOX) for unresectable colorectal cancer liver metastases (CRCLM).MethodsPatients with unresectable CRCLM were randomly assigned to receive HAI of TOMOX or FOLFOX. The primary end points were progression-free survival (PFS) measured from the date of randomisation until the date of disease progression and objective response rate (ORR). The secondary end points were overall survival (OS) measured from the date of randomisation until the date of death from any cause, disease control rate (DCR), and adverse events.Results113 patients were randomly assigned. With a median follow-up of 39.5 months, the PFS was 5.8 months [95% CI, 4.838–6.762]) and 4.6 months [95% CI, 3.419–5.781; P = 0.840], and the median OS was 17.6 months [95% CI, 13.828–21.372] and 13.1 months [95% CI, 11.215–14.985; P = 0.178] for the FOLFOX and TOMOX arm, respectively. The ORR were 26.1% vs 22.4% and DCR were 80.4% vs 71.4% in the FOLFOX and TOMOX arms. The most common severe adverse event was elevation of liver enzymes and pain, which did not differ in the two arms.ConclusionHAI chemotherapy was effective for unresectable CRCLM. HAI of FOLFOX has similar efficacy to TOMOX, and HAI of TOMOX had shorter arterial infusion time.Clinical Trial Registration https://clinicaltrials.gov/, identifier NCT02557490.

Efficacy of Ipilimumab vs FOLFOX in Combination With Nivolumab and Trastuzumab in Patients With Previously Untreated ERBB2-Positive Esophagogastric Adenocarcinoma

In metastatic esophagogastric adenocarcinoma (EGA), the addition of programmed cell death 1 (PD-1) inhibitors to chemotherapy has improved outcomes in selected patient populations. To investigate the efficacy of trastuzumab and PD-1 inhibitors with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors or FOLFOX in first-line treatment of advanced ERBB2-positive EGA. This phase 2 multicenter, outpatient, randomized clinical trial with 2 experimental arms compared with historical control individually was conducted between March 2018 and May 2020 across 21 German sites. The reported results are based on a median follow-up of 14.3 months. Patients with previously untreated, metastatic ERBB2-positive (local immunohistochemistry score of 3+ or 2+/in situ hybridization amplification positive) EGA, adequate organ function, and eligibility for immunotherapy were included. Data analysis was performed from June to September 2021. Patients were randomized to trastuzumab and nivolumab (1 mg/kg × 4/240 mg for up to 12 months) in combination with mFOLFOX6 (FOLFOX arm) or ipilimumab (3 mg/kg × 4 for up to 12 weeks) (ipilimumab arm). The primary end point was survival improvement with a targeted increase of the 12-month overall survival rate from 55% (trastuzumab/chemotherapy-ToGA regimen) to 70% in each arm. A total of 97 patients were enrolled, and 88 were randomized (18 women, 70 men; median [range] age, 61 [41-80] years). Baseline Eastern Cooperative Oncology Group performance status was 0 in 54 patients (61%) and 1 in 34 patients (39%); 66 patients (75%) had EGA localized in the esophagogastric junction and 22 in the stomach (25%). Central post hoc biomarker analysis (84 patients) showed PD-1 ligand 1 (PD-L1) combined positive score of 1 or greater in 59 patients (72%) and 5 or greater in 46 patients (56%) and confirmed ERBB2 positivity in 76 patients. The observed overall survival rate at 12 months was 70% (95% CI, 54%-81%) with FOLFOX and 57% (95% CI, 41%-71%) with ipilimumab. Treatment-related grade 3 or greater adverse events (AEs) and serious AEs occurred in 29 and 15 patients in the FOLFOX arm and in 20 and 17 patients in the ipilimumab arm, respectively, with a higher incidence of autoimmune-related AEs in the ipilimumab arm and neuropathy in the FOLFOX arm. Liquid biopsy analyses showed strong correlation of early cell-free DNA increase with shorter progression-free and overall survival and emergence of truncating and epitope-loss ERBB2 resistance sequence variations with trastuzumab treatment. In this randomized clinical trial, trastuzumab, nivolumab, and FOLFOX showed favorable efficacy compared with historical data and trastuzumab, nivolumab, and ipilimumab in ERBB2-positive EGA. The ipilimumab arm yielded similar OS compared with the ToGA regimen. ClinicalTrials.gov Identifier: NCT03409848.

Abstract 6204: Age-related disparity in treatment outcome and adverse events among patients with metastatic colorectal cancer (mCRC)

Abstract Background: The number of newly diagnosed mCRC has been increasing in not only the aging population but also those <50 years of age. However, age-related disparity in the management of patients with mCRC has not been adequately evaluated. In this study, we aimed to compare and contrast the treatment outcome and adverse events among different age groups of patients with mCRC. Methods: We used individual patient data of a clinical trial (NCT00364013) from Project Data Sphere with patients who received first-line FOLFOX or FOLFOX + panitumumab for mCRC. Patients in each treatment arm were grouped into <50 years, 50-65 years, and >65 years of age groups. Continuous and categorical variables were compared with t test and Fisher’s exact test, respectively. Survival was summarized using Kaplan-Meier method and compared using log-rank test. Cox proportional hazards model was used to determine the association of adverse events with survival. Results: Among 935 patients included, 112 (12.0%) were in the <50 group; 456 (48.8%) were in the 50-65 group; 367 (39.2%) were in the >65 group. All three groups had similar baseline characteristics. Median overall survival (OS) of both <50 (18.4, 95%CI 13.1-23.1 months) and >65 (18.0, 95%CI 16.3-22.2 months) groups were significantly shorter (p=0.008) than median OS of the 50-65 group (22.7, 95%CI 20.0-26.5 months) in the FOLFOX arm. Similar findings were present in the FOLFOX + panitumumab arm (p=0.049). Both <50 and >65 groups had a trend (p=0.09) toward shorter progression-free survival (PFS) compared to the 50-65 group. As to adverse events, in the FOLFOX arm, all grade nausea/vomiting of the <50 group was more common than that in the >50 group (70.3% vs 55.8%, p=0.05). Compared to the >50 group, the <50 group had earlier onset of neutropenia at 7.8 weeks (p=0.003) and chest pain at 5.4 weeks (p=0.008). In the FOLFOX + panitumumab arm, all grade fatigue (58.3% vs 35.7%, p=0.003), neuropathy (52.1% vs 34.7%, p=0.03) and mucositis (43.8% vs 29.5%, p=0.049) of the <50 group were more common than those in the >50 group. The duration of various adverse events were similar among the age groups. In the FOLFOX arm, severe (grade≥3) liver toxicity was associated with worse PFS (HR 3.6, 95%CI 1.3-9.8, p=0.01) and OS (HR 7.3, 95%CI 2.7-20.1, p<0.001). In contrast, severe neuropathy was associated with better PFS (HR 0.6, 95%CI 0.4-0.9, p=0.009) and OS (HR 0.5, 95% 0.3-0.8, p=0.001). In the FOLFOX + panitumumab arm, severe anemia was associated with worse PFS (HR 1.7, 95%CI 1.02-2.8, p=0.04) and OS (HR 2.8, 95%CI 1.7-4.7, p<0.001). In contrast, severe rash was associated with better PFS (HR 0.5, 95%CI 0.3-0.8, p=0.002) and OS (HR 0.3, 95% 0.2-0.5, p<0.001). Conclusions: Patients with early-onset mCRC had not only worse OS in both treatment arms but also higher incidence of adverse events. Our management approach should adapt to the unique features of this patient population. Citation Format: Lingbin Meng, Ram Thapa, Hao Xie. Age-related disparity in treatment outcome and adverse events among patients with metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6204.

Does docetaxel matter in metastatic gastric cancer? FOLFOX versus FLOT regimens as first-line treatment.

We aimed to compare the efficacy and the safety of the FOLFOX and the FLOT regimens in metastatic gastric cancer (mGC) as first-line treatment. It was a retrospective multicenter observational study. The comparisons between groups were conducted in terms of progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and hematologic adverse events. Seventy-nine patients, diagnosed with mGC between March 2012 and December 2019, treated with FOLFOX (n = 43) or FLOT (n = 36) regimens as first-line treatment were included in the study. The mPFS was 10.9 months [95% confidence interval (CI), 5.8-16.1] in the FLOT arm and 7.1 months (95% CI, 5.1-9.1) in the FOLFOX arm (P < 0.001). The ORR was 63.9% in the FLOT arm and 30.2% in the FOLFOX arm (P = 0.003). The mOS was 13.3 months (95% CI, 11.3-15.4) in the FLOT arm and 10.9 months (95% CI, 8.2-13.5) in the FOLFOX arm (P = 0.103). The hematologic adverse events in all grades were 88.4% (n = 38) in the FOLFOX arm compared with 80.6% (n = 29) in the FLOT arm (P = 0.335). The FLOT regimen might be a preferred option in mGC with an improved PFS and ORR compared with the FOLFOX regimen.

Longitudinal cumulative dose: A novel measure to assess multiple dimensions of chemotherapy adherence over time.

3522 Background: Adjuvant chemotherapy regimens take months to complete. Despite this, trials and observational studies evaluate chemotherapy adherence via measures assessed at the end of treatment (e.g. number of patients missing any dose, relative dose intensity [RDI]). This approach misses information that impacts outcomes, like treatment delays. We propose longitudinal cumulative dose (LCD) as a way to integrate the impact of dose reductions, missed doses, and dose delays at each cycle over time. Methods: We obtained data from the 2,246 participants in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC). We evaluated proportions of patients stopping treatment early and reducing (based on protocol), missing, or delaying a dose in each arm for each chemo agent at each visit. We obtained LCD, the fraction of the final standard dose a participant reached by a given day, for each participant and each chemo agent. We compared LCD medians over time and at the end of a standard regimen (24 weeks) between treatment arms and by age and performance status. We assessed agreement between oxaliplatin LCD and RDI with Fleiss’ kappa (Table). Results: Participants randomized to FOLFOX were more likely than those randomized to 5FU to stop treatment, reduce doses, miss doses, or delay visits; these differences increased over time. Median LCD for oxaliplatin in the FOLFOX arm at 24 weeks was 77%. Graphs of median LCD for 5FU showed a clear difference between arms (FOLFOX arm median LCD: 81%; 5FU arm median LCD, 96%). While 5FU LCD decreased with age in the FOLFOX arm (median LCD in those age &lt;40: 85%; 40-64, 82%; 65-75, 76%), it was similar across ages in the 5FU arm (median LCD 94%, 96%, and 96%, respectively), with smaller performance status trends. RDI and LCD showed fair agreement (Fleiss’ kappa=0.34); 19% of those with RDI over 85% had LCD under 60%. Conclusions: Visualizing LCD highlighted the timing and scale of deviations from standard administration, with major differences in 5FU LCD across arms. Next steps include evaluating if LCD predicts clinical outcomes. [Table: see text]

Contribution of Immunoscore and Molecular Features to Survival Prediction in Stage III Colon Cancer.

BackgroundThe American Joint Committee on Cancer staging and other prognostic tools fail to account for stage-independent variability in outcome. We developed a prognostic classifier adding Immunoscore to clinicopathological and molecular features in patients with stage III colon cancer. MethodsPatient (n = 559) data from the FOLFOX arm of adjuvant trial NCCTG N0147 were used to construct Cox models for predicting disease-free survival (DFS). Variables included age, sex, T stage, positive lymph nodes (+LNs), N stage, performance status, histologic grade, sidedness, KRAS/BRAF, mismatch repair, and Immunoscore (CD3+, CD8+ T-cell densities). After determining optimal functional form (continuous or categorical) and within Cox models, backward selection was performed to analyze all variables as candidate predictors. All statistical tests were two-sided. ResultsPoorer DFS was found for tumors that were T4 vs T3 (hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.19 to 2.60; P = .004), right- vs left-sided (HR = 1.52, 95% CI = 1.14 to 2.04; P = .005), BRAF V600E (HR = 1.74, 95% CI = 1.26 to 2.40; P < .001), mutant KRAS (HR = 1.66, 95% CI = 1.08 to 2.55; P = .02), and low vs high Immunoscore (HR = 1.69, 95% CI = 1.22 to 2.33; P = .001) (all P < .02). Increasing numbers of +LNs and lower continuous Immunoscore were associated with poorer DFS that achieved significance (both Ps< .0001). After number of +LNs, T stage, and BRAF/KRAS, Immunoscore was the most informative predictor of DFS shown multivariately. Among T1–3 N1 tumors, Immunoscore was the only variable associated with DFS that achieved statistical significance. A nomogram was generated to determine the likelihood of being recurrence-free at 3 years. ConclusionsThe Immunoscore can enhance the accuracy of survival prediction among patients with stage III colon cancer.

Randomized Phase III Study of FOLFOX Alone and with Pegilodecakin as Second-line Therapy in Patients with Metastatic Pancreatic Cancer (SEQUOIA).

637 Background: Effective therapies are limited for advanced metastatic pancreatic ductal adenocarcinoma (PDAC) patients (pts) who have progressed after 1st line gemcitabine-based chemotherapy (Gem). FOLFOX has clinical benefit in Gem-refractory PDAC pts. A phase 1 trial demonstrated promising activity with pegilodecakin (PEG; pegylated IL-10) and FOLFOX in Gem-refractory PDAC pts, providing rationale for the phase 3 trial (SEQUOIA; NCT02923921). Methods: SEQUOIA is a randomized phase 3 study of FOLFOX alone or with PEG in Gem-refractory PDAC pts. Pts were randomized 1:1, excluding pts with prior surgery and radiation, and received FOLFOX ( dI-Leucovorin [400 mg/m2], oxaliplatin [85 mg/m2] followed by bolus 5-FU [400 mg/m2], and a 46-48 hr infusion of 5-FU [2400 mg/m2]) on day 1 of a 14-day cycle up to 12 cycles. PEG + FOLFOX arm received PEG (0.4 mg/d if ≤80kg and 0.8mg/d if &gt; 80 kg) on Days 1-5 then Days 8-12 + FOLFOX. Pts could continue PEG monotherapy (0.8mg/d if ≤ 80 kg and 1.6 mg/d if &gt; 80 kg) after FOLFOX discontinuation. Primary objective was OS. Secondary objectives included PFS, ORR per RECIST 1.1, and safety. Assuming OS HR of 0.74, the study was powered to 85% at 2-sided α = 0.05 with ~566 pts to detect superiority of PEG + FOLFOX. Results: As of Sept 9, 2019, 567 pts were randomized to PEG + FOLFOX (283) or FOLFOX (284). The majority (94.7%) had 1st line Gem+nab paclitaxel. The mOS was similar between FOLFOX + PEG arm [5.8 months] and FOLFOX arm [6.3 months] with HR = 1.045 (95% CI [0.863, 1.265], p = 0.6565). No statistical difference was observed for PFS, mPFS was 2.1 months in both arms with HR = 0.981, (95% CI [0.808, 1.190], p = 0.8144). ORR was 4.6% on the PEG+FOLFOX arm and 5.6% on the FOLFOX arm. Grade ≥3 adverse events that were 5% higher on the PEG+FOLFOX arm included thrombocytopenia (25.2% vs. 3.6%), anemia (16.2% vs. 4.0%), neutropenia (29.5% vs. 22.7%), and fatigue (17.6% vs. 10.8%). Conclusions: The addition of PEG to FOLFOX did not improve efficacy (OS, PFS, ORR) in advanced PDAC pts who have progressed after 1st line Gem-containing therapy. Safety findings were consistent with previous data observed from PEG + chemotherapy; toxicity was manageable and tolerable. Clinical trial information: NCT02923921.

Bevacizumab in Combination With Either FOLFOX-4 or XELOX-2 in First-line Treatment of Patients With Metastatic Colorectal Cancer: A Multicenter Randomized Phase II Trial of the Gruppo Oncologico dell’Italia Meridionale (GOIM 2802)

IntroductionBiweekly schedule of XELOX-2 (capecitabine plus oxaliplatin) showed interesting results in first-line therapy of patients with metastatic colorectal cancer (mCRC). Bevacizumab plus FOLFOX-4 (oxaliplatin, folinic acid, and infusional 5-fluorouracil) is among standard first-line treatment options in this setting. We performed a phase II randomized trial in order to evaluate the activity of bevacizumab plus either FOLFOX-4 or XELOX-2 in first-line therapy of patients with mCRC. Materials and MethodsPatients with mCRC were randomized, in a 1:2 ratio, to first-line bevacizumab plus either FOLFOX-4 (Arm A), as calibration arm, or XELOX-2 (Arm B), up to 12 cycles. Patients without progression were further randomized to maintenance bevacizumab alone or with the same induction fluoropyrimidine. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival, overall survival, and toxicity. The study design was formally non-comparative, but exploratory comparison was performed. ResultsForty-five patients were randomized in arm A and 87 in arm B with an ORR of 55.6% versus 48.3% (P = .43), respectively. After a median follow-up of 47.2 months, progression-free survival was 10.0 versus 9.9 months (hazard ratio, 0.96; 95% confidence interval, 0.65-1.41; P = .84) and overall survival was 29.8 versus 25.0 months (hazard ratio, 1.21; 95% confidence interval, 0.77-1.92; P = .41), respectively. The main grade 3 to 4 toxicities (% A/B) were: neutropenia 15/3 and nausea 9/5. ConclusionThis exploratory analysis showed that biweekly XELOX-2 plus bevacizumab has a comparable ORR with FOLFOX-4 plus bevacizumab in patients with mCRC.

Cost-Effectiveness Analysis of First-Line Cetuximab Plus Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX-4) versus FOLFOX-4 in Patients with RAS Wild-Type Metastatic Colorectal Cancer.

PurposeCompared with fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) alone, cetuximab plus FOLFOX-4 has shown superior performance in terms of efficacy and tolerability in patients with RAS wide-type (wt) metastatic colorectal cancer (mCRC) in the TAILOR trial (Trial No.: EMR62202-057; ClinicalTrials.gov identifier: NCT01228734). Thus, we aimed to explore the cost-effectiveness of these two first-line regimens in patients with RAS wt mCRC from the Chinese societal perspective.MethodsFor the sake of executing the analysis, we used a Markov model containing three health states (progression-free survival (PFS), progressive disease (PD), and death) to simulate the process of RAS wt mCRC. The data regarding efficacy and safety were derived from the TAILOR trial. Transition probabilities were converted from the PFS and overall survival (OS) of both groups. Utility scores of the health states were obtained from previously published studies. Costs were computed from the perspective of Chinese society. The primary health outcome was the incremental cost-effectiveness ratio (ICER). Sensitivity analysis was utilized to investigate the effect of uncertainties on the Markov model.ResultsTreatment with cetuximab plus FOLFOX-4 was estimated to provide an increase in quality adjusted-life years (QALYs) of 0.15 QALYs at an increased cost of $19,079 compared with FOLFOX-4 alone, resulting in an ICER of $127,193/QALY, which exceeded the threshold of willingness-to-pay (WTP) of $27,934/QALY in China. Sensitivity analysis showed that the cost of PFS in the cetuximab plus FOLFOX-4 arm was the most influential factor in the Markov model.ConclusionThe combination of cetuximab and FOLFOX-4 is not a cost-effective strategy compared with FOLFOX-4 alone for the first-line treatment of patients with RAS wt mCRC from the perspective of Chinese society.

550P - Updated results of NORDIC 8, a randomised trial of cetuximab every 2 weeks with FOLFIRI or cetuximab with alternating FOLFIRI/FOLFOX in patients with RAS and BRAF wild type metastatic colorectal cancer

BackgroundCetuximab (cet) improves efficacy of first-line FOLFIRI in pts with RAS/RAFwt metastatic colorectal cancer (mCRC). Triplet chemotherapy improves efficacy further but with increased toxicity. Alternating FOLFIRI/FOLFOX is a different way to administer all 3 cytotoxic drugs. We report the updated results from Nordic 8, a multi-centre, randomised trial comparing cet with FOLFIRI (arm A) or with FOLFIRI alternating with FOLFOX (arm B). MethodsIn this investigator initiated randomised trial, 173 chemo-naïve mCRC patients received cet with FOLFIRI or cet with FOLFIRI (2 cycles) alternating with FOLFOX until PD. Main inclusion criteria were PS 0 or 1, RASwt and ESMO group 1-3 (prior to April 2014 only ESMO group 1 when 36 patients had been included)). The primary endpoint was RR (increase from 60% to 75%) and secondary endpoints were PFS, OS and safety. All endpoints were evaluated by the local investigator. ResultsFrom May 2012 to May 2018, 173 patients were randomized. Median age was 64 years (25% were at least 70 years), female 34%, PS 0 61%, ESMO group 1/2/3 64%/23%/13%. Baseline characteristics were well-balanced between the two groups. Median duration of therapy was 6.2 months in both arms and patients received a median of 11 and 12 cycles, respectively, without any difference in dose-intensity. In arm A and B overall RR was 69% and 78% (p=0.17), median PFS was 11.9 (arm A) and 11.8 months (arm B) (HR 1.10; p=0.60), and median OS was 40.7 and 39.2 months (HR 1.05; p=0.82), respectively. Most important grade ≥ 3 adverse events were neutropenia (15% vs 17%), rash (9% vs 15%), diarrhoea (7% vs 11%), fatigue (7% vs 7%), and febrile neutropenia (3% vs 1%); 20% in arm B experienced neuropathy grade 2 (no grade 3). Final and updated PFS and OS with sub-group analysis will be presented. ConclusionsCet every two weeks in combination with FOLFIRI or alternating FOLFIRI/FOLFOX is well tolerated with high RR and long OS. We recommend FOLFIRI + cet every 2 weeks in patients with RAS and BRAFwt mCRC. Clinical trial identification2011-004188-65. Legal entity responsible for the studyNordic Biomodulation Group. FundingMerck. DisclosureC. Kersten: Research grant / Funding (institution), Licensing / Royalties, Relationship is unrelated to this study: Merck KGaA. All other authors have declared no conflicts of interest.

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 &lt;5, 5-10, 10-15,&gt;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]

The parametric estimation procedure to predict long-term efficacy on survival from publication data of clinical trials for metastatic colorectal cancer (mCRC).

541 Background: In comparative clinical trials with time-to-event outcomes, the long-term treatment effect profile is clinically crucial. The conventional non-parametric measures, i.e., the median survival times and the t-year survival rates are informative but sometimes cannot be observed due to the limited study follow-up. For example, in the PEAK trial (Schwartzberg LS et al. J Clin Oncol 2014), the group contrast over 3 years could not be adequately confirmed due to the short follow-up. To predict the subsequent survival prognosis with the limited outcome data, one may estimate the survival curve using a parametric model. Here, we illustrate the parametric estimation procedure to predict long-term efficacy using the results of two randomized controlled trials for the patients with wild-type KRAS mCRC, i.e., PRIME (Douillard JY et al. J Clin Oncol 2010, Douillard JY et al. Ann Oncol 2014) and PEAK trials. Methods: We considered both the primary and updated results for the PRIME to assess the validity of the procedure, and then estimated the long-term efficacy in the two trials. We used the reconstructed overall survival (OS) data obtained by scanning the Kaplan-Meier curves in the literature. Fitting the data to the Weibull distribution, we estimated the parametric group contrast measures including the difference in the 3- and 5-years restricted mean survival times and mean survival times. Results: The extrapolated parametric OS curves from the primary PRIME results fitted well with the observed Kaplan-Meier curves for OS in the updated results. The parametric estimations demonstrated that, in the PRIME trial, panitumumab plus FOLFOX arm increased 2.0 (95% CI: 0.1-4.0), 4.0 (0.5-7.5), and 5.4 (0.3-10.5) months in survival on average over 3-, 5-years and the entire time, respectively, compared to FOLFOX arm. In PEAK trial, compared to bevacizumab plus FOLFOX arm, panitumumab plus FOLFOX arm increased 3.6 (0.7-6.5), 7.9 (2.1-13.7), and 12.8 (0.5-25.1) months in survival on average, respectively. Conclusions: The estimators for parametric survival curve would provide the informative summaries for long-term survival profile to the clinicians and patients.

Oxaliplatin-Based Adjuvant Chemotherapy for Rectal Cancer after Preoperative Chemoradiotherapy (ADORE): Long-Term Results of an Open-Label, Multicentre, Phase 2, Randomised Controlled Trial

Background: Oxaliplatin-based adjuvant chemotherapy for rectal cancer patients after preoperative chemoradiotherapy (CRT) is currently based on extrapolated results from colon cancer patients. We evaluated the role of oxaliplatin as adjuvant chemotherapy in rectal cancer patients who received preoperative CRT with fluoropyrimidine monotherapy and total mesorectal excision (TME). Methods: The ADORE is a multicentre, randomised trial in patients with postoperative ypStage II (ypT3-4N0) or III (ypTanyN1-2) rectal cancer after fluoropyrimidine-based preoperative CRT and TME. Patients were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL (5-fluorouracil 380 mg/m², leucovorin 20 mg/m²) or FOLFOX (oxaliplatin 85 mg/m², leucovorin 200 mg/m², 5-fluorouracil bolus 400 mg/m² on day 1, 5-fluorouracil infusion 2400 mg/m² for 46 hours). Stratification factors included ypStage and participating centre. Investigators were not blinded to the group assignment. Primary endpoint was disease-free survival (DFS), analysed according to the intention-to-treat principle (ClinicalTrials.gov registration number: NCT00807911). Findings: A total of 321 patients were enrolled between November 19, 2008, and June 12, 2012. The 6-year DFS rates were 68·2% in the FOLFOX arm vs 56·8% in the FL arm, with a stratified hazard ratio (HR) of 0·63 (95% CI, 0·43-0·93, p=0·018) by intention-to-treat analysis. In the subgroup analysis for DFS, FOLFOX was favourable to FL in patients with ypStage III, ypN1b, ypN2, high-grade histology, minimally regressed tumour, and absence of lymphovascular or perineural invasion. The 6-year overall survival (OS) rate was 78·1% in the FOLFOX arm vs 76·4% in the FL arm (HR 0·73 [0·45-1·19], p=0·21). In the subgroup analysis for OS, FOLFOX was favourable to FL in patients with ypN2 and minimally regressed tumour. Interpretation: Adjuvant FOLFOX improved DFS in rectal cancer patients with ypStage II/III after preoperative CRT. Adjuvant FOLFOX should be chosen based on the postoperative pathologic stage in those received preoperative CRT and TME. Trial Registration Number: ClinicalTrials.gov registration number: NCT00807911 Funding: Sanofi-Aventis, Republic of Korea Declaration of Interest: TWK received research funding from Sanofi-Aventis, Taiho, and Roche. YSH received research funding from Bayer. All other authors have no conflicts of interest to declare. Ethical Approval: All patients provided written informed consent, and the study protocol was approved by the institutional review boards of all participating institutions.

546P - Survival analysis of KRAS, NRAS, BRAF, PIK3CA wild type (wt) metastatic colorectal cancer (mCRC) patients (pts) treated with FOLFIRI plus cetuximab in the CAPRI- GOIM trial

Background: The CAPRI-GOIM trial consisted of two parts: FOLFIRI plus cetuximab in first line followed by cetuximab plus FOLFOX as second line treatment for molecularly selected mCRC pts. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rate and safety. This is an updated analysis providing the mature results for OS in KRAS, NRAS, BRAF, PIK3CA wt pts. Methods: In the CAPRI-GOIM trial 340 mCRC pts with KRAS exon 2 wt tumors were treated in first line with FOLFIRI plus cetuximab until disease progression or unacceptable toxicity. After first line therapy progression, pts (157), who achieved a clinical response with first line treatment, were randomized to FOLFOX plus cetuximab (Arm A) or to FOLFOX (Arm B). Archival tissue samples from primary tumours were centrally assessed by next generation sequencing (NGS) with the Ion AmpliSeq Colon and Lung cancer panel. Here we report mature survival data at median follow-up of 69 months (m) (cut off date: April 30, 2017) for 98 out of the 124 RAS wt patients with NGS analysis, that were representative of the 340 intention to treat patient population. Results: Median OS for these 98 pts was 34.0 m (95% CI 30.2–37.8) with PFS of 11.7 m (95% CI 10.3–13.1). Eighty six out of 98 pts had tumors that were KRAS, NRAS, BRAF, PIK3CA wt. In this cohort, OS was 35.8 m (95% CI 29.9–41.9) with PFS of 12.3 m (95% CI 10.7–14.0). PFS and OS were also evaluated according to tumour location (see Table for results).Table546PCohortMedian OS (months)Median PFS (months)RightLeftRightLeftRAS wt (n = 98)33.4 (31.7- 34.9)35.8 (29.9- 41.7)9.9 (7.9- 12.0)12.3 (11.0- 13.6)KRAS, NRAS, BRAF, PIK3CA wt (n = 86)34.0 (22.1- 46.0)35.8 (29.5- 42.3)9.9 (5.3- 14.6)12.3 (10.7- 14.0) Open table in a new tab Conclusions: Long-term follow-up analysis of pts enrolled in the CAPRI-GOIM trial showed a median OS of approximately 36 m in KRAS, NRAS, BRAF and PIK3CA wt pts. A better prognostic outcome in terms of OS and PFS was observed in left-sided as compared to right-sided tumors. Clinical trial identification: EudraCT number 2009-014041-81 Legal entity responsible for the study: Gruppo Oncologico dell'Italia Meridionale (GOIM) Funding: Cetuximab was provided by Merck Serono. Other funding: AIRC Disclosure: E. Martinelli: Advisory Board: Merck serono, Amgen. F. Ciardiello: Advisory Board: Merck Serono, Roche, Amgen, Pfizer, Bayer, Lilly. All other authors have declared no conflicts of interest.

Treatment sequence with either irinotecan/cetuximab followed by FOLFOX-4 or the reverse strategy in metastatic colorectal cancer patients progressing after first-line FOLFIRI/bevacizumab: An Italian Group for the Study of Gastrointestinal Cancer phase III, randomised trial comparing two sequences of therapy in colorectal metastatic patients

IntroductionThe optimal treatment strategy for RAS wild type (WT) mCRC is controversial. Our phase III study investigated the effect of introducing earlier (second-line) or later (third-line) cetuximab in patients progressed after FOLFIRI/bevacizumab first-line. Patients and methodsmCRC patients progressing after FOLFIRI/bevacizumab first-line were randomised to receive second-line irinotecan/cetuximab followed by third-line FOLFOX-4 (arm A) or the reverse sequence (arm B). Primary end-point was progression-free survival (PFS). ResultsAbout 54 and 56 patients were randomised in arm A and in arm B, respectively. After a median follow-up of 37.5 months, 100 PFS events were recorded. Median PFS was 9.9 months in arm A and 11.3 months in arm B (Hazard ratio [HR] 1.04, 95% confidence interval [CI]: 0.69–1.56, p = 0.854), while median overall survival was 12.3 months in arm A and 18.6 months in arm B (HR 0.84, 95% CI: 0.55–1.28; p = 0.411). No overall difference in side-effects were observed between the two treatment arms. ConclusionsThis trial did not meet the primary end-point (PFS). Like other preclinical and clinical evidences, our study seems to suggest a reduced activity of cetuximab after a first-line bevacizumab-based therapy.

PRODIGE 34 ADAGE: Adjuvant chemotherapy in elderly patients with resected stage III colon cancer—A randomized phase III trial.

TPS3628 Background: Colon cancer (CC) occurs in around 50% of the patients after 70 years. Adjuvant chemotherapy (CT) has demonstrated a benefit on disease-free survival (DFS) and overall survival after a stage III CC resection. Nevertheless, adjuvant CT is poorly used in elderly patients. There is still concern about the efficacy of doublet CT with oxaliplatin in fit elderly patients and the usefulness of fluoropyrimidine monotherapy in unfit elderly patients. The selection of patients that should be treated remains a challenge. Geriatric evaluation and tumor biology should be explored to help for patient selection. Methods: ADAGE is a multicenter, randomized phase III study comparing 3-years DFS of 2 therapeutic strategies in 2 groups of patients aged over 70 with completely resected stage III CC. Patients are included in one of the 2 groups after a multidisciplinary team evaluation; Group 1 (arm A and B) is defined as “able” to be treated with doublet CT; Group 2 (arm C and D) is defined as “unable” to be treated with doublet CT. In each group, patients are randomized according to a 1:1 ratio. Randomization is stratified according to center, gender, stage (IIIA vs IIIB vs IIIC), occlusion and/or perforation (yes vs no) and independent activity of daily living score (IADL: normal vs abnormal). Arm A and D receive LV5FU2 or capecitabine, arm B FOLFOX4 or XELOX and arm C is an observation arm. The treatment is planned for 6 months. Adjuvant CT should start within 12 weeks after surgery. Geriatric questionnaires and Lee score must be completed before randomization. Radiological assessment is performed every 6 months for 3 years after randomization and then annually for 2 years. Hypotheses (α two-sided = 5%, power = 80%) are to improve 3-years DFS from 65% (arm A) to 72% (arm B) in group 1 (756 patients required) and from 40% (arm C) to 55% (arm D) in group 2 (226 patients required). Safety is evaluated based on laboratory and clinical tests before each cycle. Exploratory analysis are planned to determine geriatric prognostic factors for DFS. A biological ancillary study is planned to allow prognostic evaluation of mismatch repair status and other molecular signatures. At the 1stof February 2017 the accrual was 246 patients. Clinical trial information: NCT02355379.

Cost minimization analysis of capecitabine versus 5-fluorouracil-based treatment for gastric cancer patients in Hong Kong

Background: EOX (epirubicin, oxaliplatin, Xeloda; capecitabine) and FOLFOX4 (5-fluorouracil (5-FU), leucovorin, oxaliplatin) are the common chemotherapy regimens used in the treatment of advanced gastric cancer (aGC) in Hong Kong. This study aimed to compare the costs of these therapies for aGC patients from both the healthcare and societal perspectives. It should be noted that, while FOLFOX4 is routinely administered in an outpatient setting in North America and Europe, inpatient setting is adopted in Hong Kong instead, incurring hospitalization cost as a result.Methods: Fifty-eight patients were identified from the electronic records in two public tertiary hospitals, with 45 and 13 receiving EOX and FOLFOX4 regimens, respectively. Healthcare cost was direct medical costs including drugs, clinic follow-up, hospitalization, diagnostic laboratories, and radiographs. Societal cost refers to indirect costs such as patient time and travel costs. Cost items were further classified as “expected” or “unexpected”. All cost data was expressed in US dollars.Results: Patients in the EOX and FOLFOX4 arm received an average of 5.3 and 7.8 cycles of treatment, respectively. The capecitabine-based regimen group had a higher expected medication cost per cycle when compared to the 5-FU-based treatment group (US$290.3 vs US$66.9, p < .001), but lower expected hospitalization costs (US$76.9 vs US$1,269.2, p < .001). The total healthcare cost and total societal cost per patient was reduced by 67.2% (US$5,691.9 vs US$17,357.4, p < .001) and 25.3% (US$3,090.5 vs US$4,135.1, p = .001), respectively, in the capecitabine-based regimen group. Sensitivity analyses based on full cycle regimen costs and net capecitabine or 5-FU/leucovorin costs still showed EOX to be less costly than FOLFOX4.Conclusion: The capecitabine-based regimen, EOX, was found to generate significant cost saving from both the healthcare and societal perspectives in regions in which FOLFOX4 is given in an inpatient setting.