Metastatic Colorectal Cancer Pts Research Articles

Outcomes with immunotherapy between Lynch syndrome vs non-Lynch syndrome microsatellite instability-high colorectal cancer.

175 Background: Alterations to mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2, can lead to microsatellite instability-high (MSI-H) tumors. MMR mutations can be inherited in Lynch syndrome (LS) but can also be a result of de novo alterations resulting in MSI-H malignancies. Treatment with immune checkpoint inhibitors (ICIs) have been shown to improve survival in such patients (pts) compared to systemic chemotherapy. However, there is a paucity of information in the literature with respect to outcomes of pts with germline vs somatic MMR mutations in MSI-H colorectal cancer (CRC). Furthermore, the presence of underlying BRAF mutation confers resistance to chemotherapy in pts with CRC, however data regarding outcomes with immunotherapy in such pts with MSI-H CRC is lacking. Methods: Pt records from the Mayo Clinic (AZ, MN, FL) between 2008-2023 denoted as MSI-H CRC, were included for retrospective review. Pt demographics, treatment courses, and genomic profiles were collected. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Outcome differences between sub-groups were accessed with the log rank test and univariate analyses were assessed with Cox-regression. Results: A total of 81 pt records were identified (n = 18 LS, n = 63 non-LS). Stage IV disease was found in 28% of LS pts vs 59% of non-LS pts at diagnosis. Pembrolizumab was the most common ICI selected for metastatic CRC pts for both LS and non-LS pts (65% vs 94%) with median treatment duration for each group 11.7 vs 8.8 months. There were no differences in OS or PFS for any stage between LS vs non-LS. Median OS for all patients was 82 months. For all stage IV patients, median OS was 44 months, and median PFS was 19 months. Interestingly, for stage IV pts treated with immunotherapy, tumors that harbored BRAF V600E mutation (n = 21) vs BRAF wild type (n = 20) had a significantly lower median OS 19 vs 113 months (HR = 2.69, p = 0.043) as well as median PFS 12 vs 95 months (HR = 2.48, p = 0.041). Conclusions: In this study, we found that patient treated with ICIs have similar outcomes in the presence of germline vs. somatic MMR mutations in MSI-H CRC. The presence of an associated BRAF V600E mutation, which occurs in non-LS MSI-H CRC conferred worse outcomes.

Updated analysis: Effect of biweekly dosing schedule of trifluridine-tipiracil (TAS-102) on rates of myelosuppression and maintenance of therapeutic efficacy in patients (pts) with previously treated metastatic colorectal cancer (mCRC).

95 Background: For surgically unresectable metastatic colorectal cancer pts, a continuum of treatment is required to improve the OS of our pts. Oral trifluridine-tipiracil (TAS-102) is FDA approved in refractory mCRC per the RECOURSE trial. As per the FDA insert, the recommended dose is 35 mg/m2 twice daily (maximum = 80 mg/day) on Days 1-5 and Days 8-12 of 28-day cycles commonly resulting in Grade 3-4 neutropenia (38%), dose delays (53%), dose reductions (14%) and requiring G-CSF support (9%). To maintain efficacy and to potentially reduce toxicity, we analyzed an alternative biweekly dosing (Days 1-5 and Days 15-19 q28 days). Methods: A retrospective analysis was completed (2019-2022) at Vanderbilt-Ingram Cancer Center in pts with refractory mCRC and appendiceal cancer (CA) who completed ≥ 12 days of TAS-102 therapy and underwent surveillance imaging every 8-12 weeks. Patient data was assessed for ECOG performance status (PS), prior lines of therapy, the use of bevacizumab and CTCAE grade of treatment-related myelotoxicity. Evaluation of progression-free survival (PFS) was completed in mCRC pts. Results: Forty-three patients met the inclusion criteria, with a mCRC:appendiceal CA ratio of 39:4. The median age = 50 y/o (range 30-80); male:female 23:20; median ECOG PS = 1; median number of prior therapies = 3; and median duration of therapy = 97 days (range: 12-396). Associated grade 3/4 hematologic toxicities included: Neutropenia 39% [Grade 3 (12.2%), Grade 4 (2.4%)]; anemia 36.5% [Grade 3 (12.2%)]. No pts required G-CSF. No incidences of neutropenic fever were reported. Five pts (11.6%) required a dose delay and 3 pts (7%) required a dose reduction due to myelosuppression. In mCRC pts, the median PFS was 2.53 months. To date, 6 pts remain on treatment (range: 97-331). Conclusions: In our updated analysis, biweekly dosing of TAS-102 (35 mg/m2 twice daily; Days 1-5 and Days 15-19 of 28-day cycles) for pts with refractory mCRC and appendiceal CA demonstrated tolerable myelosuppression, while preserving PFS in pts with mCRC. With an improved toxicity profile, this alternative TAS -102 dosing schedule may potentially broaden utilization of TAS-102 in patients with borderline PS and may be a more favorable option for future combination studies. Additional prospective data are needed to validate these findings. To our knowledge, this remains the first analysis of biweekly TAS-102 in a US patient population.

350P Postoperative histopathological, clinical and molecular risk score for patients with colorectal liver metastases

Hepatic resection is considered the optimal potentially curative treatment for colorectal liver metastases (LM). The Genetic And Morphological Evaluation (GAME) score, which includes KRAS status, tumor burden score, CEA, lymph node metastases and extrahepatic disease, has been proposed as a preoperative tool to select patients (pts) for liver resection. Nevertheless, histological characteristics of LM have been presented as potential prognostic biomarkers to be considered after resection. This study aimed to create a postoperative score including histological characteristics. Clinical and pathological data were collected from 146 metastatic colorectal cancer pts undergoing liver resection between 2004 and 2019 at Hospital de Sant Pau. Histopathological changes in liver parenchyma such as immune phenotype (IP) and histological growth pattern (HGP) were documented to identify potential prognostic factors. We calculated the GAME score of each patient and added the histological characteristics that had a prognostic value in the multivariable analysis. Of the 146 LM analyzed, twenty-three pts had a desmoplastic HGP (16%), thirty-one (22%) had a desertic IP and a fibrotic capsule was described in 22.5% of the cases. In the univariable analysis, the desmoplastic HGP and the fibrotic capsule was associated with a better overall survival (OS) (102 vs 49.3 months, HR 0.44 95% CI 0.23-0.86; p= 0.013 and 89.3 vs 46.9 months; HR 0.56 95% CI 0.33-0.98; p=0.037). The desertic IP was associated with a shorter OS (34.2 vs 58.3 months; HR 1.77 CI 1.1-2.8; p= 0.01) and remained significant in the multivariable analysis (HR 1.95, CI 95% 1.16-3.23; p= 0.012). We added 1 point to the original GAME score if a desertic immune phenotype was observed, and pts were classified in three risk groups with significant differences in survival. The high-risk group (score ≥4) had a recurrence free survival (RFS) and OS of 12.7 and 36.6 months vs 30.7 and 89.3 months in the low-risk group (score 0-1), respectively (p<0.001 and p=0.007). The desertic immune phenotype in liver metastasis of CRC has a bad prognostic value and could be considered to assess adjuvant treatment after hepatic resection.

Prognostic and Predictive Role of Body Mass Index (BMI) in Metastatic Colorectal Cancer (mCRC): A Pooled Analisys of Tribe and Tribe-2 Studies by GONO

BackgroundObesity is associated with an increased risk of development and recurrence of colorectal cancer. The role of obesity in metastatic colorectal cancer patients (pts) is still unclear, especially in those treated with triplet plus bevacizumab (bev). The aim of our study was to evaluate the prognostic and predictive role of BMI in metastatic colorectal cancer pts treated with FOLFOXIRI plus bev or FOLFIRI/FOLFOX plus bev in the TRIBE and TRIBE-2 trial. materials and MethodsA total of 1160 pts enrolled in TRIBE and TRIBE-2 trials were included. Baseline height and weight were used to assign pts to one of the following BMI categories: underweight (group A = BMI <18.5 kg/m2; 52 pts), normal (group B = BMI 18.5-29.9 kg/m2; 952 pts) and obese (group C > 30 kg/m2; 156 pts). ResultsIn our population, no differences in terms of PFS (P = .43) or OS (P = .99) resulted between 3 groups. No interaction effect between treatment arm and BMI was evident in terms of PFS (Group A HR: 0.65 [95%CI: 0.36-1.16]; Group B HR: 0.77 [95%CI: 0.67-0.88]; Group C HR: 0.67 [95%CI: 0.48-0.93]; P for interaction = .75) or OS (Group A HR: 0.57 [95%CI: 0.29-1.12]; Group B HR: 0.85 [95%CI: 0.73-0.99];Group C HR: 0.69 [95%CI: 0.48-1.01] P for interaction = .36). No statistically significant difference in terms of dose reductions due to toxicities were found according to BMI in the overall population (P = .48) and in pts treated with FOLFOXIRI plus bev (P = .57). ConclusionBMI was neither prognostic or predictive for PFS and OS in our population. Our analyses showed that the advantage of FOLFOXIRI plus bev versus FOLFIRI/FOLFOX plus bev was independent from BMI.

A randomized phase III trial of mFOLFOX7 or CapeOX plus bevacizumab versus 5-FU/l-LV or capecitabine plus bevacizumab as initial therapy in elderly patients with metastatic colorectal cancer: JCOG1018 study (RESPECT).

10 Background: It is uncertain if the addition of oxaliplatin (OX) to fluoropyrimidine plus bevacizumab (BEV) is suitable as initial therapy in elderly patients (pts) with metastatic colorectal cancer (MCRC). Therefore, we conducted a randomized controlled trial to confirm the superiority of the addition of OX in terms of progression-free survival (PFS). This JCOG trial was originally planned as a paralell study with NCCTG, but the NCCTG trial was terminated early. Methods: Key eligibility criteria included unresectable metastatic colorectal cancer, and histologically confirmed adenocarcinoma, aged 70-74 with PS 2 or 75 or older with ECOG PS 0-2. Eligible pts were randomized (1:1) to either no addition of OX or addition. Whether using 5-FU+levoleucovorin calcium (5-FU/ l-LV) or capecitabine (CAPE) was declared before study entry; options included 5-FU/ l-LV+BEV (C), CAPE+BEV (D), mFOLFOX7+BEV (E), or CapeOX+BEV (F). 5-FU/ l-LV regimen omitted bolus 5-FU from the original sLV5FU regimen. The dose of CAPE was adjusted by estimated creatinine clearance. The primary endpoint was PFS. The planned sample size was 250 pts in total to detect a hazard ratio (HR) of 0.75, with a one-sided alpha of 5% and 70% power. The decision rule is that the primary endpoint is met, and the point estimate of HR of overall survival (OS) is less than 0.8. Results: Between Sep 2012 and Mar 2019, 251 pts were randomized. 125 pts were allocated to no addition of OX and 126 pts to addition. Median age was 79, aged 70-74/75-79/80-84/85+:5%/45%/37%/13%, PS 0/1/2:53%/39%/7%. Of 251 pts, 241 pts had PFS events and 223 pts had OS events. Median PFS (mPFS) was 9.4 months (M) (95%CI 8.3–10.3) in no addition of OX and 10.0M (9.0–11.2) in addition (HR 0.837, 90.5%CI [0.673–1.042], one-sided p = 0.086). Median OS was 21.3M (18.7-24.3) in no addition and 19.7M (15.5–25.5) in addition of OX (HR 1.054 [0.810–1.372]). Response rate was 29.5% (21.2-38.8) in no addition of OX and 47.7% (38.1-57.5) in addition. Proportion of pts whose EQ-5D scores improved from baseline to post-treatment in overall score did not differ (odds ratio 0.94 (0.51-1.75)). The deaths of 1 pt in no addition of OX and in 3 pts in addition were deemed treatment-related. Conclusions: The addition of OX has no survival benefit over no addition. OX was not recommended for elderly MCRC pts as initial therapy. Clinical trial information: UMIN000008866.[Table: see text]

Phase I dose-escalation study of MCLA-158, a first-in-class bispecific antibody targeting EGFR and LGR5, in metastatic colorectal cancer (CRC).

62 Background: The WNT and EGFR signaling pathways are oncogenic and mitogenic drivers in CRC and other cancers. MCLA-158 is an ADCC enhanced human IgG1 cLC bispecific antibody identified from functional screening of CRC patient (pt)-derived organoids (PDO). MCLA-158 exposure leads to EGFR degradation in LGR5+ cancer and exhibits potent growth inhibition of RASmut and wt CRC PDOs, while minimal inhibition is observed in non-tumoral PDOs. Blockade of metastasis initiation was seen in preclinical in vivo models. MCLA-158 also demonstrated tumor regression or stasis in esophageal squamous (6/6) and gastric adenocarcinoma (6/8) PDX models selected for LGR5 and EGFR expression. Methods: Metastatic CRC pts progressing after oxaliplatin, irinotecan and fluoropyrimidines, and EGFR monoclonal antibodies if RASwt, received MCLA-158 IV every 2 weeks (q2w; 4-week cycle) in a phase I study. Safety, efficacy (per RECIST 1.1), PK and ADA were assessed. WNT and EGFR pathway components were evaluated in tumor tissue. EGFR pathway mutations (ctDNA) and soluble EGFR (sEGFR) were assessed in blood. PDOs were derived from baseline biopsies and assessed for MCLA-158 responsiveness. Results: As of 7 September 2020, 33 pts were treated over 11 dose levels (5 to 1500 mg, flat dose). At enrollment, median age was 58 years (range 35-76), ECOG PS 0/1:22/11, and 15 pts were RASmut. Pts had a median of 3 metastatic sites (range 1-12) with a median of 4 prior lines of therapy (range 1-10). A median of 2 MCLA-158 cycles (range 1-6) were administered. No dose limiting toxicity occurred. Infusion-related reactions were the most common AEs (67% of pts), occurred mostly in cycle 1 (21/22 pts), and were manageable. Other common related AEs included rash acneiform (36%), diarrhea (15%), pyrexia (9%) and asthenia/fatigue (9%). Related AEs were mostly mild or moderate; G3 related AEs were IRRs (4 pts; 12%), diarrhea and hypophosphatemia (1 pt each). The RP2D (1500 mg) was selected based on safety, PK and receptor occupancy prediction. MCLA-158 exhibited target-mediated clearance with proportional PK from 750 mg (t1/2 ~80 h at 1500 mg). Low ADA titers were seen in 3/23 pts, with no effect on PK. Target saturation is predicted at steady state serum trough levels. No clinical responses were observed during dose escalation. No/low baseline tumor EGFR expression (0-1+ IHC) was observed in 17/30 pts and non-elevated sEGFR levels ( &lt; 4 ng/mL) in 18/22 pts. More than 1 activating mutation in EGFR signaling pathway genes were identified in ctDNA from 10/20 pts. 1/4 PDOs had &gt; 30% growth inhibition with MCLA-158 ex vivo. MCLA-158 activity on PDOs correlated negatively with the presence of EGFR pathway resistance-mutations. Conclusions: Dual EGFR/LRG5 blockade with MCLA-158 was well tolerated, and the RP2D was 1500 mg IV q2w. Enrollment of pts with gastric and other non-CRC cancers at the RP2D continues in the expansion phase. Clinical trial information: NCT03526835.

Abstract 4241: Regorafenib and nivolumab or pembrolizumab combination and ctDNA response assessment in refractory colorectal cancer

Abstract Introduction: Patients with microsatellite stable (MSS) metastatic colorectal cancer (MCRC) are considered resistant to immunotherapy with PD-1 and PD-L1 inhibitors. However, a recent study of regorafenib and nivolumab (REGONIVO) reported high response rates and a median progression free survival (PFS) of more than 6 months (mo) in a cohort of 24 Japanese patients (pts) with MSS chemo-resistant MCRC. Methods: We evaluated the outcome of advanced MSS MCRC pts who were treated on a compassionate basis with PD-1 inhibitors in combination with regorafenib 80 mg PO QD x 21 days every 28 days in a single US center. We report their response rate (RR), PFS, and overall survival (OS). Results: 16 pts (15 males) were treated with a combination of regorafenib + PD-1 inhibitors and were evaluable for response. 14 pts received regorafenib + nivolumab (5 with prior anti-PD-1 treatment) and 2 pts received regorafenib + pembrolizumab (both following pembrolizumab treatment). No treatment-related G3 or above toxicities were attributed to the combination therapy. No objective responses were noted on treatment. 11 pts had progressive disease (PD) and 5 pts experienced stable disease (SD) as best response at 2 mo. The duration of SD was 4 mo in 2 pts (1 pt with prior anti-PD1 exposure), 6 mo in 1 pt (prior anti-PD1 exposure), 5 mo+ in 2 pt (1 with prior anti-PD1 exposure). When limiting the analysis to the 9 regorafenib and checkpoint-inhibitor naïve patients, 2 pts were noted to have SD (4 months and 5 mo+). ctDNA assays were evaluated at baseline and at 4 weeks of treatment in 11 patients. All 9 patients with a rise in ctDNA at 4 weeks had PD at the 2-mo imaging point. 2 patients with declining ctDNA at 4 weeks experienced SD for 4 mo 5 mo+, each. OS analysis remains immature as the median follow-up is only 5 mo. Conclusions: Regorafenib and nivolumab combination was associated with modest clinical activity in patients with MSS chemotherapy-resistant MCRC. This US-based small retrospective trial is at odds with the Japanese REGONIVO trial. ctDNA may represent a powerful tool for predicting progression prior to radiographic staging. Citation Format: Marwan Fakih, Dawnyel Chevalier, Janelle Saluja, Cecilia Lau, Chongkai Wang. Regorafenib and nivolumab or pembrolizumab combination and ctDNA response assessment in refractory colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4241.

Prognostic role of visceral fat for overall survival in metastatic colorectal cancer: A pilot study

Body composition, has been established as a risk factor for colorectal cancer diagnosis and disease progression. Aim of this study was to investigate the prognostic role of adiposity, especially visceral fat (VAT), in patients (pts) with metastatic colorectal cancer (MCRC). A retrospective cohort of 71 MCRC pts treated between 2013 and 2017 was evaluated. VAT was measured as cross-sectional (cm2) area at the L3 level divided by the square of the height (m2). A ROC analysis was performed to define a prognostic threshold according to VAT. Before first-line therapy start, 40pts (56%) had a body mass index (BMI)>25kg/m2. The obtained cut-off value for VAT was 44. Median OS was 30.97 months. At univariate analysis, primary tumor resection (HR 0.40, p=0.029), VAT>44 (HR 2.85, p=0.011) and metastasectomy (HR 0.22, p=0.005) were significantly associated with OS. By multivariate analysis, VAT>44 (HR 2.6; p=0.020) and metastasectomy were still significantly associated with OS. This exploratory study suggests a prognostic role for VAT in MCRC pts, with higher VAT values predicting worse outcome.

Prognostic role of T3/T4 ratio in metastatic renal cell carcinoma (mRCC): Preliminary results of the threeFOUR multicenter study (Meet-Uro 14).

e17093 Background: Thyroid hormones metabolism can be altered in patients (pts) with chronic diseases and/or undergoing cancer treatments. The prognostic role of T3/T4 ratio has been investigated in metastatic colorectal cancer pts in whom a high T3/T4 ratio predicted longer survival. No data are available in mRCC. Methods: We retrospectively reviewed the clinical charts of pts with mRCC treated in first line for metastatic disease at 8 Italian Oncology Units before March 2017, having at least one response assessment and baseline complete thyroid panel data available. T3/T4 was calculated as the ratio of the two value of hormones and categorized in tertiles. Results: We identified 96 pts, median age 62 years (range 27-82), 72% males. Sunitinib wad administered in 56% of pts, pazopanib in 38%, nivolumab and ipilimumab in 6%. According to Heng Score, 33% of the pts were at favorable risk, 58% at intermediate risk, 9% at poor risk. With a median follow-up time of 42.8 months, median PFS was 24.8 months, estimated median OS was 71.6 months. Tertile distribution of patients was 36.4% in the high, 29.1% in the medium and 34.5% in the low subgroup. A baseline high tertile value (≥ 0.35) predicted longer PFS (39.4 vs 21.8 1vs 4.5 months, p = 0.01), while median OS has not been reached in the three tertiles, with survival at 24 months being 69.7%, 82.1% and 91.4%, respectively in the low, medium, high group (p = ns). The high T3/T4 ratio is also strongly associated with the chance to achieve a partial or complete response (42.8% vs 39.9% vs 21%, X squared test, p &lt; 0.001). Heng prognostic model retained its prognostic role in this cohort (median OS was 77.1 vs 48.4 vs 22.3 months, p &lt; 0.001, respectively for favorable, intermediate or poor risk group) and also predicted PFS (median PFS 38.2 vs 17.2 vs 8.4 months, p = 0.004). Baseline NLR ≥ 3 predicted shorter OS (46.5 vs 77.1 months, p = 0.02) in the whole group. Conclusions: In our retrospective multicenter experience, a high T3/T4 ratio was associated with longer PFS and a higher probability to respond to the treatment. Median OS had not been reached for all the subgroups, probably due to a favorable patients selection. A longer follow-up is needed to validate the prognostic value of T3/T4 ratio in this cohort.

Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): Final results of the phase II AVETUX trial (AIO-KRK-0216).

96 Background: Single agent PD-1/L1 inhibition is efficacious in MCRC patients (pts) with high microsatellite instability (MSI-H). For the vast majority of MCRC pts with MS stable (MSS) phenotype the role of immunotherapy remains undetermined. Methods: The single arm phase II AVETUX trial combined mFOLFOX6 and cetuximab with avelumab (10mg/kg day 1 from cycle 2 onwards) in RAS/BRAF wildtype (local lab) MCRC pts. Primary endpoint was 12 month progression-free survival rate. Secondary endpoints included overall response rate (ORR), tolerability, overall survival and translational research evaluating tissue including PD-L1 expression (tumour/immune cells) and serial ctDNA. Efficacy analyses were done by intention to treat (ITT). Results: Overall 43 pts were enrolled. Median age was 61 (range 29-82), 14 pts (33%) were female and 39 (91%) left sided. 30 pts (70%) had liver mets and 17 (40%) liver mets only. 2 pts were MSI-H, one MSI-low and 40 MSS. Besides immediate and otherwise unexplained fever in 4 pts treatment was well tolerated and avelumab was not associated with unexpected adverse events to standard FOLFOX/cetuximab. Central tissue review found 4 pts to be ineligible due to low frequent KRAS or BRAF mutation (15-31%). Thus, ITT included 39 pts. The ORR was 79.5%, including 6 complete (CR) and 25 partial responses (PR). Further 5 stable diseases were noted, thus disease control rate was 92.3%; 2 pts had progression and 1 was not evaluable. Early tumor shrinkage (ETS) rate (≥20% after 8 weeks) was 79.5% (1 CR, 27 PR and 3 SD with ≥20% - &lt; 30%). In MSI-H pts 1 PR and 1 SD and in the 3 low RAS mut pts 2 PR were noted. Panel sequencing was feasible with 153 mutations detected, showing an immediate ctDNA drop within 4 weeks of treatment, mirroring the high rate of early tumor response. Notably, the 4 pts with fever had a high T cell infiltration in the tumor. Final data including the primary endpoint and translational data will be presented at the meeting. Conclusions: The AVETUX regimen was feasible producing a high rate of responses in MSS pts mainly occurring within the first 8 weeks. The noted ORR/ETS of 79.5% warrants further evaluation in a randomized trial. Clinical trial information: NCT03174405.

Neoadjuvant chemotherapy followed by liver resection for patients with metastatic colorectal cancer.

147 Background: Colorectal cancer is one of the leading causes of cancer related deaths with liver being most common site of CRC metastasis. More than 50% of the CRC patients will develop metastatic liver lesion that eventually leads to death in about 70% of them. In this retrospective review we reviewed the outcome of pts who received neoadjuvant chemotherapy followed by resection of liver lesion for metastatic colorectal cancer. Methods: 304 pts who had preoperative chemotherapy were identified from 1045 metastatic colorectal cancer patients who had liver metastasectomy at Mayo Clinic between 1997 and 2018. A retrospective review was conducted by using data from electronic medical records. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: There were 113 (37%) female and 191 (63%) male pts. Median age at primary disease diagnosis was 56.5 yrs. Two hundred forty-nine pts presented with stage IV metastatic colorectal cancer. Primary tumor locations were: 53 right-sided, 117 left-sided and 133 rectum. 152 (50%) pts had extrahepatic metastases. Two pts were found to be MSI-H, 113 MSS, 189 unknown. BRAF mutation was found in 6 patients. RAS mutation was present in 84 patients, with 124 unknown. Pts received chemotherapy for median of 2.82 months. Single agent fluoropyrimidine was administered in 38 (12%) pts and rest receiving chemotherapy doublet or triplet with fluropyrimidine plus oxaliplatin being most common regimen. The median overall survival from primary diagnosis for the entire group was 74.5 months. Median overall survival from liver metastasectomy was 60.0 months. In univariate analysis, metachronous disease, age &lt; 60 yrs, and an absence of extrahepatic lesions led to statistically significant improvement of overall survival from primary diagnosis. Metachronous and extrahepatic lesions remained statistically significant in multivariate analysis. Conclusions: Neoadjuvant chemotherapy followed by liver metastasectomy is beneficial for highly-selected metastatic colorectal cancer pts. Compared to a historical control of 30-36 months, our patient population had a median overall survival of about 5 years from resection.

A phase I clinical trial of fluorouracil (5-FU) + devimistat (CPI-613) combination in previously treated patients (pts) with metastatic colorectal cancer (MCR).

e15054 Background: MCR that failed standard lines of therapy have a poor outcome. Inhibition of glutamine metabolism potentially can synergize with chemotherapy and reverse resistance. Devimistat is a novel anti-mitochondrial agent that alters energy metabolism and redox processes, leading to apoptosis, necrosis, and autophagy. Methods: Phase Ib dose escalation (3+3 design) to determine the MTD of devimistat, when used in combination with fixed doses of bolus and infusional 5-FU, in non-resectable MCR, ECOG PS 0-3, and good organ function who have failed, or could not tolerate, prior standard therapies. A cycle was 2 weeks. Escalating doses of devimistat were given IV over 2 hrs via central line on days 1-4. On Day 2 when both devimistat and bolus 5-FU were given, devimistat was given first, followed by 5-FU bolus (400 mg/m2) followed by infusional 5-FU over 46 hrs (2,400 mg/m2) on Days 2-4. Plasma samples to measure devimistat and metabolites were collected before and after the first and last dose of devimistat on cycle 1. Results: 19 pts enrolled from 1/20/2015 to 1/16/2019. One was never treated with devimistat and was excluded from analyses. Median age was 63 (range 32-83). 10 males and 8 females. Median devimistat cycles were 4 (range 1-8). Dose levels of devimistat: 1 pt treated at 2,000 mg/m2, 1 pt treated at 2,250 mg/m2, 7 pts treated at 2,500 mg/m2, then dose was de-escalated for an additional 9 pts treated at 2,250 mg/m2. Two of 7 pts had a DLT at the devimistat 2,500 mg/m2 dose level; a grade 3 and a grade 4 creatinine level. The dose of devimistat was de-escalated to 2,250 mg/m2 with a total of 10 pts being treated without DLTs observed (2 still on treatment). Other G1-2 non-hematologic and G1-3 hematologic toxicities were observed but related to 5FU except for two episodes of G1 intravascular hemolysis. No radiologic responses were observed. Four pts had SD and two pts at 2,250 mg/m2 of devimistat continue on therapy. Median PFS and OS are currently 2.73 and 5.75 months respectively. Conclusions: Devimistat and 5FU combination demonstrated a tolerable safety profile in heavily pretreated MCR pts. Durable SDs observed at the MTD suggest antitumor activity at the 2,250 mg/m2 devimistat dose level. Clinical trial information: NCT02232152.

Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): Results of the safety run-in phase of the phase II AVETUX trial (AIO-KRK-0216).

3561Background: Single agent PD-1/L1 inhibition is efficacious in mismatch repair deficient tumours - about 5% of MCRC patients (pts). For the remaining MCRC pts the role of immunotherapy still nee...

Differential clinical outcome of metastatic colorectal cancer (MCRC) patients (pts) treated with first line FIr-B/FOx adding bevacizumab (BEV) to triplet chemotherapy according to KRAS, NRAS and BRAF genotype detected by massive parallel sequencing.

e15041 Background: KRAS/NRAS/BRAF genotypes guide tailoring of first and subsequent lines of MCRC treatment strategy. First line triplet chemotherapy/BEV associations significantly improved progression-free survival (PFS) and overall survival (OS) in overall MCRC patients. OS may be significantly worse in the prevalent KRAS c.35 G &gt; A and BRAFmutant (mt). Evaluation of differential clinical outcome in overall MCRC patients will help identify clinically relevant biomarkers to personalize treatment strategy. Methods: Tumoral samples of 67 MCRC pts treated with FIr-B/FOx (77% overall) were analyzed through a 50 genes panel (PGM/Colon Lung Cancer) by ION Torrent: 58 (86.5%) primary, 9 (13.4%) metastatic samples; 60 (89.5%) pre-, 7 (10.4%) post-treatment. KRAS, NRAS and BRAFcoding frames were analysed. Molecular diagnostic criteria for mutation detection: &gt; 50% coverage; &gt; 1% mutant allelic fraction. Clinical outcomes (PFS and OS) were evaluated and compared by log-rank. Results: Mutant KRAS2-4/ NRAS2-4/ BRAF MCRC patients were 49 (73.1%): KRAS 42 (62.6%), NRAS 15 (22.3%), BRAF 5 (7.4%). BRAF mutations were all atypical and concomitant with KRAS and/or NRAS mutations. At median follow-up 21 months (m), overall PFS and OS were 13 and 27m, and KRAS exon 2 wild-type (wt)/mt PFS 14/12m, and OS 28/21m, respectively, consistent with previously reported, and not significantly different. KRAS2-4/ NRAS2-4/ BRAF wt/mt, PFS 18/12m, OS 28/22m, not significantly different: KRAS2-4 wt/mt, PFS 13/12m, OS 27/27m, not significantly different; NRAS2-4 wt/mt, PFS 16/12m, OS 28/22m, not significantly different; c.35 G &gt; A KRAS mt showed trendy worse PFS/OS 8/14m, respectively; BRAFmt/wt trendy worse PFS 8 vs 14m and OS 11 vs 28m. Conclusions: Retrospective analysis of clinical outcome of MCRC patients treated with intensive first line BEV added to triplet chemotherapy FIr-B/FOx seems to be not significantly affected by KRAS/ NRAS/ BRAF genotype.

A curative intent trimodality approach for advanced isolated abdominal nodal metastasis in metastatic colorectal cancer: Update of a single-institutional experience.

3556 Background: To define and update survival rates and relapse patterns in patients (pts) with isolated advanced abdominal nodal metastasis secondary to colorectal cancer (CRC), treated with curative intent using aggressive trimodality therapy. Methods: Fifty-seven pts with isolated advanced abdominal lymph node metastasis (retroperitoneal and mesenteric) secondary to colorectal cancer received trimodality therapy defined as chemotherapy delivered in conjunction with external beam radiotherapy (EBRT) followed by lymphadenectomy and intraoperative radiotherapy (IORT). Infusional 5-FU was the most common radiosensitizer used (66%, 38 pts). The median dose of EBRT was 50 Gy &amp; the median dose of intraoperative radiotherapy was 12.5 Gy. End points included distant metastasis, toxicities, local failure within EBRT field, recurrence within the intraoperative radiotherapy field, and survival. Results: 49% of pts were male, median age 50.5 yrs. All patients had ECOG ≤ 1. 27 pts had primary right sided colon cancer, 16 left sided colon cancer and 14 rectal primaries. Median time from initial CRC diagnosis to development of abdominal lymph node metastatic disease was 24 months (95% CI, 23.5-45.1 months). 84% (48 pts) had paraaortic nodal metastases, 12% (7 pts) had mesenteric nodal metastases, and 3% (2 pts) had both. With a median follow up of 89.4 months, the median overall survival and 5-year estimated survival rate were 53.2 months (95% CI, 46.4-78.8 months) and 42%, respectively. Median progression free survival was 19.3 months (95% CI, 15.6-32.8 months). 21 (37%) pts never developed distant disease. Outcome was not affected by disease sidedness, rectal primary, or mutational profile. Treatment was well tolerated without any grade 3/4 toxicities. Conclusions: The use of trimodality therapy including EBRT with radiosensitizing chemotherapy, lymphadenectomy and IORT produces sustainable long-term survival in selected metastatic CRC pts presenting with isolated retroperitoneal/mesenteric nodal relapse.

Efficacy and safety of chronomodulated hepatic arterial infusion (chronoHAI) of irinotecan (I), oxaliplatin (0) and fluorouracil (F) as salvage treatment for patients (pts) with heavily pretreated liver-predominant metastatic colorectal cancer (MCC).

e14582 Background: Effective treatment options are limited for MCC pts after failure on systemic chemotherapy. The combination of I, O and F as, chronoHAI could revert prior resistance through expl...

Ziv-aflibercept (Z) in combination with FOLFIRI for second-line treatment of patients with metastatic colorectal cancer (mCRC): Interim safety data from the global Aflibercept Safety and Quality-of-Life Program (ASQoP and AFEQT) in patients age 65 or older.

588 Background: The prespecified analysis of patients (pts) ≥65 y in the VELOUR study demonstrated a safety profile similar to that of ziv-aflibercept (Z) (known as aflibercept outside the United States) plus FOLFIRI in the overall VELOUR population. The global ASQoP/AFEQT Program comprises 2 clinical studies (ASQoP [NCT01571284]; AFEQT [NCT01670721]) designed to capture QoL and safety data from a population similar to VELOUR but treated in a real-life setting. We report safety data from the fourth interim analysis of pts ≥65 y. Methods: ASQoP/AFEQT are single-arm, open-label trials evaluating Z in metastatic colorectal cancer pts previously treated with an oxaliplatin-containing regimen. Eligible pts received Z (4 mg/kg) q2w on day 1 of each cycle followed by FOLFIRI until disease progression, unacceptable toxicity, death, or investigator/pt decision. Initial starting doses of FOLFIRI and dose modifications are at treating physician’s discretion. The % of pts ≥65 y with grade (G) 3 or 4 AEs in the combined safety population of ASQoP/AFEQT are compared with the prespecified analysis in pts ≥65 y from the Z + FOLFIRI arm of VELOUR. Results: At data cutoff, the overall safety population comprised 688 pts with ≥1 completed treatment cycle; 303 (44.1%) were ≥65 y. In the overall safety population ≥1 G3/4 AE was reported in 72.2% of pts vs. 83.5% in overall VELOUR. Most G3/4 AEs were G3. There were no reports of G4 hypertension, diarrhea, or fatigue. Median number of cycles was 6 in ASQoP/AFEQT and 9 in the Z + FOLFIRI arm of VELOUR. Table shows summary of AEs in pts ≥65 y. Conclusions: This interim analysis from ASQoP/AFEQT in pts ≥65 y has identified no new safety signals and provides additional safety data suggesting an acceptable toxicity profile in this real-life setting. Clinical trial information: NCT01571284. [Table: see text]

530P - Angiogenic Switch As Predictor of Response to Chemotherapy+ Bevacizumab in Patients with Metastatic Colorectal Cancer

ABSTRACT Aim: There is a need to develop biomarkers to predict the outcome of patients with metastatic colorectal cancer (CRC) treated with chemotherapy (Ch) plus Bevacizumab (B). It has been reported that during exposure to B there is a switch in the plasma levels of angiogenesis growth factors and related cytokines called angiogenic switch (AS). It is not known if changes in these circulating factors affect the response of patients with CRC to Ch + B. The aim of this study is to determine the influence of AS in the PFS in pts with metastatic CRC treated with Ch + B. Methods: Treatment naive, ECOG 0-1, metastatic CRC pts were eligible. Patients received induction treatment with XELOX-B or XELIRI-B at standard doses x 6 cycles followed by maintenance treatment with B plus Capecitabine until progression. Angiogenic related cytokines (HGF, PIGF, MCP-3, MM-9, Eotaxin, bFGF and IL-18) were prospectively analyzed at baseline and at the time of each CT evaluation (every eight weeks). AS + was defined by A) doubling of PIGF compared to baseline or B) PIGF elevation with a simultaneous elevation of any two of bFGF, HGF, MCP-3, IL-18 or MMP-9 compared to baseline. Results: Of 62 patients enrolled, 24 (36.7%) have progressed. Median PFS is 15.6 (95% CI: 8.3 to 16.4) months for the entire population. Twenty-five pts (40.3%) were AS + , out of which 23 were detected at first on-study evaluation (week 8). 18 were classified as AS+ based on both criteria, 4 based on criteria A) and 3 based on criteria B). One year (95% CI) PFS for AS+ pts was 82.6% (53.0% to 94.4%) versus 32.9% (13.9% to 53.5%) for AS- pts (p Conclusions: There is a statistically significant improved PFS amongst metastatic CRC AS+ pts treated with first line Ch + B combination compared with AS–pts. Disclosure: All authors have declared no conflicts of interest.

Next-generation sequencing (NGS) in metastatic colorectal cancer (CRC) patients (pts) in Israel.

e14548 Background: Many metastatic CRC pts progress after exhausting all approved standard therapies but maintain a good performance status and could be candidates for further therapy. We hypothesized that a comprehensive NGS assay (FoundationOne) could identify novel therapy targets not routinely considered for CRC pts. Methods: Hybridization capture of 3,769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to ≥ 50 ng of DNA extracted from CRC FFPE specimens and sequenced to high, uniform coverage. Genomic alterations (GA) including base substitutions, small indels, copy number alterations, and select gene fusions, were characterized and reported for each pt sample. Actionable GAs were defined as those identifying anti-cancer targeted therapies on the market or in registered clinical trials. Results: Thirty three CRC pts were included in the analysis(mean age, 54.2 years; range, 28-81; 52% male). Clinical samples used for NGS originated from colon (...

Differential prognosis of metastatic colorectal cancer patients post-progression to first-line triplet chemotherapy plus bevacizumab, FIr-B/FOx, according to second-line treatment and KRAS genotype.

Clinical outcome post-progression to first-line triplet chemotherapy (CT) plus bevacizumab (FIr-B/FOx) was evaluated in metastatic colorectal cancer (MCRC) patients (pts). Second-line treatment was selected according to fitness, KRAS genotype, previous efficacy and safety. Efficacy was evaluated and compared according to treatment or KRAS genotype, using log-rank analysis. Among 54 pts, median overall survival (OS) post-progression was 12 months, significantly better in 40 (74.1%) treated compared to 14 (25.9%) who died without further treatment. Second-line surgical treatment, 4 pts (7.4%), medical treatment, 36 pts (66.7%): triplet CT plus targeted agent, 10 (18.5%); triplet regimens, 19 (35.2%); doublet/monotherapy, 7 (13%). At follow-up of 14 months, objective response rate (ORR) was 38%, metastasectomies 12.5%, progression-free survival (PFS) 10 months, OS 14 months. According to treatment, ORR, metastasectomies, PFS and OS were significantly favourable in triplet CT plus targeted agent compared to triplet, respectively: 80%, 40%, 13 months, not reached; 28%, 6%, 8 months, 11 months. PFS and OS were significantly worse in c.35 G>A mutant compared to wild-type and/or other mutant patients. Prognosis after progression to first-line FIr-B/FOx may be significantly favourable in MCRC pts re-challenged with intensive regimens, and unfavourable in c.35 G>A KRAS mutant patients.