Refractory Colorectal Cancer Research Articles

Safety and tolerability results of the GATTO study, a phase Ib study combining the anti-TA-MUC1 antibody gatipotuzumab with the anti-EGFR tomuzotuximab or panitumumab in patients with refractory solid tumors.

2524 Background: The phase I GATTO study explored the feasibility, tolerability and preliminary activity of combining gatipotuzumab (GAT), a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin-1 (TA-MUC1) and an anti-EGFR antibody. Preclinical evidence suggests a complex interaction between TA-MUC1 and EGFR on the cell surface of epithelial tumors driving carcinogenesis processes and synergistic antibody dependent cell cytotoxicity activity with the dual targeting. Methods: Initially the study enrolled in a primary phase (PP) 20 patients with EGFR positive metastatic solid tumors, for whom no standard treatment was available. The first 6 patients were enrolled into a safety run-in phase and the number of dose-limiting toxicities (DLTs) was evaluated, in order to de-escalate the doses if needed. Patients received GAT administered at 1400 mg Q2W in combination with the glyco-optimized anti-EGFR antibody tomuzotuximab (TOM) at 1200 mg Q2W. Due to the risk of infusion related reactions (IRR), the first dose of TOM was reduced to 720 mg split over 2 consecutive days and three cycles of TOM monotherapy were given before start of treatment with GAT. As this regimen was proven safe, no DLT was observed and the initial dose remained unchanged, the study was amended to enroll in an expansion phase (EP) 30 additional patients with refractory colorectal cancer (CRC), non-small cell lung cancer (NSCLC), head and neck and breast cancers. TOM and GAT were given at the same doses and GAT treatment started already one week after the first dose of the anti-EGFR antibody. Additionally investigator had the choice to use a commercial anti-EGFR antibody in place of TOM. Results: By the time of the final analysis in January 2021, 52 refractory patients were enrolled and 50 received at least one dose of both GAT and anti-EGFR antibodies. Panitumumab (PAN) was used in 9 CRC patients. Because of the difference in treatment schedule, results are summarized separately for the 20 and 30 patients in PP and EP. Overall, the combined treatment was well tolerated and no DLT was observed in the whole study, nor related SAE or death. There were no treatment emergent adverse events (TEAEs) leading to dose interruptions or reductions in the PP and 2/30 (6.7%) patients in EP stopped both TOM and GAT. 16 IRRs were reported in 8/20 (40%) PP patients, and 40 IRRs in 10 (33.3%) EP patients. Only one event of chills was severe and only 6 events were related to GAT in the EP, all others to TOM. Other frequent TEAEs were those commonly observed with anti-EGFR treatment such as skin toxicity in 17 (85%) PP and 26 (86.7%) EP patients and hypomagnesemia in 10 (50%) PP and 7 (23.3%) EP patients. Conclusions: Combination of TA-MUC1 and EGFR targeting antibody is safe and feasible. Future studies should test this combination together with chemotherapy Clinical trial information: NCT03360734.

Effectiveness and tolerability of FOLFOXIRI regimen in the third- and subsequent lines of therapy in patients with metastatic colorectal cancer.

e15584 Background: Options of therapy are limited for patients with colorectal cancer who developed disease progression during standard 5-FU-, oxaliplatin-, and irinotecan-contained regimens. There is straight information about synergy of irinotecan (SN-38) and oxaliplatin gained from fundamental and early clinical trials. We aimed to analyze effectiveness and safety of triple drug-combination of 5-FU, oxaliplatin and irinotecan (FOLFOXIRI) in heavily pretreated patients with metastatic colorectal cancer. Methods: Patients with a metastatic colorectal cancer who received more than 2 lines of standard 5-FU-, oxaliplatin- and irinotecan-based doublet regimens with or without targeted therapy were included. Reinduction of chemotherapy in previous lines was allowed. The retrospective analysis of medical histories was done. Eligible patients had to receive number of cycles that were sufficient for response rate estimation. Disease response was evaluated according to RECIST 1.1 criteria. Survival analysis was performed using the Kaplan-Meier method. Tolerability was estimated by CTCAE v. 5.0. Results: Forty-six patients were included in retrospective per protocol analysis. The median follow-up was 19 months. The median number of previous lines of chemotherapy was 2 (2-6). Primary resistance to oxaliplatin- and irinotecan-based chemo during previous lines was noted in 20 patients (43%) and 16 patients (35%), respectively, while seven patients (15%) developed the primary resistance to both agents given in a sequential order. All patients were treated with targeted therapy during previous treatment lines. The median of FOLFOXIRI cycles was 8 (range, 2-19). Two patients (4%) were treated with FOLFOXIRI without any targeted agents. The objective response rate was 33% (n = 15). The disease stabilization was reached in 43% (n = 20). The disease control rate was 76% (n = 35). Eleven patients (24%) had the progression of disease at the first follow-up. The median progression free survival and median overall survival were 6 months and 11 months, respectively. Toxicity was evaluated in 35 patients. The most common severe adverse events (grade 3 and 4) were neutropenia (46%) and fatigue (26%). Treatment was delayed in 20 patients (57%), and 13 patients (37%) required dose reduction. One patient had to discontinue treatment due to unacceptable toxicity. Conclusions: According to our study FOLFOXIRI provides the objective response and increased life expectancy in heavily pretreated patients. The further assessment of FOLFOXIRI regimen for refractory colorectal cancer in the prospective trials is needed.

Open-label phase 1 study evaluating the tolerability and anti-tumor activity of selinexor and pembrolizumab in colorectal cancer.

e15579 Background: Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide and is heterogenous in its molecular features. Checkpoint inhibitors (CPIs) are approved for only about 5% of unresectable or metastatic CRC with MSI-high (MSI-H)/deficient MMR (dMMR); however, they do not benefit the majority of advanced CRC patients. Selinexor is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound with demonstrated activity in cancers with RAS mutations which are found in ̃50% of CRC. This study aims to evaluate the combination of selinexor with pembrolizumab, an anti-PD-L1 CPI, in chemotherapy refractory CRC. Methods: This phase 1/2, open-label study enrolled patients with advanced/metastatic CRC with progression after prior chemotherapy (1-3 lines for KRAS wild-type (wt), 1-2 for KRAS mutant (mut)), initially into a selinexor monotherapy period to evaluate bioavailability/bioequivalence of a new selinexor formulation, followed by a combination therapy where patients were treated with selinexor 80 mg PO QW and pembrolizumab 200 mg IV every 3 weeks. Patients were assessed for anti-tumor activity, safety, and tolerability of the combination therapy. Results: Enrollment in this study has been completed, and 29 patients have received at least 1 dose of combination therapy: median age was 56 years, 19 (65.5%) male, and 15 (51.7%) have RAS mutations. Median number of lines of prior antineoplastic therapies was 2. Median duration of combination treatment is 39 days (range: 1-246 days). Seventeen patients (58.6%) discontinued therapy mostly due to progressive disease, and 18 patients are evaluable for response. Best response was stable disease in 7 patients (6 of them (85.7%) had RAS mut CRC), and progressive disease in 11 patients (8 of them (72.7%) had RAS wt CRC. Median progression free survival (PFS) is 120 days for patients with RAS mut CRC and 41 days for those with RAS wt CRC. Notably, none of the RAS mut had MSI-H/dMMR CRC while one RAS wt with SD had MSI-H/dMMR CRC. The most common treatment-emergent adverse events (total; ≥Grade 3) were nausea (72.4%; 0%), vomiting (41.4%; 0%), decreased appetite (34.5%; 0%), and fatigue (34.5%; 10.3%). Seven patients (24.1%) had at least 1 treatment-emergent serious adverse event. Conclusions: Selinexor in combination with pembrolizumab has demonstrated disease control in patients with chemotherapy refractory advanced/metastatic CRC. Greater anti-tumor activity was observed in patients with RAS mutations despite absence of MSI-H/dMMR. The therapy was well tolerated with no unanticipated adverse events observed. These results warrant further investigation of selinexor in combination with pembrolizumab in CRC, particularly in CRC with RAS mutations. Clinical trial information: NCT04256707.

Influence of KDR Genetic Variation on the Efficacy and Safety of Patients with Chemotherapy Refractory Metastatic CRC Who Received Apatinib Treatment

BackgroundThe aim of the present study was to investigate the influence of kinase insert domain containing receptor (KDR) genetic variation on the efficacy of treatment and safety of patients with chemotherapy-refractory metastatic colorectal cancer (CRC) receiving apatinib.MethodsA total of 108 patients with chemotherapy refractory metastatic CRC who were treated with apatinib participated in this study retrospectively. Efficacy of the patients’ treatment was evaluated. Prognosis was carried out and safety profile was documented, respectively. Blood specimens and peripheral blood mononuclear cells (PBMC) of the patients were obtained for the analysis of genetic variation and KDR gene mRNA expression, respectively. The association between genotype status and clinical outcomes was presented.ResultsObjective response rate (ORR) and disease control rate (DCR) of the 108 patients with metastatic CRC receiving apatinib treatment were 5.6% and 69.4%, respectively. Survival analysis results exhibited that the median progression-free survival (PFS) and overall survival (OS) of the 108 patients with metastatic CRC was 3.6 months (95% confidence interval (CI): 3.03–4.17 months) and 8.9 months (95% CI: 7.57–10.23 months), respectively. Subsequently, the analysis of KDR genetic variation indicated that rs2071559 was of clinical significance. The minor allele frequency of rs2071559 was 0.22 and the genotype status corresponded with Hardy-Weinberg equilibrium (P=0.949). Prognosis analysis in a dominant inheritance manner through the combination of patients with TC and CC genotype showed that the median PFS of patients with TT genotype and TC/CC genotype was 4.1 and 3.0 months, respectively (P=0.012). Furthermore, the median OS of patients with the two genotypes was 10.5 and 6.1 months, respectively (P=0.007). Additionally, multivariate Cox regression analysis of OS showed that TC/CC genotype was an independent factor for OS (Hazard ratio (HR)=0.65, P=0.021). Interestingly, mRNA expression analysis suggested that the mRNA expression of KDR in PBMC differed significantly according to rs2071559 genotype status (P<0.001).ConclusionApatinib demonstrated a potentially superior clinical outcome for patients with chemotherapy-refractory metastatic CRC. KDR polymorphism rs2071559 could be used as a potential biomarker for the prognosis evaluation of patients with CRC receiving apatinib therapy.

The efficacy and safety of anlotinib in refractory colorectal cancer: A double-blinded, placebo controlled, randomized phase III ALTER0703 trial.

65 Background: The efficacy of late line treatments for metastatic colorectal cancer (mCRC) is still limited. Antiangiogenic therapy is one of standard treatments in mCRC. Anlotinib is a multitarget tyrosine kinase inhibitor, mainly targets VEGFR1-3. This phase III trial was conducted to evaluate anti-tumor efficacy and safety of anlotinib monotherapy in refractory mCRC. Methods: Aged 18 years or older mCRC patients were enrolled in 33 Chinese hospitals. They had received at least 2 lines of chemotherapy based treatments; had ECOG PS 0-1and adequate bone marrow, liver and renal function. Enrolled patients were 2-to-1 randomly assigned into anlotinib or placebo group and stratified by previous VEGF-targeting therapy (y/n) and time from diagnosis to metastases (&lt;/≥18 months). Anlotinib (12 mg/d, oral, d1-14, q3w) or matched placebo was administered plus best supportive care. Primary end point was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), Disease Control Rate (DCR), safety and quality of life. Results: Between December 2014 and August 2016, 421 patients were enrolled (282 in anlotinib and 137 in placebo group). By the cut-off date (August 31, 2018), the median OS was 8.6 months (95% CI 7.8-9.7) in anlotinib and 7.2 months (6.2-8.8) in placebo without statistical difference (p=0.87; HR=1.02 [0.82-1.27]). The median PFS in anlotinib group (4.1 months; 3.4-4.5) was significantly improved over that in placebo (1.5 months; 1.4-1.5), with a p&lt;0.0001 and a HR of 0.34 (0.27-0.43). Improvements of ORR and DCR were observed in anlotinib over placebo (Table). In subgroup patients with RAS/KRAS/BRAF wildtype, the median OS was statistically prolonged in anlotinib (11.0 months; 8.6-14.1; n=103) than that in placebo (6.7 months; 3.5- 11.1; n=46), HR=0.68 (0.47, 0.99), p=0.043. 52.5% of patients in anlotinib and 19.7% in placebo group experienced grade 3 or above treatment related adverse events (TRAEs). The most common grade ≥3 anlotinib related adverse events were hypertension (20.9%), increased γ-GT (7.1%) and hand-foot syndrome (6.4%), which were recovered by reducing dosage. Only 2 patients in anlotinib group had grade 5 TRAE, which were both hemorrhage. Conclusions: Anlotinib could provide clinical benefits by substantially prolonged PFS with manageable toxicity for Chinese refractory mCRC patients. Although median OS did not reach significant improvement. Those with RAS/KRAS/BRAF wildtype might be the potential patients in anlotinib treatment. Clinical trial information: NCT02332499. [Table: see text]

Circulating tumor DNA in identifying resistant subclones post EGFR blockade: Implications for EGFR rechallenge.

131 Background: For patients with metastatic RAS/RAF wild-type refractory colorectal cancer anti-EGFR therapy can be reused in subsequent lines of therapy. However, it is not entirely clear if all patients derive benefit. Increasingly it is been recognized that these patients acquire mechanisms of resistance which can be detected on circulating tumor DNA-based testing. We present a series of patients who had serial testing post EGFR therapy showing its feasibility and value. This would have implications for EGFR rechallenge. Methods: We reviewed records for patients who initially were noted to have tissue RAS/RAF Wild type who received prior anti-EGFR therapy and then subsequently had at least 1 circulating tumor DNA-based testing. Included a result of patients who had comprehensive NGS based profiling for both tissue as well as ctDNA. Results: Median duration of initial prior anti EGFR therapy was around 10 months. Table shows results of patient's tissue based genomic testing in parallel with the serial circulating tumor DNA-based testing that was done later when subsequent lines of therapy were being decided. As noted, known acquired mechanisms of resistance were noted in 100% of the cases. These included KRAS, NRAS, extracellular domain mutations in EGFR and BRAF mutations. Interestingly the levels of the sub-clones expressed as variant allele fraction percentage varied and decreased over time in relation to timing of the prior EGFR exposure. Additionally, these were noted to be polyclonal and the number of clones also varied including some disappearing over time during non-EGFR based therapy (EGFR holiday). Conclusions: Patient's post EGFR blockade may have multiple mechanisms of acquired resistance that can be easily detected on noninvasive liquid biopsies. These patients likely will not benefit from EGFR rechallenge based on the results of the recently reported CRICKET (NCT02296203) and CAVE (EudraCT number: 2017-004392-32) clinical trials. Rechecking liquid biopsy plasma RAS/RAF status is one thing that may be incorporated into practice with EGFR rechallenge only if acquired mechanisms of resistance are absent. [Table: see text]

Metformin plus lrinotecan in patients with refractory colorectal cancer: a phase 2 clinical trial

BackgroundPatients with refractory colorectal (CRC) cancer have few treatment options. This trial tests the combination of metformin and irinotecan in this setting.MethodsA phase 2 single-arm trial was conducted, patients received metformin 2500 mg orally a day plus irinotecan 125 mg/m2 intravenously weekly D1 and D8 every 21 days. The primary endpoint was the disease control rate according to the Response Evaluation Criteria in Solid Tumors version 1.1 at 12 weeks.ResultsBetween December 2015 and January 2018, 41 patients were enrolled. Seventeen patients (41%) met the primary endpoint of disease control in 12 weeks; hence, the study was deemed positive. The median progression-free survival was 3.3 months (CI 95%, 2.0–4.5 months), and the median overall survival was 8.4 months (CI 95%, 5.9–10.8 months). Both mutation RAS status and disease control at 12 weeks impacted overall survival in the multivariate model (HR 2.28, CI 95%, 1.12–4.7, p = 0.02; and HR 0.21, CI 95%, 0.08–0.5, p = 0.001, respectively). The most common adverse event was diarrhoea (29.2% grade 3).ConclusionsIn this trial, metformin plus irinotecan demonstrated disease control in patients with refractory CRC. Further trials with optimised diarrhoea control are needed to confirm these results.

Combination of long-acting TRAIL and tumor cell-targeted photodynamic therapy as a novel strategy to overcome chemotherapeutic multidrug resistance and TRAIL resistance of colorectal cancer

Chemotherapeutic multidrug resistance (MDR) is the major hindrance for clinical therapy of colorectal cancer (CRC). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with selective cytotoxicity might overcome MDR of CRC cells. Unfortunately, cross-resistance to TRAIL has been detected in many CRC cells, suggesting the need to combine TRAIL with sensitizers to combat refractory CRC. Our purpose is to explore the potential of combination therapy of TRAIL and tumor-cell targeted photodynamic therapy (PDT) in combating CRC with both chemotherapeutic MDR and TRAIL resistance.Methods: Tumor cell-targeted PDT was performed using a Ze-IR700 photosensitizer with high affinity for epidermal growth factor receptor (EGFR). The impact of PDT on the gene expression of CRC cells was revealed by RNA sequencing. The synergistic antitumor effect of long-acting TRAIL and PDT was evaluated in mice bearing tumor grafts of CRC cells with both chemotherapeutic MDR and TRAIL resistance.Results: Chemotherapeutic MDR and TRAIL resistance are common in CRC cells. Pretreatment of CRC cells with tumor cell-targeted PDT significantly (10-60 times) increased the sensitivity of these CRC cells to TRAIL by upregulating death receptors. Combination therapy, but not monotherapy, of long-acting TRAIL and PDT greatly induced apoptosis of CRC cells, thus efficiently eradicated large (~150 mm3) CRC tumor xenografts in mice.Conclusions: Tumor cell-targeted PDT extensively sensitizes CRC cells to TRAIL. Combination therapy of long-acting TRAIL and PDT is promising to combat CRC with both chemotherapeutic MDR and TRAIL resistance, which might be developed as a novel strategy for precision therapy of refractory CRC.

Tolerance and Efficacy of Regorafenib according to UGT Pharmacogenetical Status in the Treatment of Metastatic Refractory Colorectal Cancer

Introduction: Regorafenib is a multi tyrosin-kinase inhibitor prescribed in metastatic refractory colorectal cancer treatment. Its toxicity is significant but inconstant. The metabolism of regorafenib includes oxydation via cytochrome P3A4, then glucuroconjugation. A pharmacogenetical approach of mutational status of Uridine-Diphospho-Glucuronosyltransfersase (UDP-glucuronosyl-transferase, UGT) could be a strategy to optimise the use of regorafenib. Patients and Method: This is a restrospective, unicentric study. All adult patients treated with regorafenib for a metastatic colorectal cancer in our center between 2013 and 2017 were analysed. UGT1A1 polypmorphism was previously researched in the laboratory after written informed consent. Results: Thirty-five patients received regorafenib during the study period. A TA repetition in UGT1A1 gene was present for 16 patients including two Gilbert syndrome. There were no more adverse events on patients with a heterozygous TA repetition or with a Gilbert syndrome compared with patients without UGT polymorphism, whatever the dosage at initiation of regorafenib. Adverse events grade 2 or superior, and grade 3 or superior tended to be more noticeable when the starting dose was 120 or 160 mg per day compared to 80 mg per day, but not statistically significant. No difference was observed on progression-free survival neither depending on UGT status nor depending on initating dose of regorafenib. Conclusion: This is a preliminary study evaluating safety of regorafenib according to UGT1A1 polymorphism. Larger and prospective studies are needed to evaluate dose-escalation strategy in patients with variable activity of glucuroconidation, especially Gilbert syndrome, or with abnormalities in other UGT enzymes such as UGT1A9.

Precision Medicine for the Management of Therapy Refractory Colorectal Cancer.

In this analysis, we examined the efficacy, feasibility, and limitations of molecular-based targeted therapies in heavily pretreated metastatic colorectal cancer (mCRC) patients after failure of all standard treatments. In this single-center, real-world retrospective analysis of our platform for precision medicine, we mapped the molecular profiles of 60 mCRC patients. Tumor samples of the patients were analyzed using next-generation sequencing panels of mutation hotspots, microsatellite instability testing, and immunohistochemistry. All profiles were reviewed by a multidisciplinary team to provide a targeted treatment recommendation after consensus discussion. In total, we detected 166 mutations in 53 patients. The five most frequently found mutations were TP53, KRAS, APC, PIK3CA, and PTEN. In 28 cases (47% of all patients), a molecularly targeted therapy could be recommended. Eventually, 12 patients (20%) received the recommended therapy. Six patients (10%) had a clinical benefit. The median time to treatment failure was 3.1 months. Our study demonstrates the feasibility and applicability of using targeted therapies in daily clinical practice for heavily pretreated mCRC patients. This could be used as a targeted treatment option in half of the patients.

A phase I/II study of JX-594 oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer

A phase I/II study of JX-594 oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer

Safety and efficacy of AMG 820, an anti-colony-stimulating factor 1 receptor antibody, in combination with pembrolizumab in adults with advanced solid tumors

BackgroundTo determine the safety and efficacy of the anti-colony-stimulating factor 1 receptor (anti-CSF1R) monoclonal antibody AMG 820 in combination with pembrolizumab in patients with select solid tumors.Patients and methodsPatients had...

Prognostic Value of the Pace of Tumor Progression as Assessed by Serial 18F-FDG PET/CT Scan and Liquid Biopsy in Refractory Colorectal Cancer: The CORIOLAN Trial

Simple SummaryManagement of chemorefractory colorectal cancer patient is challenging, and reliable tools which can predict individual patient prognosis and help the decision making are needed. In this study, we hypothesized that the natural pace of cancer growth and progression, as assessed by early changes of a number of imaging and circulating biomarkers which are surrogates of tumor burden (i.e., metabolically active tumor volume, carcinoembryonic antigen, circulating tumor cells and circulating tumor DNA), could predict patient prognosis. By prospectively recruiting 47 eligible patients who had measurements of these biomarkers taken two weeks apart in the absence of any active anti-cancer treatment, we failed to demonstrate our hypothesis. On the other hand, we found that baseline assessment of the same biomarkers was associated with survival outcomes. Larger studies are needed to confirm these findings and translate them into applications for clinical practice.Introduction: Decision making in refractory colorectal cancer (rCRC) is challenging, with limited data available to predict patient outcome. We conducted a study to assess the pace of cancer progression as a potential prognostic and decision tool. Methods: CORIOLAN was a prospective, single-center, single-arm trial recruiting refractory CRC patients with an ECOG performance status of ≤1 and an estimated life expectancy of ≥12 weeks. 18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan and blood sample collection were carried out at baseline and after 2 weeks with no cancer treatment given between these timepoints. The primary objective was to evaluate the association between pace of cancer progression as defined by changes of the whole-body metabolically active tumor volume (WB-MATV) and overall survival (OS). Exploratory objectives included evaluation of the prognostic value of circulating cell-free DNA (cfDNA), circulating tumor cells (CTCs) and carcinoembryonic antigen (CEA). Results: 47 eligible patients who had received a median number of 5 (range 2–8) prior treatments were enrolled. At the time of analysis, 45 deaths had occurred, with 26% of patients dying within 12 weeks. The median OS was 6.3 months (range 0.4–14.3). The median relative delta between WB-MATV at baseline and 2 weeks was +21%. Changes of WB-MATV, however, failed to predict OS (hazard ratio (HR) 1.3, p = 0.383). Similarly, no association was observed between changes of any of the circulating biomarkers investigated and prognosis. By contrast, high WB-MATV (4.2 versus 9.4 months; HR 3.1, p = 0.003), high CEA (4.4 versus 7.0 months; HR 1.9, p = 0.053), high cfDNA (4.7 versus 7.0 months; HR 2.2, p = 0.015) and high CTC count (3.3 versus 7.5 months; HR 6.5, p < 0.001) at baseline were associated with worse OS. Conclusions: In this study, approximately 1 out of 4 refractory CRC patients who were judged to have a life expectancy >12 weeks actually died within 12 weeks. Baseline assessment of WB-MATV, cfDNA, CTCs and CEA, but not early change evaluation of the same, may help to refine patient prognostication and guide management decisions.

477P Genomically-matched therapy in refractory CRC according to ESCAT

Next Generation Sequencing (NGS) emerges as an actionability-searching strategy in the molecularly heterogeneous context of colorectal cancer (CRC)1, but its clinical impact remains unknown in a refractory setting. We aim to determine the value of NGS in terms of enrolment in genomically-guided clinical trials (gCT) in a cohort of metastatic CRC (mCRC) patients (pts) according to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT[E]) 2. 1Muzny et al, Nature 2012; 2Mateo et al, Ann Oncol 2018. Target population are pts with refractory mCRC included in NGS program (DNA seq for mutations [mut], amplifications [amp] or deletions [del] and RNA seq for fusions [fus]) for therapeutic purposes from 2015-2019. 159 pts have been identified, 122 left-sided (LC) vs 37 right-sided (RC). Basal molecular profile locally performed showed: 80 pts RAS WT (E IA), all treated with anti-EGFR; 9 pts BRAF V600E (E IA), 6/9 received BRAF-inhibitors; 3 pts MSI (E IB), 2/3 received immunotherapy. NGS (149 mut panel, 29 amp/del panel, 27 fus panel) was performed on archival FFPE samples of primary tumors (85%) and metastases (15%) of 113 LC and 36 RC. 10 pts have insufficient material. NGS unveiled druggable alterations different from basal profile in 24 pts (16%): 2 ERBB2 amp (EIB), 6 KRAS G12C mut (EIIIA), 3 ERBB2 mut (EIIIA), 5 PIK3CA mut in RAS –BRAF WT (EIVA), 3 BRAF nonV600E mut (EIVA), 4 RNF43 mut (EIVA), 1 MET amp (EIVA), distributed as 7 RC (19%) and 17 LC (15%). Only 4 pts were included in gCT, 5 deteriorated clinically and 15 were enrolled in other unmatched trials or received SoC because lack of slots in gCT. NGS unravels 16% of ESCAT-defined druggable alterations with final inclusion rate in gCT of 4/159 pts. Further data is needed to better define the value of NGS in mCRC, considering the evolving landscape of gCT and biomarkers, as well as basal tumor biology and clonal selection.

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.

Mechanism of action of a T cell-dependent bispecific antibody as a breakthrough immunotherapy against refractory colorectal cancer with an oncogenic mutation

T cell-dependent bispecific antibody (TDB)-induced T cell activation, which can eliminate tumor cells independent of MHC engagement, is expected to be a novel breakthrough immunotherapy against refractory cancer. However, the mechanism of action of TDBs has not been fully elucidated thus far. We focused on TDB-induced T cell–tumor cell contact as an important initial step in direct T cell-mediated tumor cell killing via transport of cytotoxic cell proteases (e.g., granzymes) with or without immunological synapse formation. Using an anti-EGFR/CD3 TDB, hEx3, we visualized and quantified T cell–tumor cell contact and demonstrated a correlation between the degree of cell contact and TDB efficacy. We also found that cytokines, including interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) secreted by activated T cells, damaged tumor cells in a cell contact-independent manner. Moreover, therapeutic experiences clearly indicated that hEx3, unlike conventional anti-EGFR antibodies, was effective against colorectal cancer (CRC) cells with mutant KRAS, BRAF, or PIK3CA. In a pharmacokinetic analysis, T cells spread gradually in accordance with the hEx3 distribution within tumor tissue. Accordingly, we propose that TDBs should have four action steps: 1st, passive targeting via size-dependent tumor accumulation; 2nd, active targeting via specific binding to tumor cells; 3rd, T cell redirection toward tumor cells; and 4th, TDB-induced cell contact-dependent (direct) or -independent (indirect) tumor cell killing. Finally, our TDB hEx3 may be a promising reagent against refractory CRC with an oncogenic mutation associated with a poor prognosis.

The UPMC Hillman Cancer Center Approach to the Management of Colorectal Cancer During the COVID-19 Pandemic Era

The UPMC Hillman Cancer Center Approach to the Management of Colorectal Cancer During the COVID-19 Pandemic Era

Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer.

Improving response to epidermal growth factor receptor (EGFR)-targeted therapies in patients with advanced wild-type (WT) RAS colorectal cancer (CRC) remains an unmet need. In this preclinical work, we evaluated a new therapeutic combination aimed at enhancing efficacy by targeting cancer cell metabolism in concert with EGFR. We hypothesized that combined blockade of glutamine metabolism and EGFR represents a promising treatment approach by targeting both the “fuel” and “signaling” components that these tumors need to survive. To explore this hypothesis, we combined CB-839, an inhibitor of glutaminase 1 (GLS1), the mitochondrial enzyme responsible for catalyzing conversion of glutamine to glutamate, with cetuximab, an EGFR-targeted monoclonal antibody in preclinical models of CRC. 2D and 3D in vitro assays were executed following treatment with either single agent or combination therapy. The combination of cetuximab with CB-839 resulted in reduced cell viability and demonstrated synergism in several cell lines. In vivo efficacy experiments were performed in cell-line xenograft models propagated in athymic nude mice. Tumor volumes were measured followed by immunohistochemical (IHC) analysis of proliferation (Ki67), mechanistic target of rapamycin (mTOR) signaling (pS6), and multiple mechanisms of cell death to annotate molecular determinants of response. In vivo, a significant reduction in tumor growth and reduced Ki67 and pS6 IHC staining were observed with combination therapy, which was accompanied by increased apoptosis and/or necrosis. The combination showed efficacy in cetuximab-sensitive as well as resistant models. In conclusion, this therapeutic combination represents a promising new precision medicine approach for patients with refractory metastatic WT RAS CRC.

P-233 Metformin combined with irinotecan in patients with refractory colorectal cancer: A phase 2 trial

Patients with advanced colorectal cancer (CRC) have few and expensive treatment options. The combination of irinotecan and metformin had been tested in animal models with promising results. The primary end-point of this study was to determine if metformin combined with irinotecan increases the disease control rates in patients with CRC. The secondary endpoints were progression-free survival (PFS); overall survival (OS); and toxicity rates.

18F-FDG PET scan and liquid biopsy as tools to assess the pace of tumor progression and to predict overall survival (OS) in refractory colorectal cancer (rCRC): The CORIOLAN trial.

e16012 Background: Decision making in rCRC patients (pts) who have exhausted all available therapies is challenging. Clinical trials, treatment re-challenge and best supportive care are possible options. There are limited data, however, to predict pt outcome and guide treatment choices. Methods: CORIOLAN was a prospective, single-centre, single-arm trial. Eligible pts had to have an ECOG PS of ≤1, a life expectancy of ≥12 weeks (wks) and had to have received prior standard chemotherapy and targeted agents. No cancer treatment was allowed within 4 wks prior to study entry. 18F-FDG PET scan and blood sample collection were carried out at baseline and after 2 wks. No treatment was given between these timepoints, while further management was left to the treating physician. The primary objective was to evaluate the association between tumour metabolic progression index as defined by changes of the whole-body metabolically active tumour volume (WB-MATV) and OS. Exploratory objectives included evaluation of the prognostic value of circulating biomarkers such as cell-free DNA (cfDNA), circulating tumour cells (CTCs, CellTracks Analyzer II, CellSearch) and CEA. Validated cut-off values, Kaplan-Meier method, Cox proportional hazards model and logrank tests were used (R version 3.5.1). Results: From 2012 to 2018, 47 eligible pts were enrolled. Median age: 65 years (38-82). ECOG PS 1: 64%. Males: 53%. Left-sided tumours: 71%. Metastases: lung (83%), liver (66%), lymph-nodes (45%), peritoneum (30%), bone (21%). Known RAS/BRAF mutations: 57%/0%. Median number of prior treatments: 5 (2-8). At the time of analysis, 45 deaths had occurred, with 26% of pts dying within 12 wks. The median relative delta between WB-MATV at baseline and after 2 wks was +21%. Changes of WB-MATV, however, failed to predict OS (p≥0.383). Similarly, no association was observed between changes of any of the circulating biomarkers investigated and prognosis. By contrast, low WB-MATV (9.4 vs 4.2 months, HR 0.65, p = 0.003), low cfDNA (7.0 vs 4.7 months, HR 0.58, p = 0.015), low CTC count (7.5 vs 3.3 months, HR 0.67, p &lt; 0.001) and low CEA (7.0 vs 4.4 months, HR 0.58, p = 0.053) at baseline were associated with longer OS. Conclusions: This study confirms the inaccuracy of life expectancy estimation for rCRC pts based on a physician judgement largely relying on conventional criteria. Baseline assessment of WB-MATV, cfDNA, CTCs and CEA, but not early change evaluation of the same, may help to refine pt prognostication and guide management decisions. Clinical trial information: NCT01591590 .