Chemotherapy-refractory mCRC Research Articles

Transverse Colon Primary Tumor Location as a Biomarker in Metastatic Colorectal Cancer: A Pooled Analysis of CCTG/AGITG CO.17 and CO.20 Randomized Clinical Trials.

Sidedness is prognostic and predictive of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). Transverse colon has been historically excluded from several analyses of sidedness and the optimal division between left- and right-sided colorectal cancer is unclear. We investigated transverse colon primary tumor location as a biomarker in mCRC. Pooled analysis of CCTG/AGITG CO.17 and CO.20 trials of cetuximab in chemotherapy-refractory mCRC. Outcomes of patients with RAS/BRAF wild-type (WT) mCRC from CO.17 and KRAS WT mCRC from CO.20 were analyzed according to location. A total of 553 patients were analyzed, 32 (5.8%) with cancers from the transverse, 101 (18.3%) from right, and 420 from (75.9%) left colon. Transverse mCRC failed to reach significant benefit from cetuximab versus best supportive care (BSC) for overall survival [OS; median, 5.9 vs. 2.1 months; HR, 0.63; 95% confidence interval (CI), 0.28-1.42; P=0.26] and progression-free survival (PFS; median, 1.8 vs. 1.3 months; HR, 0.57; 95% CI, 0.26-1.28; P=0.16). Analyzing exclusively patients randomized to cetuximab, right-sided and transverse had comparable outcomes for OS (median, 5.6 vs. 5.9 months; HR, 0.82; 95% CI, 0.50-1.34; P=0.43) and PFS (median, 1.9 vs. 1.8 months; HR, 0.78; 95% CI, 0.49-1.26; P=0.31). Patients with left-sided mCRC had superior outcomes with cetuximab compared with transverse for OS (median, 9.7 vs. 5.9 months; HR, 0.42; 95% CI, 0.27-0.67; P=0.0002) and PFS (median, 3.8 vs. 1.8 months; HR, 0,49; 95% CI, 0.31-0.76; P=0.001). Location was not prognostic in patients treated with BSC alone. Transverse mCRC has comparable prognostic and predictive features with right-sided mCRC.

Efficacy and Safety of Apatinib in the Treatment of Chemotherapy-Refractory Metastatic Colorectal Cancer: A Systematic Review.

The purpose of this study was to systematically review the current evidence on apatinib and offer a better understanding of its safety and efficacy in metastatic colorectal cancer (mCRC) patients who have not responded to standard chemotherapies. This systematic review was conducted using research from the last 10 years (May 30, 2012, to May 30, 2022) and was obtained from the following databases: PubMed, PubMed Central (PMC), ScienceDirect, and Google Scholar. After removing duplicates, screening titles and abstracts, and applying eligibility criteria and quality appraisal, 11 articles were left for this systematic review (one meta-analysis, eight non-randomized studies, and two traditional reviews). Out of the 11 studies, six were on apatinib monotherapy, while three were on apatinib combination therapy. Apatinib has demonstrated efficacy in the monotherapy and combination therapy trials and has exhibited an acceptable safety profile as the adverse events were predominantly graded 1-2 and could be easily managed. Therefore, apatinib is an encouraging candidate for third-line therapy in chemotherapy-refractory mCRC patients. This conclusion should be confirmed and validated by studies with larger, randomized clinical trials to gain better insight and to directly compare the efficacy and safety of apatinib with all current third-line therapies together so that clinicians can easily assess which treatment modality is superior for chemotherapy-refractory mCRC patients.

Pembrolizumab plus azacitidine in patients with chemotherapy refractory metastatic colorectal cancer: a single-arm phase 2 trial and correlative biomarker analysis

BackgroundDNA mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is not responsive to pembrolizumab monotherapy. DNA methyltransferase inhibitors can promote antitumor immune responses. This clinical trial investigated whether concurrent treatment with azacitidine enhances the antitumor activity of pembrolizumab in mCRC.MethodsWe conducted a phase 2 single-arm trial evaluating activity and tolerability of pembrolizumab plus azacitidine in patients with chemotherapy-refractory mCRC (NCT02260440). Patients received pembrolizumab 200 mg IV on day 1 and azacitidine 100 mg SQ on days 1–5, every 3 weeks. A low fixed dose of azacitidine was chosen in order to reduce the possibility of a direct cytotoxic effect of the drug, since the main focus of this study was to investigate its potential immunomodulatory effect. The primary endpoint of this study was overall response rate (ORR) using RECIST v1.1., and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Tumor tissue was collected pre- and on-treatment for correlative studies.ResultsThirty chemotherapy-refractory patients received a median of three cycles of therapy. One patient achieved partial response (PR), and one patient had stable disease (SD) as best confirmed response. The ORR was 3%, median PFS was 1.9 months, and median OS was 6.3 months. The combination regimen was well-tolerated, and 96% of treatment-related adverse events (TRAEs) were grade 1/2. This trial was terminated prior to the accrual target of 40 patients due to lack of clinical efficacy. DNA methylation on-treatment as compared to pre-treatment decreased genome wide in 10 of 15 patients with paired biopsies and was significantly lower in gene promoter regions after treatment. These promoter demethylated genes represented a higher proportion of upregulated genes, including several immune gene sets, endogenous retroviral elements, and cancer-testis antigens. CD8+ TIL density trended higher on-treatment compared to pre-treatment. Higher CD8+ TIL density at baseline was associated with greater likelihood of benefit from treatment. On-treatment tumor demethylation correlated with the increases in tumor CD8+ TIL density.ConclusionsThe combination of pembrolizumab and azacitidine is safe and tolerable with modest clinical activity in the treatment for chemotherapy-refractory mCRC. Correlative studies suggest that tumor DNA demethylation and immunomodulation occurs. An association between tumor DNA demethylation and tumor-immune modulation suggests immune modulation and may result from treatment with azacitidine.Trial registration ClinicalTrials.gov, NCT02260440. Registered 9 October 2014, https://clinicaltrials.gov/ct2/show/NCT02260440.

A cost-utility analysis of SIR-Spheres Y-90 resin microspheres versus best supportive care in the treatment of unresectable metastatic colorectal cancer refractory to chemotherapy in the UK

Background Limited treatment options are available in chemotherapy-refractory or -intolerant metastatic colorectal cancer (mCRC). The objective of the present analysis was to evaluate the cost-utility of SIR-Spheres Y-90 resin microspheres relative to best supportive care (BSC) in the treatment of chemotherapy refractory mCRC from the perspective of the UK national healthcare payer. Methods A cost-utility model was developed in Microsoft Excel to simulate transitions from progression-free survival to post-progression survival and death in patients with mCRC. Unit costs were captured in 2019 pounds sterling (GBP) based on the literature, formulary listings, and National Health Service (NHS) England reference costs. Future costs and effects were discounted at 3.5% per annum. A series of one-way sensitivity analyses, and probabilistic sensitivity analysis (PSA) were conducted. Results The base case analysis showed that SIR-Spheres Y-90 resin microspheres would result in an increase in discounted quality-adjusted life years gained from 0.69 quality-adjusted life years (QALYs) to 1.50 QALYs, with an associated increase in cost from GBP 15,268 to GBP 34,168 yielding an incremental cost-utility ratio of GBP 23,435 per QALY. PSA showed that there would be a 56% likelihood that SIR-Spheres Y-90 resin microspheres would be cost-effective relative to BSC at a willingness-to-pay threshold of GBP 30,000 per QALY gained. Conclusions This cost-utility analysis showed that, relative to BSC, SIR-Spheres Y-90 resin microspheres would be a cost-effective treatment option for patients with mCRC in the UK setting from the national healthcare payer perspective.

Results from the safety lead-in for a phase II study of pembrolizumab in combination with binimetinib and bevacizumab in patients with refractory metastatic colorectal cancer (mCRC).

4031 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition and VEGF inhibition have immunomodulatory effects (upregulation of tumor major histocompatibility complex-I expression, enhanced T-cell infiltration, reduced MDSCs and Tregs in tumors) supporting clinical evaluation of combined MEKi (B), anti–PD-1 (P), and anti-VEGF (BV) in pts with mCRC. We hypothesize that the combination of binimetinib, pembrolizumab, and bevacizumab (BPBV) will result in greater clinical benefit than pembrolizumab alone. Methods: Patients with chemotherapy-refractory mCRC were evaluated (20 planned in the safety lead-in and 50 planned for total accrual). B was dosed at 45mg PO BID, P was administered at 200mg IV Q21 days, and BV was administered at 7.5mg/kg IV Q21 days. Primary objectives were safety, tolerability, and investigator-assessed ORR by RECIST 1.1. Clinical benefit rate (CR+PR+SD) and progression-free survival were secondary endpoints. Descriptive statistics were used to summarize safety and clinical activity. Results: As of January 9, 2020, 21 pts (10 KRAS/NRASmt, 11 RASwt, 21 MSS) were enrolled into the safety lead-in and were evaluable. The median number of prior therapies was 6. The BPBV combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 38%, respectively. The most frequent related Gr 3-4 AEs were aceniform rash, diarrhea, and hypertension (19%, 14%, 14% respectively). No treatment-related Gr 5 AEs occurred. A total of 17 patients were evaluable for response. Confirmed PR was observed in 2 pts (12%). SD was noted in 14 patients (82%) leading to a clinical benefit rate of 94%. 1 patient had PD as the best response to treatment. Median PFS was 6.4 months (95% CI 4.2-8.9). Molecular determinants, immune biomarkers, and updated tumor assessments of response will be presented. Conclusions: B + P + BV demonstrated a tolerable safety profile and improvements in ORR and clinical benefit rate compared to those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts were durable, suggesting benefit of this novel combination in a patient population refractory to immune therapies. Clinical trial information: NCT03475004 .

Apatinib Monotherapy for Chemotherapy-Refractory Metastatic Colorectal Cancer: A Multi-centre, Single-Arm, Prospective Study

Angiogenesis inhibitors are of considerable interest for treating metastatic colorectal cancer (mCRC). This trial evaluated the efficacy and safety of apatinib in chemotherapy-refractory mCRC. Apatinib 500 mg was administered daily to patients who had progressed after two or more lines of standard fluorouracil-based chemotherapy. Primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Overall, 48 patients were enrolled. ORR and DCR were 8.3% (4/48) and 68.8% (33/48), respectively. Median PFS and OS were 4.8 (95% confidence interval [CI], 3.653–5.887) and 9.1 months (95% CI, 5.155–13.045), respectively, and did not differ between subgroups stratified by previous anti-angiogenic therapies. The most prevalent grade 3–4 adverse events were hypertension (12.5%), hand-foot syndrome (HFS, 10.4%), thrombocytopenia (10.4%), and proteinuria (8.3%). Low baseline neutrophil/lymphocyte ratio (NLR, hazard ratios [HR], 0.619; P = 0.027), early carbohydrate antigen 19–9 (CA19–9) decrease (HR, 1.654; P = 0.016), and HFS (HR, 2.087; P = 0.007) were associated with improved PFS. In conclusion, apatinib monotherapy demonstrated encouraging efficacy with manageable toxicities in chemotherapy-refractory mCRC. Previous anti-angiogenic therapies did not influence outcomes. Baseline NLR, early CA19-9 decrease, and HFS could predict the efficacy of apatinib.

Trifluridine/tipiracil: A practical guide to its use in the management of refractory metastatic colorectal cancer in Australia.

Trifluridine/tipiracil is available on the Australian Pharmaceutical Benefits Scheme for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-vascular endothelial growth factor agents and anti-epidermal growth factor receptor agents. This article reviews trifluridine/tipiracil clinical data and presents practical information on its use in the management of refractory mCRC in Australia. Whereas the primary mechanism of action of fluoropyrimidines such as fluorouracil (5-FU) and capecitabine is enzyme inhibition of nucleotide synthesis, trifluridine/tipiracil primarily acts by incorporation into DNA, resulting in DNA dysfunction. Trifluridine/tipiracil has activity in patients with 5-FU-resistant tumors and can be considered in patients with prior intolerance or toxicity to 5-FU. In the pivotal phase III RECOURSE trial evaluating trifluridine/tipiracil in chemotherapy-refractory mCRC, efficacy benefits were observed across all a priori prognostic subgroups including those defined by age (≥65 and ≥75 years), geographical origin, primary tumor site or KRAS status. Trifluridine/tipiracil therapy benefits appropriately selected patients who have an ECOG performance status of 0 or 1, with no more than mild hepatic impairment or mild-to-moderate renal impairment, and who are capable of adhering to oral therapy safely. Appropriate dosing, monitoring for adverse events and effective management of side effects are essential.

Duration of previous treatment as a prognostic factor in metastatic colorectal cancer treated with trifluridine/tipiracil.

We herein describe the findings from the trifluridine/tipiracil (TAS-102) Compassionate Use program in Latvia, set up prior to marketing authorization for the management of pretreated patients with metastatic colorectal cancer (mCRC). The efficacy and safety of TAS-102 in patients with refractory mCRC were evaluated in the phase III trial RECOURSE. A previous report confirmed neutropenia and duration of previous treatment for mCRC as prognostic factors in TAS-102 users. The aim of the present study was to analyze possible prognostic factors, such as neutropenia, in TAS-102 responders. A retrospective analysis of 14 patients who received TAS-102 chemotherapy in two institutions in Latvia (Clinic of Oncology of Pauls Stradins Clinical University Hospital and Oncology Centre of Riga East University Hospital) was performed. Grade 3-4 neutropenia was observed in 28% of the patients. In patients with grade 3-4 neutropenia the median progression-free survival (mPFS) was 7 months, whereas in those without neutropenia the mPFS was 5 months [hazard ratio (HR)=0.24, P=0.033]. In 64% of the patients, the duration of previous treatment was >18 months. In patients treated for >18 months from the start of first-line mCRC treatment the mPFS was 7 months, whereas in those treated for ≤18 months from the start of first-line mCRC treatment the mPFS was 5 months (HR=0.15, P=0.029). Therefore, a longer time from mCRC diagnosis until disease progression may be used to select chemotherapy-refractory mCRC patients for TAS-102 treatment. Furthermore, severe neutropenia may be considered as a surrogate marker for predicting TAS-102 treatment outcomes.

Assessment of the cardiac safety between cetuximab and panitumumab as single therapy in Chinese chemotherapy-refractory mCRC.

ObjectiveThe cardiac safety of cetuximab and panitumumab, particularly as single agents, has not been investigated extensively. This trial was designed to specifically evaluate the cardiac safety of cetuximab and panitumumab as single therapy in Chinese chemotherapy-refractory metastatic colorectal cancer (mCRC) patients.Patients and methodsSixty-one patients received cetuximab at an initial dose of 400 mg/m2 intravenously over 120 minutes on day 1 (week 1), followed by a maintenance dose of 250 mg/m2 intravenously over 60 minutes on day 1 of each 7-day cycle. Forty-three patients received panitumumab at a dose of 6 mg/kg intravenously every 14 days. Routine laboratory tests and electrocardiogram (ECG) were performed at baseline, during therapy and after the treatment (4th and 10th months). The incidence of elevation of troponin I ultra (TNI Ultra), abnormal ECGs, cardiac events and noncardiac adverse events (AEs) were recorded and analyzed.ResultsThe incidence of elevation of TNI Ultra between the two groups had no significance (p=0.681), and TNI Ultra+ was observed more frequently in patients with metastases to more than three organs and they received fourth or above lines of chemotherapy. The most frequent abnormal ECG manifestations were nonspecific ST changes and QTc prolongation in the two groups. At 10 months after treatment, most of the abnormal ECG manifestations were reversed. The most common cardiac AEs of cetuximab and panitumumab included palpitations, dyspnea, chest pain and arrhythmias requiring treatment. Most of the events were mild and transient. The incidence of cardiac AEs had no significant difference between the two groups. Rash was still the most common noncardiac AE in both groups.ConclusionCetuximab and panitumumab showed favorable cardiac safety as single agents for Chinese chemotherapy-refractory mCRC patients. But monitoring for cardiac AEs is still necessary throughout the entire treatment process.

Results of the Quad wild type arm of the AGITG ICECREAM study: A randomised phase II study of cetuximab alone or in combination with irinotecan in patients with refractory metastatic colorectal cancer with no mutations in KRAS, NRAS, BRAF or PIK3CA.

3572 Background: Cetuximab (cet) increases survival in RAS wild-type (WT) metastatic colorectal cancer (mCRC) in first-line and chemorefractory patients (pts). Adding irinotecan (iri) to cet in refractory pts who had progressed on iri increased response and delayed progression in the BOND trial, which was conducted prior to recognition that RAS mutations are predictive of EGFR-inhibitor (EGFR-I) resistance. Subsequent trials in chemorefractory pts used single agent EGFR-I as standard. In the era of biomarker selection, the benefit of continuing iri versus single agent EGFR-I had not been resolved. Methods: ICECREAM is a randomised phase II trial evaluating cet v cet + iri in chemotherapy-refractory mCRC, stratified for KRAS G13D mutation (previously reported) or no mutations in KRAS, NRAS, BRAF and PI3KCA (Quad WT ). EGFR-I naïve, ECOG PS 0-1 pts, progressing within 6 months of iri and refractory (or intolerant) to fluoropyrimidine and oxaliplatin were randomised to cet 400mg/m2 IV loading then 250mg/m2 weekly +/- iri 180mg/m2q2 wks. The primary endpoint was progression-free survival at 6 months (6m PFS); secondary endpoints were response rate (RR), overall survival (OS), toxicity and quality of life (QOL). Results: From Nov 2012 to June 2016, 48 Quad WT pts were recruited: 2 ineligible (not iri-refractory, BRAF mutation) wre not included for analyses and a further 2 not evaluable for response. Characteristics were balanced between cet (n = 21) v cet-iri (n = 25), except for sex (male 62 v 72%) and primary site (left 95 v 68%). 6m PFS rate was 14% v 41%; HR 0.39 (95% CI: 0.20–0.78, p = 0.008). RR was 10% (2 PR) v 36% (1 CR, 8 PR); p = 0.04. Toxicities were higher with cet-iri; at least one grade 3/4 adverse event in 50 v 23%. No differences in global or specific QOL were seen. Conclusions: The AGITG ICECREAM trial confirms a significant synergy for the addition of iri to cet and improved PFS in Quad WT chemorefractory mCRC, echoing data in molecularly unselected pts. Clinical trial information: ACTRN12612000901808.

Profiling circulating tumor (ct)DNA mutations after panitumumab treatment in patients with refractory metastatic colorectal cancer (mCRC) from the phase III ASPECCT study.

3523 Background: ASPECCT was a clinical trial performed in the chemotherapy-refractory third-line mCRC setting (N = 1010). This biomarker analysis explores the mutational landscape in panitumumab monotherapy subjects. Analysis of plasma ctDNA at baseline and post-treatment (PT) by next-generation sequencing provides a snapshot of the main changes in key genes before and after therapy. Methods: CtDNA collected at baseline and PT was analyzed for mutations using the Plasma Select-R™ 63-gene panel (0.1% limit of detection). Gain or loss of mutation was defined at the amino acid level. Net change is the sum of mutations gained minus the sum of mutations lost. A single individual could have both net gain and/or net loss of mutations within a single gene. Results: Significant tumor clonal diversification was observed during therapy. In 238 subjects with paired plasma samples,29% of subjects had multiple mutations in the same gene at baseline and 41% of subjects had multiple mutations in the same gene PT. At least 10% of subjects demonstrated an on-therapy acquired mutation in at least one of the following genes: APC, EGFR, ALK, HER4, TP53, AR, KRAS, BRAF, PDGFRA, STK11, ESR1, FBXWT, and KIT (ordered by frequency). New mutations were noted both inside and outside the EGFR pathway. Unexpectedly, patients with a large decrease in mutant DNA burden after anti-EGFR treatment were also seen. EGFR pathway genes with significant net gain were: KRAS, EGFR, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1. Non-EGFR pathway mutations gained included: APC, CDK6, SMARCB1, FBXW7, TERT, RB1, CTNNB1, and IDH1. Conclusions: This 63-gene plasma analysis suggests that there are significant dynamic changes in clonal mutational fraction under anti-EGFR selection. Our analysis reveals that increasing global tumor heterogeneity is associated with poorer overall survival. A subset of patients demonstrated an overall decrease in tumor heterogeneity on panitumumab therapy (28%), indicating that under anti-EGFR selective pressure mutational heterogeneity can also decrease. Clinical trial information: NCT01001377.

Pharmacokinetics of cetuximab and tumor uptake of 89Zr-cetuximab as potential predictive biomarkers for benefit of cetuximab in patients with advanced colorectal cancer.

e15117 Background: One third of patients with RAS wild-type metastatic colorectal cancer (mCRC) do not benefit from anti-EGFR inhibitors. Thus, predictive biomarkers to identify patients with primary resistant mCRC are urgently needed. Methods: Patients with chemotherapy refractory mCRC received 500 mg/m2 cetuximab 2-weekly (NCT02117466 and NCT01691391). Patients underwent a 89Zr-cetuximab PET/CT 6 days post-injection after a therapeutic dose of cetuximab. In case of lack of tumor targeting on 89Zr-cetuximab PET, the cetuximab dose was escalated. Pharmacokinetic (PK) analyses included 89Zr-cetuximab plasma levels, EGFR saturation in skin, soluble EGFR (sEGFR), and tumor uptake and biodistribution on 89Zr-cetuximab PET. We defined treatment benefit as response or stable disease (according to RECIST v1.1) at 2 months. Results: Of the 44 patients, median age was 64 years, 25% had a right-sided primary tumor, 5 patients had a BRAF mutated (mt) tumor and 62% had treatment benefit. Cetuximab treatment dose was escalated to maximally 1250 mg/m2 in 8 patients. Visual and semiquantitative data of 89Zr-cetuximab uptake in the tumor, biodistribution and plasma activity 6 days post-injection were not correlated with treatment benefit. Although EGFR saturation in skin after 2 cycles cetuximab had a wide range (21 – 98%), saturation did not correlate with treatment benefit. On-treatment levels of sEGFR were higher than baseline (median 4.1 vs 2.0 ng/ml; p < 0.001), but levels and change of sEGFR did not correlate with PK or treatment efficacy. PFS and OS correlated with right-sided mCRC (p < 0.001 and p = 0.002 respectively) and the presence of a BRAF mt (p < 0.001 and p = 0.004 respectively). In a multivariate Cox-regression only BRAF mt remained correlated with PFS and OS (p = 0.003 and p = 0.027). Conclusions: Interpatient variances in PK and tumor uptake of 89Zr-cetuximab as performed in this setting do not predict treatment benefit of cetuximab in patients with mCRC. In contrast, BRAF status correlated with treatment benefit and warrants further research to confirm the predictive value. Clinical trial information: NCT02117466 and NCT01691391.

Change in metabolic tumor activity on 18F-FDG PET after a single dose of cetuximab to predict for treatment benefit, PFS, and OS in patients with advanced colorectal cancer.

11519 Background: Despite RAS selection, one third of patients with metastatic RAS wild-type colorectal cancer (mCRC) do not benefit from anti-EGFR inhibitors. Therefore, an additional or more accurate predictive biomarker is needed to identify patients with primary resistant mCRC. Methods: In the IMPACT-CRC trial (NCT02117466) patients with chemotherapy refractory mCRC received 500 mg/m2 cetuximab every 2 weeks. Before the first dose and just before the second dose, patients underwent a 18F-FDG PET/CT (FDG PET). PET scans were quantitatively assessed by manual tumor delineation of ≤ 5 lesions, 2 per organ. Outcome is reported in total lesion glycolysis (TLG), defined as metabolic tumor volume times mean standard uptake value of the tumor. An optimal threshold to assess metabolic response was defined as decrease in TLG ≥15%. Quantitative data were correlated with CT evaluation after 8 weeks of treatment according to RECIST v1.1. Results: Out of 35 patients, 1 was excluded due to an infusion reaction. Median age was 64 years, 74% was male, 4 patients had a BRAF mutated tumor and 9 patients had right-sided primary tumors. 62% of patients had stable disease or partial response on CT after 8 weeks. At the time of this analysis, 88% of patients had progressive disease and 71% had died. Of the patients with right-sided tumors 11% had treatment benefit, compared to 80% in the left-sided group (p = 0.001). None of the 9 metabolic non-responders had treatment benefit, whereas 83% of the metabolic responders had treatment benefit according to RECIST v1.1. After adjustment for age, WHO score, BRAF mutation, sex and primary tumor site, FDG PET response remained correlated with PFS and OS (p = 0.002 and p = 0.014). Conclusions: Early evaluation of metabolic response after 1 dose of cetuximab is highly and independently predictive for treatment benefit with a 100% negative predictive value. Implementation of early FDG-PET evaluation in daily clinical practice can prevent unnecessary toxicity, costs of ineffective treatment and allows timely treatment adjustment for patients with mCRC undergoing anti-EGFR treatment. Clinical trial information: NCT02117466.

Cost-effectiveness of cetuximab and panitumumab for chemotherapy-refractory metastatic colorectal cancer.

BackgroundCetuximab and panitumumab are monoclonal antibodies targeting the epidermal growth factor receptor. Both drugs are active against RAS wild type metastatic colorectal cancer after chemotherapy failure, with similar efficacy and toxicity profiles. However, their cost and limited survival benefits may compromise incorporation in the Brazilian public healthcare system, the Unified Heath System (Sistema Único de Saúde) (SUS).MethodsA cost-effectiveness analysis was conducted using a Markov model from the Brazilian Public health perspective and a lifetime horizon in patients with RAS -wt mCRC. Transition probabilities and mortality rates were extracted from randomized studies. Treatment costs were obtained from price tables regulated by the Brazilian Health Ministry. The World Health Organization recommendation of three times GDP per capita was used to define the cost-effectiveness threshold.ResultsThe use of cetuximab or panitumumab for chemotherapy-refractory mCRC patients resulted in 0.22 additional life-years relative to BSC, with incremental cost-effectiveness ratios (ICERs) of $58,240 and $52,772 per LY, respectively. That exceeds the pre-specified threshold for cost-effectiveness. Acquisition of biological agents was the major driver of increased costs.ConclusionsOur economic evaluation demonstrates that both cetuximab and panitumumab are not a cost-effective approach in RAS-wt mCRC patients. Discussion about drug price should be prioritized to enable incorporation of these monoclonal antibodies in the SUS.

X-TRAP: Phase I/II study of capecitabine (X) plus ziv-aflibercept (TRAP) in metastatic colorectal cancer (mCRC).

687 Background: Patients (pts) with chemotherapy refractory mCRC have a poor prognosis, with a median survival of approximately 6 months (mos). Ziv-aflibercept is FDA-approved in combination with FOLFIRI for the 2nd line treatment of mCRC, but its tolerability and activity in pts with chemotherapy refractory disease is unknown. We designed a phase I/II study of X+TRAP to define the recommended phase II dose (RPTD), and assess the safety, tolerability, and clinical activity for the combination. Methods: Eligible pts with refractory, advanced solid tumors were enrolled in a 3+3 dose escalation cohort (ESC) to identify the RPTD. Cycle length was 21 days. Radiographic assessment occurred every 3 cycles. X was administered po bid on days 1-14. The dose of X was 850 mg/m2 bid in ESC cohort 1 and 1,000 mg/m2 bid in ESC cohort 2. TRAP was administered on day 1 of each cycle (6 mg/kg IV). Pts with mCRC that had progressed on all standard therapies were then enrolled in a single-arm, phase II expansion cohort (EXP) and treated at the RPTD. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Results: As of 6/19/2015, 55 pts were evaluable for toxicity (13 ESC; 42 EXP) and 47 pts were evaluable efficacy (12 ESC; 35 EXP). In the phase I ESC cohorts, 3 DLTs occurred (1/6 cohort 1; 2/6 cohort 2): GI perforation (1), oral mucositis (1), and fatigue (1). The RPTD was X (850 mg/m2 po bid, days 1-14) and TRAP (6 mg/kg IV, day 1). In the ESC and EXP cohorts, there were no treatment related grade 4/5 adverse events (AEs). The most frequently reported treatment related AEs (grades 2+3; grade 3) were palmar-plantar erythrodysesthesia (36%; 5%), hypertension (29%; 20%), and oral mucositis (18%; 4%). Median follow up in the phase II EXP cohort was 9.3 mos (95% C.I., 6.5–11.1). Median PFS was 4.1 mos (95% C.I., 2.3-4.8). Response assessment in 35 pts (n; %): partial response (PR) (2; 6%); stable disease (SD) (12; 34%); SD > 6 mos (2; 6%). Median OS was 9.3 mos (95% C.I., 6.2–n/a). Conclusions: The combination of X+TRAP demonstrated an acceptable safety profile, with encouraging clinical activity at the RPTD. Recruitment for the phase II EXP cohort is now complete. Clinical trial information: NCT01661972.

P-230 Cost effectiveness of Selective Internal Radiation Therapy (SIRT) using yttrium-90 resin microspheres for the treatment of patients with inoperable colorectal liver metastases in France

Introduction: Treatment options for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) are limited. Selective internal radiation therapy (SIRT) using yttrium-90 (90Y)-labelled resin microspheres (SIR-Spheres; Sirtex, Sydney, Australia) has been shown to be a well-tolerated and effective treatment in patients with inoperable liver-dominant chemotherapy-refractory mCRC. The aim of this analysis was to assess the cost-effectiveness of SIRT with SIR-Spheres 90Y resin microspheres compared to best supportive care (BSC) from the perspective of the national health service in France. Methods: Survival data from a comparative retrospective cohort study of 90Y-resin microspheres vs. BSC in chemotherapy-refractory mCRC was analysed and used in a state-transition cost-effectiveness model, using Quality Adjusted Life Years (QALYs) gained as the measure of effectiveness. The model included costs for treatment acquisition, pre-treatment work-up and delivery of microspheres, and chemotherapy. Additionally, costs of managing adverse events and a cost of death were included. Utility data were taken from a recent NICE economic evaluation in mCRC. A wide range of sensitivity analyses were performed on utility, overall survival and costs. The one-way sensitivity analysis varied each parameter between its lower and upper bound and investigated the effect on the cost per QALY. The probabilistic analysis simultaneously sampled each parameter from its appropriate distribution (beta for utilities, normal for costs and multivariate normal for survival curve parameters) for 1,000 simulations and investigated the uncertainty around the cost per QALY. The scenario analysis explored alternative parametric curves for overall survival, alternative sources for utility values and alternative assumptions for the proportion of time spent in the pre- and post-progression health states. Results: The results show an increase in overall survival for patients receiving 90Y-resin microspheres compared to BSC by a mean of 1.15 life years (2.12 vs. 0.98 years), with a corresponding increase in quality adjusted life years (1.50 vs. 0.70). The associated costs for SIRT and BSC are €48,552 vs. €23,300, respectively. The additional costs are due to the SIRT treatment and the cost associated with extension to life. The cost per QALY is €30,610. Sensitivity analyses show that the model is robust to changes in parameters. Scenario analysis results demonstrate that the cost per QALY is not sensitive to alternative assumptions for survival curves, utilities or progression, varying only between €28,363 and €31,940. The one-way sensitivity analysis found that the parameters that had the biggest effect are those relating to the curve used to model overall survival. The probabilistic sensitivity analysis found that the probability of 90Y-resin microspheres being cost effective at a willingness-to-pay threshold of €33,506/QALY (1xGDP) is 69%. Conclusion: This analysis demonstrated that the use of 90Y-resin microspheres is a cost-effective option in the treatment of patients with chemotherapy-refractory liver-dominant mCRC in France. The results are robust to a wide range of sensitivity analyses, which ensures the predictability of the results.

Selective transarterial radioembolisation of unresectable liver-dominant colorectal cancer refractory to chemotherapy.

The target lesion response (according to the Choi criteria), safety and survival following selective or superselective transarterial radioembolisation using yttrium-90-resin microspheres ((90)Y-RE) were evaluated in patients with unresectable, chemotherapy-refractory colorectal cancer liver metastases (mCRC). A prospective case series evaluated 52 consecutive patients with mCRC who were treated at a single centre following a median of 2 lines of chemotherapy. Nearly half (46.2 %) of the 52 patients had a prior resection of the liver. At baseline, mCRC was limited to the liver (in 56.9 %), liver plus extra-hepatic metastases (23.5 %) or liver plus lung micro-nodules (19.6 %). Disease control rates of target lesions (partial response plus stable disease) at 3 and 6 months post-(90)Y-RE were 59 and 29 %, respectively. Target lesions were sufficiently downsized in two patients for hepatic resection and in one patient for radiofrequency ablation. Median Kaplan-Meier survival was 11.0 months (95 % confidence interval: 8.0-14.0 months) overall and 12.0 months in liver-only disease (±lung micro-nodules). Determinants of prolonged survival were response at 3 months (P = 0.046), ≤5 liver nodules (P = 0.004), single-liver-lobe involvement (P = 0.037), tumour-to-whole liver ratio <25 % (P = 0.021) and absence of extrahepatic metastases (P = 0.045). Adverse events possibly related to the nontarget distribution of (90)Y-RE were grade 1 (90)Y-RE-induced liver disease (n = 1), grade 2 and 3 gastric ulcers (n = 2). These results confirm the effectiveness and safety of selective (90)Y-RE in patients with chemotherapy-refractory mCRC, showing (90)Y-RE's potential as a bridging therapy to subsequent resection even in this end-stage population.

DEBIRI and capecitabine in refractory prevalently liver metastases of colorectal cancer: A phase II study.

724 Background: Treatment options for metastatic colorectal cancer (mCRC) patients refractory to chemotherapy are limited and clinical outcome is poor. In mCRC patients with liver-dominant disease hepatic locoregional therapy might be a treatment option. In this pilot study we evaluated the safety, tolerance, and efficacy of drug-eluting beads irinotecan (DEBIRI) in combination with capecitabine in the treatment of patients with mCRC with predominally liver disease. Methods: Twenty patients affected by liver metastasis of colorectal cancer were included in this study. All patients had progression of disease after two or more lines of chemotherapy and liver was the major or the predominant site of disease. DEBIRI, beads loaded with 100 mg irinotecan, was administered biweekly via hepatic artery. All patients assumed capecitabine 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks, until disease progression. Primary endpoints were safety, tolerance and overall responce rate (ORR); secondary endpoints were progression free servival (PFS) and overall survival (OS). Results: Twenty patients underwent a total of 54 DEBIRI treatments of the 66 planned; the median number was 3 (range 2-4) administrated for patients. Grade 1-2 toxic effects included fatigue (70%), diarrhea (45 %), anemia (45%), elevated liver enzymes (45%), nausea (40%), neutropenia (35%) and thrombocytopenia (25%). One grade 3 diarrhea and a case of acute vasospastic angina were observed and required patient hospitalization, but no deaths at 30 days post occurred. Two partial responses were reported (10%) with ORR of 60%. PFS and OS were 4 and 7, 3 months respectively. Univariate analysis showed that patients with KRAS wild-type, good ECOG performance status and single lobe metastases have a better prognosis. Multivariate analysis confirmed that only the good clinical conditions represent an important positive prognostic factor (p=0.03). Conclusions: DEBIRI with capecitabine seem to be a safe, technically feasible and well-tolerated treatment in chemotherapy refractory mCRC with prevalently liver metastases. It has a moderate but not negligible activity in this heavily treated group of patients and deserves further studies in a larger series.

Phase II Trial of Cetuximab plus Irinotecan for Oxaliplatin- and Irinotecan-Based Chemotherapy-Refractory Patients with Advanced and/or Metastatic Colorectal Cancer: Evaluation of Efficacy and Safety Based on KRAS Mutation Status (T-CORE0801)

Background: Mutations in the KRAS gene have been identified as negative predictors of response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy by patients with metastatic colorectal cancer (mCRC). However, it has been based on the study of mainly Caucasian mCRC patients. This prospective study investigated the relationship between the mutation status of EGFR-related genes including KRAS and the response rate (RR) to cetuximab plus irinotecan therapy in Japanese mCRC patients. Methods: Samples taken from 43 chemotherapy-refractory mCRC patients who had undergone cetuximab plus irinotecan therapy at 11 medical centers in Japan were subjected to direct DNA sequencing to determine the KRAS, BRAF, PIK3CA, NRAS, and AKT1 mutation status. The clinical outcome after the treatment was evaluated for each mutation status. Results:KRAS mutations were detected in 31.7% of 41 eligible patients. The RR to cetuximab plus irinotecan therapy was found to be 17.9 and 0% in the KRAS wild-type and mutant subgroups, respectively. Conclusion: Despite the identification of a lower-than-expected RR to treatment by the KRAS wild-type subgroup, KRAS mutation status appears to be a useful predictive marker of response to cetuximab plus irinotecan therapy in Japanese mCRC patients.

P-0237 - Cost Effectiveness of Selective Internal Radiation Therapy (SIRT) Using YTTRIUM-90 Resin Microspheres for the Treatment of Patients with Inoperable Colorectal Liver Metastases in the UK

Introduction: Treatment options for chemotherapy-refractory metastatic colorectal cancer (mCRC) are limited. Selective internal radiation therapy (SIRT) using yttrium-90 (Y)-labelled resin microspheres (SIR-Spheres; Sirtex, Sydney, Australia) has been shown to be a well-tolerated, effective and cost-effective treatment in patients with inoperable liver-dominant chemotherapy-refractory mCRC. The aim of this analysis was to assess the sensitivity of the cost-effectiveness of SIRT compared to best supportive care (BSC) from the perspective of the UK NHS. Methods: Survival data from a comparative retrospective cohort study of Y-resin microspheres vs. BSC in chemotherapy-refractory mCRC were analysed and used in a state-transition cost-effectiveness model, using Quality Adjusted Life Years (QALYs) gained as the measure of effectiveness. The model included costs for treatment acquisition, pre-treatment work-up and delivery of microspheres, and chemotherapy. Additionally, costs of managing AEs and a cost of death were included. Utility data were taken from a recent NICE economic evaluation in mCRC. Awide range of sensitivity analyses were performed on utility, overall survival and costs. The one-way sensitivity analysis varied each parameter between its lower and upper bound and investigated the effect on the cost per QALY. The probabilistic analysis simultaneously sampled each parameter from its appropriate distribution (beta for utilities, normal for costs and multivariate normal for survival curve parameters) for 1,000 simulations and investigated the uncertainty around the cost per QALY. The scenario analysis explored alternative parametric curves for overall survival, alternative sources for utility values and alternative assumptions for the proportion of time spent in the preand post-progression health states.