Chemotherapy-refractory Metastatic Colorectal Cancer Research Articles

TAS-102 Plus Bevacizumab as an Effective and Well Tolerated Regimen in Chemotherapy-Refractory Advanced Colorectal Cancers – A Single Institution Retrospective Analysis

Objective There are limited data on the utility of TAS-102 plus bevacizumab in patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) treated in India. Methods Patients diagnosed with chemotherapy-refractory mCRC, defined as having received at least prior oxaliplatin and irinotecan–based chemotherapy between January 2017 and January 2022, and who began treatment with a combination of TAS-102 and bevacizumab were retrospectively analyzed for demographic variables, survivals, and prognostic parameters. The primary endpoint of the study was estimation of the median overall survival (OS) by the Kaplan–Meier method. Results The data of 143 patients satisfied the prespecified inclusion criteria and were included for analysis. There was a predominance of left-sided CRCs (78%) and patients having greater than two sites of distant metastases (87%), with 41% of patients with at least two lines of prior therapy. With a median follow-up of 11.6 months, the median OS of the entire cohort was 10.9 months, while the median progression-free survival was 4.4 months. The combination was well tolerated, with the most common grade 3/4 side effects being neutropenia (25%), anemia (6%), and thrombocytopenia (4%). Dose modifications in TAS-102 were required in 20% of patients, though this did not entail permanent cessation of TAS-102 in any patient. The presence of a resected primary was prognostic for improved OS (p < 0.001), while signet ring histology predicted inferior OS (p < 0.001). Conclusion The combination of TAS-102 and bevacizumab is an efficacious and safe therapeutic option in patients with mCRC who have received at least two lines of prior systemic therapy. There were no requirements for cessation of the combination in the current study, underlying the well-tolerated nature of the combination.

Association between sidedness and survival among chemotherapy refractory metastatic colorectal cancer patients treated with trifluridine/tipiracil or regorafenib.

The impact of sidedness on survival of later-line treatment in patients with metastatic colorectal cancer (mCRC) is undetermined. This study aimed to investigate the association between sidedness and survival among chemotherapy refractory patients with mCRC treated with trifluridine/tipiracil (TAS-102) or regorafenib or both. Patients with mCRC treated with TAS-102 or regorafenib between 2015 and 2020 was retrospectively collected. Patients were stratified into TAS-102 first and regorafenib first, then subdivided into TAS-102 followed by regorafenib (T-R) and regorafenib followed by TAS-102 (R-T) groups. The oncologic outcomes were presented with time-to-treatment failure (TTF) and overall survival (OS). After matching, 376 TAS-102 patients and 376 regorafenib patients were included for outcomes comparison. TTF had insignificant differences while OS was significantly different between TAS-102 and regorafenib groups. Median TTF and OS were 1.9 months versus 2.0 months (P = .701) and 9.1 months versus 7.0 months (P = .008) in TAS-102 and regorafenib, respectively. The OS benefits were consistent regardless primary tumor location. Subgroup analysis with 174 T-R patients and 174 R-T patients was investigated for treatment sequences. TTF and OS had significant differences in both groups. Median TTF and OS were 8.5 months versus 6.3 months (P = .001) and 14.4 months versus 12.6 months (P = .035) in T-R and R-T groups, respectively. The TTF and OS benefits were persisted regardless primary tumor location. TAS-102 first provided a better survival benefit in chemotherapy refractory patients with mCRC across all sidedness. Further prospective studies are warranted to validate our conclusions.

Objective response after immune checkpoint inhibitors in a chemotherapy-refractory pMMR/MSS metastatic rectal cancer patient primed with experimental AlloStim® immunotherapy

BackgroundImmune Checkpoint Inhibitor (ICI) immunotherapy is most effective in immune effector cell infiltrated ‘hot’ tumor lesions, such as occurs in deficient mismatch repair, microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC). However, most all metastatic CRC tumors are mismatch repair proficient/microsatellite stable (pMMR/MSS) ‘cold’ lesions, without significant immune cell infiltration, and are unresponsive to ICI. AlloStim®, is an experimental, allogeneic immunomodulatory cell therapy designed to convert ‘cold’ metastatic tumor lesions to ‘hot’ inflamed lesions. After AlloStim® immunotherapy, this cold to hot inflammatory mechanism can make it difficult to distinguish between pseudoprogression and actual progression on restaging CT scans, as inflamed metastatic lesions can appear larger and occult disease can appear as new small lesions.MethodsTo explore whether radiological progression after AlloStim® immunotherapy is due to immune-flare or disease progression, we administered a short course of a combination ICI therapy to a pMMR/MSS chemotherapy-refractory metastatic colorectal cancer patient enrolled in the StimVax Phase IIb clinical study that presented with radiological progression after AlloStim® immunotherapy. Our rationale was that an accelerated response to ICI should occur if the lesions were inflamed, while if the enlarged lesions were due to disease progression there would not be a response.ResultsHere we report a rapid, significant reduction in tumor burden in response to ICI administration in an AlloStim® primed pMMR/MSS mCRC patient with retroperitoneal and lung metastases.ConclusionThis rare objective response to ICIs in a pMMR/MSS mCRC patient supports further evaluation of the combination of AlloStim® with ICI immunotherapy in MSS mCRC and other cold or ICI refractory tumors.Trial registrationNational Library of Medicine (NLM) at the National Institutes of Health (NIH). Registered 22 June 2020, https://clinicaltrials.gov/study/NCT04444622.

Phase I prospective trial of TAS-102 (trifluridine and tipiracil) and radioembolization with 90Y resin microspheres for chemo-refractory colorectal liver metastases

BackgroundExtrahepatic disease progression limits clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Trifluridine and tipiracil (TAS-102) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer.MethodsSequential lobar TARE using 90Y resin microspheres in combination with TAS-102 in 28-day cycles were used to treat adult patients with bilobar liver-dominant chemo-refractory mCRC according to 3 + 3 dose escalation design with a 12-patient dose expansion cohort. Study objectives were to establish safety and determine maximum tolerated dose (MTD) of TAS-102 in combination with TARE.ResultsA total of 21 patients (14 women, 7 men) with median age of 60 years were enrolled. No dose limiting toxicities were observed. Treatment related severe adverse events included cytopenias (10 patients, 48%) and radioembolization-induced liver disease (2 patients, 10%). Disease control rate in the liver lobes treated with TARE was 100%. Best observed radiographic responses were partial response for 4 patients (19%) and stable disease for 12 patients (57%).ConclusionsThe combination of TAS-102 and TARE for patients with liver-dominant mCRC is safe and consistently achieves disease control within the liver.Trial registrationClinicalTrials.gov identifier NCT02602327 (first posted 11/11/2015).

PD32 Cost-Utility Of Selective Internal Radiation Therapy Using Y-90 Resin Microspheres For Chemotherapy-Refractory Metastatic Colorectal Cancer In Brazil

IntroductionThere were an estimated 55,102 new cases of colorectal cancer (CRC) in Brazil in 2020, comprising 9.3 percent of all newly diagnosed cancers, and making it the third most common cancer in the Brazilian population. Up to half of all patients with CRC will develop liver metastases, and the prognosis for these patients is poor. The objective of the present analysis was to evaluate the cost-utility of selective internal radiation therapy (SIRT) using Y-90 resin microspheres versus best supportive care (BSC) in patients with unresectable, liver-dominant, chemotherapy-refractory metastatic CRC (mCRC).MethodsA three-state partitioned survival model was developed in Microsoft Excel to evaluate the cost-utility of SIRT using Y-90 resin microspheres versus BSC. Membership of the three model states of pre-progression, post-progression and death was governed by parametric models of Kaplan-Meier data from a retrospective, interventional study. Costs associated with SIRT using Y-90 resin microspheres, BSC, and adverse events were obtained from Brazilian sources and reported in 2021 United States dollars (USD). Future costs and effects were discounted at 5 percent. One-way and probabilistic sensitivity analyses (PSA) were performed. A willingness-to-pay threshold of USD 53,936 was used based on a 2017 review of Brazilian healthcare technology adoption.ResultsThe base case analysis showed that Y-90 resin microspheres would result in an increase of 0.76 QALYs versus BSC, increasing quality-adjusted life expectancy from 0.67 QALYs to 1.43 QALYs. The improvement in quality-adjusted life expectancy was accompanied by an increase in costs from USD 9,884 to USD 40,399 over the model time horizon, corresponding to an increase of USD 30,515, and yielding an incremental cost-utility ratio (ICUR) of USD 40,265 per QALY gained. PSA showed there was a 90.8 percent likelihood of cost-effectiveness at USD 53,936 per QALY gained.ConclusionsSIRT using Y-90 resin microspheres was cost-effective versus BSC in the treatment of unresectable, liver-dominant mCRC patients and should be considered for incorporation in the Brazilian Private Healthcare System.

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.

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.

Does the efficacy of regorafenib differ in chemotherapy refractory metastatic colorectal cancer patients who had mucinous pathology compared to those who had non-mucinous pathology?

Purpose: To investigate the importance of mucinous histopathology on the assessment of tumor response in patients with metastatic colorectal cancer (mCRC) receiving regorafenib. Materials and method: All patients diagnosed with histologically confirmed mCRC in 2 oncology centers between 2013 and 2018 were retrospectively analyzed. Among 678 patients diagnosed with mCRC, 103 patients were treated with regorafenib. Ninety-four of these patients who had used at least 2 cycles of regorafenib and evaluable for treatment response were included in the analysis. Histopathologically, 18 patients with mucinous adenocarcinoma and 76 patients with nonmucinous adenocarcinoma were compared in terms of response rate and survival durations. Results: Median follow-up duration of 6 months, median age of the patients was 61 (34-77) years. While 19.1% of the patients had mucinous histology, 80.9% had nonmucinous histology. The overall response rate was significantly lower in the mucinous subgroup than the nonmucinous subgroup (5.6% vs 43.4%, respectively, P = 0.003). Similarly, both progression-free survival (3.0 vs 4.0 months, respectively, P = 0.011) and overall survival duration were shorter in the mucinous subgroup (3.0 vs 7.0 months, P = 0.016, respectively) compared with the nonmucinous subgroup. Conclusion: The histological subgroup may predict tumor response in mCRC patients receiving regorafenib. Its efficacy on nonmucinous histology had significantly more favorable than mucinous subtype.

Prognostic and Predictive Biomarkers in Patients with Metastatic Colorectal Cancer Receiving Regorafenib.

Regorafenib is a tyrosine kinase inhibitor approved by the FDA for the treatment of patients with chemotherapy refractory metastatic colorectal cancer (mCRC). Regorafenib inhibits signaling through multiple receptors associated with angiogenesis, metastasis, and tumor immunity. Here, we report biomarker results from LCCC1029, a randomized, placebo-controlled, phase II trial of chemotherapy ± regorafenib in patients with second-line mCRC. A panel of 20 soluble protein biomarkers (termed the Angiome) was assessed in the plasma of 149 patients from the LCCC1029 trial both at baseline and along the treatment continuum. Baseline protein levels were analyzed for prognostic and predictive value for progression-free survival (PFS) and overall survival (OS). Changes in protein levels during treatment were analyzed for potential pharmacodynamic effects. Six markers (HGF, IL6, PlGF, VEGF-R1, OPN, and IL6R) were found to be prognostic for PFS. Nine markers (IL6, TIMP-1, PlGF, VCAM-1, ICAM-1, OPN, TSP-2, HGF, and VEGF-R1) were prognostic for OS. Higher baseline levels of OPN (P intx = 0.0167), VCAM-1 (P intx = 0.0216), and PDGF-AA (P intx = 0.0435) appeared to predict for PFS benefit from regorafenib compared with placebo. VCAM-1 was also potentially predictive of OS benefit from regorafenib compared with placebo (P intx = 0.0124). On-treatment changes of six markers reflected potential on-target effect of regorafenib. Consistent results were observed in an Italian cohort where 105 patients with late-stage mCRC received regorafenib monotherapy. The key findings of this study suggest that VCAM-1 may be a predictive biomarker for regorafenib benefit, while multiple protein markers may be prognostic of outcome in patients with mCRC.

A meta-analysis comparing regorafenib with TAS-102 for treating refractory metastatic colorectal cancer.

ObjectiveWe performed this meta-analysis to compare the efficacy and toxicity of regorafenib and TAS-102.MethodsElectronic databases were searched to identify studies comparing the efficacy and safety of regorafenib and TAS-102 in patients with chemotherapy-refractory metastatic colorectal cancer using pooled analyses.ResultsThree clinical trials were included in this analysis. Regarding the reasons for treatment discontinuation, regorafenib was significantly associated with disease progression (odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.21–0.50) and adverse events (OR = 4.38, 95% CI = 2.69–7.13). However, overall (OR = 0.97, 95% CI = 0.81–1.17) and progression-free survival (OR = 1.01, 95% CI = 0.86–1.18) did not significantly differ between the groups. The most common treatment-related adverse events in the regorafenib group were neutropenia (OR = 0.06, 95% CI = 0.03–0.11), hand–foot syndrome (OR = 50.34, 95% CI = 10.44–242.84), and liver dysfunction (OR = 34.51, 95% CI = 8.30–143.43). Conversely, the incidence of thrombocytopenia did not differ between the two groups.ConclusionsRegorafenib and TAS-102 have similar efficacy but different adverse event profiles. Differences in the toxicity profiles of the two drugs will help guide treatment selection.

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.

Phase I prospective trial of TAS-102 (trifluride and tipiracil) and radioembolization with 90Y resin microspheres for chemo-refractory colorectal liver metastases.

110 Background: Clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) is limited by extrahepatic disease progression. TAS-102 (trifluride and tipiracil) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer. We aimed to evaluate the safety of the combination of TAS-102 and 90Y resin TARE in a Phase I dose-escalation trial. Methods: Adult patients with bilobar liver-dominant chemo-refractory mCRC were treated with sequential Y90 resin TARE (body surface area dosimetry) in combination with TAS-102 (20mg/m2, 27mg/m2, and 35mg/m2) in 28-day cycles according to 3+3 dose-escalation design. Beginning with cycle 3, TAS-102 was administered as monotherapy until disease progression or development of intolerable toxicity. Primary objectives were to determine maximum tolerated dose (MTD) of TAS-102, to assess toxicity, and to establish safety of TAS-102 in combination with 90Y TARE. Results: A total of 14 patients (10 women, 4 men) have been treated to date. Among 9 patients enrolled in the dose-escalation phase, no dose limiting toxicities were observed. The MTD of TAS-102 in combination with Y90 was 35mg/m2, which was selected for the dose expansion phase. Severe adverse events (AEs) included: neutropenia (46%); anemia (23%); and thrombocytopenia (8%), which were attributed to TAS-102. All other AEs were mild and transient. At least one follow-up imaging study has been obtained for 13 patients, and 10 patients have completed trial participation. Disease control rate in the liver was 100%. Conclusions: The combination of TAS-102 and 90Y TARE for patients with liver-dominant mCRC is safe and consistently achieved disease control within the liver. Severity and incidence of AEs is within the expected range of TAS-102 and 90Y TARE monotherapy. A dose-expansion phase with planned enrollment of 12 patients is ongoing. Clinical trial information: NCT02602327.

Abstract C057: A phase I study to access the safety and efficacy of valecobulin (CKD-516), oral vascular disruption agent, in combination with irinotecan in patients with previously treated metastatic colorectal cancer

Abstract Background: Tumor neovascularization is a critical step for tumor growth and results in structurally and functionally abnormal tumor blood vessels. Vascular disrupting agents (VDAs) destroy established tumor vessels, subsequently causing tumor ischemia and necrosis. Valecobulin is an orally available VDA that acts as an inhibitor of tubulin polymerization. Thus valecobulin affects the central regions that are often resistant to conventional chemotherapy agents. Valecobulin combined with irinotecan showed significantly improved anti-cancer activity in colorectal cancer (CRC) bearing mouse models. On the basis of this background, we conducted a phase I dose-finding study of valecobulin in combination with biweekly irinotecan in CRC patient who had failed standard therapies including irinotecan basis regimen. Methods: Patients with metastatic CRC refractory to previous chemotherapy including one irinotecan containing regimen were enrolled in dose escalation cohort (Part A, traditional 3+3 design) and expansion cohort (Part B). The primary objective was to determine the recommended dose of expansion cohort in Part A, and to evaluate the antitumor activity and safety in Part B. All patient received valecobulin 5, 7, 9, or 11 mg/m2 PO on Day 1-5 and Day 8-12 (5 days of treatment followed by 2 days of rest) in combination with irinotecan 120 (Level 1-4) or 150 mg/m2 IV (Level 5) on Day 1 (14 days treatment cycle). Adverse events (AEs) and antitumor activity were evaluated using CTCAE V4.03 and RECIST V 1.1, each other. Results: A total 16 patients were enrolled to Part A, and 23 patients to Part B. Of 39 patients(≥19 years), 26(66.8%) were male, median age was 59 years(30-74). Past treatment history showed that most patients have already received 2nd (n=10; 25.6%), 3rd (n=12; 30.8%) or 4th line (n=13; 33.3%) chemotherapy. There was no dose limited toxicity until Level 5 and valecobulin 11 mg/m2 and irinotecan 120 mg/m2 (Level 4) was determined to the recommended dose of Part B according to reduction trend in whole treatment period. Among total 39 patients, the median progression-free survival was 126 days (95% CI: 83-175) and the overall survival was 361 days (95% CI: 240-526). PR was observed in 1 patient (2.9%) and SD was 26 (76.5%) among evaluable 34 patients. Common grade 3/4 AEs (&amp;gt;10%) regardless of cause included neutrophil decrease 51.3%, diarrhea 30.7% and vomiting 15.4%. The major cardiovascular events which were other VDAs’ common toxicity, were not observed. There were no treatment-related deaths. Conclusions Valecobulin in combination with irinotecan demonstrated a manageable safety profile and preliminary antitumor activity in chemotherapy refractory metastatic colorectal cancer. Citation Format: Tae Won Kim, Jeong Eun Kim, Hyeong-Seok Lim, Young Suk Park, Won Ki Kang, Sang Joon Shin, Joong Bae Ahn, Sae-Won Han, Tae-You Kim. A phase I study to access the safety and efficacy of valecobulin (CKD-516), oral vascular disruption agent, in combination with irinotecan in patients with previously treated metastatic colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C057. doi:10.1158/1535-7163.TARG-19-C057

A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer

BackgroundPatients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC.MethodsAll patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS).ResultsA total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1–14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60–84%). Median PFS and OS were 3.9 months (95% CI, 2.3–4.5) and 7.1 months (95% CI: 5.8–10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes.ConclusionThe combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study.Trial registrationThis clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

Apatinib monotherapy for chemotherapy-refractory metastatic colorectal cancer: A multicenter, single-arm, prospective study.

3527 Background: Apatinib is an oral highly-selective tyrosine kinase inhibitor (TKI) that blocks vascular endothelial growth factor receptor 2 (VEGFR-2). This exploratory study evaluated the efficacy and safety of apatinib monotherapy in patients with chemotherapy-refractory metastatic colorectal cancer. Methods: In this multicenter, single-arm, prospective study, 48 patients with metastatic colorectal cancer who had failed at least two lines standard chemotherapies including fluorouracil, oxaliplatin and irinotecan were recruited from 14 centers in Guangdong, China. Apatinib at a 500mg dose was administered daily continuously. Each cycle was 4 weeks (28 days). The primary endpoint was progression free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and toxicity. Results: A total of 48 patients was enrolled in the study from September 3, 2015 to June9, 2017. Four patients achieved a partial response, and 22 achieved stable disease, representing a response rate of 8.3% and a disease control rate of 60.4%. Median follow-up time was 10.3 months. Median progression-free survival (PFS) and overall survival (OS) of evaluable patients (n=41) were 4.7 months (95% confidence interval [CI] 3.7-5.9) and 9.7 months (95% CI 5.9-13.6). The most common grade 3 or 4 adverse events (AE) were hypertension (12.5%), hand-foot syndrome (10.4%), thrombocytopenia (10.4%), proteinuria (8.3%) and mucositis oral (6.3%). Conclusions: Apatinib monotherapy shows promising efficacy and manageable toxicities in patients with chemotherapy-refractory metastatic colorectal cancer. Further phase 3 trial is warranted. Clinical trial information: ChiCTR1900020503.

What is a clinically meaningful survival benefit in refractory metastatic colorectal cancer?

Assessment of the clinical benefit of cancer treatments can be highly subjective, influenced by both perspective and context. Such assessments are required in regulatory and policy decision-making, but consistency between jurisdictions is often lacking. Clear and consistent standards for determining when a treatment offers a meaningful benefit, relative to the current standard of care, can help to address issues of equity and transparency in health technology assessment. For metastatic colorectal cancer (mcrc), no standardized Canadian definition of clinically meaningful benefit has yet been proposed. Colorectal Cancer Canada therefore convened a group of medical oncologists expert in colorectal cancer to review the literature about clinical significance. The resulting consensus is intended to apply to any therapeutic agent being considered in the setting of chemotherapy-refractory mcrc. It was agreed that overall survival is the appropriate measure of clinical efficacy in chemorefractory mcrc. As quantitative targets for efficacy, an improvement of 2 months or more in median overall survival or a hazard ratio for survival of 0.75 or lower (or both) are proposed as the threshold for clinically meaningful benefit. That threshold could be influenced by a treatment's effect on quality of life. Treatment toxicity is also relevant to the assessment of clinical benefit in this setting, specifically when significant differences in treatment tolerability are evident.

LBA-004 - Efficacy and safety results from IMblaze370, a randomised Phase III study comparing atezolizumab+cobimetinib and atezolizumab monotherapy vs regorafenib in chemotherapy-refractory metastatic colorectal cancer

LBA-004 - Efficacy and safety results from IMblaze370, a randomised Phase III study comparing atezolizumab+cobimetinib and atezolizumab monotherapy vs regorafenib in chemotherapy-refractory metastatic colorectal cancer

Abstract A026: Analysis of cetuximab responses in PDX cohorts of different carcinomas

Abstract Introduction: Gene amplification and/or protein overexpression of EGFR have been observed in a variety of carcinomas, including lung, colorectal, urinary bladder, breast, head/neck, esophageal, and gastric carcinomas. Increase in EGFR expression has been observed to be associated with advanced stage and an unfavorable prognosis in some carcinoma, e.g., non-small cell lung carcinoma (NSCLC) and colorectal carcinoma (CRC). Cetuximab is a recombinant human/mouse chimeric monoclonal antibody against EGFR, which was approved for treating EGFR-expressing metastatic CRC (mCRC) without activating KRAS mutation, and squamous cell carcinoma of the head and neck (SCCHN)(1,2). However, response to cetuximab treatment in CRC seems to have no correlation with EGFR expression. Furthermore, preclinical studies demonstrate cetuximab treatment can inhibit tumor growth in a variety of indications, including gastric cancer, with drug efficacy positively correlated with EGFR expression level. Response to cetuximab may involve different biologic pathways in different indications. Methods: We collected genomics data and cetuximab efficacy data for PDX cohorts of 26 CRC, 27 gastric carcinoma, and 37 NSCLC. We used linear mixed model to compare the tumor growth rates of different tumors under cetuximab treatment, and to analyze the interaction between EGFR expression level and tumor growth, as compared to the traditional method using tumor growth inhibition (TGI) as efficacy endpoint. In addition, we developed a machine learning protocol to identify potential biomarkers for cetuximab treatment in these carcinomas at both gene levels and pathway levels. Results: By our new analysis method using machine learning, we have made some new discoveries using our available datasets. First, under cetuximab treatment, tumor growth rate of CRC is significantly higher than that of NSCLC and gastric carcinoma. Second, for gastric cancer we confirmed that EGFR overexpression resulted in better response to cetuximab treatment, while we found the association of overexpression of PROX1 with drug resistance. Third, for CRC, while we somehow confirmed the earlier observation of RAS-signature score correction with the cetuximab resistance based on TGI, we also attempted to identify additional gene changes significantly better correlated with efficacy according to our new analysis method using machine learning. Fourth, we are also revealing new observation by performing the same in NSCLC, where our previous attempts using TGI failed. We will report our new findings in the upcoming presentations. Conclusions: Cetuximab treatment in different indications results in significantly different results, which can be correlated with genetic makeup of different cancers. Our new analysis method using machine learning can be a powerful tool to reveal new predictive insights of drug response.

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.