Abstract Background We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. Methods APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. Results Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m 2 twice daily; days 1–5 and 8–12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8–45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5–6.5), 14.1 months (95% CI 12.2–19.3), 37.0% (95% CI 24.3–51.3), 81.5% (95% CI 68.6–90.8), and 5.8 months (95% CI 4.29–6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. Conclusion Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.
Introduction: Trifluridine/tipiracil (TAS-102) and Regorafenib (REG) have shown promising activity in patients with heavily pretreated metastatic colorectal cancer (mCRC). The aim of this study was to compare the efficacy and safety of TAS-102 and REG alone in patients with mCRC refractory to standard chemotherapies. Methods: From May 2014 to December 2017, 135 patients with mCRC were treated with TAS-102 or REG as salvage-line therapy. Efficacy, safety and clinical outcomes were retrospectively evaluated. Inclusion criteria were histologically confirmed colorectal adenocarcinoma; refractory or intolerant to fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF therapy and anti-EGFR antibody (for tumours with wild-type RAS); measurable or evaluable lesion; age ≥ 20 years; Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2; and written informed consent. The clinical outcomes were evaluated using the Cox's proportional hazard models. Results: Among 135 patients, 77 received TAS-102 (median age 77 y, male 49%, ECOG PS 0 62%, RAS wt 43%) and the other 58 received REG (median age 66 y, male 53%, ECOG PS0 64%, RAS wt 51%). With a median follow-up of 5.8 months (range, 1.5 to 19.0), median progression-free survival was statistically longer in the TAS-102 group than in the REG group (TAS-102 2.9 vs REG 2.0 months; HR = 0.591, p = 0.0035). No significant difference in overall survival between TAS-102 and REG (TAS-102 10.4 vs REG 9.2 months; HR = 1.14, p = 0.57) was observed. Conclusion: TAS-102 and REG showed equivalent survival benefit in the treatment of mCRC which had progressed after standard therapies.
Abstract Purpose Although early tumor shrinkage (ETS) is a predictor of improved overall survival (OS), the association between ETS and health-related quality of life (HRQOL) remains unclear for patients with metastatic colorectal cancer (mCRC) treated with first-line cetuximab plus chemotherapy. Methods The data were collected from a prospective trial that assessed HRQOL using the EORTC QLQ-C30. The impact of ETS on HRQOL was estimated using a linear mixed-effects model for repeated measures. Results ETS was achieved in 82 (64.1%) of 128 mCRC patients treated with first-line cetuximab plus chemotherapy, and these patients had a significantly longer OS than those without ETS (HR, 0.38; 95% CI, 0.20–0.72; P = .002). Asymptomatic patients with ETS had a favorable OS, while symptomatic patients without ETS had a worse OS (2-year OS rates, 77.8% vs. 42.5%). Symptomatic patients with ETS had similar outcomes as asymptomatic patients without ETS (2-year OS rates, 64.1% vs. 67.0%). For symptomatic patients, ETS was associated with improved HRQOL scores between baseline and 8 weeks: the mean changes for patients with and without ETS were 5.86 and -4.94 for global health status (GHS)/QOL, 26.73 and 3.79 for physical functioning, and 13.58 and -3.10 for social functioning, respectively. The improved HRQOL was comparable to that of asymptomatic patients without ETS. For asymptomatic patients, ETS showed a decreased deterioration in HRQOL. Conclusion Our findings highlight the importance of ETS for HRQOL and prognostic estimates, and assessing ETS may provide clinically useful information for physicians and patients to make more informed decisions.
3550 Background: Oxaliplatin/Fluoropyrimidine chemotherapy is an established adjuvant treatment for colon cancer (CC). Neurotoxicity from oxaliplatin is cumulative, dose limiting, and potentially irreversible. The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project was established to prospectively analyze data from several randomized trials to test whether 3-month (arm 3) of oxaliplatin-based adjuvant (FOLFOX4/ mFOLFOX6 or XELOX) is non-inferior in terms of disease-free survival to 6-month (arm 6) treatment in patients (pts) with stage III CC, with less toxicity. Methods: We present the compliance and safety of the phase III ACHIEVE trial (JFMC47) as one of the IDEA project. Results: From 2012 to 2014, 1,313 patients were randomized from 244 centers and 1,301 (651 in arm 3 and 650 in arm 6) included in the intention-to-treat (ITT) population. Baseline characteristics and proportion of mFOLFOX6 vs XELOX were well balanced (25.0% vs 75.0%). Among the safety population (N = 1,277, 98% of ITT population), there was a treatment-related death. Compliance was higher in arm 3 than in arm 6: treatment completion rate in pts receiving all the planned cycles were 86.3% in arm 3 and 61.4% in arm 6, and consistent higher rate either mFOLFOX6 or XELOX was observed in arm 3 than arm 6 (87.6% vs 69.6% in mFOLFOX6; 85.9% vs 58.7% in XELOX). Therapy was permanently interrupted due to toxicity in 11.5% in arm 3 and 28.7% in arm 6. The overall incidence of grade3-4 toxicity events was 28.7% in arm 3 and 42.8% in arm 6. Grade 2 or higher neuropathy was more frequent in arm 6 than in arm 3: 36.5 % vs 13.6%. However, toxicity events depended on the FU backbone with more grade 3-4 neutropenia on mFOLFOX6 (30.4% vs 12.4%), and more grade 3-4 anorexia (1.9% vs 5.1%) and grade 3-4 diarrhea (1.3% vs 5.5%) on XELOX. Conclusions: Both mFOLFOX6 and XELOX were safe and well tolerated. The grade3-4 main toxicities did vary according to FU backbone. Observed toxicity was significantly higher in the 6-month arm compared to that of the 3-month arm; compliance was lower in the standard 6-month arm. Clinical trial information: UMIN 000008543.
3608 Background: Circulating tumor DNA (ctDNA) analysis can be used to predict the risk of recurrence by detecting molecular residual disease (MRD) in patients with colorectal cancer (CRC). We are conducting a prospective observational study to monitor MRD status in patients with clinical stage II–IV or relapsed CRC amenable to radical surgical resection (GALAXY study), as part of the CIRCULATE-Japan, a nationwide ctDNA-guided precision adjuvant therapy project. Methods: Analysis of ctDNA is being performed at pre- and post-surgery timepoints and will continue periodically for up to 2 years using Signatera, a personalized, tumor-informed ctDNA assay that is designed to track 16 patient-specific somatic variants based on whole-exome sequencing of tumor tissue. The association of peri-operative ctDNA status with clinicopathological characteristics was investigated. Results: As of January 13, 2021, 941 patients have been enrolled in the GALAXY study, of which 400 patients had their pre-operative ctDNA status evaluated. Of the 400 patients, baseline ctDNA was detected in 92% (367/400) of the patients: consisting of 35 patients with pathological stage (pStage) I, 135 with pStage II, 152 with pStage III, and 78 with pStage IV or relapsed disease (pStage IV/R). Patient-specific Signatera assays targeting 16 variants were designed for 100% of the patients. Out of the 6400 designed variants 99.3% passed quality control in the plasma analysis and produced the final results. Among 4425 genes selected for 400 patients, 3330 genes were selected for only one patient, while TP53 was the most commonly selected in 113 patients (28%). Median ctDNA levels, measured in mean tumor molecules per mL of plasma and ctDNA detection rate, stratified by stage are presented in table. Positive ctDNA status post-surgery was significantly associated with advanced pStage, pT and pN, and lymphovascular invasion. Of the 13 patients with recurrence, 10 were detected with a positive ctDNA at 4-weeks post-surgery, before confirmation of recurrence by the radiological imaging. Conclusions: Preoperative ctDNA detection rates were observed to be in >90% in patients with pStage II–III by personalized ctDNA assay based on unique somatic variants, specific to each patient. ctDNA- based MRD detected post-surgery (4W) was significantly associated with certain known clinicopathological factors for recurrence with ctDNA positivity associated with a very short-term of recurrence. Clinical trial information: 000039205. [Table: see text]
648 Background: Carcinoembryonic antigen (CEA) decrease was faster and greater in cetuximab (cet) treatment than bevacizumab treatment and correlated with prolonged survival in mCRC pts receiving FOLFIRI plus cet (Michl M, et al. Ann Oncol 2016). We investigated if the CEA decrease is a surrogate for DpR reported to be associated with clinical outcomes. Methods: This study evaluated the association between the percentage of CEA decrease or DpR and clinical outcomes in pts with KRAS exon 2 wild-type from 2 phase II trials of 1st-line therapy; JACCRO CC-05 of cet plus FOLFOX ( n= 57, UMIN000004197) and CC-06 of cet plus SOX ( n= 61, UMIN000007022). The association was analyzed using Spearman’s rank correlation coefficient. The cut-off value of 75% CEA decrease was used for CEA response to discriminate CEA responders according to the previous report. The DpR was defined as the percentage of tumor shrinkage at the nadir as compared with the baseline values. Results: In total of 113 pts of the 2 trials in the full analysis set, 92 were eligible for analyses of both CEA and DpR. In the population consists of 92 evaluable pts, median progression-free survival (PFS) was 9.1 months, and median overall survival (OS) was 36.2 months. Median CEA decrease was 67.4% and median time to CEA nadir was 2.8 months similar to median time to DpR of 3.0 months. The DpR was associated with PFS and OS (r s = 0.56; P< 0.0001, r s = 0.39; P= 0.0090, respectively); moreover, CEA decrease correlated with PFS (r s = 0.56, P< 0.0001) as well as OS (r s = 0.35, P= 0.019). CEA responders showed significantly longer PFS [11.8 vs. 5.5 months; hazard ratio (HR) 0.46; 95% Cl, 0.28–0.73; P= 0.0009] and numerically longer OS (36.2 vs. 23.5 months; HR 0.57; 95% CI, 0.30-1.05; P= 0.072) than CEA non-responders. The CEA decrease was statistically significantly associated with DpR (r s = 0.44, P< 0.0001). Conclusions: Our study demonstrates that DpR and CEA response both correlated with clinical outcomes of 1st-line treatment with cet plus oxaliplatin-based chemotherapy. The CEA decrease may serve as a surrogate for DpR in 1st-line cet treatment.
•Treatment guidelines recommend resection of oligometastatic CRC.•Optimal perioperative systemic therapy has not been fully defined.•The COSMOS-CRC-03 study evaluates the ctDNA's prognostic value for oligometastatic cancer.•The AURORA trial tests mFOLFOXIRI plus bevacizumab post-surgery.•We designed these studies to stratify patients based on a ctDNA assay. International treatment guidelines recommend tumor resection for patients with oligometastatic colorectal cancer (CRC). Despite this, recurrence occurs in ∼60% of patients post-surgery, indicating that the role and optimal type of perioperative systemic therapy has not been fully defined. In the COSMOS-oligo trials, comprising two studies, we are evaluating the potential role of circulating tumor DNA (ctDNA) analysis in clinical decision making and exploring adjuvant therapy strategies for patients with resectable metastatic CRC. The COSMOS-CRC-03 study aims to evaluate the prognostic value of post-operative minimal residual disease as detected by ctDNA and to explore the role of ctDNA in detecting disease recurrence. We plan to assess the predictive accuracy of ctDNA results for recurrence using blood collected 28 days post-surgery. We will additionally explore whether regular post-operative ctDNA test can detect recurrence earlier than standard imaging. Post-operative adjuvant therapy will not be administered to ctDNA-negative patients. The complementary AURORA trial is a randomized phase II study designed to test whether post-operative mFOLFOXIRI plus bevacizumab is superior to standard mFOLFOX6 for patients with metastatic CRC when the ctDNA status is positive after curative-intent surgery for patients enrolled in the COSMOS-CRC-03 study. Both studies will only include patients with resectable distant metastases of CRC. We designed these studies to stratify patients based on the results of a ctDNA assay and to determine the optimal treatment for patients at the highest risk for recurrence. International treatment guidelines recommend tumor resection for patients with oligometastatic colorectal cancer (CRC). Despite this, recurrence occurs in ∼60% of patients post-surgery, indicating that the role and optimal type of perioperative systemic therapy has not been fully defined. In the COSMOS-oligo trials, comprising two studies, we are evaluating the potential role of circulating tumor DNA (ctDNA) analysis in clinical decision making and exploring adjuvant therapy strategies for patients with resectable metastatic CRC. The COSMOS-CRC-03 study aims to evaluate the prognostic value of post-operative minimal residual disease as detected by ctDNA and to explore the role of ctDNA in detecting disease recurrence. We plan to assess the predictive accuracy of ctDNA results for recurrence using blood collected 28 days post-surgery. We will additionally explore whether regular post-operative ctDNA test can detect recurrence earlier than standard imaging. Post-operative adjuvant therapy will not be administered to ctDNA-negative patients. The complementary AURORA trial is a randomized phase II study designed to test whether post-operative mFOLFOXIRI plus bevacizumab is superior to standard mFOLFOX6 for patients with metastatic CRC when the ctDNA status is positive after curative-intent surgery for patients enrolled in the COSMOS-CRC-03 study. Both studies will only include patients with resectable distant metastases of CRC. We designed these studies to stratify patients based on the results of a ctDNA assay and to determine the optimal treatment for patients at the highest risk for recurrence.
21 Background: The presence of circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who are at risk of recurrence and aid with postsurgical risk stratification. ~80% of stage II and only 50% of stage III colorectal cancer (CRC) patients are cured by surgery alone. A tumor-uninformed plasma-only approach for MRD assessment accelerates the turnaround time, enabling rapid adjuvant chemotherapy (ACT) treatment decision making, optimizing the impact on patient outcomes. Methods: A subset of samples from GALAXY, an observational arm of the CIRCULATE-Japan study (UMIN000039205), were analyzed for postsurgical ctDNA detection at a landmark time point (LMT) defined as 4 weeks after curative surgery in pathological stage II or III CRC patients. In a prospective lead-in to clinical validation, 80 patients meeting pre-specified eligibility criteria were randomly selected with enrichment for recurrence to 50% while maintaining the stage II:III recurrent (R)/nonrecurrent (NR) ratio to that observed in GALAXY. Residual plasma samples were analyzed with the Tempus xM assay (xM), a tumor-uninformed ctDNA MRD assay that integrates methylation and genomic variant MRD classifiers to deliver a binary MRD call. All calls were blinded to clinical outcomes. The methylation-based classifier detects fragments with CRC methylation signatures in differentially methylated regions trained by sequencing CRC and presumed-healthy samples on a 6Mbp panel. The variant-based MRD classifier detects highly prevalent CRC variants. Artifacts, CHIP, and germline variant filtering algorithms were also applied. Results: Of the 80 patients (pts), 70 [Stage II n= 29 (41%), Stage III n= 41 (59%)] were evaluable (36 R and 34 NR). At the LMT and with at least 1-year follow-up, 18/36 R pts had detectable ctDNA (xM MRD+) and 30/34 NR pts had undetectable ctDNA (xM MRD-), providing a sensitivity of 50% and specificity of 88%. Additionally, xM MRD+/- status strongly correlated with disease-free survival (DFS) with a hazard ratio (HR) of 5.09, adjusted to account for a 24% recurrence rate in GALAXY. In an updated, ongoing longitudinal analysis of the 4 false positive pts, 2 were Stage III, MRD+ from both the methylation and genomic classifiers, received ACT, and have likely cleared their ctDNA without any sign of clinical recurrence. An adjusted sensitivity and specificity analysis resulted in xM clinical performance of 53% (20/38 R) and 94% (30/32 NR), respectively. Conclusions: xM is a novel tumor-uninformed assay that demonstrated remarkable performance to detect clinical recurrence at a LMT, and a clinically meaningful correlation with DFS. A larger clinical validation study including longitudinal analysis, correlation with ACT, and outcomes from the GALAXY study is currently underway.
