108 Background: In VOLTAGE-A, CRT (50.4 Gy with capecitabine of 1,650 mg/m2) followed by five cycles of consolidation Nivo (240 mg q2 weeks [W]) and radical surgery showed 30% of pathological complete response (pCR) in pts with MSS and 60% in MSI-H T3–4 NanyM0 LARC. Here, we report survival outcomes and functional results. Methods: All 39 MSS and 5 MSI-H pts were included in the VOLTAGE-A from Jan 2017 to Oct 2019. Survival outcomes, late adverse events, and patient-reported outcome measurements for urogenital and anal functions were analyzed. Urinary function was evaluated using the International Prostate Symptom Score (I-PSS) periodically at 1W, 1, 3, 6, and 12 months (M), postoperatively. Sexual function in sexually active male pts was evaluated using the International Index of Erectile Function (IIEF) score at 3, 6, and 12M, postoperatively. Anal function was evaluated using the Wexner score, low anterior resection syndrome (LARS) score, and fecal incontinence severity index (FISI) score at 1-year post-surgery. All functional scores were evaluated preoperatively. Results: With a median follow-up of 44.8M (range, 25.7-58.9M), the 3-year relapse-free survival (RFS) and 3-year overall survival (OS) rates were respectively 79.5% and 97.4% in MSS, and 100% each in MSI-H pts. Of the MSS pts, those with pCR, clinical CR (cCR) according to the MSKCC criteria, high PD-L1 expression (tumor proportion score [TPS] ≥1%), and CD8/eTreg ratios of ≥2.5 had a trend of better 3-year RFS and OS than those without. During the follow-up period, one patient developed CTCAE grade 3 immune-related colitis, which was diagnosed 20M after the last dose of Nivo. Postoperative functional results were acceptable in both populations; pre-surgical median I-PSS scores were 3, whereas postsurgical values were 5 (1W), 5.5 (1M), 5 (3M), 4 (6M), and 4 (12M); median IIEF score was 20 at pre-surgery and 6 (3M), 6 (6M), and 8 (12M) at post-surgery; median scores of Wexner, LARS, and FISI were 2, 23, and 7 at pre-surgery, and 9, 30, and 17 at 1-year post-surgery, respectively. Conclusions: Preoperative CRT followed by Nivo showed promising survival outcomes in both MSS and MSI-H LARC pts. The therapeutic effect of pCR, cCR, and certain biomarkers analyzed by pre-CRT samples could be used as prognostic predictors in MSS pts. Clinical trial information: NCT02948348 .[Table: see text]
TPS264 Background: The BEACON CRC trial demonstrated survival benefit of combination therapy with encorafenib (ENCO) + cetuximab (CET) +/- binimetinib (BINI) in patients with RAS wild-type (WT)/ BRAF V600E mutant metastatic colorectal cancer (mCRC). However, prognosis of those patients still be poor after the refractoriness to the BEACON combination therapy. One of resistant mechanisms to BRAF inhibitor has been reported as MAPK alterations including RAS mutation, similar to those for anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC. Promising results of rechallenge therapy with anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC and with combination of BRAF inhibitor + MEK inhibitor in patients with BRAF V600 mutant melanoma suggest the treatment strategy of rechallenge therapy with the BEACON triplet therapy in patients with RAS WT/ BRAF V600E mutant mCRC. Methods: TRIDENTE trial is a multicenter phase II trial to assess efficacy and safety of rechallenge therapy with ENCO + BINI + CET in patients with RAS WT/ BRAF V600E mutant mCRC after the refractoriness to either the BEACON doublet or triplet therapy. Key eligibility criteria includes RAS WT/ BRAF V600E mutant mCRC; ≥ 20 years old; ECOG PS 0-1; refractory or intolerant to at least one fluoropyrimidine-based regimen (including irinotecan or oxaliplatin); refractory or intolerant to anti-PD-1 antibody if patients with MSI-high; history of previous combination therapy containing ENCO + CET with at least partial response by RECIST v1.1; confirmed disease progression within 4 weeks after last administration of previous ENCO; ≥ 4 months of period between the last administration of previous ENCO and the start of study treatment. Enrolled patients receive the combination therapy with ENCO (300 mg, QD), BINI (45 mg, BID), and CET (initially 400 mg/m2, and subsequently 250 mg/m2, QW) as the study treatment. Primary endpoint is the objective response rate (ORR) by investigators’ assessment in patients receiving at least one dose of study treatment. A target sample size is calculated to be 21 on the hypothesis that the threshold ORR is 3% and expected ORR is 20%, with a significant level of 5% (one-sided) and power of 80%. Secondary endpoint includes progression-free and overall survivals, disease control rate, and safety. Exploratory molecular analysis is performed using targeted next-generation sequencing in circulating-tumor DNA at the timepoints of baseline and discontinuation of study treatment. As of September 19, 2022, 8 patients have been enrolled. Clinical trial information: jRCTs031210511 .
3530 Background: Angiogenesis factors have been reported as prognostic and predictive biomarkers of angiogenesis inhibitors for mCRC (Weickhardt AJ. Br J Cancer 2015. Tabernero J. Ann Oncol 2018). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemo in 1L treatment in patients (pts) with RAS wild-type mCRC. Methods: Serial plasma samples were prospectively collected at the time points of pre- and post-treatments in mCRC pts receiving biologics in either 1L or 2nd-line (2L) chemo. From Sep 2017 to Dec 2020, 497 pts were enrolled [1L chemo plus bevacizumab (1L BEV, n=102), 1L chemo plus anti-EGFR antibody (1L aEGFR, n=100), 2L chemo plus bevacizumab (n=100), 2L FOLFIRI plus RAM (n=99), 2L FOLFIRI plus aflibercept (n=85) and other treatment (n=11)]. Total of 17 plasma angiogenesis factors (HGF, PlGF, VEGF-A, VEGF-D, Angiopoietin-2, IFN-γ, IL-6, IL-8, sNeuropilin-1, TSP-2, OPN, sVEGFR1, sVEGFR2, sVEGFR3, sICAM-1, sVCAM-1, and TIMP-1) were analyzed by the multiplex assay with Luminex® technology. Interactions of their pre-treatment measurements with treatment groups on PFS and OS were assessed via Cox proportional hazards model. The strength of interactions was estimated using a propensity score weighting analysis, and the continuous plasma angiogenesis variables were categorized according to the median. The significance level in the interaction was defined as p≤0.1. Results: 133 pts were included in adjusted RAS wild-type 1L cohort (1L BEV: n=33, 1L aEGFR [reference]: n=100). Baseline characteristics of adjusted RAS wild-type 1L cohort were as follows; median age 64 years; male 62.4%; left-sided tumor 88.7%; triplet chemo 15.0%. Propensity-score weighted Cox model for OS showed significant interactions in IL-8 (median 8.03 pg/mL, high: HR 1.738, p=0.0838, Low: HR 0.479, p=0.2624, interaction p=0.0283), sVEGFR-1 (median 1,350 pg/mL, high: HR 0.333, p=0.1770, Low: HR 1.311, p=0.3004, interaction p=0.0777), and sVCAM-1 (median 1,020,000 pg/mL, high: HR 0.100, p=0.0558, Low: HR 1.616, p=0.1765, interaction p=0.0011). In terms of PFS, there were significant interactions in IL-8 (high: HR 1.322, p=0.0418, Low: HR 0.517, p=0.0528, interaction p=0.0752) and sVCAM-1 (high: HR 0.285, p=0.0414, Low: HR 1.200, p=0.7725, interaction p=0.0156). Conclusions: Pre-treatment plasma IL-8 and sVCAM-1 could be predictive biomarkers for efficacy of biologics combined with chemo in 1L treatment of RAS wild-type mCRC. Clinical trial information: UMIN000028616. [Table: see text]
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