Session VII: Colorectal Cancer II
SESSION VII WEBCAST (with Slides - needs a registration)
Late-Breaking Abstract-6: Safety, feasibility, tolerability, and preliminary efficacy of perioperative systemic therapy for resectable colorectal peritoneal metastases: pilot phase of a randomised trial (CAIRO6)
The authors conclude that the pilot trial of the randomized CAIRO6trial shows that perioperative systemic therapy appears feasible, safe, tolerable, and able to induce radiological and pathological tumor response in pts with isolated colorectal peritoneal metastases. These findings justify the continuation of the currently ongoing phase 3 trial, which will provide the first intention-to-treat overall survival comparison of perioperative systemic therapy and cytoreductive surgery with HIPEC alone in these pts.
The authors conclude that responses to Sotorasib (AMG 510) were seen in pts with previously treated CRC, with the majority achieving disease control, resulting in a PFS longer than that anticipated with the current standard of care. Encouraging antitumor activity was also observed in the subset of pts with other GI tumors, with one confirmed partial response in a patient with appendiceal cancer and the majority of patients with pancreatic cancer (6/8) achieving stable disease. Toxicities were tolerable, and most treatment-related AEs were grade 1 or 2. The phase 2 part of the trial is ongoing (CodeBreak100: NCT03600883)
Servier Satellite Symposium:
The authors conclude that although several pts achieved longer disease control, this phase II study of eribulin for pts with BRAF V600E mutant mCRC did not meet the primary endpoint. Pts with low maximum VAF or without RAS/AKT or EMT-related gene alterations at the baseline exhibited a longer PFS. Biomarker analyses, including RNA sequencing using pretreated tissues, are ongoing.
The authors conclude that spartalizumab, dabrafenib and trametinib are well-tolerated in BRAFV600E CRC pts. Favorable response rate (33% ORR) and durability relative to historical controls (12% ORR for dabrafenib/trametinib alone). Single-cell RNAseq analysis of paired baseline and day 15 biopsies delineate gene expression changes in tumor cell and immune cell compartments that may suggest mechanistic links underlying potential cooperativity. The trial recently expanded to enroll an additional 15 MSS BRAFV600 CRC pts with no prior BRAF inhibitor or immunotherapy.
Short Oral-28: A randomized phase II trial of mFOLFOX6-based standard of care alone or in combination with Ad-CEA vaccine plus avelumab in patients with previously untreated metastatic colorectal cancer (mCRC)
The authors conclude that mFOLFOX plus Bevacizumab + Avelumab + AdCEA is well tolerated (6 pts treated on safety lead-in, 5-FU bolus dropped after death from neutropenic typhlitis with bowel perforation; no unexpected toxicities; transient grade 1-2 fever, flu-like illness and/or injection site reactions were common (88%) in pts receiving AdSCEA; one patient had an Avelumab-related grad 2 arthralgia. A total of 20 pts were randomized, 10 to each arm, 2 pts on SOC + IO treatment had BRAFV600 mutant disease. ORR was 50% for both treatment arms and the median PFS was similar. There were no objective responses among pts (n=4) who crossed over to SOC + IO treatment after progression on SOC alone. This study closed to accrual after a futility analysis predicted a low likelihood of achieving a prolongation of mPFS (target 18 months), compared to the historic value of 10 months. Addition of Avelumab + AdCEA to SOC increased CD8 and or CD4 multifunctional T-cell responses to cascade MUC1 and brachyury, compared to SOC alone.
Short Oral-29: Long-term survival after hyperthermic intraperitoneal chemotherapy using mitomycin C or oxaliplatin in colorectal cancer patients with synchronous peritoneal metastases: a nationwide comparative study
The authors conclude that both oxaliplatin and mitomycin O are justified as a chemotherapeutic drug during HIPEC for colorectal peritoneal metastases, as no overall survival benefit could be approved from one regimen over another.
Short Oral-30: Adjuvant systemic chemotherapy versus active surveillance following upfront resection of isolated synchronous colorectal peritoneal metastases: propensity score-matched analysis of a nationwide registry.
The authors conclude that adjuvant systematic chemotherapy is associated with improved OS following upfront resection of isolated synchronous colorectal peritoneal metastases. Although randomized trials are needed to eliminate any influence of residual confounding and allocation bias on this association, the results of this study may be used for clinical decision-making in this increasing, understudied patient group for whom no data are available and no randomized trial are ongoing.
The authors conclude that this analysis is the largest available cohort of colon cancer peritoneal metastases pts uniformly treated with contemporary systemic chemotherapy (CT) and radical surgery. Radical surgical resection with systemic CT is associated with excellent survival outcomes in optimaöly resected pts with colon cancer peritoneal metastases. The delivery of care within a highly specialized multidisciplinary unit is associated with a very high complete resection rate and a very low postoperative morbidity and mortality. On multivariable analysis N0 stage, absence of signet ring histology and absence of any visceral or small bowel involvement were the only factors associated with better survival.
The authors conclude that in this exploratory post-hoc analysis conducted in a minority of pts from theIMblaze370 trial, the following trends were observed: There was no clear enrichment of markers for the response due to the low number of responders in all three arms. Atezolizumab + cobimetinib showed benefit over regorafenib in pts with certain tumor subsets, including those with PI3K/Akt mutation and pts with the WNT pathway wild-type tumors. Atezolizumab + cobimetinib showed benefit over Atezolizumab alone in pts with low TMB or low tumor-infiltrating lymphocytes.
The authors conclude that in pts with initially RAS-mutated mCRC, RAS mutations rapidly disappeared during the 1st-line therapy in liquid biopsy. The conversion happened independent of type and intensity of chemo- and anti-VEGF therapy and without significant tumor mass reduction. Methylated WIF1 promotor analyses specifically confirmed the persistent release of ctDNA in NeoRAS wt status. May pts with the conversion of initial RAS-mutated status benefit from treatment with anti-EGFR antibodies analogous to RAS wild type tumors?
The authors conclude that using a personalized tumor-informed ctDNA assay, MRD was detected in 49% of oligometastatic pts after treatment with curative intent (higher compared to early-stage CRC: 18% detected, consistent with published relapse rates). Quantitatively, the observed levels of ctDNA were also higher than early-stage CTC ctDNA levels, median 5.13 MTM/ml, (range 0.11-13.274) vs. 1.28 (0.13-872.2). Further investigation in this cohort is needed to assess the impact of adjuvant chemotherapy and how this informs clinical outcomes using ctDNA analysis.
The authors conclude that tumor-infiltrating CD3 lymphocytes and CD8 macrophages improve long-term survival in mCRC pts treated with chemotherapy, independent of MSI and BRAF. Pts with low infiltration of CD3 lymphocytes had no survival benefit of a more intensified chemotherapy regimen.
The authors conclude that dMMR status is a poor prognostic marker in colon cancers with lymphatic spread (stage III), but not in stage II. This stage-dependent difference is not explained by differences in density of TILs, administration of adjuvant chemotherapy, or variations in CDX2 expression.
The authors conclude that the combination of regorafenib of 80mg and NIVO 240mg IV q2wk was the recommended dose for the expanded cohort. The combination of regorafenib and NIVO demonstrated modest clinical efficacy in MSS refractory CRC. Pre- and post samples are being collected in the expanded cohort and the correlatives will be presented at a future congress including PD-L1 status. The plan is to enroll a total of 40 pts in the expanded cohort to further evaluate the efficacy.
The authors conclude that the international collaborative study shows concordance between liquid and tumor tissue biopsies for RAS mt (similar trends in each met sites between Spanish and Japanese trials; the impact of tumor burden as well as organ specificity on the concordance). The utility of BEAMing digital PCR IVD technology in mCRC pts may depend on the metastatic site (no need to consider the cut-off level for pts with liver met alone; careful attention should be given to pts with peritoneal met alone with lesions size <20mm and lung met alone with lesions size <20mm and<10 lesions.