ORAL: Gastrointestinal Cancer – Gastroesophageal, Pancreatic, and Hepatobiliary

ATTRACTION-5: A phase 3 study of nivolumab plus chemotherapy as postoperative adjuvant treatment for pathological stage III (pStage III) gastric or gastroesophageal junction (G/GEJ) Cancer.

The phase III ATTRACTION-5 trial compared the efficacy and safety of adjuvant treatment using nivolumab (NIVO) plus chemotherapy (CT) versus placebo plus CT in patients with stage III gastric or gastroesophageal junction (G/GEJ) cancer. Adjuvant chemotherapy after D2 or more extended gastrectomy is a widely used standard of care for pStage III G/GEJ cancer in Asia. However, standard adjuvant chemotherapy has shown limited efficacy for pStage III G/GEJ cancer. A total of 755 patients underwent randomization from February 2017 to August 2019: 377 were assigned to the N+C arm and 378 to the P+C arm. While the combination of NIVO and CT did not show a statistically significant improvement in relapse-free survival (RFS) compared to the placebo arm (HR, 0.90; 95.72% CI, 0.69–1.18; P=0.4363) 3-year RFS rates of 68.4% (95% CI, 63.0–73.2) in the N+C arm and 65.3% (95% CI, 59.9–70.2) in the P+C arm., some favourable outcomes were observed in patients with performance status one, stage III C, and positive PD-L1 expression. Overall survival (OS) results were consistent with the primary RFS findings. The safety profile of NIVO plus CT was similar to the known safety profile of NIVO alone and adjuvant chemotherapy. However, there were higher endocrine-related adverse events in the nivolumab arm.

Perioperative PD-1 antibody toripalimab plus SOX or XELOX chemotherapy versus SOX or XELOX alone for locally advanced gastric or gastro-oesophageal junction cancer: Results from a prospective, randomized, open-label, phase II trial.

The combination of PD-1 antibody and chemotherapy was shown to be effective in advanced gastric or gastro-oesophageal junction (GEJ) cancer, but has not yet been investigated in the context of locally advanced patients. A randomized phase II trial assessed the effectiveness of combining PD-1 antibody toripalimab with CT in patients with locally advanced G/GEJ cancer. Adding toripalimab increased the proportion of patients achieving tumor regression grade from 20% to 44% with statistical significance. This suggests that the combination therapy can potentially improve treatment outcomes in this patient population. Importantly, the safety profile of toripalimab plus CT was found to be acceptable, with no new safety concerns identified. Perioperative PD-1 antibody toripalimab plus chemotherapy demonstrated a significantly improved pathological regression and might be a promising option for patients with locally advanced resectable gastric or GEJ cancer.

Is Timing Everything? Immunotherapy in Localized Gastroesophageal Junction and Gastric Cancer

The adjuvant use of NIVO did not show improved OS in G/GEJ cancer, similar to the results observed in the ATTRACTION 4 trial for metastatic disease. This suggests that single-agent checkpoint inhibitor therapy may not be sufficient. Alternative immunotherapy agents or combination therapies should be explored, targeting specific subsets such as CLAUDIN 18.2, FGFR, and HER2-positive patients. Patients with PD-L1 positive tumor proportion score (TPS) benefited from adjuvant NIVO, but they represented only 14% of the population. Notably, 60-80% of TPS-negative patients may test positive for the combined positive score (CPS). Further investigation is needed to assess outcomes in CPS-positive and microsatellite instability-high (MSI-high) populations. The positive trial, CHECKMATE 577, demonstrated the benefits of adjuvant NIVO in both TPS-positive and negative patients. Also, delayed NIVO treatment initiation showed better disease-free survival than earlier therapy.

A phase II trial compared toripalimab combined with SOX or XELOX chemotherapy versus chemotherapy alone in locally advanced G/GEJ cancer. Adding toripalimab led to a significant improvement in pathologic complete response rate and major responses. T downstaging was the primary benefit, while nodal downstaging was not significant. MSI and CPS status are still awaited, but the DANTE trial showed MSI-high and CPS ≥10% of patients had the greatest impact.

Efficacy, safety and patient reported outcomes (PROs) from the phase III IMbrave050 trial of adjuvant atezolizumab (Atezo) + bevacizumab (Bev) vs active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation.

The IMbrave050 study is a Phase III trial in HCC (hepatocellular carcinoma) that demonstrated an improvement in recurrence-free survival with adjuvant treatment following curative intent resection or ablation. Pts were randomized to Arm A (atezo + bev) or Arm B (active surveillance). 334 pts in both Arms A and B. The combination of atezolizumab and bevacizumab (Atezo+Bev) showed a statistically significant improvement in recurrence-free survival compared to active surveillance. With a median follow-up time of 17.4 mo (clinical cutoff date: 21 Oct 2022), IRF-RFS HR was 0.72 (95% CI: 0.56, 0.93; P = 0.0120). The safety profile of the treatment was manageable and consistent with each agent and the underlying disease. Patient quality of life and functioning scores were high initially and did not deteriorate significantly during treatment. Atezo+Bev regimen may become a practice-changing adjuvant treatment option for high-risk HCC patients.

Health-related quality of life (HRQoL) in the phase 3 KEYNOTE-966 study of pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) versus placebo plus gem/cis for advanced biliary tract cancer (BTC).

In the randomized, double-blind, phase 3 KEYNOTE-966 trial (N = 1069; NCT04003636), pembro + gem/cis significantly improved OS versus placebo + gem/cis (HR 0.83; 95% CI 0.72-0.95; P = 0.0034) and had an expected and manageable safety profile as first-line therapy for unresectable locally advanced or metastatic BTC. Combining pembrolizumab with gemcitabine and cisplatin (GP) as the first-line treatment for advanced biliary tract cancer (BTC) maintained health-related quality of life (HRQoL). Longitudinal analysis showed similar changes in HRQoL scores between the pembrolizumab and control groups in multiple domains, including global health status, physical functioning, role functioning, jaundice, pain, and overall quality of life. The time to confirm deterioration in HRQoL was also comparable between the two groups. These findings and previously reported efficacy and safety data provide further support for pembrolizumab plus GP as a new first-line treatment option for advanced BTC.

Outcomes by occurrence of immune-mediated adverse events (imAEs) with tremelimumab (T) plus durvalumab (D) in the phase 3 HIMALAYA study in unresectable hepatocellular carcinoma (uHCC).

The Phase III HIMALAYA study assessed the effectiveness of the STRIDE (Single tremelimumab Regular Interval Durvalumab) regimen and durvalumab monotherapy in treating unresectable HCC (uHCC). Results revealed that STRIDE significantly improved OS compared to the standard treatment sorafenib. Durvalumab monotherapy was also found to be non-inferior to sorafenib in terms of OS. An improvement in OS was seen with STRIDE in pts with imAEs vs pts without (HR, 0.73; 95% CI, 0.56–0.95). OS rates at 6, 12, and 24 months (mo) were higher for STRIDE in pts with imAEs vs pts without. Although immune-mediated adverse events (imAEs) are known side effects of immune checkpoint inhibitors, the majority of imAEs in the study were of low grade, and discontinuations due to imAEs were rare. An exploratory analysis was conducted to investigate the impact of imAEs on OS, and it was determined that the occurrence of imAEs did not hinder the survival benefits of STRIDE. Long-term survival was observed with STRIDE regardless of imAE occurrence. These findings support the efficacy of STRIDE as a viable treatment option for uHCC in a diverse global population.

Putting the Patient First: PROs and Immune-Related Uh-Ohs

Clinical trials prioritize patient perspectives by involving them in decision-making and treatment planning. The HIMALAYA trial showed that adverse events from STRIDE Regimen occur early, within 3 months, and patients experiencing these events had better OS. Different options are available for advanced HCC treatment, including the Atezo+Bev regimen, STRIDE Regimen, and VEGF-TKIs (vascular endothelial growth factor tyrosine kinase inhibitors), each with distinct side effects. Patient-reported outcomes (PROs) are vital in assessing treatment effectiveness, especially when multiple options or modest benefits exist. PROs cover disease symptoms, side effects, bother, and quality of life (QOL). PRO integration faces challenges such as standardization, patient burden, compliance, and time constraints. Atezo+Bev adjuvant therapy did not significantly affect QOL in resected HCC, but surgical recovery effects should be considered. Pembrolizumab addition showed a small but significant survival improvement in advanced cholangiocarcinoma. Durvalumab addition did not worsen QOL or symptoms in KEYNOTE 966 and TOPAZ-1 studies. Adjuvant studies should include longer follow-ups and patient-reported toxicities for comprehensive treatment assessment. PRO utilization is a step toward patient-centric care, but further research and economic evaluation are needed.

Short-course neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer: A multicenter randomized phase-II trial (NORPACT-1).

The NORPACT-1 trial compared neoadjuvant FOLFIRINOX CT to upfront surgery for resectable pancreatic head cancer (rPC). The trial included 140 patients from Nordic centers, and resection rates were similar in both groups. Adverse events were observed in both groups, with gastrointestinal toxicity and neutropenia being common. However, the median overall survival was 25.1 months in the neoadjuvant group and 38.5 months in the upfront surgery group, showing no statistically significant difference. The percentage of patients alive at 18 months was 60% in the neoadjuvant group and 73% in the upfront surgery group. Pathology analysis showed better R0 and N0 rates in the neoadjuvant group, but this did not improve survival. These findings do not support neoadjuvant FOLFOX as the standard of care for rPC, and long-term effects require further follow-up.

Liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): 12- and 18-month survival rates from the phase 3 NAPOLI 3 trial.

The NAPOLI-3 trial, conducted globally across 18 countries and 187 sites, compared NALIRIFOX with Gemcitabine and Paclitaxel (GEM+PTX) in gastrointestinal cancer (GIC) patients. Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gem+NabP group; median PFS was 7.4 months versus 5.6 months. It showed significant improvements in OS and PFS for NALIRIFOX patients. Median (95% CI) duration of response was 7.3 (5.8–7.6) and 5.0 (3.8–5.6) months in patients who received NALIRIFOX and Gem+NabP, respectively. These positive outcomes were consistently observed at 12 and 18 months, making NALIRIFOX a recommended frontline treatment for untreated pancreatic cancer. NALIRIFOX also had higher tumor response rates, better disease control, and longer response duration than GEM+PTX. The GEM+PTX arm had slightly higher hematologic toxicity, while the NALIRIFOX arm had more gastrointestinal toxicity. However, no new safety concerns emerged, and NALIRIFOX had a longer treatment duration. Overall, NALIRIFOX offers significant survival benefits and manageable toxicity, supporting its use as a reference regimen for frontline untreated pancreas cancer.

Tucatinib and trastuzumab for previously treated HER2-positive metastatic biliary tract cancer (SGNTUC-019): A phase 2 basket study

The SGNTUC-019 study investigated the effectiveness of combining a Tyrosinase inhibitor (TIB) with Trastuzumab (TRA) for patients diagnosed with HER2-positive metastatic biliary tract cancer (MBTC), a rare and difficult-to-treat form of cancer. Of the 30 patients involved, 46.7% achieved a confirmed objective response, and the disease control rate was 76.7%. The combination treatment had manageable safety, with grade 3 or higher adverse events in 60% of patients. Accurate testing methods were crucial in identifying patients benefitting from the treatment. Patients identified as HER2-positive by central testing methods exhibited higher response rates than HER2-negative patients. The study supports TIB and TRA combination as a viable treatment for HER2-positive MCTC, validating HER2 as a predictive biomarker.

Results from the pivotal phase (Ph) 2b HERIZON-BTC-01 study: Zanidatamab in previously-treated HER2amplified biliary tract cancer (BTC).

Biliary tract cancer (BTC) is a rare and challenging disease with limited treatment options. HER2 amplification or overexpression is found in a subset of BTC patients, but no approved HER2-targeted treatments exist for BTC. Zanidatamab, a unique HER2-targeted bispecific antibody, showed promise in a phase 1 trial by demonstrating manageable safety and antitumor activity in patients with HER2-expressing BTC. In a pivotal Phase 2b study, Zanidatamab demonstrated an overall response rate of 41.3% and a disease control rate of 68.8% in BTC patients who had progressed after prior treatment. The median duration of response and PFS was 12.9 months and 5.5 months, respectively. Zanidatamab's safety profile was manageable, with infusion-related reactions and diarrhea being the most common adverse events. Ongoing studies are exploring Zanidatamab's potential in combination with other drugs for treating HER2-positive BTC.

Targets and Triplets in Pancreaticobiliary Tumors

The LBA4005, 4006, 4007, and 4008 trials were discussed. The NAPOLI-3 trial compared NALIRIFOX to Gemcitabine plus NAB-Paclitaxel as first-line treatment for metastatic pancreatic cancer. NALIRIFOX showed statistically significant improvements in overall survival (OS) and progression-free survival (PFS), but the benefits were considered modest compared to the current standard of care. The high cost of NALIRIFOX raises concerns about its cost-effectiveness. The NORPACT-1 study examined neoadjuvant chemotherapy for pancreatic cancer. Upfront surgery showed trends toward better overall survival than neoadjuvant FOLFIRINOX, despite the neoadjuvant group having higher rates of successful resection and negative disease. The study had limitations, but ongoing trials, like the Alliance A021806 and REOPANC-3 trials, aim to provide a clearer answer on neoadjuvant therapy for resectable pancreatic cancer. Different subtypes of biliary cancers exhibit distinct molecular features, particularly regarding HER2 overexpression. HER2 targeting agents have shown promise, including monoclonal antibodies, TKIs, bispecific monoclonal antibodies, and drug antibody conjugates. Trials with trastuzumab, tucatinib, and Zanidatamab demonstrated impressive responses in biliary cancer patients. Standardization of HER2 positivity definition is necessary, and ongoing research focuses on resistance mechanisms and sequencing of different agents. Promising therapeutic strategies include bispecific antibodies, antibody-protein conjugates, and HER2-targeting CAR T-cells for the future of biliary cancer treatment.

Video No M04. American Society of Clinical Oncology (ASCO) 2023 Conference, 2nd -6th June, Chicago

ORAL: Gastrointestinal Cancer—Colorectal and Anal

~ 95% of mCRC patients are pMMR/MSS and derive no benefit from 1st generation immune checkpoint inhibitors (ICI). The session discussed an AtezoTRlBE study that evaluated the potential benefit of adding atezolizumab, an immune checkpoint inhibitor, to the standard treatment of FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer (mCRC) patients. The primary endpoint of the study was Progression-Free Survival (PFS), and it had a sample size of 201 patients. At a median follow-up of 37.0 months, the study confirmed that the addition of atezolizumab to the standard treatment significantly extended PFS (13.1 vs 11.5 months, HR 0.69) in molecularly unselected mCRC patients with no difference in response rate. The preliminary analysis of Overall Survival (OS) also showed a trend towards longer survival with atezolizumab (HR 0.81). Additionally, the study found that the benefit of atezolizumab was heterogenous in patients with pMMR tumors (tumors with proficient mismatch repair) based on their tumor mutational burden (TMB) and Immunoscore IC. Patients with high TMB and Immunoscore IC had a greater benefit in terms of both PFS and OS.

HER2+ (IHC 3+ or IHC 2+/ISH+) mCRC represents ~2-3% of mCRC and is associated with resistance to EGFR-targeted therapy. The DESTINY-CRC02 study, a multicenter, randomized, Phase 2 trial, evaluated the efficacy and safety of Trastuzumab deruxtecan (T-DXd) in patients with HER2-overexpressing/amplified (HER2+) mCRC. The study included 42 patients with RAS wild-type or mutant and BRAF wild-type mCRC who had previously received standard chemotherapy. The patients were randomly assigned to receive either T-DXd at a dose of 5.4 mg/kg or 6.4 mg/kg. The findings showed promising antitumor activity in HER2+ mCRC patients treated with both doses of T-DXd. The response rates were higher in patients receiving T-DXd at 5.4 mg/kg compared to 6.4 mg/kg (37.8 vs 27.5%). Patients with IHC 3+ HER2 status had a greater antitumor response at the 5.4 mg/kg dose than IHC 2+/lSH+ HER2 status. T-DXd demonstrated antitumor activity in patients with (28.6%) and without (39.7%) RAS mutations and in those who had prior anti-HER2 therapy (41.2%) at the 5.4 mg/kg Q3W dose. T-DXd demonstrated a higher safety profile at the 5.4 mg/kg dose. Drug-related interstitial lung disease (ILD) or pneumonitis rates were lower with the 5.4 mg/kg dose. Hence, T-DXd at a dose of 5.4 mg/kg (a single agent) is optimal for this patient population due to its positive benefit-risk profile.

The Destiny-CRC02 assessed the efficacy and safety of the lower dose T-DXd compared to the standard dose. The study showed promising results with a lower dose of 5.4 mg/kg every three weeks, demonstrating an improved toxicity profile and comparable efficacy for colorectal cancer treatment. According to a meta-analysis, it is crucial to test for HER2 overexpression prior to initiation of 1st line treatment as it has a predictive role in avoiding EGFR inhibitors and in the selection of HER2-targeted therapy. HER2 amplifications in mCRC is typically left sided and RAS WT. The data from the MOUNTAINEER trial suggests that both tissue-based and blood-based methods can be used to identify HER2+ mCRC. Studies such as MyPathway, DESTINY-CRC02 and MOUNTAINEER indicate that Trastuzumab+Pertuzumab, T-DXd with a dose of 5.4 mg/kg, and Tucatinib + trastuzumab (FDA approved) are potential treatments for initial line HER2+ mCRC treatment, with T-DXd being recommended as the in subsequent line for patients with RAS wild-type and HER2+ tumors. Several studies have targeted PD-L1 with the addition of chemotherapy and VEGF inhibitors, and positive results were observed for the primary endpoint in the AtezoTRIBE study. ImmunoScore IC was considered a promising biomarker for predicting the benefit of ICIs in microsatellite stable colorectal cancer.

The Scandinavian NeoCoI trial is a Phase III randomized clinical trial which compared the effectiveness of neoadjuvant chemotherapy and standard treatment in patients with locally advanced colon cancer (LACC). Neoadjuvant chemotherapy, which involves administering chemotherapy before surgery, is a widely accepted approach in many types of cancer and has potential benefits. The treatment plan in the trial involved two arms: Arm A received standard upfront surgery, while Arm B received neoadjuvant chemotherapy before surgery. The preferred chemotherapy regimens were three cycles of CAPOX or four cycles of FOLFOX. Adjuvant chemotherapy was not mandatory. The trial demonstrated that neoadjuvant chemotherapy is not superior to standard upfront surgery in terms of disease-free survival (DFS) and OS for patients with colon cancer. However, the neoadjuvant approach may have more favorable outcomes in terms of the number of chemotherapy cycles, reduced risk of chemotherapy toxicity, certain surgical complications, and downsizing and downstaging of the tumor.

The PRODIGE 23 phase III trial, a UNICANCER GI trial, compared total neoadjuvant therapy (TNT) with mFOLFOXIRINOX to preoperative chemoradiation in patients with locally advanced rectal cancer (LARC). The trial included 461 patients randomly assigned to the TNT or chemoradiation arm. The primary and secondary endpoints were assessed with a mature 7-year follow-up. The study found that induction chemotherapy with mFOLFOXIRINOX had a manageable safety profile and did not negatively impact subsequent therapy for stage II/III rectal cancer. Reduction in metastasis rate was observed in TNT group compared to SoC group (52.8 vs 65.1%). 7 year Disease free survival & metastasis free survival were 67.6 vs 62.5% and 73.6 vs 65.4%, respectively. Quality of life scores were higher in the TNT group during follow-up, and the incidence of male erectile dysfunction was lower. 7 year OS rate was 81.9 vs 76.1%. The findings also showed that induction chemotherapy with mFOLFOXIRINOX before chemoradiotherapy improved OS in patients with LARC. The benefits of metastasis-free survival were durable without increasing local recurrences. The safety profile remained unchanged, and the quality of life was similar or improved compared to the preoperative chemoradiation group. Therefore, TNT with mFOLFOXIRINOX should be considered one of the best options for treating patients with LRAC.

The FOWARC phase III study compared the long-term outcomes of neoadjuvant mFOLFOX6 chemotherapy with or without radiation versus fluorouracil plus radiation for LARC. Preoperative fluorouracil chemoradiotherapy has been the standard treatment, but it has not significantly improved DFS or OS, with 30% of patients still developing distant metastasis. The study aimed to investigate if early intensified chemotherapy could reduce distant metastasis and improve disease-free survival, as well as partially replace radiation therapy, which is associated with increased morbidity and impaired quality of life. 495 patients were randomized to receive FU-RT, FLOFOX-RT or only FOLFOX. Small studies showed promising responses with neoadjuvant chemotherapy alone, but no randomized controlled trials were conducted before this study (FOWARC). The study found that mFOLFOX6 with or without radiation had similar long-term DFS, local control, and OS compared to fluorouracil with radiation. mFOLFOX6 without radiation did not compromise local control or long-term survival. The ypTNM staging after neoadjuvant treatment was a strong prognostic factor, with patients achieving ypstage 0-1 showing very good survival and local control.

In the management of LACC, high-quality surgical resection is considered the mainstay of treatment, specifically employing techniques such as complete mesocolic excision with central vascular ligation and en-bloc resection. The aim was to decrease the risk of incomplete resection and improve local control by reducing tumor cell shedding and treating micro-metastases earlier. Additionally, the response to neoadjuvant therapy can guide treatment decisions based on the tumor's biology. In LARC, a comprehensive assessment of the patient and tumor is crucial to determine the most significant threat and priority. Different treatment sequencing options, including induction and consolidation strategies, are employed based on factors such as tumor regression, organ preservation, and response assessment during neoadjuvant therapy. High-quality surgery remains critical for achieving local control, with careful tissue handling and operative planning to preserve sphincter function when possible.

The GOZILA study investigated NeoRAS wild-type (WT) mCRC, which refers to the change from RAS mutant (MT) to RAS WT status after systemic therapy in 478 patients. This change in RAS status, observed in 20-80% of patients with RAS MT mCRC, has shown potential benefits from anti-EGFR therapy in previous small-scale studies. The study analyzed data from the GOZILA study, utilizing ctDNA genotyping, and found that 9.8% of patients with tissue RAS MT mCRC who received systemic therapy had NeoRAS WT with no RAS MTs and non-CH somatic alterations. The absence of liver metastasis and mutations in RAS genes other than KRAS exon 2 were associated with the development of NeoRAS WT mCRC. Anti-EGFR therapy may be effective in some patients with NeoRAS WT mCRC.

The phase III FIRE-4 study explored the influence of baseline liquid biopsy results on the efficacy of first-line treatment with FOLFIRI plus Cetuximab in patients with tissue RAS WT mCRC. 672 patients were randomized to receive either FOLFIRI+ cetuximab as induction and maintenance therapy (Arm1) or FOLFIRI + cetuximab as induction therapy followed by 5-FU/Capecitabine + bevacizumab as maintenance therapy (Arm2). The findings showed that liquid biopsies performed at baseline identified a significant number of RAS and BRAF mutations in patients classified as RAS WT based on tissue tests. These mutations had strong predictive and prognostic relevance. However, the emergence of RAS and BRAF mutations during therapy, especially with prolonged use of EGFR antibodies, did not impact survival. Liquid biopsies at baseline can be a valuable tool to identify patients who may benefit from anti-EGFR treatment. However, liquid biopsies during treatment did not provide additional guidance for treatment decisions.

The phase III PARADIGM trial demonstrated that panitumumab significantly improved OS compared to bevacizumab in both the left-sided and overall populations. Specifically, in left-sided mCRC, the median OS was 37.9 months with panitumumab versus 34.3 months with bevacizumab. In patients with MSS/MSI-L and RAS/BRAF WT mCRC, OS was significantly longer with panitumumab in left-sided tumors but not in right-sided tumors. Response rates and resection rates were also higher with panitumumab in left-sided MSS/MSI-L and RAS/BRAF WT mCRC. However, for patients with MSI-H and/or RAS/BRAF mutations, OS was similar or inferior with panitumumab compared to bevacizumab, regardless of tumor sidedness. These findings support panitumumab plus mFOLFOX6 as a first-line therapy option for patients with left-sided mCRC and MSS/MSI-L and RAS/BRAF WT.

In advanced colorectal cancer, the presence of heterogeneity poses challenges for accurate genomic profiling. Plasma (liquid) biopsy may capture genomic heterogeneity better than tissue biopsy, with factors such as tumor bulk, location, and timing influencing the shedding of circulating tumor DNA. Studies like PARADIGM and FIRE-4 have shown that adding panitumumab to chemotherapy improves survival compared to bevacizumab in patients with left-sided tumors. Both liquid and tissue biopsies have advantages and limitations in the clonal RAS profiling of colorectal cancer. Confirming the loss of RAS mutation through tissue biopsy before initiating anti-EGFR therapy is recommended outside of clinical trials. Adding ctDNA analysis to tissue testing may enhance the detection of clinically relevant mutations. Ultimately, the biopsy approach should be tailored to the individual patient's clinical circumstances.

Video No:M08. American Society of Clinical Oncology (ASCO) 2023 Conference, 2nd -6th June, Chicago