The American Society of Clinical Oncology (ASCO) recently held its 2023 Gastrointestinal Cancers Symposium in San Francisco, California, US. The meeting focused on multidisciplinary approaches in gastrointestinal (GI) cancer treatment, research, and care. Among its highlights were new data in metastatic colorectal cancer (mCRC) and metastatic pancreatic and gastric/gastroesophageal junction (GEJ) adenocarcinoma.

Refractory Metastatic Colorectal Cancer

Trifluridine/tipiracil (FTD/TPI) plus bevacizumab showed promising efficacy in a randomized phase II trial of heavily pretreated patients with mCRC. The global phase III SUNLIGHT trial was conducted to confirm these findings.

The SUNLIGHT trial included 492 patients with histologically confirmed mCRC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1, and who received 1 – 2 prior chemotherapy regimens in an advanced setting, including fluoropyrimidines, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody (if considered medically appropriate), and/or anti-EGFR monoclonal antibody for RAS wild-type tumors. Patients were randomized to receive FTD/TPI (35 mg/m² twice daily on days 1–5 and 8–12 of each 28-day cycle) alone or combined with bevacizumab (5 mg/kg on days 1 and 15). Overall survival (OS) was the primary endpoint.

The discussant, Dustin A. Deming, MD (University of Wisconsin–Madison, Wisconsin, US) noted that FTD/TPI plus bevacizumab should be considered as the preferred non-targeted or non-biomarker-driven regimen in refractory mCRC. In addition, he highlighted that this study also has implications for future clinical trials in the third- and fourth-line settings, where FTD/TPI plus bevacizumab should be a treatment option.

Metastatic Pancreatic Ductal Adenocarcinoma

Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the US and Europe for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who progress on gemcitabine-based therapy. The randomized, open-label, phase III NAPOLI-3 trial investigated the efficacy and safety of NALIRIFOX (irinotecan liposome injection, 5-FU/LV, and oxaliplatin) compared with gemcitabine plus nab-paclitaxel (Gem+NabP) as first-line therapy in patients with mPDAC.

A total of 770 patients with untreated mPDAC received either NALIRIFOX or Gem+NabP. Randomization was stratified by ECOG performance status, geographic region, and presence or absence of liver metastases. The primary endpoint was OS; secondary endpoints were PFS, overall response rate, and safety.

After a median follow-up of 16.1 months, a statistically significant improvement in OS was seen with NALIRIFOX with a median OS of 11.1 months vs. 9.2 months in the Gem+NabP arm (HR, 0.84; 95% CI: 0.71, 0.99; P = 0.04). The NALIRIFOX cohort also saw significant PFS improvements: 7.4 months vs. 5.6 months (HR, 0.70; 95% CI: 0.59, 0.84; P = 0.0001). These OS and PFS benefits were consistent across the stratification groups.

Based on the positive results, the investigators called for NALIRIFOX to become the new reference regimen for patients with untreated mPDAC. The discussant, Laura W. Goff, MD, MS (Vanderbilt University Medical Center, Nashville, Tennessee, US) noted that, for fit patients, these results support the NALIRIFOX regimen as the new reference regimen for the first-line treatment of mPDAC. However, she highlighted that both regimens have high toxicity rates and different toxicity profiles, which may be a factor in the treatment decision-making process for patients who are unfit and unable to tolerate an aggressive regimen.

Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma

Claudin-18.2 (CLDN18.2) is expressed in normal gastric mucosa cells and retained in metastatic gastric/GEJ (mG/GEJ) tumor cells. Zolbetuximab is an experimental monoclonal antibody that targets CLDN18.2. The phase III, global, double-blind SPOTLIGHT trial compared zolbetuximab plus folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) vs. placebo plus mFOLFOX6 as the first-line treatment for patients with CLDN18.2-positive/HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma.

Treatment-naïve patients with CLDN18.2-positive/HER2-negative locally advanced unresectable or mG/GEJ adenocarcinoma were randomized to zolbetuximab IV 800 mg/m² plus mFOLFOX6 IV for four 42-day cycles vs. placebo plus mFOLFOX6. Patients whose disease had not progressed continued for >4 cycles with zolbetuximab or placebo, plus folinic acid and 5-FU at investigator’s discretion. The primary endpoint was PFS per RECIST v1.1 by independent review committee.

A total of 565 patients were randomized. The primary endpoint was met: PFS was significantly improved with zolbetuximab plus mFOLFOX6 (median PFS: 10.61 months vs. 8.67 months; HR, 0.751; P = 0.0066). OS was also significantly improved (median OS: 18.23 months vs. 15.54 months; HR, 0.750; P = 0.0053). The most common treatment-related AEs with zolbetuximab plus mFOLFOX6 were nausea (82.4% vs. 60.8% in zolbetuximab vs. placebo arms, respectively), vomiting (67.4% vs. 35.6%), and decreased appetite (47.0% vs. 33.5%). The incidences of serious treatment-emergent AEs were similar between both arms (44.8% vs. 43.5%).

The investigators concluded that zolbetuximab plus mFOLFOX6 may be a new option for patients with locally advanced or mG/GEJ adenocarcinoma. The discussant, David Wang, MD, PhD (University of Texas, Southwestern Medical Center, Dallas, Texas, US) noted that zolbetuximab is the first molecularly targeted therapy with an OS benefit in the first-line treatment of HER2-negative advanced gastric cancer. However, he highlighted that the assay for CLDN18.2 expression needs to be more widely available and the interpretation of a positive result should be standardized.