The 2024 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium was held from January 18th–20th 2024, in San Francisco, California, USA. The symposium focused on multidisciplinary care, with GI experts from around the globe offering valuable perspectives on cancers of the oesophagus and stomach, pancreas, small bowel and hepatobiliary tract, and the colon, rectum, and anus. The first session, of particular interest, focused on gastric and oesophageal cancers.
Gastro-oesophageal cancers represent some of the most prevalent cancers worldwide, with an estimated 1.7 million new cases per year. Oesophageal squamous cell carcinoma (ESCC), oesophageal adenocarcinoma, gastro-oesophageal junction adenocarcinoma, and gastric adenocarcinoma are a group of aggressive malignancies that are inherently heterogeneous, and have poor prognosis. When combined, they represent the third leading cause of cancer-related deaths globally.1 Neoadjuvant chemotherapy followed by surgery is the current standard of care for most resectable, advanced gastric and oesophageal cancers, and has shown consistent benefits in treatment. Neoadjuvant chemotherapy increases downstaging and rates of R0 resection in primary tumours, enables earlier treatment of occult metastatic disease, and does not compromise the ability to proceed to curative surgery. However, post-surgery recurrence remains a concern, with approximately one in four patients with gastro-oesophageal cancers relapsing within a year of treatment. Now, advances in immunotherapy are reshaping the treatment landscape for these patients. In recent years, immune checkpoint inhibitors in combination with chemotherapy have emerged as an effective therapeutic strategy for metastatic gastric and oesophageal cancers.
Although less common in Western countries, squamous cell carcinoma makes up 90% of global oesophageal cancer cases. While adenocarcinoma has validated molecular targets to guide treatment (e.g., HER2), the lack of reliable therapeutic biomarkers in ESCC remains a major challenge. In two insightful abstract presentations, experts shared their novel research on the therapeutic potential of immune checkpoint inhibitors camrelizumab and tiragolumab for ESCC combination treatment with chemotherapy.
Yin Li, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, opened the first abstract session by highlighting the need for novel multimodal treatments to overcome post-surgery recurrence of locally advanced ESCC. Li presented his team’s findings in ESCORT-NEO, the first Phase III, open-label, randomised study comparing efficacy and safety of neoadjuvant camrelizumab, an anti-PD-1 monoclonal antibody, plus chemotherapy, versus chemotherapy alone (cisplatin and paclitaxel), in patients with resectable, locally advanced ESCC. Compared to the control group receiving paclitaxel and cisplatin only, patients who received camrelizumab in combination with paclitaxel and cisplatin showed a significantly higher pathologic complete response (pCR), with a 10.9% increase in favour of the immunotherapy group (95% confidence interval [CI]: 1.48–9.80; P=0.0034), accompanied by a tolerable safety profile. Furthermore, the use of albumin-bound paclitaxel with cisplatin and camrelizumab, instead of regular paclitaxel, resulted in an increased pCR difference (23.5%) compared with the control group (95% CI: 3.28–20.06; P<0.0001).
Chih-Hung Hsu, National Taiwan University Hospital, Taipei City, Taiwan, followed on the ESCORT-NEO trial by presenting another promising immune checkpoint inhibitor for ESCC, tiragolumab, in the SKYSCRAPER-08 study. He emphasised that survival benefit of combination therapy for ESCC is modest, and additional treatment strategies are needed to improve patient outcomes. TIGIT, a novel co-inhibitory receptor and immune checkpoint expressed on activated T cells, natural killer cells, and regulatory T cells, is implicated in several cancers, including ESCC. Tiragolumab, a human anti-TIGIT monoclonal antibody, may increase antitumour responses when combined with other immunotherapies, such as the PD-L1 inhibitor atezolizumab, and chemotherapy. Hsu reported a significantly higher median independent review facility-assessed progression-free survival (PFS) in the tiragolumab, atezolizumab, and chemotherapy group, compared to the placebo and chemotherapy group (hazard ratio [HR]: 0.56; 95% CI: 0.45, 0.70; P<0.0001). The median overall survival (OS) was also significantly higher for the tiragolumab, atezolizumab, and chemotherapy group compared to the placebo and chemotherapy group (15.7 months versus 11.1 months, respectively; HR: 0.70; 95% CI: 0.55, 0.88; P=0.0024). Grade III–IV treatment-related adverse events occurred in 59.6% (tiragolumab + atezolizumab + chemotherapy) and 56.4% (placebo + chemotherapy) of patients, and Grade V adverse events in 2.6% (tiragolumab + atezolizumab + chemotherapy) and 0.9% (placebo + chemotherapy) of patients. Hsu highlighted the potential of tiragolumab, atezolizumab, and chemotherapy combination strategies to improve PFS and OS in patients with ESCC.
Other abstract presentations focused on exciting new developments in the treatment of gastric cancer (GC) and gastro-oesophageal junction (GOJ) cancer. The combination of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy has increasingly been accepted as the perioperative standard of care in GC/GOJ cancer. Recently, PD-1 blockade with chemotherapy has become a standard therapy in first-line metastatic GC/GOJ cancer.
Yelena Janjigian, Memorial Sloan Kettering Cancer Center, New York, USA, presented her team’s promising findings in the global MATTERHORN study, which assessed the benefit of durvalumab, a PD-1-blocking antibody, in combination with FLOT, for the treatment of GC/GOJ cancer, across different geographic regions. Compared to placebo and FLOT, durvalumab in combination with FLOT improved complete and near-complete pathological responses by 12% in Asia, Europe, North America, and South America (odds ratio: 2.19; 95% CI: 1.58–3.04; P<0.00001). Improvement in pCR with durvalumab and FLOT, versus placebo and FLOT, was also observed across subgroups by country. The team observed similar trends across regional subgroups for combined complete and near-complete response rate. The study is ongoing, to assess if these benefits translate into improved event-free survival (EFS) and OS, before this approach can be adopted as standard of care.
In addition to durvalumab, pembroluzimab has also emerged as an effective PD-1 blocking antibody in combination with perioperative chemotherapy, to treat patients with locally advanced, resectable GC/GOJ cancer. The Phase III KEYNOTE-585 study, presented by Kohei Shitara, National Cancer Center Hospital East, Kashiwa, Japan, evaluated the benefit of FLOT and pembroluzimab in patients with GC/GOJ cancer, compared to placebo and FLOT. Both EFS and pCR favoured the pembroluzimab and FLOT group, with a 10% difference in pCR (95% CI: 1.3–19.7), and a 66% versus 57% rate of 24-month EFS. However, no significant difference was observed for 24-month OS. No new safety concerns were reported.
As highlighted in this important session, treatment for metastatic ESCC, GC, and GOJ cancer requires a multimodal approach. A new era of immune checkpoint inhibitors is transforming the treatment landscape for these cancers, with anti-PD-1 antibodies offering the potential to extend survival in patients with an historically dismal prognosis. Moving forward, defining more precise biomarkers to identify patient subgroups who will benefit the most from combination therapies will be crucial.
