Highlights on gastrointestinal cancer: colorectal and anal

Prof Hans Prenen, a medical oncologist at the University Hospital Antwerp, Belgium, provided a comprehensive overview of critical studies presented at ASCO 2024 in the rapid oral abstract session on colorectal and anal cancer. Four presentations were selected, focusing on metastatic colon cancer (mCC) and rectal cancer.

The first two presentations related to mCC, specifically targeting a specific subgroup.

The first study, the MOUNTAINEER trial, presented the final results for HER2-positive, RAS wild-type colon cancer treated with tucatinib plus trastuzumab. This phase 2 study evaluated the efficacy of the combination therapy. There was also a separate arm, Arm C, where patients received tucatinib alone, with the option to cross over to the combination therapy upon progression or lack of response. The primary endpoint was the response rate, and the results were quite promising. The overall response rate was nearly 40% in this refractory disease setting. Key outcomes include a median PFS of 8 months and a median DoR of 15.2 months. The OS was 23 months, with 27% of patients experiencing a long-term response lasting more than a year. This combination of the oral drug tucatinib with trastuzumab was generally well-tolerated, with some patients experiencing low-grade diarrhoea or fatigue. HER2 testing can be performed via IHC or NGS, either in blood or tissue, and all these techniques are effective in identifying HER2-positive mCC patients.

The second presentation in mCC was the CodeBreak 300 study. This study, which had previously been presented at ESMO 2023 and published in the New England Journal of Medicine, focused on chemorefractory disease in patients with KRAS G12C-mutated mCC. In this trial, patients were treated with sotorasib at either a high dose (960 mg) plus panitumumab or a lower dose of sotorasib (240mg) plus panitumumab. There was also a control group where the treatment was chosen by the investigator. Each group included approximately 50 patients. The final analysis of OS was presented at ASCO 2024. The results showed a trend towards improved OS with the combination therapy. However, it’s important to note that the study was not powered to detect a significant difference in survival. Despite this, the combination of sotorasib 960 mg plus panitumumab demonstrated improved PFS and response rates. These findings support the potential use of high-dose sotorasib plus panitumumab as an option for chemorefractory KRAS G12C-mutated mCC.

The first of the two presentations on rectal cancer was a large Chinese study involving 458 patients. This trial randomised patients with locally advanced rectal cancer (LARC) who had high-risk factors into two groups: one receiving total neoadjuvant therapy (TNT) with long-course radiotherapy, and the other receiving standard chemoradiotherapy. The high-risk factors included either T4 tumours, T3 tumours with extramural venous invasion, an involved mesorectal fascia, or large lymph nodes. In Arm A, patients received TNT, which included one cycle of CAPOX, followed by two cycles of CAPOX in combination with radiotherapy, and then three additional cycles of CAPOX before surgery. In Arm B, patients underwent chemoradiotherapy with capecitabine, followed by surgery and adjuvant CAPOX. The results were noteworthy. The three-year DFS rate was significantly higher in the TNT arm, at 77%, compared to 68% in the standard chemoradiotherapy arm. Additionally, there was a higher pCR rate in the TNT arm, with 27.5% versus 9.8% in the standard treatment arm.

The last presentation focused on a specific subgroup of rectal cancer patients with microsatellite instability-high (MSI-high) tumours, which constitute about 5-10% of rectal cancers. Previous studies have demonstrated that PD-1 blockade can lead to a near 100% complete RR in these patients. At ASCO, updated results were presented on the sustained clinical complete response in this subgroup. In total, 48 patients were included in the study, with 42 patients completing six months of immunotherapy. All 42 patients achieved a complete response following this treatment regimen. The approach involved administering six months of immunotherapy and then conducting follow-up evaluations. If residual disease was detected, patients could proceed to chemoradiotherapy and surgery. However, none of the patients required additional chemoradiotherapy or surgery in this trial. The updated results showed that 24% of the patients maintained a sustained complete response for over two years. In conclusion, six months of PD-1 blockade alone produced very durable, recurrence-free responses in patients with locally advanced MSI-high rectal cancer, eliminating the need for chemotherapy, radiotherapy, or surgery. The anticipation is high for these findings to be integrated into clinical practice to benefit patients.