Researchers at City of Hope have found that a small subset of patients with the most common type of metastatic colorectal cancer are responsive to checkpoint blockade immunotherapy.
“When we stratified the patients by the presence or absence of liver metastases, we noted that about 20% of patients without liver metastases had a major response to anti-PD-1 or anti-PD-L1 therapy, while none of the patients with liver metastases experienced a positive response,” said Marwan Fakih, M.D., co-director of the Gastrointestinal Cancer Program and the Judy & Bernard Briskin Distinguished Director of Clinical Research at City of Hope. “Colorectal cancer patients without liver metastases could benefit from immunotherapy considerably more than patients with liver metastases.”
Colorectal cancer is the third most common cancer and the leading cause of cancer-related deaths in the United States, according to the Centers for Disease Control and Prevention (CDC). City of Hope’s findings are significant because immunotherapy traditionally has been seen as ineffective against microsatellite stable (MSS) colorectal cancer, which represents 95% of all metastatic colorectal cancer cases. These patients have few treatment options once they become resistant to chemotherapy.
The study was published in JAMA Network Open.
MSS colorectal cancers are characterized by low tumor mutation burden (TMB) and low immune infiltration compared with microsatellite instability–high (MSI-H) colorectal tumors. Programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibition has led to robust clinical benefit in MSI-H colorectal cancers, but limited antitumor activity has been observed in colorectal cancers with MSS.
Studies reporting on PD-1/PD-L1–targeting therapy in advanced metastatic colorectal cancer have been limited by their small sample sizes and lack of multivariate analysis that integrates the site of the original tumor (sidedness), results of molecular analysis, and TMB.
This retrospective study included 95 City of Hope patients with MSS metastatic colorectal cancer who received immune checkpoint inhibitor PD-1/PD-L1 targeted therapy once their disease became resistant to chemotherapy. The median time of disease progression for patients who did not have liver metastases was four months compared to one and a half months for those whose cancer had spread to the liver.
When colorectal cancer spreads to the liver, some patients can undergo surgery to remove all tumors; however, sometimes these tumors cannot be removed surgically. That’s when chemotherapy is used, but “chemotherapy is destined to stop working, and we have to look into additional treatment options,” Fakih said, adding, “To our knowledge, this is the largest study to evaluate the impact of PD-1/PD-L1 targeting on patient response as stratified by site of metastatic disease.”
The researchers note that several studies have pointed to the potential of immunotherapy in CRC patients without liver metastases. These include the Japanese REGONIVO (Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer) trial, which reported that patients with liver metastases had a response rate of 8.3% (1 of 12), whereas patients with lung metastases without liver involvement had a response rate of 63.6% (7 of 11).
Also, the combination of regorafenib plus toripalimab (a PD-1 inhibitor) led to a response rate of 30.0% in patients with MSS colorectal cancer without liver metastases, whereas patients with liver metastases had a response rate of just 8.7%. (Wang et al., Oncologist, 2020).
According to the study authors, these data and more, suggest a potential clinical benefit to regorafenib plus a PD-1– or PD-L1–targeting agent and that clinicians can expect a preferential response in patients without hepatic metastatic disease.
Fakih says advanced colorectal cancer patients with liver metastases should not be considered for PD-1/PD-L1-based therapy. Instead, other novel investigational strategies are recommended.
“For patients without liver metastatic disease, PD-1/PD-L1-based therapies, particularly those combining these agents with tyrosine kinase inhibitors (TKI), hold significant promise,” he said, noting that TKIs that target the tumor vasculature modify the tumor environment and make it more responsive to PD-1/PD-L1 therapy.
