new research colon cancer

Drug Regimen Boosts Survival of People with Advanced Colorectal Cancer

May 24, 2023 , by Edward Winstead

The SUNLIGHT trial was the first phase 3 study involving people with treatment-resistant metastatic colorectal cancer to show an improvement in overall survival versus an existing treatment.

A new treatment regimen may help improve the survival of some people with advanced colorectal cancer, according to results from an international clinical trial.

The new regimen includes bevacizumab (Avastin) and the combination of trifluridine and tipiracil (Lonsurf) . Both therapies had previously been approved by the Food and Drug Administration (FDA) for the treatment of some people with colorectal cancer.

The trial, called SUNLIGHT , included nearly 500 people with advanced colorectal cancer that had gotten worse after at least two prior treatment regimens. Participants were randomly assigned to receive trifluridine – tipiracil alone or combined with bevacizumab.

After a median follow-up of 14 months, the group that received the combination therapy survived for a median of 10.8 months , compared with 7.5 months for the group that received trifluridine – tipiracil alone.

The combination therapy also increased how long patients lived without their cancer getting worse, called progression-free survival, by several months (a median of 5.6 months versus 2.4 months).

The study’s lead investigator, Josep Tabernero, M.D., Ph.D., of the Vall d’Hebron University Hospital in Barcelona, Spain, and his colleagues reported the findings in the New England Journal of Medicine on May 4.

The results “confirm that trifluridine – tipiracil plus bevacizumab is an effective treatment option” for patients with previously treated metastatic colorectal cancer, Dr. Tabernero said earlier this year when he presented the study’s preliminary findings at the American Society of Clinical Oncology’s GI Cancers Symposium .

SUNLIGHT was the first phase 3 study involving people with treatment-resistant metastatic colorectal cancer to demonstrate an improvement in overall survival versus an existing treatment, he added.

“This study sets a new standard for the care of patients with metastatic colorectal cancers that have stopped responding to other treatments,” said Carmen Allegra, M.D., who works with NCI’s  Cancer Therapy Evaluation Program  and was not involved in the study.

The new findings demonstrate that the combination therapy is more beneficial for these patients than trifluridine – tipiracil, Dr. Allegra added.  

Taiho Oncology, which manufactures trifluridine – tipiracil, funded the trial. FDA is reviewing an application for the use of trifluridine – tipiracil in combination with bevacizumab for previously treated metastatic colorectal cancer, according to the company.

Combining therapies in the SUNLIGHT trial

Several small studies have suggested that adding bevacizumab to trifluridine – tipiracil might benefit patients with previously treated metastatic colorectal cancer . Dr. Tabernero and his colleagues developed the SUNLIGHT trial to confirm these results.

Trifluridine – tipiracil and bevacizumab are given in different ways (as a tablet taken by mouth and intravenously , respectively) and attack cancer cells through different mechanisms.

Trifluridine causes DNA damage that may lead to the death of cancer cells, while tipiracil helps maintain blood concentrations of trifluridine by blocking an enzyme that degrades it.

Bevacizumab blocks the activity of a protein called VEGF. This helps starve tumors of oxygen and nutrients  by preventing them from growing new blood vessels —a process known as angiogenesis.  

Combination benefits patients treated previously with bevacizumab

Participants in the trial had received prior treatments such as fluoropyrimidine , irinotecan (Camptosar) ,  oxaliplatin (Eloxatin) , bevacizumab or another drug that blocks VEGF, and/or a  drug that blocks EGFR , another protein involved in tumor growth.

About 70% of the study participants in both groups had tumors with a mutation in a RAS gene such as KRAS . These mutations occur in about half of all people with advanced colorectal cancer and may limit a patient’s treatment options.   

In the SUNLIGHT trial, however, the combination therapy seemed to be effective regardless of whether a patient’s tumor had a RAS mutation.

Those study participants who had previously received bevacizumab also benefited from the addition of bevacizumab to trifluridine – tipiracil. That finding, the researchers wrote, adds to evidence supporting a role for continuing to use angiogenesis inhibitors after the cancer progresses on regimens that include these drugs.

The most common side effects experienced by patients in both groups were neutropenia (a condition caused by too few neutrophils, a type of white blood cell), nausea, and anemia (a low red blood cell count).

Neutropenia and hypertension were more common in the combination therapy group. Hypertension is associated with the class of drugs that includes bevacizumab.

“The combination did have additional side effects, but it appears that most patients tolerated the agents reasonably well,” Dr. Allegra said.

The use of the combination therapy “would need to be weighed for each patient given the associated side effects and additional [financial] cost,” he added.

Dr. Tabernero and his colleagues answered an important question by documenting the overall survival benefit conferred by this regimen for some patients with advanced colorectal cancer, according to Oladapo Yeku, M.D., Ph.D., and Dan L. Longo, M.D., of Massachusetts General Hospital, the authors of an accompanying editorial . They wrote that improved progression-free survival, which had been shown in phase 2 trials of the combination, “does not necessarily correspond with an effect on overall survival.”

The phase 3 trial, they noted, “provides a rigorous test of the combination on survival in this patient population.”

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Immunotherapy with two novel drugs shows activity in colorectal cancer

A combination of two next-generation immunotherapy drugs has shown promising clinical activity in treating patients with refractory metastatic colorectal cancer, a disease which has not previously responded well to immunotherapies, according to a Dana-Farber Cancer Institute researcher.

The results of an expanded phase 1 trial of the two drugs, botensilimab and balstilimab, are to be presented at the ASCO Gastrointestinal Cancers Symposium Jan. 19-21 in San Francisco. The study is led by Benjamin L. Schlechter, MD , a senior physician in the Gastrointestinal Cancer Treatment Center at Dana-Farber.

The trial included 70 patients with metastatic colorectal cancer who had been previously treated with several lines of drugs, including immunotherapies. These patients all had tumors termed microsatellite stable, or MSS, meaning that their genes for repairing certain types of DNA damage were intact. MSS colorectal tumors account for the vast majority of colorectal cancers, and the first generation of immunotherapy drugs have had little effect on them. While immunotherapy has succeeded in microsatellite unstable (MSI) colorectal cancers, only about 3-5% advanced colorectal cancers are MSI and there are no approved immunotherapies for the far more common MSS colorectal cancers.

The two-drug combination being tested in the expanded phase 1a/1b trial of patients with metastatic MSS colorectal cancers were novel, next-generation antibodies. Botensilimab is an antibody directed against the T-cell receptor cytotoxic T-lymphocyte-associated antigen 4, or CTLA-4, which is an immune checkpoint that regulates T-cell activation. Balstilimab is a novel monoclonal antibody designed to block PD-1 – another immune checkpoint protein – from interacting with PD-L1 and PD-L2. By inhibiting this interaction, balstilimab is aimed at freeing the immune system to attack cancers.

The patients in the trial were followed for a median of 7 months after receiving the drug combination. During that period, 23% of the patients had a reduction in the size of their tumors, and the median duration of response was not reached. The disease control rate – the percentage of patients with metastatic cancer who had a complete or partial response and stable disease – was 76%. The 12-month overall survival was 63%. The main population of patients who benefited from the combination were those who did not have active metastatic cancer in their liver.

Treatment-related adverse events occurred in 91% of patients, including grade 3 in 40% and grade 4 in 3%. Twelve percent of patients discontinued both drugs because of adverse events.

The researchers concluded that “in patients with heavily pretreated metastatic MSS colorectal cancer, botensilimab plus balstilimab continues to demonstrate promising clinical activity with durable response, and was well tolerated, with no new immune-mediated safety signals.”

“Harnessing the power of immune therapy in refractory colorectal cancer has been a key goal of multiple clinical trials in advanced colorectal cancer, but in MSS colorectal cancer efforts have been universally disappointing,” said Schlechter. “These data are a meaningful and important advance in the care of this very sick population.”

Based on these findings, a randomized phase 2 trial in patients with MSS colorectal cancer is currently enrolling.

Funding for this research comes from Agenus, Inc.

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