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Drug Regimen Boosts Survival of People with Advanced Colorectal Cancer

, by Edward Winstead

A 3-D illustration of anatomy in the lower abdomen of a male showing tumors in the colon and rectum.

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.

Credit: iStock

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 trifluridinetipiracil 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 trifluridinetipiracil 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 trifluridinetipiracil 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 trifluridinetipiracil, Dr. Allegra added.  

Taiho Oncology, which manufactures trifluridinetipiracil, funded the trial. FDA is reviewing an application for the use of trifluridinetipiracil 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 trifluridinetipiracil might benefit patients with previously treated metastatic colorectal cancer. Dr. Tabernero and his colleagues developed the SUNLIGHT trial to confirm these results.

Trifluridinetipiracil 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 trifluridinetipiracil. 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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