Investigational Drug-Chemoradiotherapy Combo Improves Treatment Responses in Patients With Advanced Rectal Cancer

The researchers hypothesize that treatment with the investigational drug combined with chemoradiotherapy may reduce the need for invasive surgery to remove the rectum and surrounding tissue in this patient population.

Treatment with neoadjuvant chemoradiotherapy was more effective in patients with locally advanced rectal cancer who first received the investigational drug galunisertib, according to findings from a new study recently published in Lancet Oncology.

Of note, neoadjuvant chemoradiotherapy is a combination of radiation and chemotherapy administered to patients prior to surgery to reduce the size of any tumors. This treatment regimen, according to the study investigators, has been the standard of care for this patient population for more than 10 years. At first, treatment consisted of radiotherapy alongside the chemotherapy fluorouracil.

This regimen, however, was associated with poor complete pathologic response rates (the lack of all signs of cancer in tissue samples).

In the past three years, care teams started adopting treatment regimens of chemoradiotherapy using combinations of radiotherapy with the chemotherapies leucovorin, fluorouracil and oxaliplatin (FLOFOX) or leucovorin, fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX).

This treatment method has historically elicited complete pathologic response rates of 25% to 28%. Recently, investigators have used these findings and have started analyzing the effects of adding immune checkpoint inhibitors to treatment regimens to see if it improves response rates. The aim, according to the study authors, is to reduce the need for invasive surgeries following chemoradiation.

Galunisertib is a transforming growth factor beta (TGF-b) inhibitor. Cancer cells mutate TGF-b signals, transforming them from tumor suppressors into tumor promoters. The mutated signals help spread cancerous cells to neighboring healthy cells by suppressing the immune system’s defenses and protecting the tumor from natural cell death.

In this study, the investigators hypothesized that adding galunisertib to chemoradiation would improve complete pathologic response rates compared with historical rates of 8% to 13%.

Of the 38 enrolled patients, 12 (32%) derived a complete pathologic clinical response at a median follow-up of 27 months.

Three of the 38 patients were not evaluable for various reasons including one enrolling in hospice care during their course of chemoradiotherapy.

More than half (71%) of the remaining patients who completed their treatment proceeded to undergo a total mesorectal excision, which is an invasive surgery to remove the rectum and surrounding tissue. Five of these 25 patients achieved a complete response after surgery. Of the 20 patients who did not achieve a complete response, eight had less than 10% of their tumors remaining.

Only 10 (29%) patients who had a complete response after chemoradiotherapy were permitted to pursue non-surgical management of their disease. Some of the patients who derived a complete clinical response following the investigational drug and chemoradiation treatment ultimately chose to have surgery because they said it was for peace of mind and to cut down on future monitoring appointments.

At a final analysis of the data in February 2022, two patients had died. The most common side effects were nausea, headaches, fatigue and rashes.

“We found that the addition of galunisertib to standard of care neoadjuvant chemoradiation more than doubled the response rates observed in historical controls,” study author Dr. Kristina H. Young, a radiation oncologist and medical director of radiation oncology at Providence Cancer Center in Portland, Oregon, said in an interview with CURE®. “Typically, response to neoadjuvant therapy correlates with disease-free survival.

“Right now, many pharmaceutical companies are developing TGF-b-targeting therapies, so we are hopeful that this trial provides the necessary support for a larger randomized study comparing standard of care total neoadjuvant therapy to total neoadjuvant therapy with TGF-b blockade, with a goal of increased rates of organ preservation.”

By increasing response rates in patients with locally advanced rectal cancer and subsequently reducing the need for potentially invasive surgeries, organ preservation rates increase.

Young encouraged patients with locally advanced rectal cancer to consider participating in clinical trials, including future galunisertib clinical trials.

“Participation in clinical trials can be daunting, but I hope this study encourages patients to consider participation in clinical trials when available,” she said. “When we have a randomized phase 3 trial, I hope patients will be interested in participating.”

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