Multitasking Drug Emerges for Patients with Metastatic Colorectal Cancer

There hasn’t been an experimental drug that showed survival benefit in colorectal cancer patients who have progressed on approved therapies for eight years—until now. Unfortunately, this novel agent doesn’t work for everyone and researchers are determined to find out why.

The multitasking, small-molecule drug called regorafenib, which uniquely blocks several different cancer-growth pathways, could become the first drug approved for this patient population since the approval of Avastin in 2006.

The phase 3 trial called CORRECT showed that regorafenib improved survival by a median of 1.4 months, increasing the survival rate from 5 months with placebo to 6.4 months with the drug. Although it represents a small bump in median survival, it’s a 29 percent increase in overall survival in a hard-to-treat patient population.

“This is one of those things which I hope we can educate people about, that it implies that every patient lives a month longer. That’s not true,” says Axel Grothey, MD, of the Mayo Clinic in Rochester, Minn., and lead author of the trial who presented results at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium in San Francisco on Jan. 21. “Some patients don’t benefit at all. One patient lived almost a year.” Researchers typically look at the median number, not the average, when analyzing study results. The median is the middle number of a rather large range.

Jason Faris, MD, a medical oncologist at Massachusetts General Hospital Cancer Center who specializes in gastrointestinal cancers, says the fact that the drug demonstrated a statistically significant benefit in survival is exciting.

“This excitement must, of course, be weighed against the magnitude of the absolute gain in overall survival that those patients experienced compared to placebo-treated patients, which was only 1.4 months," he says. "Nonetheless, demonstrating an overall survival benefit in a population who largely—more than 80 percent—have been exposed to three or more prior regimens or more is impressive.”

I expect regorafenib will be a valuable additional option for some, but not all, patients with metastatic colorectal cancer. The real advance with regorafenib will come when we figure out which patients benefit from it. It's not a cure, but it will extend lives.

The CORRECT trial randomized 760 patients who had metastatic colorectal cancer, with 505 patients receiving regorafenib once daily for three-week cycles and 255 patients receiving placebo with best supportive care. The trial was stopped in October because preliminary results favored the regorafenib arm, and patients on the placebo arm were offered the opportunity to cross over. Common side effects reported included hand-foot rash, fatigue and diarrhea.

The drug controlled the disease in nearly half of patients, delaying or reducing tumor growth in 44.8 percent of patients as opposed to 15.3 percent in the placebo arm. This shows the drug may have a future as a maintenance therapy, Grothey says.

One reason it may work in this patient population is that it targets multiple cancer pathways, including blocking the vascular endothelial growth factor receptor (VEGFR) that signals blood vessel growth to the tumor, and c-KIT, an oncogene involved in cancer growth. It’s believed that when tumors metastasize and progress on several different treatments, they take advantage of several different growth pathways. While most targeted agents block one pathway, regorafenib may block several.

The rate at which the CORRECT trial enrolled patients illustrates the need for additional treatment options, Grothey says. While many trials take years to accrue patients, the regorafenib study finished its enrollment in 10 months—16 months ahead of schedule. The next step will be to examine quality of life aspects and determine patient and tumor characteristics that may help predict which patients would benefit from the drug.

“This is the beginning of a journey to better understand regorafenib,” Grothey says. Biomarker analysis results are expected to be presented at this year’s annual meeting of the American Society of Clinical Oncology in June, but for now, it doesn’t appear that KRAS mutation status plays a part, which is good news for the 30 to 50 percent of colorectal cancer patients whose tumors have a KRAS mutation and don’t benefit from drugs that target the epidermal growth factor receptor (EGFR), such as Erbitux (cetuximab) and Vectibix (panitumumab).

Following Grothey’s presentation, Herbert Hurwitz, MD, of Duke University Medical Center, said that based on the phase 3 results, regorafenib will most likely receive Food and Drug Administration (FDA) approval, joining the list of therapeutics for metastatic colorectal cancer. Hurwitz also noted that the trial only included patients who did not have severe symptoms of their disease, and that the biomarker analysis will be important in deciding patients who will receive the most benefit from regorafenib.

In June, the FDA gave regorafenib fast track designation, which could lead the way to a faster submission process and, ultimately, approval. In the meantime, Bayer is working on an early access study, which is estimated to open within the next few months and will allow patients with no other treatment options to receive the drug while also further monitoring its side effects.

Kate Murphy, director of research communication with the advocacy organization Fight Colorectal Cancer, said the drug, if approved, will fill an unmet need in metastatic colorectal cancer treatment. “I expect regorafenib will be a valuable additional option for some, but not all, patients with metastatic colorectal cancer,” she says. “The real advance with regorafenib will come when we figure out which patients benefit from it. It’s not a cure, but it will extend lives.”

To further educate patients about the study and other research presented at the ASCO Gastrointestinal Cancers Symposium, Fight Colorectal Cancer is hosting a free webinar on Feb. 8 (8 p.m. to 9:30 p.m. EST). To register for the webinar “Report from the2012 ASCO GI Cancers Symposium,” visit https://www1.gotomeeting.com/register/353843265). An archived version should be available at fightcolorectalcancer.org/awareness/webinars.

Regorafenib is also being tested in gastrointestinal stromal tumors (GIST), as well as liver and kidney cancers.

Update: Regorafenib is now available in an expanded access program (Regorafenib available in expanded access program for colon cancer). On May 23, the drug's maker filed for FDA approval.