Tanios Bekaii-Saab, MD
Treating patients with chemorefractory advanced colorectal cancer (CRC) has undergone a significant transformation in recent years, with the approvals of regorafenib (Stivarga) in September 2012 and TAS-102 (Lonsurf) in September 2015. Now, with two agents approved, the optimal sequence for these therapies becomes the next relevant question.
In the pivotal phase III CORRECT study,1
regorafenib improved overall survival (OS) by 6.4 months compared with 5.0 months with placebo (HR, 0.77; 95% CI, 0.64-0.94; P
= .0052). Furthermore, progression-free survival (PFS) was 2.0 months with regorafenib versus 1.7 months with placebo (HR, 0.49; 95% CI, 0.42-0.58).
In the pivotal phase III RECOURSE trial,2
median OS with TAS-102 was 7.1 months compared with 5.3 months with placebo (HR, 0.68; P
<.0001). Median PFS in the TAS-102 arm was 2.0 months versus 1.7 months with placebo (HR, 0.48; P
“We have more than one option, which is a good problem to have,” Tanios Bekaii-Saab, MD, associate professor, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center. “To get an idea of how to sequence these therapies, you can look at the phase III data from the two studies that led to the approvals for the targeted agent regorafenib and cytotoxic TAS-102.”
In the CORRECT trial, 49% of patients had received ≥3 prior treatments. The median age of patients was about 61 years and approximately 78% were Caucasian. Patients in the trial had an ECOG performance status (PS) of 0 (52.5%) and 1 (47.5%).
In the RECOURSE trial, the median age of patients was 63 years and the majority (60%-63%) received ≥4 prior lines of therapy. Approximately 20% of patients had received prior treatment with regorafenib. All patients were enrolled with an ECOG PS of 1 (44%) or 0 (56%).
“The RECOURSE study looking at TAS-102 had about 20% of patients who had prior regorafenib. The CORRECT study looking at regorafenib was before TAS-102 approval,” noted Bekaii-Saab. “From a practical purpose standpoint right now, and the way we are doing it in clinic, is after you get to the third- or fourth-line of therapy, we introduce regorafenib first. Once a patient progresses, then we can administer TAS-102.”
The clinical responses seen in each trial were similar, given the number of prior therapies received, explained Bekaii-Saab. The response rate with regorafenib was 1% compared with 0.4% with placebo, and 1.6% of patients responded to TAS-102 versus 0.4% with placebo.
“Both regorafenib and TAS-102, because of their placement, you won’t have actual response,” said Bekaii-Saab. “You do have tumor shrinkage, although that does not qualify as a partial response by RECIST criteria, but you still see drops in the cancer markers.”
Despite a lack of responses defined by RECIST criteria, a unique response known as cavitation was seen with regorafenib in patients with lung metastases. In 108 patients from the phase III CORRECT trial with lung metastases,3
38.7% treated with regorafenib experienced cavitation compared with 0% with placebo.
“There is a very interesting study with regorafenib as a follow up to the CORRECT trial,” said Bekaii-Saab. “There was an interesting phenomenon that was observed, which was that when you look at the tumors within the lung, they tend to cavitate. What that means is that you’re essentially killing cancer cells from within, without changing the size of the tumor.”
Overall, patients who experienced lung metastases cavitation were less likely to progress compared with those who did not have cavitation. Of the 27 patients who experience cavitation in the regorafenib arm, 29.6% (n = 8) had progressive disease at week 8 compared with 60.9% (n = 28) in the 46 patients without cavitation (P
“If patients have lung cavitations, they tend to have tumor shrinkage, they tend to live longer, and they tend to have better PFS,” said Bekaii-Saab. “There is an effect on the tumor, it’s just not as much shrinkage as it is cavitation and stabilization of disease.”
Selecting Therapy Based on AEs
In addition to variations in patient populations and the type of response seen in the clinical trials, each therapy is associated with a unique toxicity profile. Bekaii-Saab suggested that treatment could further be tailored, based on these unique side effects. "For practical purposes right now, and to follow the spirit of the trials, we are going with regorafenib first and TAS-102 second,” he said. Although, he did mention that “there were some exceptions.”