Patient Populations Provide Sequencing Clues in Chemorefractory CRC

Treating patients with chemorefractory advanced colorectal cancer has undergone a significant transformation in recent years. Now, with two agents approved, the optimal sequence for therapies regorafenib and TAS-102 becomes the next relevant question.

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 <.0001).

“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 = .015).

Selecting Therapy Based on AEs

“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.”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.”

In the CORRECT trial, the most common grade 3/4 adverse events (AEs) with regorafenib were hand-foot skin reaction (16.6%), fatigue (9.6%), hypertension (7.2%), diarrhea, (7.2%), and rash (5.8%). The most common severe AE was hepatotoxicity. Additionally, AEs led to a dose reduction or interruption in 67% of patients, warranting careful monitoring.

For TAS-102 the most frequently reported grade 3/4 AE was neutropenia, which was experienced by 38% of patients treated with the chemotherapy. Overall, febrile neutropenia occurred in 4% of patients, with 9% receiving G-CSF. The other most frequently reported grade 3/4 AEs of concern with TAS-102 were anemia (18%), thrombocytopenia (5%), diarrhea (3%), nausea (2%), and vomiting (2%).

Optimizing Regorafenib Dosing

“Let’s say a patient has significant liver function abnormalities or significant hand and foot syndrome from prior capecitabine, then we would consider moving TAS-102 ahead of regorafenib,” said Bekaii-Saab. “There are also other instances where a patient may have significant bone marrow toxicities from prior therapy, and those patients would be less of a candidate for TAS-102 before regorafenib.”A leading question following the approval of regorafenib is whether the most appropriate dose was selected for the phase III trial. Of patients treated with the approved 160 mg dose, nearly 80% will require a dose modification, according to Bekaii-Saab. In most cases, the dose is reduced to 120 mg/day or even lower to 80 mg/day.

A variety of dosing strategies have been developed to pre-emptively adjust for these dose modifications. In some situations, regorafenib is started at a lower dose and then titrated to 160 mg/day. Additionally, an alternating treatment strategy with 1-week on regorafenib and 1-week off has been utilized, Bekaii-Saab noted.

“There are a lot of different dosing strategies going around without any validated data,” he said. “The alternating strategy, in my opinion, is probably the least effective because you lose that antiangiogenic pressure. I would rather just give regorafenib continuously. Giving regorafenib at a lower dose, like 120 mg or 80 mg, are acceptable strategies."

A randomized phase II study, known as ReDOS, has been initiated to explore the optimal starting dose for regorafenib. The study will compare a lower dose of regorafenib with the standard 160-mg/day dose along with a preventive strategy for hand-foot skin reaction using clobetasol propionate. In the lower dose arm, patients will begin treatment at 80 mg/day with an upward titration to the full 160 mg/day.

The primary endpoint of the study, which hopes to enroll 120 patients with mCRC, is the amount of time needed to complete 2 courses of treatment and the rates of progression in each group. Other endpoints will focus on OS, PFS, safety, and changes in quality of life. The Academic and Community Cancer Research United is sponsoring the study in collaboration with the National Cancer Institute (NCT02368886).

“We are hoping to capture the right dose with the escalating dosing strategy,” said Bekaii-Saab, the principal investigator of the trial. “We should hopefully have a readout from ReDOS by the end of the year, and that might help us understand more on how to optimize the dosing of regorafenib.”


  1. Grothey A, Van Cutsem E, Sobrero A, et al. CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013; 381(9863):303-312.
  2. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. N Engl J Med. 2015;372:1909-1919.
  3. Ricotta R, Verrioli A, Ghezzi S, et al. Cavitation of lung metastases induced by regorafenib in patients with colorectal carcinoma: Data from the phase III CORRECT study. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 2015.