Regorafenib Retains Safety and Efficacy in Subgroup Analysis of CONSIGN

The safety and efficacy profile of regorafenib in patients with previously treated colorectal cancer (CRC) is similar between US patients and the global study population enrolled in the phase IIIb CONSIGN study, according to Udit Verma, MD, at the 2016 Gastrointestinal Cancers Symposium.

Udit Verma, MD

The safety and efficacy profile of regorafenib in patients with previously treated colorectal cancer (CRC) is similar between US patients and the global study population enrolled in the phase IIIb CONSIGN study, according to Udit Verma, MD, at the 2016 Gastrointestinal Cancers Symposium.1

Regorafenib blocks the activity of multiple proteins involved in tumor angiogenesis, oncogenesis, and the tumor microenvironment. In the phase III CORRECT study,2conducted in 760 patients with metastatic CRC who had disease progression on all available standard therapies, regorafenib improved overall survival (OS) and progression-free survival (PFS) compared with placebo.

CORRECT was followed by CONSIGN,3an open-label, single-arm, phase IIIb study of 2872 patients with treatment-refractory metastatic CRC conducted in 186 sites across 25 countries. CONSIGN replicated the safety and PFS findings of CORRECT.

"CONSIGN validated the findings from CORRECT, in a far larger number of patients, the global study population of 2872 patients in CONSIGN," said Verma, associate professor of internal medicine in hematology/oncology, University of Texas Southwestern Medical Center, Dallas.

He presented results from a retrospective subgroup analysis of 364 patients enrolled in CONSIGN in the United States. Patients were treated with regorafenib at 160 mg once daily for the first 3 weeks of each 4-week cycle. Treatment was continued until disease progression, death, or unacceptable toxicity. The primary endpoint was safety, which was monitored and evaluated continuously throughout the study, including a 30-day follow-up period. PFS (per investigator) was the sole efficacy variable assessed.

"It seems that the patients enrolled in the US may have been somewhat sicker patients as compared to worldwide, and a lot of these patients have been much more extensively treated before as compared to some of the other countries," he said.

The median age of the US patients was 60 years, 62% had Eastern Cooperative Oncology Group performance status 1, 59% hadKRAS-mutant tumors and 38% hadKRASwild type tumors (KRASmutant status was unknown in 3%). The primary site of disease was the colon in 74%, rectum in 21%, and colon and rectum in 6%. Three fourths (74%) were treated with at least three prior regimens for metastatic disease.

US patients' median duration of regorafenib treatment was 2.3 months, their median number of cycles was 3, and 55% of the patients started at least 3 treatment cycles. Some 82% had at least one treatment interruption or delay, 45% had at least one reduction in the dose of regorafenib, and 57% had an interruption or delay >5 days. Eighty-eight percent of the dose reductions were a result of adverse events. The median duration of dose reduction was 12.0 days, with 39% of dose reductions lasting >5 days.

"The safety profile was very much similar to that in the randomized CORRECT trial, with the most common side effect being hand-foot skin reaction, which was true with the earlier trial, as well as the other side effects such as hypertension and diarrhea," said Verma. "All of these are manageable side effects."

Grade ≥3 treatment-emergent adverse effects (AEs) occurred in 81% of US patients, and were considered to be drug related in 53%. The most common drug-related grade ≥3 treatment-emergent AEs were hand-foot skin reaction (16%), hypertension (15%), and fatigue (11%). Grade ≥3 treatment-emergent hepatic laboratory toxicities, regardless of relation to study drug, included an increase in bilirubin in 9%, an increase in aspartate aminotransferase in 6%, and an increase in alanine aminotransferase in 3%.

Grade ≥3 treatment-emergent hematologic toxicities, regardless of relation to study drug, were anemia in 5%, thrombocytopenia in 2%, and neutropenia in 1%.

Eight percent of patients discontinued regorafenib for drug-related treatment-emergent AEs, and 24%, overall, discontinued study treatment regardless of relation to study drug.

"PFS was in line with that of the global cohort and the CORRECT study," Verma said. The median PFS was 2.3 months. PFS was similar irrespective ofKRASstatus: median PFS was 2.1 months in US patients with KRAS wild-type tumors and 2.3 months in those withKRAS-mutant tumors.

References

  1. Verma U, Arriaga YE, Lenz H-J, et al. Regorafenib for previously treated metastatic colorectal cancer (mCRC): A subgroup analysis of 364 patients in the USA treated in the international, open-label phase IIIb CONSIGN study. J Clin Oncol. 2016;34(suppl 4S; abstr 735).
  2. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 (381):303-312.
  3. Van Cutsem E, Ciardello F, Seitz J-F, et al. Results from the large, open-label phase 3b CONSIGN study of regorafenib in patients with previously treated metastatic colorectal cancer. Ann Oncol. 2015;26 (suppl 4; abstr LBA05).