SAN FRANCISCO (FRONTLINE MEDICAL NEWS) – The order in which targeted therapies are given to patients with previously treated metastatic colorectal cancer can have a marked impact on overall survival, according to results of the REVERCE trial reported at the 2018 GI Cancers Symposium.

Investigators led by Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, enrolled in the multicenter, phase 2, randomized trial 101 patients with mainly KRAS wild-type metastatic colorectal cancer who had previously received fluoropyrimidine, oxaliplatin, and irinotecan, but not any therapy targeting epidermal growth factor receptor (EGFR).

The patients were treated with regorafenib (Stivarga), an oral multitargeted kinase inhibitor, or cetuximab (Erbitux), an antibody to EGFR, until progression or unacceptable toxicity, and then switched to the alternate agent. Cetuximab was given with or without irinotecan.

Main results at a median follow-up of 29.0 months showed that median overall survival was almost 6 months longer when regorafenib was given first as compared with when cetuximab was given first, a difference translating to a 39% reduction in risk of death with the former sequence.

“These results suggest that overall survival was longer with regorafenib as the first treatment followed by cetuximab than that of the current standard sequence,” Dr. Shitara said. “Efficacy was observed in almost all subgroups.”

Progression-free survival on the first treatment did not differ significantly by agent, but on the second treatment, it was almost 3.5 months longer with cetuximab. “This might contribute to the overall survival difference,” he proposed.

The specific biologic mechanisms driving the differing efficacy of the two sequences are still unclear, but one possibility is that regorafenib downregulates MAP kinase and certain other signaling molecules, sensitizing cells to subsequent anti-EGFR therapy, Dr. Shitara said. “Biomarker analyses are still ongoing. We hope that further biomarker analysis will clarify the reason for the survival difference.”

The data did not reveal any unexpected safety signals. Although quality of life scores were lower with regorafenib during each treatment period, scores for all time on treatment were similar for the two sequences.

Clinical implications

“The amount of difference in overall survival [between sequences] was pretty striking. These were patients in second line and third line,” commented session chair Michael J. Hall, MD, of Fox Chase Cancer Center, Philadelphia.

The findings are therefore a good reminder of how simple treatment choices such as sequence of drugs can affect colorectal cancer outcomes, for better or worse, he said in an interview.

“This trial adds excitement to the idea that there is still a lot of work to be done in sequencing of therapies and also our understanding of how induction of molecular events by one therapy, for instance, the cetuximab leading to RAS mutations, then affects how the downstream therapies work,” Dr. Hall maintained. “So maybe we need to think more intelligently about that.”

Study details

The REVERCE investigators planned to enroll 180 patients in the trial but stopped after 101 patients because of slow accrual. Most of those studied had previously received bevacizumab.

About 70% of patients in the regorafenib-first group needed a dose reduction at some point, compared with about 30% in the cetuximab-first group, a difference likely related to the longer duration of treatment for the former, Dr. Shitara speculated.

Median overall survival was 17.4 months when regorafenib was given first and 11.6 months when cetuximab was give first (hazard ratio, 0.61; P = .029), according to data reported at the symposium, which was sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

In subgroup analyses, the regorafenib-first strategy yielded significantly better overall survival among patients with left-sided tumors (HR, 0.51; P = .011), but not among those with right-sided tumors (HR, 0.88).

The regorafenib-first strategy had similar benefit when restricted to patients with RAS/RAF wild-type tumors (18.2 vs. 12.7 months; HR, 0.60; P = .036).

Analysis of blood samples collected after the first agent indicated that 26% of patients had emergence of a RAS mutation after receiving cetuximab. However, these patients did not appear to have worse overall survival, according to Dr. Shitara.

Progression-free survival on the first agent was 2.4 months in the regorafenib-first group and 4.2 months in the cetuximab-first group, a nonsignificant difference. In contrast, for the second treatment, it was 5.2 months in the regorafenib-first group and just 1.8 months in the cetuximab-first group (HR, 0.29; P less than .0001).

Dr. Shitara disclosed that he receives honoraria from Abbvie, Novartis, Ono Pharmaceutical, and Yakult; has a consulting or advisory role with Astellas Pharma, Bristol-Myers Squibb, Lilly, Pfizer, and Takeda; and that his institution receives research funding from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Lilly, MSD, Taiho Pharmaceutical, and Yakult. The trial was funded by Bayer Yahin.

SOURCE: Shitara et al. GI Cancers Symposium Abstract 557