SAN FRANCISCO — A strategy that had minimal impact on chemotherapy success made a significant difference in targeted therapies’ impact on colorectal cancer survival, according to a small randomized study.
Giving regorafenib (Stivarga) before cetuximab (Erbitux) resulted in a median overall survival (OS) of 17.4 months as compared with 11.6 months when cetuximab preceded regorafenib. Moreover, finishing treatment with cetuximab resulted in a more prolonged second progression-free interval (PFS2), whereas PFS1 did not differ significantly according to the drug sequence, reported Kohei Shitara, MD, of the National Cancer Center Hospital East in Kashiwa in Japan, and colleagues.
A subgroup analysis showed a consistent advantage in favor of regorafenib followed by cetuximab, including almost a 9-month difference among patients with left-sided tumors, they reported here at the Gastrointestinal Cancers Symposium.
“The safety and quality of life were comparable between the two arms, and but was generally lower during regorafenib treatment,” said Shitara. “There were no unexpected adverse-event signals. A biomarker analysis is still ongoing.”
Shitara noted that the results apply only to patients with RAS/BRAF wild type tumors.
Though preliminary, the findings suggest that lessons learned from sequencing studies of chemotherapy may not apply in the era of targeted therapies, said Michael J. Hall, MD, of Fox Chase Cancer Center in Philadelphia.
“Back into the 1990s and into the 2000s, we spent a lot of time doing sequence studies with chemotherapy, and sometimes it mattered and sometimes it didn’t,” Hall told MedPage Today. “It never really mattered to the degree that they showed in this study. This was a huge difference.”
“The findings started me thinking about whether the cetuximab might have caused mutations in the tumor that were worse later on for the therapies that followed. With more molecularly targeted therapies now, do we need to think more about a sequence? If we’re inducing these mutations that are going to drive the tumors in bad ways, we might not want to do that,” added Hall, who was not involved in the study.
Both regorafenib and cetuximab have indications for treating metastatic colorectal cancer. Both agents are members of the EGFR-inhibitor class, and the optimal sequence for EGFR-targeted therapies has yet to be determined, Shitara noted.
Investigators at 29 centers in Japan enrolled patients in a phase II randomized trial to evaluate regorafenib followed by cetuximab — or the reverse sequence — in patients with RAS/BRAF wild-type metastatic colorectal cancer. Treatment with the initial drug continued until disease progression, at which time patients switched to the second drug drug in the sequence.
All patients had previously received combination therapy with a fluoropyrimidine, oxaliplatin, and irinotecan. Investigators had the option to give cetuximab with or without irinotecan.
The trial had a primary endpoint of OS. Key secondary endpoints included PFS1, PFS2, safety, and quality of life. Serial biomarker analyses, including oncogenic alterations in circulating tumor DNA and various serum proteins, were an exploratory endpoint of the trial.
The trial had an accrual target of 180 patients, but enrollment ended because of slow accrual after 101 patients had been randomized and treated.
The results showed a 5.8-month difference in survival for patients who initiated treatment with regorafenib. The difference represented a 39% reduction in the survival hazard in favor of the regorafenib-first sequence (95% CI 0.39-0.96, P=0.029).
Analysis of secondary endpoints showed a median PFS1 of 2.4 months for patients who received regorafenib first and 4.2 months for those who began treatment with cetuximab, which did not achieve statistical significance (HR 0.97, 95% CI 0.82-1.54, P=0.91). In contrast, median PFS2 was significantly longer with the regorafenib-first sequence (5.2 versus 1.8 months, HR 0.29, 95% CI 0.17-0.50, P<0.0001).
Subgroup analysis did not identify patient groups that appeared to benefit more from starting with cetuximab. Shitara said that 81 of the 101 patients had left-sided primary tumors. In that subgroup, patients who started treatment with regorafenib had a median OS of 20.5 months compared with 11.9 months for those who received cetuximab first. The difference represented a 49% reduction in the hazard ratio (95% CI 0.30-0.86, P=0.011).
The study was supported by Bayer Yakuhin.
Shitara disclosed relevant relationships with AbbVie, Novartis, Ono Pharmaceutical, Yakult, Astellas, Bristol-Myers Squibb, Lilly, Pfizer, Takeda, Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Merck Sharp and Dohme, and Taiho Pharmaceutical.