Clinical Summary: 

• Design/Population: The phase 3 CR-SEQUENCE trial evaluated treatment sequencing in patients with unresectable, RAS wild-type, left-sided metastatic colorectal cancer. Patients were randomized to first-line FOLFOX plus panitumumab followed by FOLFIRI plus bevacizumab or the reverse sequence.
• Key Outcomes: The primary end point of 36-month total progression-free survival rate was not met, although numerical improvements favored the anti-EGFR–first sequence. Significant improvements in first-line response rate and first-line progression-free survival were observed with panitumumab-based first-line therapy.
• Clinical Relevance: These findings support the use of anti-EGFR therapy in the first-line setting for RAS wild-type, left-sided metastatic colorectal cancer, particularly when maximizing tumor response and disease control is a priority.

Ramón Salazar, MD, PhD, Catalan Institute of Oncology, Barcelona, Spain, discusses results from the phase 3 CR-SEQUENCE trial evaluating whether the sequencing of biologic therapies influences outcomes in patients with RAS wild-type, left-sided metastatic colorectal cancer.

Although the study did not meet its primary end point of improving total progression-free survival (PFS) through second-line treatment, the anti-EGFR–first strategy produced significantly higher response rates and longer first-line PFS compared with a bevacizumab-first approach. Overall survival (OS) data remain immature, and ongoing analyses will assess whether molecular hyperselection using circulating tumor DNA (ctDNA) can further refine treatment sequencing. 

Dr Salazar presented these findings at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. 

Transcript: 

Hi, I’m Dr Ramón Salazar from the Catalan Institute of Oncology in Barcelona, and I have just presented an abstract on behalf of my coinvestigators at the Spanish TTD Cooperative Group, coinciding with the 40th anniversary of our cooperative group.

The study is called CR-SEQUENCE, and in this study we tried to test whether the sequencing of biologics in the first- and second-line treatment of metastatic RAS wild-type, left-sided colorectal cancer matters.

As you know, for some years the guidelines recommended anti-EGFR therapy first for these patients, but essentially based on retrospective subgroup analyses. More recently, the PARADIGM study, a prospective randomized study conducted in an Asian population, confirmed improved overall survival and response rates with anti-EGFR therapy in the first-line setting. However, our study was specifically looking at sequencing.

We randomized patients with advanced, nonresectable, RAS wild-type, left-sided colorectal cancer to 1 of 2 treatment sequences. SEQ1 was anti-EGFR first: FOLFOX plus panitumumab in first line, followed upon progression by FOLFIRI plus bevacizumab. SEQ2 was the reverse sequence.

The primary objective was total PFS rate at 36 months, meaning progression from randomization through second-line progression. Secondary objectives included total PFS, first-line PFS, second-line PFS, response rate, overall survival, and we also built in a very ambitious liquid biopsy program to evaluate molecular hyperselection through panels of resistance mutations in circulating tumor DNA.

The main results showed that the primary objective was not met. There was a numerical improvement for sequence 1, with a 36-month total PFS rate of 22% versus 17% for sequence 2. Median total PFS was 22 months versus 20 months, again numerically favoring sequence 1, but this was not statistically significant.

What did produce clinically relevant and statistically significant results were the end points related to first-line treatment, including response rate and first-line PFS. The response rate was 81% for sequence 1 and 64% for sequence 2, and this difference was statistically significant. Median first-line PFS was 14 months for sequence 1—I remind you that sequence 1 is anti-EGFR first—and 12 months for sequence 2. This was also statistically significant. Overall survival data are still immature, but we can already observe a numerical advantage favoring sequence 1. We will continue follow-up over the coming months and years and will present the final overall survival analysis in due course.

To conclude, the primary end point was not met. The 36-month total PFS rate showed only a numerical advantage for sequence 1. However, first-line outcomes, including response rate and progression-free survival, were both clinically meaningful and statistically significant in favor of the anti-EGFR-first sequence. Overall survival data remain immature, and the molecular hyperselection subgroup analyses, together with longer-term survival follow-up, are ongoing.

Source: 

Salazar R, Gomez MA, Jimenez-Fonseca P, et al. Phase III CR-SEQUENCE trial of FOLFOX+panitumumab followed by FOLFIRI+bevacizumab (SEQ1) versus FOLFOX + bevacizumab followed by FOLFIRI + panitumumab (SEQ2) in previously untreated RAS wild-type, left-sided, unresectable metastatic colorectal cancer. Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. Abstract 3512.