The combination of Cyramza (ramucirumab) and Lonsurf (trifluridine/tipiracil) did not significantly improve overall survival (OS) compared to Lonsurf alone in patients with heavily pretreated metastatic colorectal cancer (mCRC), according to results from the phase 3 IKF-AIO-RAMTAS trial presented at the 2024 ESMO Congress. The trial, which aimed to evaluate the synergistic potential of Cyramza and Lonsurf, found that the median OS was 7.46 months in the combination arm versus 7.06 months in the control arm.
Primary Endpoint Not Met
The primary endpoint of the trial, overall survival, was not met. Dr. Stefan Kasper-Virchow, lead study author and professor of medical oncology at University Hospital Essen in Germany, noted that the trial did not meet its primary endpoint in the intention-to-treat population. However, subgroup analyses revealed potential benefits in specific patient populations.
Subgroup Analysis
Subgroup analysis indicated that female patients and those with left-sided tumors experienced improved survival outcomes with the combination therapy. Specifically, the median OS in patients with left-sided tumors (67.1%) was 8.2 months with Cyramza/Lonsurf versus 6.9 months with Lonsurf alone. Female patients (45.1%) experienced a median OS of 9.3 months with Cyramza/Lonsurf versus 7.8 months with Lonsurf alone.
Progression-Free Survival
Additional findings demonstrated a significant improvement in progression-free survival (PFS) with the combination, at 2.37 months versus 2.07 months in the Lonsurf monotherapy arm. This benefit was observed across nearly all subgroups.
Safety and Tolerability
Treatment-related side effects occurred in 85.8% of patients in the combination arm versus 73.7% of those in the monotherapy arm. Grade 3 or greater treatment-related side effects occurred in 55.9% and 36.8% of patients, respectively. Side effects of special interest related to Cyramza, mainly hypertension and proteinuria, occurred in 28.9% of patients in the combination arm. Neutropenia, leukopenia, fatigue, nausea, and diarrhea were among the most common side effects in both arms.
Trial Design and Patient Population
The IKF-AIO-RAMTAS trial enrolled patients with advanced mCRC following progression or intolerance to fluoropyrimidines, oxaliplatin, irinotecan, antiangiogenic agents, and anti-EGFR antibodies, if appropriate. Patients were randomized to receive intravenous Cyramza and oral Lonsurf, or Lonsurf alone. The primary endpoint was OS, with secondary endpoints including PFS, objective response rate (ORR), disease control rate (DCR), safety, and quality of life (QOL).
Baseline characteristics were similar in both arms, with a median age of 62 years and 45.1% of patients being female. Most patients had microsatellite stable tumors (59.8%), an ECOG performance status of 0 (52.8%), a primary tumor localized to the left side (67.1%), and RAS-mutated (61.7%) and BRAF V600E wild-type disease (95.6%).
Implications for Treatment
While the combination of Cyramza and Lonsurf did not meet its primary endpoint of improving overall survival in heavily pretreated mCRC patients, the observed improvement in progression-free survival and potential benefits in specific subgroups warrant further investigation. The results suggest that certain patient populations, such as female patients and those with left-sided tumors, may derive greater benefit from this combination therapy.
