Adding Cyramza (ramucirumab) to Lonsurf (trifluridine/tipiracil) failed to significantly improve survival compared with Lonsurf alone in heavily pretreated metastatic colorectal cancer (mCRC), according to findings from the phase 3 IKF-AIO-RAMTAS trial presented at the 2024 ESMO Congress.
Findings showed that the median overall survival (the time when a patient with cancer is still alive; OS) was 7.46 months in the investigational arm (213 patients) versus 7.06 months in the control arm (215 patients), with a total of 83.6% and 86.5% of events having occurred, respectively.
“The IKF-AIO-RAMTAS trial did not meet its primary end point of OS in the [intention-to-treat] population,” Dr. Stefan Kasper-Virchow, lead study author and professor of medical oncology at University Hospital Essen in Germany, said in a presentation of the data. “Subgroups with benefit were female patients and patients with left-sided tumors.”
Study Highlights
- The primary end point of the trial, overall survival, was not met. This means that the combination of Cyramza and Lonsurf did not significantly extend the lives of patients with heavily pretreated metastatic colorectal cancer compared to Lonsurf alone.
- While the overall survival benefit was not significant, the trial did identify subgroups that might benefit from the combination. Female patients and those with left-sided tumors showed improved survival outcomes with Cyramza/Lonsurf.
- Although the combination did not improve overall survival, it did significantly extend progression-free survival, meaning patients lived longer without their disease worsening.
- The combination of Cyramza and Lonsurf was generally well-tolerated, with a similar safety profile to Lonsurf alone. However, there was a higher incidence of treatment-related side effects, especially those related to Cyramza.
Results from the subgroup analysis indicated that the median OS in patients with left-sided tumors (287 patients; 67.1%) was 8.2 months with Cyramza/Lonsurf versus 6.9 months with Lonsurf alone. Female patients (193 patients; 45.1%) experienced a median OS of 9.3 months with Cyramza/Lonsurf versus 7.8 months with Lonsurf alone.
Lonsurf is approved for the treatment of patients with chemotherapy-refractory mCRC, and Cyramza, a VEGFR2-directed antibody, is indicated for use in combination with FOLFIRI (a chemotherapy regimen with leucovorin calcium, fluorouracil and irinotecan hydrochloride) for the treatment of patients with mCRC following disease progression on frontline FOLFOX (a chemotherapy regimen with leucovorin calcium, fluorouracil and ocaliplatin) plus Avastin (bevacizumab). Coupled with the knowledge that antiangiogenic agents including bevacizumab, aflibercept, Cyramza, Stivarga (regorafenib) and Fruzaqla (fruquintinib) have antitumor activity in mCRC, investigators sought to evaluate the synergistic potential of Cyramza and Lonsurf.
IFK-AIO-RAMTAS is a trial that enrolled patients with advanced mCRC following progression or intolerance to fluoropyrimidines, oxaliplatin, irinotecan, antiangiogenic agents including Avastin, aflibercept, Cyramza, or Stivarga, and anti-EGFR antibodies if appropriate. An ECOG performance status of 0 or 1 (fully active or with some restrictions for physically strenuous activity) was required, and prior treatment with Lonsurf was not allowed.
Patients underwent random assignment to intravenous Cyramza and oral Lonsurf, or Lonsurf alone. Follow-up occurred every eight weeks.
The main focus of the trial was to assess OS. Secondary end points were progression-free survival (the time during and after treatment when a patient with cancer is alive without disease worsening; PFS), objective response rate (the percentage of patients with a complete or partial response to treatment; ORR), disease control rate (DCR), safety and quality of life (QOL).
The baseline characteristics were “equal in both arms and representative for this patient population,” Kasper-Virchow said. In the total population (428 patients) the median age was 62 years and 45.1% of patients were female. Most patients were microsatellite stable (tumors with a relatively normal number of repetitive DNA sequences; 59.8%), had an ECOG performance status of 0 (52.8%), a primary tumor that was localized to the left side (67.1%), and RAS-mutated (61.7%) and BRAF V600E wild-type disease (95.6%).
Regarding patients’ prior treatment history, in the overall population the time from first metastasis to randomization was 23.9 months and the median number of prior lines of therapy was three. Most patients had received at least two prior lines of therapy (62.6%) and received prior antiangiogenic therapy (87.6%), the duration of which was less than 12 months in most cases (65.4%).
Additional findings demonstrated a significant improvement in PFS with the combination, according to Kasper-Virchow, at 2.37 months versus 2.07 months in the Lonsurf monotherapy arm, with 93.9% and 94.4% of events having occurred, respectively. The benefit was observed across “nearly all” subgroups, Kasper-Virchow said.
The ORR was 1.9% in both arms, “as expected in a heavily pretreated patient population,” though the DCR was “significantly improved” in the combination arm, at 39.4% versus 31.6% with Lonsurf alone.
Regarding safety, 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 (severe) or greater treatment-related side effects occurred in 55.9% and 36.8% of patients, respectively. Grade 3 or greater treatment-related side effects related to Cyramza occurred in 39.3% of patients in the combination arm, and grade 3 or greater treatment-related side effects related to Lonsurf occurred in 48.8% and 36.8% of patients in the combination and monotherapy arms, respectively.
Any side effect of special interest related to Cyramza occurred in 28.9% of patients in the combination arm –– mainly hypertension (high blood pressure) and proteinuria (high levels of protein in urine) –– and treatment-related serious side effects occurred in 15.6% and 5.3% of patients in the combination and monotherapy arms, respectively.
In the combination arm, 18.3% of patients required dose modification with Cyramza and more patients required dose modification with Lonsurf, at 40.8% versus 24.2% in the monotherapy arm.
Treatment-related side effects that occurred in at least 10% of patients in the combination arm (211 patients) were neutropenia (lower than normal number of neutrophils, a type of white blood cell, in blood, which help the body against infections; all grade, 46.4%; grade ≥3, 32.2%), leukopenia (lower than normal levels of leukocytes, a type of white blood cell; all grade, 22.7%; grade ≥3, 10.4%), fatigue (all grade, 20.9%; grade ≥3, 2.4%), nausea (all grade, 22.7%; grade ≥3, 0.9%) and diarrhea (all grade, 17.1%; grade ≥3, 2.8%). The rates of treatment-related side effects in the Lonsurf monotherapy arm were comparable: neutropenia (all grade, 36.8%; grade ≥3, 22.0%), leukopenia (all grade, 19.1%; grade ≥3, 10.5%), fatigue (all grade, 19.1%; grade ≥3, 0.5%), nausea (all grade, 18.7%; grade ≥3, 1.0%) and diarrhea (all grade, 12.0%; grade ≥3, 2.4%).
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