Ramucirumab Plus TAS-102 Fails to Improve OS in Heavily Pretreated mCRC

The addition of ramucirumab (Cyramza) to trifluridine/tipiracil (Lonsurf; TAS-102) failed to demonstrate a statistically significant improvement in overall survival (OS) vs TAS-102 alone in patients with heavily pretreated metastatic colorectal cancer (mCRC), according to findings from the phase 3 IKF-AIO-RAMTAS trial (NCT03520946) that were presented at the 2024 ESMO Congress.¹

Findings showed that the median OS in the intent-to-treat (ITT) population was 7.46 months (95% CI, 6.41-8.57) in the investigational arm (n = 213) vs 7.06 months (95% CI, 6.11-8.28) in the control arm (n = 215; HR, 0.871; 95% CI, 0.708-1.073; P =.1941), 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 ITT population,” Stefan Kasper-Virchow, MD, 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.”

Results from the subgroup analysis indicated that the median OS in patients with left-sided tumors (n = 287; 67.1%) was 8.2 months with ramucirumab/TAS-102 vs 6.9 months with TAS-102 alone (HR, 0.77; 95% CI, 0.60-1.00; P =.05). Female patients (n = 193; 45.1%) experienced a median OS of 9.3 months with ramucirumab/TAS-102 vs 7.8 months with TAS-102 alone (HR, 0.71; 95% CI, 0.52-0.98; P =.04).

TAS-102 is approved for the treatment of patients with chemotherapy-refractory mCRC, and ramucirumab, a VEGFR2-directed antibody is indicated for use in combination with FOLFIRI for the treatment of patients with mCRC following disease progression on frontline FOLFOX plus bevacizumab (Avastin).^2,3 Coupled with the knowledge that antiangiogenic agents including bevacizumab, aflibercept, ramucirumab, regorafenib (Stivarga), and fruquintinib (Fruzaqla) have antitumor activity in mCRC, investigators sought to evaluate the synergistic potential of ramucirumab and TAS-102.

IFK-AIO-RAMTAS is an open-label, multicenter, investigator-initiated trial conducted across 43 centers in Germany that enrolled patients with advanced mCRC following progression or intolerance to fluoropyrimidines, oxaliplatin, irinotecan, antiangiogenic agents including bevacizumab, aflibercept, ramucirumab, or regorafenib, and anti-EGFR antibodies if appropriate. An ECOG performance status of 0 or 1 was required and prior treatment with TAS-102 was not allowed.¹

Patients underwent random assignment to 8 mg/kg of intravenous ramucirumab on days 1 and 15 plus 35 mg/m² of oral TAS-102 on days 1 to 5 and 8 through 12 every 4 weeks, or TAS-102 alone. Follow-up occurred every 8 weeks.

The primary end point was OS in the ITT population. Secondary end points were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), safety, and quality of life (QOL).

“We assumed a median OS of 7.1 months for the control arm based on the data of the phase 3 RECOURSE trial [NCT01607957], and we wanted to show a benefit of 2.5 months,” Kasper-Virchow said.

Patients were stratified by prior anti-angiogenic therapy (<12 months vs ≥12 months), BRAF mutation (yes vs no), and RAS mutation (yes vs no).

The baseline characteristics were “equal in both arms and representative for this patient population,” Kasper-Virchow said. In the total population (n = 428) the median age was 62 years (range, 25-90) and 45.1% of patients were female. Most patients were microsatellite stable (59.8%) and 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 (range 0.1-149.6) and the median number of prior lines of therapy was 3 (range, 1-11). Most patients had received at least 2 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 (95% CI, 2.07-2.96) vs 2.07 months (95% CI, 1.97-2.14) in the TAS-102 monotherapy arm (HR, 0.774; 95% CI, 0.636-0.949; P =.0110), 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 (P =1.0), “as expected in a heavily pretreated patient population,” though the DCR was “significantly improved” in the combination arm, at 39.4% vs 31.6% with TAS-102 alone (P =.0336).

Regarding safety, treatment-related adverse effects (TRAEs) occurred in 85.8% of patients in the combination arm vs 73.7% of those in the monotherapy arm (P =.0023). Grade 3 or greater TRAEs occurred in 55.9% and 36.8% of patients, respectively (P <.001). Grade 3 or greater TRAEs related to ramucirumab occurred in 39.3% of patients in the combination arm, and grade 3 or greater TRAEs related to TAS-102 occurred in 48.8% and 36.8% of patients in the combination and monotherapy arms, respectively.

Any AE of special interest related to ramucirumab occurred in 28.9% of patients in the combination arm––mainly hypertension and proteinuria––and treatment-related serious AEs 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 ramucirumab and more patients required dose modification with TAS-102, at 40.8% vs 24.2% in the monotherapy arm (P =.0003).

TRAEs that occurred in at least 10% of patients in the combination arm (n = 211) were neutropenia (all grade, 46.4%; grade ≥3, 32.2%), leukopenia (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 TRAEs in the TAS-102 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%).

“We also measured QOL using the EORTC QLQ-C30 GHS questionnaire and the EQ-5D-5L score. The QOL was comparable between both arms and maintained over all evaluated time points at 4 weeks, 8 weeks, and 12 weeks,” Kasper-Virchow said.

In conclusion, Kasper-Virchow said, “The addition of ramucirumab to TAS-102 resulted in increased hemato-toxicity and dose reductions of TAS-102. More patients received additional therapies after end of treatment in the monotherapy arm [47% vs 37%], and compared with the phase 3 SUNLIGHT trial [NCT04737187], patients had [received] more prior therapies [63% vs 2.5% >2 lines] and more patients had prior antiangiogenic therapies [87% vs 72%]. Interestingly, adding ramucirumab selectively prolonged OS in female patients. Similar results were observed in other ramucirumab combination trials like the phase 3 RAISE [(NCT01183780) HR: female, 0.735; male, 0.947], RAINFALL [(NCT02314117) HR, 0.577 vs 0.928], and RAINBOW [(NCT01170663) HR, 0.672 vs 0.814] trials.”

Disclosures: Dr Kasper-Virchow reported honoraria, involvement in an advisory committee, and research funding pertaining to Amgen, ArtTempi, AstraZeneca, BeiGene, BMS, Daiichi Sankyo, Lilly, Merck Healthcare, MSD, Novartis, Onkowissen.de, Roche, Seagen, Servier, and Takeda.

References

1. Kasper S, Hofheinz RD, Stintzing S, et al. Randomized phase III trial of ramucirumab in combination with TAS102 (trifluridine/tipiracil) vs. TAS102 monotherapy in heavily pretreated metastatic colorectal cancer. The IKF-AIO-RAMTAS trial. Presented at: 2024 ESMO Congress; September 12-17, 2024; Barcelona, Spain. Presentation LBA25.
2. Lonsurf. Prescribing information. Taiho Oncology; 2023. Accessed September 15, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/207981s012lbl.pdf
3. Cyramza. Prescribing information. Eli Lilly and Company; 2020. Accessed September 15, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125477s034lbl.pdf