LBA25 - Randomized phase III trial of ramucirumab in combination with TAS102 (Trifluridin/Tipiracil) vs. TAS102 monotherapy in heavily pretreated metastatic colorectal cancer: The RAMTAS/IKF643 trial of the German AIO (AIO-KRK-0316)

Background

Patients (pts) with chemotherapy-refractory metastatic colorectal cancer (mCRC) have limited therapeutic options. Trifluridin/tipiracil (FTD/TPI) is a standard of care in pts progressing on two lines of combination therapies. Antiangiogenic biologicals are active combination partners across multiple lines of mCRC treatment. Against this background, we conducted a randomized phase III trial to compare the efficacy and safety of FTD/TPI with or without ramucirumab (ram) in pts with heavily pretreated mCRC.

Methods

Pts with mCRC previously treated with oxaliplatin, irinotecan, fluoropyrimidin, anti-EGFR antibodies (when indicated) and anti-angiogenics were randomized 1:1 to FTD/TPI (35 mg/m² d1-5 and 8-12, q4w) with (arm A) or without (arm B) ram (8 mg/kg d1+15, q4w). Primary endpoint was overall survival (OS). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and safety.

Results

From Dec 2018 to Jan 2023, 428 pts (213 in arm A and 215 in arm B) were enrolled at 43 centers in Germany. Median age was 62 (range 25-90); 45.1% were female; 61.7% had RAS mutations, and 67.1% had left sided tumors. In total, 62.6% pts had received >2 prior treatments for mCRC. In arm A there were more TRAEs ≥3 (55.9% vs 36.8%; mainly hypertension and neutropenia) and more dose reductions of FTD/TPI (40.8 vs 24.2%). No new safety signals emerged. With a median OS of 7.46 months for arm A vs. 7.06 months for arm B (HR 0.871; p=0.1941) the primary study endpoint was not met. Median PFS was 2.37 in arm A vs 2.07 in arm B (HR 0.774; p=0.011). DCR was higher in the ram/FTD-TPI arm (39.4% vs. 31.6%; p=0.0336). Interestingly, the OS of female pts (HR 0.712; p=0.0371) and pts with left-sided tumor (HR 0.770; p=0.0469) was improved with ram combination therapy.

Conclusions

The RAMTAS trial did not meet its primary endpoint of OS in the ITT population. However, adding ram to FTD/TPI selectively improved survival in heavily pretreated female pts and pts with left-sided mCRC. These findings support the personalization of treatment decisions in pts with mCRC failing multiple lines of standard therapy.

Clinical trial identification

NCT03520946; EudraCT 2017-004162-99.

Editorial acknowledgement

The Frankfurt Institute of Clinical Cancer Research IKF GmbH, Frankfurt, Germany.

Legal entity responsible for the study

The Frankfurt Institute of Clinical Cancer Research IKF GmbH, Frankfurt, Germany.

Funding

Lilly Deutschland GmbH.

Disclosure

S. Kasper-Virchow: Financial Interests, Personal and Institutional, Funding: Lilly, Roche, BMS; Financial Interests, Personal, Advisory Board: Lilly, Servier, MSD, Daiichi Sankyo, AstraZeneca, Amgen, GSK, Novartis, Pierre-Fabre; Financial Interests, Personal, Invited Speaker: Lilly, Servier, Merck Healthcare. R.D. Hofheinz: Financial Interests, Personal, Advisory Board: Amgen, BMS, MSD, Sanofi, Roche, AstraZeneca, Lilly, Roche, merck, Daichi, Nordic Pharma, AbbVie, BeiGene. S. Stintzing: Financial Interests, Personal, Advisory Board: Amgen, Bayer, Lilly, Pierre_Fabre, Merck KgaA, MSD, Roche, Sanofi, Taiho, Takeda; Financial Interests, Personal, Invited Speaker: Leo Pharma, AstraZeneca, Sysmex; Financial Interests, Institutional, Research Grant: Merck KGaA, Pierre-Fabre, Roche; Non-Financial Interests, Advisory Role: CV6. T.J. Ettrich: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Bayer, Amgen, MSD, Merck, Ipsen, Sanofi Aventis, Pierre-Fabre Pharma, Incyte, Lilly, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: MSD, Ipsen, Eisai; Financial Interests, Institutional, Research Grant: Servier. U. Graeven: Financial Interests, Personal, Other: Boehringer Ingelheim, Amgen, AstraZeneca, BMS, MSD, Novartis, SanofiAventis, Fujifilm, Cellrion, Ipsen, Boehringer Ingelheim, GSK; Financial Interests, Personal, Stocks or ownership: Biontech; Financial Interests, Personal, Advisory Board: Amgen, MSD; Financial Interests, Institutional, Funding: Ipsen, Macrogenics. C. Mueller: Financial Interests, Personal, Advisory Board: Lilly, Amgen, BMS. A. Stein: Financial Interests, Institutional, Advisory Board: BMS, MSD, Amgen, Merck, Daiichi Sankyo, Roche, GSK, Servier, TAIHO; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Writing Engagement: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: BMS, MSD, Servier, German Cancer Aid, Pierre Fabre, Merck; Financial Interests, Institutional, Steering Committee Member: Novartis; Non-Financial Interests, Member: DGHO, ASCO. D.P. Modest: Financial Interests, Personal, Invited Speaker: Takeda, Taiho, Amgen, Servier, Merck, Onkowissen, MSD, AstraZeneca, PierreFabre, GSK, Medison, COR2ED, JE, 21up, Seagen,; Financial Interests, Personal, Advisory Board: Amgen, Servier, Merck, MSD, Takeda, G1, Onkowissen, PierreFabre, AstraZeneca, Regeneron; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Coordinating PI: Servier. S. Al-Batran: Financial Interests, Personal, Advisory Board: Lilly, Bristol Myers Squibb, MSD Sharp & Dohme; Financial Interests, Personal, Invited Speaker: MCI Deutschland GmbH; Financial Interests, Personal, Ownership Interest, CEO: Institut für Klinische Krebsforschung IKF GmbH; Financial Interests, Institutional, Research Grant: Sanofi, Roche, Celgene, Lilly, Eurozyto, Immutep, Ipsen, Bristol Myers Squibb, MSD Sharp & Dohme, AstraZeneca, German Cancer Aid (Krebshilfe), German Research Foundation, Federal Ministry of Education and Research. M.H.H. Schuler: Financial Interests, Personal, Invited Speaker: Amgen, Bristol Myers Squibb, Janssen, Roche, GSK, MSD; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Janssen, Novartis, Roche, Sanofi, Takeda, Tacalyx, MSD; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, AstraZeneca, Janssen; Non-Financial Interests, Principal Investigator, Member, Study Steering Board: Janssen; Non-Financial Interests, Principal Investigator, Member, Study Steering Committee: Amgen. All other authors have declared no conflicts of interest.