Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: The phase 3 randomized SUNLIGHT study.

Author(s): Josep Tabernero, Gerald W. Prager, Marwan Fakih, Fortunato Ciardiello, Eric Van Cutsem, Elena Elez, Felipe Melo Cruz, Lucjan Wyrwicz, Daniil Stroyakovskiy, Zsuzsanna Papai, Pierre-guillaume Poureau, Gabor Liposits, Chiara Cremolini, Igor Bondarenko, Dominik Paul Modest, Karim A. Benhadji, Ronan Fougeray, Catherine Leger, Nadia Amellal, Julien Taieb

Source: J Clin Oncol 41, 2023 (suppl 4; abstr 4) 10.1200/JCO.2023.41.3_suppl.4

Dr. Anjan Patel's Thoughts

In the SUNLIGHT study, Lonsurf + bevacizumab was found to be superior to bevacizumab alone in the 3L setting of mCRC, independent of mutation status. First 3L mCRC where the control group was an active compound instead of a placebo. OS was superior, with a clinically meaningful difference of 10.8 vs. 7.5 months. This is now the SOC 3L option in mCRC, in my opinion.

BACKGROUND

Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (Bev) demonstrated promising efficacy in a randomized phase 2 trial of heavily pretreated patients (pts) with metastatic colorectal cancer (mCRC). SUNLIGHT was conducted to confirm these findings.

METHODS

The global phase 3 SUNLIGHT study enrolled pts aged ≥18 years with histologically confirmed mCRC, ECOG PS 0/1, and treated with 1-2 prior chemotherapy regimens in an advanced setting, including fluoropyrimidines, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody (if medically considered) and/or anti-EGFR monoclonal antibody for RAS wild-type tumors. Pts were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle) alone or combined with Bev (5 mg/kg on days 1 and 15). Primary endpoint was overall survival (OS).

RESULTS

Between Nov 2020 and Feb 2022, 492 pts were randomised to receive FTD/TPI + Bev (n = 246) or FTD/TPI (n = 246). Baseline characteristics were balanced between arms. FTD/TPI + Bev significantly extended OS over FTD/TPI, median OS was 10.8 months vs 7.5 months, respectively (HR, 0.61; 95% CI, 0.49, 0.77; P< 0.001). OS rates at 12 months were 43% in the FTD/TPI + Bev arm and 30% in the FTD/TPI arm. Median progression-free survival was 5.6 months in the FTD/TPI + Bev arm and 2.4 months in the FTD/TPI arm (HR, 0.44; 95% CI, 0.36,0.54; P< 0.001). Grade ≥3 adverse events (AEs) were not significantly increased in the FTD/TPI + Bev arm vs the FDT/TPI arm (72.4% vs 69.5%). No new safety signals were noted.

CONCLUSIONS

FTD/TPI + Bev provided a statistically significant and a clinically meaningful 3.3-month improvement in OS, extending mOS up to 10.8 months, with a 39% reduction in the HR of death in pts with refractory mCRC and with a predictable and acceptable safety profile. Clinical trial information: NCT04737187.

Author Affiliations

Vall d’Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain; , Medical University of Vienna, Vienna, Austria; , City of Hope National Comprehensive Cancer Center, Duarte, CA; , Precision Medicine Department, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy; , Department of Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Herent, Belgium; , Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), UVic-UCC, Barcelona, Spain; , Núcleo de Pesquisa e Ensino da Rede São Camilo, Sao Paulo, Brazil; , Department of Oncology and Radiotherapy, Maria Sklodowska-Curie National Cancer Research Institute, Warsaw, Poland; , Moscow City Oncological Hospital #62, Moscow Area, Russian Federation; , Medical Oncology, Duna Medical Centre, Budapest, Hungary; , Institut de Cancérologie, Brest, France; , Department of Clinical Research, University of Southern Denmark, Odense, Denmark; , Department of Translational Research and New Technologies, University of Pisa, Pisa, Italy; , Department of Oncology and Medical Radiology; Dnipropetrovsk Medical Academy, Dnipro, Ukraine; , Charité Universitätsmedizin Berlin, Berlin, Bagun, Germany; , Taiho Oncology, Inc., Princeton, NJ; , Servier International Research Institute, Suresnes, France; , Université Paris-Cité, (Paris Descartes), Georges Pompidou European Hospital, SIRIC CARPEM, Paris, France;

Trastuzumab Rezetecan in Human Epidermal Growth Factor Receptor 2–Expressing Advanced Gastric Cancer or Gastroesophageal Junction Adenocarcinoma and Colorectal Cancer: A Multicenter, Open-Label, Phase I Trial

Encouraging phase I signal for this HER2-targeted Antibody-drug conjugate (ADC) in heavily pretreated GI cancers, 45% overall response rate (ORR) and 16.3mo median overall survival (OS) in HER2-positive gastric compares favorably with T-DXd benchmarks, and the 40.5% objective response rate (ORR) with 22.7mo OS in HER2-positive colorectal cancer (CRC) is notable. The 2% ILD rate looks meaningfully better than T-DXd’s reported range, which could be a real differentiator. Hematologic toxicity is substantial but manageable. Small China-only phase I, but worth watching closely as this advances.

Postoperative Hepatic Arterial Infusion With Oxaliplatin After Surgery of Four or More Colorectal Liver Metastases: A Randomized Phase II Trial

For high-risk patients with four or more colorectal liver metastases, adjuvant hepatic arterial infusion oxaliplatin roughly doubled hepatic recurrence-free survival versus standard IV chemotherapy (25 vs. 12 months), with recurrence-free survival (RFS) benefit as well. Overall survival (OS) didn't reach significance but the absolute difference and 5-year OS of 62% versus 47% suggest a real effect worth confirming in phase III. Toxicity was higher in the hepatic arterial infusion (HAI) arm but manageable with no treatment-related deaths. Generalizability remains the challenge, these needs specialized centers with HAI expertise, but worth keeping in mind for your highest-risk resected liver met patients.

Randomized Phase II/III Trial Comparing Hepatectomy, Followed by mFOLFOX6 With Hepatectomy Alone for Liver Metastasis From Colorectal Cancer: Long-Term Results of JCOG0603

The mature overall survival (OS) data from this Japanese randomized trial answer the question the initial publication left open, and the answer is no, adjuvant mFOLFOX6 after hepatectomy for resectable colorectal liver metastases does not improve overall survival (HR 1.07, P=.74), despite the previously reported DFS benefit. Five-year OS was numerically worse in the chemotherapy arm (73% vs 80%), though not significantly so. The disease-free survival (DFS) benefit was likely confounded by oxaliplatin-induced hepatic changes obscuring imaging and imbalances in post-recurrence therapy. Selection of patients and those with curable vs incurable intent surgery may have led to some bias in my opinion.

Tumor Debulking in Combination With Chemotherapy in Multiorgan Metastatic Colorectal Cancer: The ORCHESTRA Randomized Clinical Trial

Open-label, phase 3 clinical trial, 382 patients were randomized to receive chemotherapy alone or chemotherapy plus tumor debulking. The overall survival rates were not statistically different, with a median overall survival in the chemotherapy alone group of 27.5 m vs 30.0 m in the chemotherapy plus tumor debulking group hence tumor debulking added to palliative systemic chemotherapy did not result in significantly improved survival compared with chemotherapy alone in patients with multiorgan metastatic colorectal cancer.

Atezolizumab plus FOLFOX for Stage III Mismatch Repair–Deficient Colon Cancer

This is a strong adjuvant signal in resected stage III dMMR colon cancer, adding atezolizumab to mFOLFOX6 cut the risk of recurrence or death in half and improved 3-year DFS from 76% to 86%. OS hasn’t separated yet, but that may be confounded by immunotherapy at relapse. Toxicity was higher, as expected, with more grade 3–4 events and immune-related adverse events (AE)s, but overall manageable. This feels practice changing for stage III dMMR disease.