TAS-102 Shows OS Benefit With Bevacizumab in mCRC Ineligible for Intensive Therapy

Eric Van Cutsem, MD, PhD

The frontline combination of trifluridine/tipiracil (TAS-102; Lonsurf) in combination with bevacizumab (Avastin) demonstrated an overall survival (OS) benefit compared with capecitabine and bevacizumab as treatment of patients with unresectable metastatic colorectal cancer (mCRC) who are not eligible for a standard chemotherapy regimen, resulting in a difference of almost 5 months, according to the final analysis of the phase 2 TASCO1 trial (NCT02743221).1

In results presented during the 2021 Gastrointestinal Cancers Symposium, the trifluridine/tipiracil and bevacizumab arm had a median OS of 22.31 months (95% CI, 18.00-23.69) compared with 17.67 months (95% CI, 12.58-19.81) in the capecitabine and bevacizumab arm (HR, 0.78; 95% CI, 0.55-1.10).

“This study was not comparative so no formal statistical analysis is presented and survival is a secondary end point,” clarified Eric Van Cutsem, MD, PhD, head of the Digestive Oncology Unit at the University Hospital Gashuisberg in Leuven, Belgium.

The multinational, open-label, randomized, noncomparative study included patients with colorectal cancer who had not received prior systemic chemotherapy for their unresectable metastatic disease. Additionally, they were ineligible for intensive therapy due to investigator judgment, for such reasons as advanced age, low tumor burden, ECOG performance status, and comorbidities.

Patients were randomized 1:1 between the 2 treatment arms based on RAS status, ECOG performance status, and region. In the trifluridine/tipiracil and bevacizumab arm (n = 77), trifluridine/tipiracil was administered at 35 mg/m2 twice daily orally on days 1 through 5 and 8 through 12 every 4 weeks plus 5 mg/kg of intravenous bevacizumab on days 1 and 15 every 4 weeks. The capecitabine and bevacizumab arm (n = 76) consisted of 1250 or 1000 mg/m2capecitabine twice daily orally for 2 of every 3 weeks and 7.5 mg/kg of intravenous bevacizumab on day 1 of every 3-week cycle. Treatment continued until progression, unacceptable toxicity, or investigator/patient decision.

The primary end point was progression-free survival and secondary end points included OS, objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety.

For the primary analysis for PFS the cutoff date was January 15, 2018, and was based on 100 PFS events. The final analysis was conducted after the end of the study cutoff date of September 1, 2020.

The median age of all patients was 75 years (range, 33-91) with 43% over 75 years. The majority of patients were male (57%), White (97%), had an ECOG performance status of 1 (50%), RAS-mutant disease (57%), BRAF wild-type disease (69%), left-sided tumors (68%), and had at least 3 metastatic sites (73%). Three-fourths of patients had not received prior adjuvant therapy. The most common reason for ineligibility for intensive therapy was advanced age (46%) followed by tumor burden (19%).2

In the primary analysis, the median PFS was 9.2 months (95% CI, 7.59-11.56) in the trifluridine/tipiracil and bevacizumab arm versus 7.8 months (95% CI, 5.55-10.15) in the capecitabine and bevacizumab arm (HR, 0.71; 95% CI, 0.48-1.06). At 12 months, the PFS rate was 40% with trifluridine/tipiracil versus 30% with capecitabine.

At the end of the study, 14.29% of patients in the trifluridine/tipiracil arm were still alive and 86.84% were dead whereas 13.16% were alive and 85.71% were dead in the capecitabine arm. Of the 21 patients not included, 4 were considered lost to follow-up and 17 were censored.1

Treatment discontinuation occurred due to adverse events (AEs) in 23.38%, due to progressive disease in 61.04%, and for other reasons in 11.84% in the trifluridine/tipiracil arm whereas 22.37%, 65.79%, and 15.59% discontinued from the capecitabine arm due to AEs, progressive disease, and other reasons, respectively.

At 6 months, the OS rate in the trifluridine/tipiracil arm was 85% versus 83% in the capecitabine arm, the rates were 76% and 67% at 12 months, respectively, 62% and 47% at 18 months, and 38% and 34% at 2 years.

Subgroup analyses favored the trifluridine/tipiracil arm with most variables, especially for patients with BRAF mutant disease (HR, 0.17), ECOG performance status as the reason for intensive therapy ineligibility (HR, 0.33), and female gender (HR, 0.44). Right-sided tumors, however, seemed to favor the capecitabine arm (HR, 1.49).

Sixty percent of patients in the trifluridine/tipiracil arm went on to receive at least 1 subsequent therapy versus 41% in the capecitabine arm. The most common subsequent therapies across the 2 arms were fluorouracil, capecitabine, irinotecan, oxaliplatin, and bevacizumab.

In the updated safety analysis, the safety profile was unchanged from the initial analysis, Van Cutsem noted. He said that patients had a good tolerance for trifluridine/tipiracil and bevacizumab.

The most common grade 3/4 hematologic AEs with trifluridine/tipiracil and bevacizumab were neutropenia (46.8%), anemia (13%), and neutrophil count decrease (19.5%). Common grade 3/4 non-hematologic AEs with trifluridine/tipiracil and bevacizumab were hypertension (13.0%) and vomiting (5.2%).

These 2 combinations will be examined further in the comparative, open-label, randomized phase 3 SOLSTICE trial (NCT03869892) in patients with mCRC who are not candidates for intensive therapy.

_References

_{1. Van Cutsem E, Danielewicz I, Saunders MP, et al. Phase II study evaluating trifluridine/tipiracil + bevacizumab and capecitabine + bevacizumab in first-line unresectable metastatic colorectal cancer (mCRC) patients who are noneligible for intensive therapy (TASCO1): Results of the final analysis on the overall survival. J Clin Oncol. 2021;39(suppl):14.}

_{2. Van Cutsem E, Danielewicz I, Saunders MP, et al. Trifluridine/tipiracil plus bevacizumab in patients with untreated metastatic colorectal cancer ineligible for intensive therapy: the randomized TASCO1 study. Ann Oncol. 2020;31(9):1160-1168. doi:10.1016/j.annonc.2020.05.024}