TAS-102 Plus Bevacizumab Misses PFS End Point in Frontline Unresectable Metastatic CRC

The frontline combination of trifluridine/tipiracil (TAS-102; Lonsurf) and bevacizumab (Avastin) was not found to result in a significant improvement in progression-free survival (PFS) over capecitabine and bevacizumab in patients with unresectable metastatic colorectal cancer (mCRC) who are not eligible to receive intensive therapy, missing the primary end point of the phase 3 SOLSTICE trial (NCT03869892).¹

Because no deleterious effects and no new safety signals were observed in either of the treatment arms, the trial will continue as planned.

Findings from the primary analysis of SOLSTICE will be shared at an upcoming medical meeting, according to Servier.

“We remain committed to improving outcomes in mCRC and we will continue to follow patients as planned in order to perform the main secondary end point analysis on overall survival [OS] in 2023,” Patrick Therasse, MD, PhD, head of Late Stage and Life Cycle Management and deputy head of Oncology and Immuno-Oncology Therapeutic Area at Servier, stated in the press release. “The clinical value of [TAS-102] in its current indications remains unchanged, and the ongoing phase 3 SUNLIGHT trial [NCT04737187] is proceeding as planned.”

The open-label, randomized, multicenter phase 3 SOLSTICE trial enrolled patients with unresectable mCRC who were not candidates to receive, or did not require, intensive therapy. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 to 2, acceptable organ function, and available RAS mutational status.²

Patients could not have received prior systemic anticancer therapy for unresectable mCRC, nor could they have symptomatic central nervous system (CNS) metastases, have undergone major surgery within 4 weeks before randomization, or a history of allergic reactions attributed to compounds of comparable composition to any of the study drugs. They also could not have participated in another interventional study within 4 weeks before randomization.

A total of 856 study participants were randomized 1:1 to receive frontline treatment with TAS-102 at a twice-daily dose of 35 mg/m² 5-days-on and 2-days-off over 2 weeks plus bevacizumab at a dose of 5 mg/kg given every 2 weeks on days 1 and 15 every 4 weeks vs capecitabine at a twice-daily dose of 1250 mg/m² on days 1 through 14 of each cycle, every 3 weeks, and bevacizumab.

The primary end point of the trial was PFS, and secondary end points included OS, overall response rate (ORR), disease control rate (DCR), duration of response, and time to treatment failure.

The first patient was enrolled to the trial in March 2019.

In the ongoing, international, open-label, controlled, 2-arm phase 3 SUNLIGHT trial, investigators are comparing the safety and efficacy of TAS-102 plus bevacizumab with that of TAS-102 alone in patients with refractory mCRC.³

To be eligible to participate, patients must have histologically confirmed unresectable adenocarcinoma of the colon or rectum, previously determined RAS mutational status, measurable disease per RECIST v1.1 criteria, an estimated life expectancy of at least 12 weeks, and an ECOG performance status of 0 or 1.

Moreover, patients also needed to have received a maximum of 2 previous chemotherapy regimens for advanced CRC and had demonstrated disease progression or intolerance to their last regimen.

Patients could not be currently receiving or have received anticancer therapies within 4 weeks before randomization, they could not have symptomatic CNS metastases that are neurologically unstable or required increased doses of steroids, severe or uncontrolled active acute or chronic infection, nor could they have active or a history of interstitial lung disease and/or pneumonitis or pulmonary hypertension. Patients also could not have hepatitis B or C virus or be carrier of human immunodeficiency virus.

The primary end point of the trial is OS and secondary end points include PFS, ORR, DCR, treatment-emergent adverse effects, and quality of life (QoL).

“Metastatic CRC patients who are not well enough to undergo intensive chemotherapy have limited options, and QoL is a priority,” Thierry André, MD, professor at Saint Antoine Hospital, and lead investigator of SOLSTICE, stated in a press release. “We are continuously searching for new ways to give these patients efficient treatment with low toxicities.”

In September 2015, the FDA approved TAS-102 for the treatment of adult patients with mCRC who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents.⁴

More recently, in February 2019, the FDA approved TAS-102 for use in adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with at least 2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.⁵

References

1. Servier announces outcome from the primary analysis of the phase III SOLSTICE trial assessing LONSURF (trifluridine/tipiracil) + bevacizumab in a 1st line setting for patients with unresectable mCRC non-eligible for intensive therapy. News release. Servier. October 22, 2021. Accessed October 22, 2021. https://bwnews.pr/3pubhw4
2. Phase III study in first-line treatment of patients with metastatic colorectal cancer who are not candidates for intensive therapy. (SOLSTICE). ClinicalTrials.gov. Updated September 30, 2020. Accessed October 22, 2021. https://clinicaltrials.gov/ct2/show/NCT03869892
3. Phase III study of trifluridine/tipiracil in combination with bevacizumab vs trifluridine/tipiracil single agent in patients with refractory metastatic colorectal cancer (SUNLIGHT). ClinicalTrials.gov. Updated August 3, 2021. Accessed October 22, 2021. https://clinicaltrials.gov/ct2/show/NCT04737187
4. Taiho Pharmaceutical announces FDA approval of LONSURF (trifluridine and tipiracil) for refractory metastatic colorectal cancer (mCRC). News release. Taiho Pharmaceutical Co., Ltd. September 24, 2015. Accessed October 22, 2021. https://bit.ly/3vDc92n
5. FDA approves LONSURF (trifluridine/tipiracil) for adult patients with previously treated advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. News release. Taiho Pharmaceutical Co., Ltd. February 26, 2019. Accessed October 22, 2021. https://bit.ly/3vBohAN