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Pairing a novel cytotoxic agent with bevacizumab (Avastin) failed to improve progression-free survival (PFS) versus standard therapy in older patients with metastatic colorectal cancer (mCRC) ineligible for intensive therapy, a randomized trial showed.

Investigator-assessed PFS was 9.4 months with trifluridine/tipiracil (Lonsurf) plus bevacizumab and 9.3 months with capecitabine plus the angiogenesis inhibitor. PFS by blinded central review gave trifluridine/tipiracil a small advantage, but the difference did not meet prespecified requirements for statistical significance.

The treatments had different safety profiles, but no new safety signals emerged for either arm of the trial, reported Thierry André, MD, of Sorbonne University and Saint-Antoine Hospital in Paris, at the .

"Trifluridine/tipiracil plus bevacizumab did not show statistically significant superiority in terms of PFS assessed by investigator, but there was a trend in favor of trifluridine/tipiracil and bevacizumab with a hazard ratio of 0.87," said André. "PFS in both arms in the selected population, with a median age of 73, was clinically meaningful, 9.4 versus 9.3 months...Quality-of-life data will be available soon, and data on OS [overall survival] is expected in 2023."

Statistical assumptions for the phase III included an estimated median PFS of 7.5 months for the control arm. The estimate was derived from the phase II , a randomized comparison of the same two regimens, which yielded a median PFS of 9.23 months with trifluridine/tipiracil-bevacizumab and 7.8 with capecitabine-bevacizumab (HR 0.71).

However, a comparing capecitabine alone versus capecitabine-bevacizumab yielded a median PFS of 9.1 months for the combination, said ESMO invited discussant Demetris Papamichael, MD, PhD, of Bank of Cyprus Oncology Center in Nicosia.

"The investigators were prompted to conduct SOLSTICE by the encouraging results of TASCO1," said Papamichael. "I appreciate that cross-trial comparisons can be very challenging ... but it appears that this [capecitabine-bevacizumab] arm underperformed in TASCO1."

Trifluridine/tipiracil is approved as monotherapy for mCRC in third or later lines. Preclinical data showed that combining the agent with bevacizumab resulted in greater anti-tumor activity as compared with either drug alone, said André. Other laboratory evidence suggested bevacizumab increases trifluridine accumulation in tumor DNA.

The phase III confirmed trifluridine/tipiracil's clinical activity in treatment-refractory mCRC. A established the clinical activity of trifluridine/tipiracil plus bevacizumab in treatment-refractory mCRC, and TASCO1 provided preliminary evidence that the combination is superior to capecitabine-bevacizumab, although the confidence intervals for the hazard ratio included 1.00. OS, a secondary endpoint, was significantly improved with trifluridine/tipiracil (HR 0.78, 95% CI 0.32-0.98).

A majority of patients with mCRC are older than 65, including 30% who are 75 or older, André noted. Older patients are a heterogeneous population, ranging from the very fit to the very frail.

About 15%-20% of patients with mCRC are not suitable for intensive chemotherapy combinations. Reasons include advanced age, low tumor burden, poor performance status, and comorbidities, as well as patient choice. Current clinical guidelines recommend a fluoropyrimidine (such as capecitabine) with or without bevacizumab as first-line treatment for these patients.

Few clinical trials in mCRC have focused specifically on patients who are ineligible for intensive chemotherapy, André continued. SOLSTICE involved 856 patients with previously untreated mCRC and considered ineligible for intensive therapy for a variety of reasons. They were randomized to trifluridine/tipiracil-bevacizumab or capecitabine-bevacizumab and treated until disease progression or intolerable toxicity.

The primary endpoint was PFS by investigator assessment. PFS by central review was a prespecified sensitivity analysis.

The patient population had a median age of 73, and more than half the patients were 75 or older. About 45% of the patients had undergone surgery and about 25% had received neoadjuvant or adjuvant systemic therapy. The most common reason for ineligibility for intensive therapy was advanced age (42%), followed by patient preference (18%), performance status (14%), low tumor burden (12%), and comorbidities (11%).

The primary analysis showed a 13% reduction in the hazard ratio in favor of trifluridine/tipiracil, which did not reach statistical significance (95% CI 0.75-1.02). PFS by blinded central review yielded PFS values of 10.6 months for the trifluridine/tipiracil arm and 9.3 months for the capecitabine arm, representing a 15% reduction in the hazard ratio. The P value of 0.0265 was just short of the prespecified value of 0.021.

A prespecified subgroup analysis showed a modest to moderate advantage for trifluridine/tipiracil for most groups, particularly men, patients with neutrophil:lymphocyte ratio <5, and KRAS wild type tumors.

With regard to adverse event profiles, the notable differences were more neutropenia in the trifluridine/tipiracil arm and more hand-foot syndrome in the capecitabine arm.

Despite the lack of difference in the primary endpoint, trifluridine/tipiracil might be an attractive option for certain subgroups of older patients with mCRC, said Papamichael, emphasizing that older patients are not a homogenous patient population. Use of a geriatric screening instrument to evaluate older patients could inform clinical decision-making about treatment options for mCRC, he said.

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