TAS-102/Bevacizumab Prolongs OS, PFS in Patients With mCRC and Maintained ECOG PS of 0 or 1

Patients with metastatic colorectal cancer (mCRC) who maintained an ECOG performance status (PS) of 0 or 1 throughout third-line treatment with trifluridine/tipiracil (TAS-102; Lonsurf) plus bevacizumab (Avastin) experienced prolonged survival vs TAS-102 alone and may be eligible for further lines of therapy during their care continuum, according to findings from a post-hoc analysis of the phase 3 SUNLIGHT trial (NCT04737187) that were presented at the 2023 ASCO Annual Meeting.¹

Earlier data from the trial showed that the addition of bevacizumab to TAS-102 significantly extended overall survival (OS) vs TAS-102 alone, with a median OS of 10.8 months compared with 7.5 months, respectively (HR, 0.61; 95% CI, 0.49-0.77; P < .001).² Based on these findings, a supplemental new drug application seeking the approval of the combination in patients with refractory mCRC is now under priority review by the FDA.³ 

Data from the post-hoc analysis exploring the effects of third-line TAS-102 plus bevacizumab on ECOG PS in the SUNLIGHT population showed that of the 491 patients with a baseline ECOG PS of 0 or 1, those who received the bevacizumab combination had improved median time to ECOG PS worsening from 0 or 1 to 2 or greater vs those who received TAS-102 alone, at 9.3 months vs 6.3 months, respectively (HR 0.54; 95% CI, 0.43-0.67; P < .001).¹ In this analysis, median OS was prolonged in patients with maintained ECOG PS who received TAS-102 plus bevacizumab, at 10.58 months (95% CI, 9.03-11.24) vs 8.71 months (95% CI, 7.39-10.18) in those who received TAS-102 alone (HR, 0.78; 95% CI, 0.61-0.99).

Similarly, those who continued to have an ECOG performance status of 0 or 1 experienced improved progression-free survival (PFS) with TAS-102 plus bevacizumab vs TAS-102 alone, at 5.22 months (95% CI, 4.17-5.75) and 2.55 months (95% CI, 2.10-3.58), respectively (HR, 0.49; 95% CI, 0.40-0.61).

“This trial may completely change the landscape beyond second-line treatment for CRC,” study author Julien Taieb, MD, said in an interview with OncLive^®.

In the interview, Taieb, who is head of the Gastroenterology and Gastrointestinal Oncology Department at the Georges Pompidou European Hospital at Université de Paris in France, discussed the importance of combining fluoropyrimidines with bevacizumab, key findings from the SUNLIGHT trial and the post-hoc analysis, and how these results may shake up the CRC treatment paradigm.

OncLive: What is the mechanism of action of TAS-102, and what is the rationale for adding bevacizumab to this fixed-dose combination?

Taieb: TAS-102 is a new fluoropyrimidine that acts more on DNA than RNA in the process of distracting multiplying cells like cancer cells. It’s a new mode of action for fluoropyrimidines [that is] completely different from 5-fluorouracil, S-1, or capecitabine, which are generally used in CRC. There is a strong rationale to use fluoropyrimidines in this cancer because all the fluoropyrimidines that were used previously were effective. We also know from [what was observed with] the other fluoropyrimidines is that [these agents in] combination with bevacizumab improve patient outcomes, especially PFS and sometimes OS. Investigating the combination of this new fluoropyrimidine with bevacizumab was completely logical.

What patient population was observed in the SUNLIGHT trial?

SUNLIGHT has a purely third-line population. All patients received 2 previous lines of treatment. [Since this trial is] in the third-line setting, [it has] a strict recruitment process. Patients generally previously received [standard] fluorouracil, leucovorin, and oxaliplatin [FOLFOX] or leucovorin calcium, fluorouracil, and irinotecan hydrochloride [FOLFIRI] chemotherapy combinations, plus or minus bevacizumab already in the first and second lines for some patients. The addition of bevacizumab in the third-line setting to TAS-102 was compared with TAS-102 alone.

What key efficacy findings with TAS-102 and bevacizumab have previously been reported from SUNLIGHT?

OS was improved by the addition of bevacizumab to TAS-102 in the third-line setting. The improvement is clinically relevant, a 3-month improvement that was not expected in such heavily pretreated patients. We are [seeing] an OS of more than 10 months in this trial, which is good in this heavily pretreated population of patients with mCRC.

It was also important to see that PFS was also improved at 3 months. The time to degradation of ECOG PS, the time [for the] patients to become more tired with poor quality of life, was also [improved] by 3 months with the addition of bevacizumab. All the results are consistent and clinically convincing.

What was the rationale for the post-hoc analysis of ECOG PS in SUNLIGHT, and what were the key findings?

We wanted to see whether ECOG PS degradation occurred and in how many patients it occurred [in]. We also [wanted to determine] the ECOG PS of patients when they progressed. This is important because if a patient has a poor ECOG PS, they may not receive further lines of therapy.

In both arms of SUNLIGHT, even better in the arm with bevacizumab, the rate of patients with a good PS at the end of treatment was high, meaning most of these patients were eligible for 1 additional line of therapy with another compound after disease progression. This is reassuring. When you [administer] this line, you are not excluding the patient from receiving other compounds that were already on the market before the publication of SUNLIGHT.

Additionally, the patients [who maintained] their good PS [of] 0 or 1, were generally still in good PS at the end of the study, and they had a better OS improvement than that [observed] in the general population. In patients with a little PS degradation, the improvement with bevacizumab was also good. All patients seem to benefit from the combination of TAS-102 and bevacizumab, with minimal increases in adverse effects [AEs] from the treatment, which is also important for patients.

What should be known about the safety profile of TAS-102 plus bevacizumab?

TAS-102 has [a] low [rate of] clinical toxicities. The main toxicity is neutropenia, which can be a problem for continuing the treatment, but is not a real problem from the patient perspective, because they don’t feel that their white blood cell count is low. We can also use growth factors for these patients to try to counteract the AEs that can happen. Clinically, patients generally [fared] well with the drug.

Adding bevacizumab to [TAS-102] will add the AEs of bevacizumab, which is also a well-tolerated drug. The main AE [with bevacizumab] is hypertension because this is an antiangiogenic drug that can change patients’ blood pressure. In rare cases, patients can also have proteinuria and other classical AEs. However, in patients with mCRC, gastrointestinal [GI] oncologists are well trained with bevacizumab since 2004, and we know how to manage these kinds of AEs.

How might this combination influence the mCRC treatment paradigm in the future?

A few years ago, this beyond-second-line treatment felt like the last chance for patients. Now, we have a robust third-line standard with TAS-102 plus bevacizumab. [This combination can be used in] more than 90% of our patients because the only patients not eligible for [this regimen] are those with previous bevacizumab [intolerability] or those with bone marrow dysfunctions, which are rare.

[This combination also] moves other drugs to the fourth or fifth lines. Now, the third line [seems] as good as the first and second lines because we have a good OS of 10 months for these patients and a good treatment that is well tolerated and [may become] a new standard. Probably after [this trial with] TAS-102 and bevacizumab, the global survival of patients with CRC will be changed in forthcoming trials that we will see in 4 to 5 years from now.

What would be the significance of an FDA approval of this combination in patients with mCRC?

It is important that [this combination gets] approved because we are mixing 2 drugs that are already known to be effective in the disease. There is nothing fantastically new, but the synergy of these 2 drugs is good, and it may change practice around the world. In the United States, and in Europe and Asia, everyone is convinced by these results and will use this combination as a standard third-line treatment.

What main message would you like colleagues to know about this combination and the SUNLIGHT trial?

Now when we have a patient progressing on FOLFOX and FOLFIRI with targeted agents according to the molecular status of the disease, we can safely and with good expectation for efficacy [use] TAS-102 and bevacizumab. I recommend this and no other combination. Oral drugs will come…that may be used later. We will see depending on the approvals of these other drugs because some are new in the CRC landscape.

What other research efforts were you excited to learn more about at the 2023 ASCO Annual Meeting?

A fantastic presentation on rectal cancer, the long-term outcomes of the [phase 3] PRODIGE 23 trial [NCT01804790], was presented by Thierry Conroy, MD, [of the Institut de Cancérologie de Lorraine in France] and showed an improvement in OS and disease-free survival compared with the [phase 3] RAPIDO trial [NCT01558921] that did not induce any OS improvement. Also, the plenary session [presentation on the phase 2/3 PROSPECT trial (NCT01515787)], presented by Deborah Schrag, MD, MPH, [of Memorial Sloan Kettering Cancer Center in New York, New York], which was also published in the New England Journal of Medicine, [showed] that the landscape of rectal cancer will be quite different for patients with nonmetastatic disease in the future.

Disclosures: Dr Taieb reports consulting or advisory roles with Amgen, AstraZeneca, BMS, Merck KGaA, MSD, Novartis, Pierre Fabre, Roche, and SERVIER; and speaker’s bureau roles with Amgen, Merck, MSD, Pierre Fabre, and SERVIER.

References

1. Taieb J, Prager GW, Fakih M, et al. Effects of trifluridine/tipiracil in combination with bevacizumab on ECOG-PS in refractory metastatic colorectal cancer: an analysis of the phase 3 SUNLIGHT trial. J Clin Oncol. 2023;41(16):suppl.3594. doi:10.1200/JCO.2023.41.16_suppl.3594
2. Tabernero J, Prager GW, Fakih M, et al. Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: the phase 3 randomized SUNLIGHT study. J Clin Oncol. 2023;41(4):suppl.4. doi:10.1200/JCO.2023.41.4_suppl.4
3. US Food and Drug Administration accepts for priority review Taiho Oncology’s supplemental new drug application for the use of trifluridine/tipiracil (Lonsurf) in combination with bevacizumab for refractory metastatic colorectal cancer (mCRC). News release. Taiho Oncology, Inc. April 18, 2023. Accessed July 5, 2023. https://www.taihooncology.com/us/news/2023-04-18_toi_snda_acceptance_lonsurf_combo/