In the Journals

TAS-102, bevacizumab promising for refractory colorectal cancer

Trifluridine and tipiracil in combination with bevacizumab appeared safe and effective for the treatment of patients with metastatic colorectal cancer in the refractory setting, according to results from the C-TASK FORCE study published in The Lancet Oncology.

The researchers noted the oral nucleoside antitumor combination of trifluridine and tipiracil (Lonsurf, Taiho Oncology) — also called TAS-102 — plus bevacizumab (Avastin, Genentech) warrants further investigation.

“Combination chemotherapy regimens with cytotoxic drugs and molecularly targeted agents were known to have increased the survival time of patients with metastatic colorectal cancer compared with standard-of-care treatment,” Takayuki Yoshino, MD, medical oncologist at the National Cancer Center Hospital East in Japan, and colleagues wrote. “... However, effective treatments are limited for patients refractory or intolerant to all available anticancer agents anticancer agents, including cytotoxic drugs, and molecularly targeted agents, including TAS-102 monotherapy.”

Preclinical studies designed to evaluate TAS-102 in combination with bevacizumab demonstrated enhanced activity against colorectal cancer xenografts compared with either agent alone. However, the combination regimen’s activity in the second-line setting is unknown.

Yoshino and colleagues conducted the investigator-initiated, open-label, single-arm, multicenter, phase 1/phase 2 trial to assess the efficacy and safety of TAS-102 plus bevacizumab to treat 25 patients with metastatic colorectal cancer. Patients were refractory or intolerant to standard therapies except for regorafenib (Stivarga, Bayer).

The researchers used a dose escalation design in phase 1 (n = 6) to determine the recommended dosing for phase 2 (n = 19). Patients who received TAS-102 at level 1 experienced no dose-limiting toxicities and this was deemed the recommended dose for phase 2.

Patients received 35 mg/m² oral TAS-102 twice daily on days 1 through 5 and 8 through 12 in a 28-day cycle, plus 5 mg/kg IV bevacizumab for 30 min every 2 weeks.

Centrally assessed PFS at 16 weeks served as the primary endpoint. Secondary endpoints included investigator-assessed PFS at 16 weeks, centrally assessed PFS at 8 and 24 weeks, time to treatment failure, OS and adverse events in all enrolled patients. Primary analysis included data from the first 21 patients enrolled and treated with the recommended dose.

Median follow-up was 11.4 months.

In the primary analysis, 42.9% (80% CI, 27.8-59) of patients achieved 16-week PFS. Nine patients did not have a centrally assessed progression event.

The rate of 16-week PFS among all patients enrolled was 60% (95% CI, 39-79).

Centrally assessed PFS was 64% (95% CI, 43-82) at 8 weeks and 24% (95% CI, 9-45) at 24 weeks.

Median PFS was 3.7 months (95% CI, 2-5.4) by central assessment and 5.6 months (95% CI, 3.4-7.6) by investigator assessment. Researchers reported median OS of 11.4 months (95% CI, 7.6-13.9) and median time to treatment failure of 5.6 months (95% CI, 3.4-7.6).

The most common grade 3 or worse adverse events included neutropenia (72%), leucopenia (44%), anemia (16%), febrile neutropenia (16%) and thrombocytopenia (12%).

No patients discontinued treatment due to drug-related toxicity, and no treatment-related deaths occurred.

In addition, the researchers investigated the frequency of common mutations, and found RAS, TP53, APC and PIK3CA were not associated with PFS or OS following treatment.

“However, considering the existing treatment strategy for metastatic colorectal cancer, a preferred regimen in the first-line setting differs among wild-type RAS/BRAF, mutant RAS and mutant BRAF tumors in the latest guidelines,” Yoshino and colleagues wrote. “Hence, we believe survival outcomes such as PFS or OS according to RAS/BRAF mutational status could become important for further investigation.”

The researchers acknowledged the study was limited by its nonrandomized design and small sample size

Phase 2 studies are ongoing or planned to evaluate the combination as maintenance therapy postinduction chemotherapy, or compared with capecitabine and bevacizumab as first-line therapy in patients who are ineligible for intensive therapy.

An additional limitation to this study included its inclusion criteria, which excluded patients previously treated with regorafenib, Fotios Loupakis, MD, PhD, and Sara Lonardi, MD, from the department of clinical and experimental oncology at the Istituto Oncologico Veneto-IRCCS in Italy, wrote in an accompanying editorial.

“Is that, nowadays, the real clinical situation for most patients?” they wrote. “So far, data are scarce and the choice of the optimal sequencing of TAS-102 and regorafenib is left to the treating physician.”

Loupakis and Lonardi also noted a similar limitation with regard to previous bevacizumab exposure.

“Currently, many patients are given bevacizumab after progression and the small sample of the C-TASK FORCE could not give many answers to these detailed questions,” they wrote. “Notwithstanding, the positive results pave the way for further research and the refractory setting will not be the end of the line for the clinical development of this interesting combination.” – by Kristie L. Kahl

Disclosures: Taiho Pharmaceutical funded the study. Yoshino reports grants from Boehringer Ingelheim and GlaxoSmithKline. Please see the full study for a list of all other researchers’ relevant financial disclosures. Loupakis and Lonardi report no relevant financial disclosures.

Trifluridine and tipiracil in combination with bevacizumab appeared safe and effective for the treatment of patients with metastatic colorectal cancer in the refractory setting, according to results from the C-TASK FORCE study published in The Lancet Oncology.

The researchers noted the oral nucleoside antitumor combination of trifluridine and tipiracil (Lonsurf, Taiho Oncology) — also called TAS-102 — plus bevacizumab (Avastin, Genentech) warrants further investigation.

“Combination chemotherapy regimens with cytotoxic drugs and molecularly targeted agents were known to have increased the survival time of patients with metastatic colorectal cancer compared with standard-of-care treatment,” Takayuki Yoshino, MD, medical oncologist at the National Cancer Center Hospital East in Japan, and colleagues wrote. “... However, effective treatments are limited for patients refractory or intolerant to all available anticancer agents anticancer agents, including cytotoxic drugs, and molecularly targeted agents, including TAS-102 monotherapy.”

Preclinical studies designed to evaluate TAS-102 in combination with bevacizumab demonstrated enhanced activity against colorectal cancer xenografts compared with either agent alone. However, the combination regimen’s activity in the second-line setting is unknown.

Yoshino and colleagues conducted the investigator-initiated, open-label, single-arm, multicenter, phase 1/phase 2 trial to assess the efficacy and safety of TAS-102 plus bevacizumab to treat 25 patients with metastatic colorectal cancer. Patients were refractory or intolerant to standard therapies except for regorafenib (Stivarga, Bayer).

The researchers used a dose escalation design in phase 1 (n = 6) to determine the recommended dosing for phase 2 (n = 19). Patients who received TAS-102 at level 1 experienced no dose-limiting toxicities and this was deemed the recommended dose for phase 2.

Patients received 35 mg/m² oral TAS-102 twice daily on days 1 through 5 and 8 through 12 in a 28-day cycle, plus 5 mg/kg IV bevacizumab for 30 min every 2 weeks.

Centrally assessed PFS at 16 weeks served as the primary endpoint. Secondary endpoints included investigator-assessed PFS at 16 weeks, centrally assessed PFS at 8 and 24 weeks, time to treatment failure, OS and adverse events in all enrolled patients. Primary analysis included data from the first 21 patients enrolled and treated with the recommended dose.

Median follow-up was 11.4 months.

In the primary analysis, 42.9% (80% CI, 27.8-59) of patients achieved 16-week PFS. Nine patients did not have a centrally assessed progression event.

The rate of 16-week PFS among all patients enrolled was 60% (95% CI, 39-79).

Centrally assessed PFS was 64% (95% CI, 43-82) at 8 weeks and 24% (95% CI, 9-45) at 24 weeks.

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Median PFS was 3.7 months (95% CI, 2-5.4) by central assessment and 5.6 months (95% CI, 3.4-7.6) by investigator assessment. Researchers reported median OS of 11.4 months (95% CI, 7.6-13.9) and median time to treatment failure of 5.6 months (95% CI, 3.4-7.6).

The most common grade 3 or worse adverse events included neutropenia (72%), leucopenia (44%), anemia (16%), febrile neutropenia (16%) and thrombocytopenia (12%).

No patients discontinued treatment due to drug-related toxicity, and no treatment-related deaths occurred.

In addition, the researchers investigated the frequency of common mutations, and found RAS, TP53, APC and PIK3CA were not associated with PFS or OS following treatment.

“However, considering the existing treatment strategy for metastatic colorectal cancer, a preferred regimen in the first-line setting differs among wild-type RAS/BRAF, mutant RAS and mutant BRAF tumors in the latest guidelines,” Yoshino and colleagues wrote. “Hence, we believe survival outcomes such as PFS or OS according to RAS/BRAF mutational status could become important for further investigation.”

The researchers acknowledged the study was limited by its nonrandomized design and small sample size

Phase 2 studies are ongoing or planned to evaluate the combination as maintenance therapy postinduction chemotherapy, or compared with capecitabine and bevacizumab as first-line therapy in patients who are ineligible for intensive therapy.

An additional limitation to this study included its inclusion criteria, which excluded patients previously treated with regorafenib, Fotios Loupakis, MD, PhD, and Sara Lonardi, MD, from the department of clinical and experimental oncology at the Istituto Oncologico Veneto-IRCCS in Italy, wrote in an accompanying editorial.

“Is that, nowadays, the real clinical situation for most patients?” they wrote. “So far, data are scarce and the choice of the optimal sequencing of TAS-102 and regorafenib is left to the treating physician.”

Loupakis and Lonardi also noted a similar limitation with regard to previous bevacizumab exposure.

“Currently, many patients are given bevacizumab after progression and the small sample of the C-TASK FORCE could not give many answers to these detailed questions,” they wrote. “Notwithstanding, the positive results pave the way for further research and the refractory setting will not be the end of the line for the clinical development of this interesting combination.” – by Kristie L. Kahl

Disclosures: Taiho Pharmaceutical funded the study. Yoshino reports grants from Boehringer Ingelheim and GlaxoSmithKline. Please see the full study for a list of all other researchers’ relevant financial disclosures. Loupakis and Lonardi report no relevant financial disclosures.