Regorafenib/TAS-102 Induces Clinically Meaningful DCR in Refractory Metastatic CRC

Markus H. Moehler, MD

Third-line treatment of patients with metastatic colorectal cancer (CRC) using regorafenib (Stivarga) plus oral fluoropyrimidine TAS-102 (trifluridine/tipiracil; Lonsurf) provides clinically meaningful disease control with toxicities consistent with the safety profiles of either agent, according to data from the phase I dose-escalation trial REMETY presented at the 2020 Gastrointestinal Cancers Symposium.¹

Of 12 patients treated at dose level 1 (n = 6) and dose level 2 (n = 6), 7 patients achieved stable disease after 8 weeks, with a disease control rate (DCR) of 58.3%, reported the investigative team led by Markus H. Moehler, MD, from the University Medical Center of the Johannes Gutenberg University Mainz, Germany, in a poster presentation at the symposium.

With >12 months of follow-up for all patients, the median overall survival had not been reached, as only 6 events occurred. The estimated median progression-free survival (PFS) based on the full analysis set of 12 patients was 3.81 months (95% CI, 1.51-5.29). The PFS rate at 6 months was 0.11 (95% CI, 0.0-0.3), and no PFS was observed at 12 months after initiation of TAS plus regorafenib.

Dose level 1 was comprised of TAS-102 at 25 mg/m² twice daily, and regorafenib at 120 mg/day. TAS-102 was given on days 1 to 5 and 8 to 12 of 28-day cycles, and regorafenib was given on days 2 to 22. At dose level 2, the dose of TAS was increased to 35 mg/m² twice daily, while the regorafenib dose remained at 120 mg/day.

One dose-limiting toxicity (DLT) was observed in 1 of the 6 patients dosed at level 1. At dose level 2, there were 2 DLTs among 2 of the 6 patients dosed at this level. All DLTs were grade-3 hypertension, with regorafenib determined to be the cause.

“The results indicate a recommended phase II dose of 25 mg/m² of TAS-102 twice daily and 120 mg of regorafenib daily,” the researchers commented in their poster.

At the recommended phase II dose, the DCR was 83.3% compared with 33.3% at dose level 1. No remissions were observed at either dose level. Historical data in patients with metastatic refractory CRC show a DCR of 41% with regorafenib alone² and 44% for TAS-102 alone,³ the investigators noted.

“So far, the risk-benefit assessment of the combination is positive, taking into consideration that hypertension is clinically manageable and no additional DLT was attributed to TAS-102,” the investigations concluded.

REMETY is a multicenter, open-label, nonrandomized, dose-escalation phase I study evaluating the safety and antitumor activity of TAS-102 administered in combination with regorafenib in patients with metastatic CRC. The primary objective of the trial was to determine the safety, feasibility, and the recommended phase II dose of the combination in patients with metastatic CRC who have progressed after standard therapy.

To be eligible for the trial, patients must have had metastatic disease not amenable to surgical resection with curative intent; measurable disease, defined as at least 1 unidimensional measurable lesion on a computed tomography scan as defined by RECIST 1.1; an ECOG performance status <2; and life expectancy of at least 3 months. Adequate bone marrow, renal, and hepatic function was required in order to participate.

Prior treatment lines must have encompassed at least 1 fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and, in the case of RAS-wildtype tumors, an anti-EGFR treatment. Patients treated with oxaliplatin in an adjuvant setting must have progressed during or within 6 months of completion of adjuvant therapy to be considered as a prior treatment line.

The time since the diagnosis of locally advanced or metastatic CRC was a median of 1.0 month (range, 0.0-7.0) and the time since resection was a median of 24.5 months (range, 3.0-74.0). TNM T stage was TX in 3 patients (25.0%), T3 in 5 patients (41.7%), and T4a in 4 (33.3%); TNM N stage was NX in 2 patients (16.7%), N0 in 3 (25.0%), N2 in 1 (8.3%), N2a in 2 (16.7%), and N2b in 4 (33.3%); and TNM M stage was M1a in 5 patients (41.6%) and M1b in 7 (58.3%). Histopathologic grade was G1 in 1 patient (8.3%), G2 in 7 (58.3%), and G3 in 4 (33.3%).

All observed toxicities were consistent with the safety profiles of the individual agents. A total of 152 adverse events (AEs) were observed, but only 5 were determined to be serious. The most common AEs were hypertension (n = 5), a decreased neutrophil count (n = 5), diarrhea (n = 4), fatigue (n = 4), and nausea (n = 4). No DLT resulted in treatment discontinuation.

The most common grade ≥3 toxicities were hypertension (n = 3; all grade 3), a decrease in neutrophil count (n = 3; 1 grade 4), a decrease in white blood cell count (n = 2; both grade 3); and ileus (n = 2; 2 grade 4).

References

1. Moehler MH, Stein A, Trojan J, et al. Regorafenib with TAS-102 (REGOTAS) in metastatic colorectal cancer patients who progressed after at least two standard therapies: efficacy and safety results of a multicenter phase I study (REMETY). J Clin Oncol. 2020;38(suppl 4; abstr 158). bit.ly/2uvdQUb.
2. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312. doi: 10.1016/S0140-6736(12)61900-X.
3. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-1919. doi: 10.1056/NEJMoa1414325.

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