Published October 7, 2022 | Version 1 as of Oct 7,2022
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Regorafenib monotherapy as second-line treatment of patients with RAS-mutant advanced colorectal cancer (STREAM): an academic, multicenter, single-arm, two-stage, phase 2 study

Creators

  • 1. Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori- IRCCS-Fondazione G. Pascale, Napoli (ITALY)
  • 2. Medical Oncology Unit, S. Carlo Hospital, Potenza, Italy
  • 3. Experimental Pharmacology Unit, Istituto Nazionale Tumori- IRCCS-Fondazione G. Pascale, Napoli, Italy
  • 4. Pathology Unit, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Napoli, Italy
  • 5. Nuclear Medicine Unit, Istituto Nazionale Tumori- IRCCS-Fondazione G. Pascale, Napoli, Italy
  • 6. Radiology Unit, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Napoli, Italy
  • 7. Clinical Trial Unit, Istituto Nazionale Tumori- IRCCS-Fondazione G. Pascale, Napoli, Italy
  • 8. Hospital sacro cuore di Gesu, Fatebenefratelli, Benevento, Italy
  • 9. Medical Oncology, Precision Medicine department, University of Campania Luigi Vanvitelli, Naples, Italy
  • 10. Colorectal Oncological Surgery, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Napoli, Italy

Description

Background

Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with RAS mutant metastatic colorectal cancer (mCRC).

Regorafenib, an oral multikinase inhibitor, prolonged overall survival (OS) in chemorefractory setting.

Methods

STREAM was an academic, multicenter, single-arm phase 2 trial, evaluating the activity of regorafenib in RAS mutant mCRC, in terms of the rate of patients who were progression-free after 6months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin and bevacizumab. According to Simon’s two-stage design, ≥ 18 patients 6mo-PF were needed in the overall population (N=46). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS) and OS. Early metabolic response by [18F]-FDG PET/CT scan was an exploratory endpoint. EudraCT Number:2015-001105-13

Results

The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. ORR was 10.9%, Disease Control Rate 54.6%, median (m)PFS 3.6 months (mo) (95%CI 1.9-6.7), mOS 18.9 mo (95%CI 10.3-35.3), mPFS2 (from study entry to subsequent-line progression) was 13.3mo (95%CI=8.4-19.7). Long responders patients (>6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade≥3 events occurred in 39.1% patients, mostly hand-foot syndrome (13%), fatigue and hyperbilirubinemia (6.5%). Baseline metabolic assessment was associated with OS in multivariate analysis, while early metabolic response was not associated with clinical outcomes. 

Conclusion

The study did not meet its primary endpoint. However, regorafenib was well tolerated and did not preclude subsequent treatments. Patients with good prognostic features (single metastatic site and  lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline [18F]-FDG PET/CT might be useful to select patients with favorable outcome.

A chemotherapy-free interval with regorafenib might be worth of further studies as second-line treatment in selected patients with RAS mutant mCRC.

 

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