REGINA Data Support Further Evaluation of Neoadjuvant Regorafenib, Nivolumab, and SCRT in Rectal Cancer


Key Takeaways

  • The combination of regorafenib, nivolumab, and SCRT showed early efficacy in stage II-III rectal cancer.
  • High toxicity rates led to a reduction in the regorafenib dose to improve safety.
 Francesco Sclafani, MD, PhD

Francesco Sclafani, MD, PhD

The neoadjuvant combination of regorafenib, nivolumab, and short-course radiotherapy (SCRT) demonstrated early activity in patients with stage II to III rectal cancer, meeting the predefined statistical criteria for the interim analysis of the phase 2 REGINA trial (NCT04503694), and thus warranting further exploration in this population.1

Data presented during the 2024 ESMO Gastrointestinal Cancers Congress indicated that of the 36 total patients who entered the study, 27 underwent surgery and 8 experienced a clinical complete response (cCR) and opted for the watch-and-wait approach. In the subset of patients with mismatch repair–proficient (pMMR)/microsatellite stable (MSS) disease who entered the study (n = 30), 24 patients underwent surgery and 5 achieved a cCR and opted to watch-and-wait.

“Promising rates of pathological CR and watch-and-wait adoption were observed regardless of the mismatch repair status,” Francesco Sclafani, MD, PhD, a consultant medical oncologist at the Institut Jules Bordet, Hôpital Universitaire de Bruxelles, in Brussels, Belgium, said in a late-breaking presentation of the data. “Given the unexpectedly high toxicity rate, in the second stage of the study, the regorafenib dose will be reduced to 60 mg per day to improve the treatment safety profile.”

Although there has been progress in the management of locally advanced rectal cancer, novel therapeutic approaches are still needed to improve patient outcomes, Sclafani said. The majority of rectal cancer cases are pMMR/MSS and are known to be resistant to checkpoint inhibitors, but existing data suggest that the combination of checkpoint inhibitors, multikinase inhibitors, and radiotherapy may be synergistic.

The multicenter, single-arm, phase 2 REGINA study enrolled patients aged 18 years and older with stage cT3/T4a and Nany or CT1-2 and N+ rectal cancer as documented by a baseline pelvic MRI.1,2 Patients were required to have an ECOG performance status of 0 to 1, and tumor with distal border below the peritoneal reflection and within 15 cm from the anal verge. They also needed to have acceptable hematological, renal, and hepatic function. Patients could have pMMR/MSS or mismatch repair­–deficient (dMMR)/microsatellite instability­–high (MSI-H) disease. After the first safety analysis, they needed to have CRM+ and lateral pelvic N+ disease only, Sclafani noted.

After a tumor biopsy was done, blood and stool samples were collected, and a DCE-CWI MRI was performed in week 1, they received induction treatment comprised of 2 infusions nivolumab at 240 mg every 14 days plus regorafenib at 80 mg daily for two weeks. SCRT was then administered at 25 Gy. For the consolidation phase, patients went on to receive 3 infusions of nivolumab plus regorafenib at the same doses for 3 weeks. Seven to 8 weeks after SCRT, patients went on to surgery or opted for the watch-and-wait approach. Patients then had the option to receive adjuvant chemotherapy. Tumor biopsies and DCE-DWI MRI were conducted at baseline, week 2, and post-treatment.

The primary end point of the study is CR, which was defined as pathological or clinical CR at 1 year.

The Simon 2-stage design was utilized for the study, with 36 patients in the first stage. If 5 or more CRs were achieved, the second stage of the study would include 24 patients. The null hypothesis, which was a true CR rate of 12%, was tested against a 1-sided alternative and rejected if there were 12 or more CRs (α = 5%, β = 20% for a true CR rate of ≥24). Two interim safety analyses were performed after 6 and 12 patients, respectively.

The median patient age was 64.5 years (range, 29-86), and 50% were male. Most patients had an ECOG performance status 0 (89%) and 22% had a distal tumor. Regarding disease stage, 92% had cT3 disease and 72% had cN1-2 disease. Twenty-five percent of patients threatening mesorectal fascia involvement and 17% had lateropelvic N+ disease. Just under half of patients (44%) had at least 1 RAPIDO high-risk feature, which included T4, N2, LPLN+, and CRM+ disease. Fourteen percent of patients had dMMR/MSI-H disease.

A total of 36 patients began induction therapy, and 83% completed it. The majority of patients (97%) completed SCRT. Ninety-four percent of patients started consolidation therapy and 61% completed it. Six percent of patients experienced a delay to SCRT of greater than 7 days due to toxicity, and 14% experienced a delay to surgery of greater than 14 days for the same reasons.

All patients experienced any-grade adverse effects (AEs) and all of them were related to treatment. Grade 3 or higher AEs were experienced by 61% of patients and 56% of the cases were related to treatment. More than half of patients (64%) experienced serious AEs, 53% of which were treatment related. Moreover, any-grade post-operative complications were experienced by 36% of patients and they were grade 3 or higher for 17% of patients.

The most common AEs included gastrointestinal disorders (any-grade, 92%; grade ≥3, 28%); general disorders and administration site conditions (69%; 14%); metabolism and nutrition disorders (58%; 17%); musculoskeletal and connective tissue disorders (58%; 11%); skin and subcutaneous tissue disorders (50%; 11%); renal and urinary disorders (39%; 6%); investigations (36%; 8%); respiratory, thoracic, and mediastinal disorders (31%; 3%); infections and infestations (28%; 8%); blood and lymphatic disorders (22%; 14%); nervous system disorders (22%; 0%); endocrine disorders (19%; 0%), and vascular disorders (17%; 11%).

Disclosures: Dr Sclafani disclosed serving in consultancy or advisory roles and receiving honoraria from AMAL Therapeutics, Amgen, Bayer, Bristol Myers Squibb, Dragonfly Therapeutics, GlaxoSmithKline, Merck, Nordic Pharma, Roche, and Servier; receiving institutional research funding from Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Merck, MSD, Pierre-Fabre, Roche, and Sanofi; and receiving travel grants from Amgen, Bayer, Lilly, Merck, Roche, and Servier. He also serves as the secretary of the EORTC Gastrointestinal Cancer Tract Group.


  1. Sclafani F, Bregni G, Assaf I, et al. LBA2 interim efficacy analysis of REGINA, a phase II trial of neoadjuvant regorafenib (rego), nivolumab (nivo), and short-course radiotherapy (SCRT) in stage II-III rectal cancer (RC). Ann Oncol. 2024;35(suppl 1):S212-S213. doi:10.1016/j.annonc.2024.06.006
  2. Neoadjuvant regorafenib in combination with nivolumab and short-course radiotherapy in stage II-III rectal cancer (REGINA). Updated June 4, 2024. Accessed July 3, 2024.
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