Neoadjuvant regorafenib, nivolumab, SCRT combination looks good for rectal cancer

Treatment with the combination of regorafenib, nivolumab, and short-course radiotherapy (SCRT) in the neoadjuvant setting has induced response in stage II-III rectal adenocarcinoma in the phase II REGINA trial, meeting the predefined statistical criteria.

Interim data showed that of the 36 adult patients (median age was 64.5 years, 50 percent male) who received the neoadjuvant treatment combination, 27 underwent surgery, after which eight achieved pathologic complete response (CR) and 16 (59 percent) had major pathologic response (mPR). One patient withdrew from the trial prior to surgery and was excluded. The remaining eight patients achieved clinical CR and opted for watch-and-wait surveillance. [ESMO GI 2024, abstract LBA2]

Results were similar in the subset of 30 patients with mismatch repair–proficient (pMMR)/microsatellite stable (MSS) disease. Twenty-four patients underwent surgery, of which six achieved pathologic CR and 14 had mPR. One patient withdrew from the trial and was excluded, and the remaining five had clinical CR and opted for watch-and-wait surveillance.

“Promising rates of pathologic CR and watch-and-wait [surveillance] adoption were observed regardless of the mismatch repair status,” said lead study author Dr Francesco Sclafani from the Institut Jules Bordet, Hôpital Universitaire de Bruxelles, in Brussels, Belgium.

The neoadjuvant treatment administered to patients included an induction phase with two infusions of nivolumab 240 mg every 14 days and oral regorafenib 80 mg daily for 2 weeks, followed by SCRT at 25 Gy. After this, there was a consolidation phase with three infusions of nivolumab 240 mg every 14 days plus oral regorafenib 80 mg daily for 3 weeks. Surgery was carried out at a median of 8.6 weeks after SCRT. Adjuvant chemotherapy was optional.

High toxicity rates

Safety data showed that any-grade adverse events (AEs) occurred in all patients, and all these AEs were deemed related to treatment. Grade 3 or higher AEs were documented in 61 percent of patients, with the events being treatment-related for 56 percent. Serious AEs occurred in 64 percent, including those that were related to treatment for 53 percent. Additionally, any-grade postoperative complications were documented in 36 percent of patients, with the complications being grade 3 or higher for 17 percent.

Gastrointestinal disorders were the most frequent AEs (any-grade: 92 percent; grade ≥3: 28 percent), followed by general disorders and administration site conditions (any-grade: 69 percent; grade ≥3: 14 percent), metabolism and nutrition disorders (any-grade: 58 percent; grade ≥3: 17 percent); musculoskeletal and connective tissue disorders (any-grade: 58 percent; grade ≥3: 11 percent); skin and subcutaneous tissue disorders (any-grade: 50 percent; grade ≥3: 11 percent); and renal and urinary disorders (any-grade: 39 percent; grade ≥3: 6 percent), among others.

“Given the unexpectedly high toxicity rate, in the second stage of the study, the regorafenib dose will be reduced to 60 mg/day to improve the treatment safety profile,” Sclafani said.

In REGINA, 92 percent of patients had cT3 disease and 72 percent had cN1-2 disease; 14 percent had dMMR/MSI-H disease. Most had an ECOG performance status 0 (89 percent), and 22 percent had a distal tumour. Threatening mesorectal fascia involvement was identified in 25 percent of patients and lateropelvic N+ disease in 17 percent. There were 44 percent who had at least 1 RAPIDO high-risk feature, which included T4, N2, LPLN+, and CRM+ disease.

The majority of patients (83 percent) completed induction therapy, 97 percent completed SCRT, and 61 percent completed consolidation therapy. A delay to SCRT of greater than 7 days occurred in 6 percent of patients due to toxicity, while a delay to surgery of greater than 14 days occurred in 14 percent for the same reason.

“Despite the recent advances in the management of locally advanced rectal cancer, novel treatment strategies are needed to improve oncological outcomes,” Sclafani noted, adding that the findings from REGINA support further investigation of the combination of regorafenib, nivolumab, and SCRT as neoadjuvant therapy for locally advanced rectal cancer.