LBA2 - Interim 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)

Background

Effective strategies to tackle the immune resistance of pMMR/MSS tumors are lacking. Studies suggest a synergistic effect between immune checkpoint inhibitors, multi-kinase inhibitors and radiotherapy. We report the interim efficacy analysis of REGINA, a multicenter, single-arm, phase II trial of neoadjuvant Rego, Nivo, and SCRT for patients (pts) with stage II-III rectal adenocarcinoma (NCT04503694).

Methods

Treatment included an induction phase with 2 infusions of Nivo 240 mg IV q14 and Rego 80 mg/day PO for 2 weeks (W), followed by SCRT (25 Gy), and a consolidation phase with 3 infusions of Nivo 240 mg IV q14 and Rego 80 mg/day PO for 3W. Surgery was carried out 7-8W after SCRT (watch & wait [w&w] allowed). Adjuvant chemotherapy was optional. Rectal biopsies and DCE-DWI MRI were done at baseline, W2 and after treatment. Blood/stool samples were collected. The primary endpoint was complete response (CR) (pathological [p] or clinical [c] CR at 1 year). The Simon 2-stage design was used (1^st stage n=36; if ≥5 CR, 2^nd stage n=24). The null hypothesis (true CR rate of 12%, based on the Stockholm III trial) was tested against a 1-sided alternative and rejected if ≥12 CR (α=5%, β=20% for a true CR rate of ≥24%).

Results

36 pts were recruited at 9 Belgian centers. Baseline characteristics: males (50%), median age 64.5 yrs, ECOG PS 0 (89%), low rectum (22%), pMMR/MSS (83%), cT3 (92%), cN+ (72%), MRF+ (25%), latero-pelvic N+ (17%). Treatment completion: induction (83%), SCRT (97%), consolidation (61%). Overall and treatment-related grade ≥3 adverse events occurred in 61% and 56% of pts, respectively. Surgery was done in 27 pts (1 withdrew prior to surgery). 8 (30%) had pCR, and 16 (59%) major pathological response (mPR, Dworak TRG ≥3). A further 8 pts opted for w&w due to cCR. Among the 24 pts with resected pMMR/MSS tumors, 6 (25%) had pCR, 2 (8%) ypTisN0, and 14 (58%) mPR. A further 5 pts opted for w&w due to cCR.

Conclusions

The predefined statistical criteria were met, supporting further investigation of the combination of Rego, Nivo and SCRT as neoadjuvant therapy for locally advanced RC. In the 2^nd stage of the study, the Rego dose will be reduced to 60 mg/day to improve safety.

Clinical trial identification

NCT04503694; First posted August 7, 2020.

Legal entity responsible for the study

Institut Jules Bordet.

Funding

Bayer.

Disclosure

F. Sclafani: Financial Interests, Personal, Advisory Board: AMAL Therapeutics, Bayer, BMS, Dragonfly Therapeutics, GSK, Nordic Pharma, Roche; Financial Interests, Personal, Invited Speaker: Amgen, Merck, Servier; Financial Interests, Institutional, Research Grant: Amgen, Astellas, AstraZeneca, Bayer, BMS, Merck, MSD, Pierre Fabre, Roche, Sanofi; Non-Financial Interests, Leadership Role, Secretary: EORTC Gastrointestinal Tract Cancer Group; Other, Travel grants: Amgen, Bayer, Lilly, Merck, Roche, Servier. H. Prenen: Financial Interests, Institutional, Advisory Board: Amgen, Roche, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Bayer, Ipsen, Sanofi. K. Geboes: Financial Interests, Institutional, Advisory Board: BMS, MSD, Ipsen, Servier. All other authors have declared no conflicts of interest.