Phase II study of durvalumab following neoadjuvant chemoRT in operable rectal cancer: NSABP FR-2.

Abstract

99 Background: Although immunotherapy shows no benefit in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitor use. Using a “window-of-opportunity” study design, this prospective phase II trial will determine the safety and activity of this approach with the anti-PD-L1 agent durvalumab (MEDI4736). Methods: Stage II/III patients (pts) with MSS rectal cancer undergoing standard NCCN guideline-compliant neoadjuvant chemoradiotherapy (CRT) followed by definitive surgery were eligible. Treatment included durvalumab (750mg IV infusion once every 2 wks) for 4 total doses beginning within 3-7 days after CRT completion followed by surgery within 8-12 wks of the final CRT dose. Primary end point (EP): Improvement in modified neoadjuvant rectal cancer (mNAR) score (goal 10.6) compared to historical controls (15.6) targeting a 20% DFS RR reduction and 3-4% absolute OS improvement. Secondary EPs: toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, and exploratory assessments of tumor-infiltrating lymphocytes, tumor Immunoscore, circulating immunologic profiles, and molecular predictors of response. We test H0: mNAR ≥15.6 vs HA: mNAR <15.6 at alpha 0.10 one-sided with statistical significance defined as p<0.1. Results: From May 2018 to October 2020, 45 pts were enrolled with 40 pts evaluable for mNAR. Mean mNAR was 12.03 (80% CI: 9.29-14.97) (p=0.06 one-sided). pCR=22.2%; cCR=31.1%; R0 resection=81.0%, and sphincter preservation=71.4%. Side effects were consistent with both CRT and durvalumab safety profile. Most common grade 3 AEs included diarrhea, lymphopenia, and back pain. There was one grade 4 AE (elevated amylase/lipase) and no grade 5 AEs. Remaining secondary and correlative immunologic end points are still being assessed. Conclusions: Durvalumab immediately following CRT prior to surgery for definitive management of rectal cancer was safe and without unexpected short-term toxicities. The primary end point of mean mNAR score was significantly less than our historical control, warranting further investigation. Correlative analyses for immunologic markers of response including PD-(L)1 expression and Immunoscore are ongoing. NCT 03102047. Support: AstraZeneca-Medimmune, NSABP Foundation. Clinical trial information: NCT03102047.

Immunotherapies in non-metastatic gastrointestinal cancers

“…Available data show five pCR among 18 operated patients (28%) [62]. The phase II NSABP FR-2 reports that 40 evaluable patients similarly treated improved their mean mNAR score [63]. No unexpected toxicities were reported in these two trials.…”

Neoadjuvant immunotherapy for colorectal cancer: Right regimens, right patients, right directions?

“…However, the improved pCR rate of this clinical trial does not seem to exceed that of the TIMING trial, where the pCR rate increased to 38% in the MSS status subgroup ( 26 ). Then, NSABP FR-2 (NCT03102047) study added a NAICI treatment regimen with durvalumab between NACRT and surgery, and the outcomes of this clinical trial obtained a pCR of 22.2% and a cCR of 31.1% in MSS rectal cancer patients ( 84 ). BFH-NCRTPD (NCT04911517) reached a similar CR rate of 58.3% with a small sample.…”

“…Locally advanced CRC (LACRC) invading adjacent tissues and/or regional lymph nodes occur in 36% of initially diagnosed patients, and distant metastatic diseases occur in 22%. According to the statistics reported by the National Cancer Institute (USA), the 5-year overall survival (OS) rates for colon and rectal cancers are 64% and 67%, respectively (2).…”

A Review of Scheduling Strategies for Radiotherapy and Immune Checkpoint Inhibition in Locally Advanced Rectal Cancer

“…Most trials ( n = 7) scheduled ICB after radiotherapy. [ 27 – 33 ] Four prescribed immunotherapy during the radiation treatment, [ 34 – 37 ] one prescribed it before, [ 38 ] and one included two arms that would incorporate it either before or after radiotherapy. [ 39 ] The sections below aim to offer an overview of the studies that have yielded results on the effects of combination ICB and radiotherapy in RC.…”