First Results from the Phase I Dual Rectal Angiogenesis Mek Inhibition Radiotherapy (DreamTherapy) Trial in Locally Advanced Rectal Cancer

629 Background: We conducted a phase II study of preoperative chemoradiation (CRT) with S-1, a novel oral fluoropyrimidine, plus oxaliplatin in patients (pts) with locally advanced rectal cancer. Tumor ADCs were measured by DW-MRI and were evaluated as a predictive marker for pathologic responses. Methods: Radiotherapy was delivered to a total 50.4 Gy. The recommended doses were determined by a previous phase I study; oxaliplatin 50 mg/m2/week on D1, 8, 22 and 29, and S-1 80 mg/m2/day on D1-14 and D22-35. Total mesorectal excision was performed within 6 ± 2 weeks. Primary endpoint was pathologic complete response (pCR) rate. The value of tumor ADCs by DW-MRI was measured before and after CRT, and was correlated with pathologic responses after surgery. Results: A total of 38 patients were enrolled; 22 (57.9%) were men and the median age was 54 years (range, 28-67). Of 35 patients who underwent curative surgery, 28 patients underwent sphincter-saving operations. There was no grade 4 toxicity, and grade 3 toxicities included leukopenia (2.7%), neutropenia (2.7%), anorexia (2.7%), nausea (2.7%) and diarrhea (8.8%). The pCR rate was 25.7% (8/35, 95% CI [10.9-42.1]) and additional 10 patients (28.6%) showed near total regressions of tumor. Tumor ADCs by DW-MRI were calculated in 38 patients (including phase I part). The post-CRT ADC and the ADC changes (ΔADC) were significantly correlated with pCR rate (post-CRT ADC: 1.52±0.46 vs. 1.07±0.58, p=0.037, ΔADC: 44.5% vs. -7.6%, p=0.026). Conclusions: Preoperative CRT with S-1 plus oxaliplatin showed promising results in pathologic responses and favorable toxicities profiles. Tumor ADC by DW-MRI seems to be a useful method for predicting responses. No significant financial relationships to disclose.

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Voltage: Investigator-initiated clinical trial of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable locally advanced rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3606 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3606-3606 ◽

Cited By ~ 3

Author(s):

Takayuki Yoshino ◽

Hideaki Bando ◽

Yuichiro Tsukada ◽

Koji Inamori ◽

Satoshi Yuki ◽

...

Keyword(s):

Clinical Trial ◽

Rectal Cancer ◽

Phase I ◽

Phase Ii ◽

Tumor Regression ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Fisher Exact Test

3606 Background: Chemoradiotherapy (CRT) with surgery (S) is standard for patients (pts) with locally-advanced rectal cancer (LARC), and nivolumab (nivo) is active in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivo and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. Methods: Phase I included testing of a recommended phase II dosing schedule (RP2S). Efficacy and safety were studied in phase II pts and those given RP2S in phase I. In Cohort A-1, for microsatellite stable (MSS) LARC pts, the primary endpoint was centrally confirmed pathologic complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR = 10% and 30% was 37 pts, with a 1-sided alpha of 5% and power of 90%. Cohort A-2 was exploratory and included a maximum of 5 MSI-H pts. Results: Nivo 240 mg q2 weeks x 5 cycles, following CRT but pre-S, was the RP2S. From 1/17 to 6/18, 37 pts were enrolled in Cohort A-1. Eleven pts (30%; 90% CI 18-44%) showed pCR (AJCC grade (gr) 0). Including the 3 pts (8%) graded AJCC 1, 14 (38%) had major pathologic responses. In addition, clinical CR was observed in 1 pt (3%) refusing S after nivo. Both MSI-H LARC Cohort A-2 pts showed pCRs. Immune-related severe adverse events were observed in 2 pts (gr 3 myasthenia and gr 2 interstitial nephritis); both fully recovered and had S. No treatment-related deaths were observed. pCR rates of 60% (6/10) and 19% (5/27) (p = 0.038, Fisher exact test) were seen in pts with tumor cells with PD-L1 ≥1% and < 1% IHC staining, respectively, performed on biopsy samples taken pre-CRT. Rates of 62% (8/13) and 10% (1/10) (p = 0.029) were seen in 23 pts with samples analyzable by flow cytometry, according to CD8+ lymphocyte /regulatory T cell (CD8/Treg) ratios ≥2 and < 2, respectively. Conclusions: A promising pCR rate of 30%, with mild toxicity, was shown in MSS LARC pts treated with nivo plus radical S. PD-L1 expression and elevated CD8/Treg ratio may be better predictors of nivo benefit, warranting further study in a larger cohort. Clinical trial information: NCT02948348.

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