A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study final results.

Abstract

LBA3513 Background: The combination of capecitabine plus long course radiotherapy (RT) is the standard preoperative therapy in cT3-4 cN+ rectal cancer. pathologic complete remission (pCR) can be considered as surrogate endpoint of efficacy of treatment in terms of disease-free survival (DFS). Preclinical data points heavily toward a strong synergy between RT and immune treatments. Methods: This is a prospective phase II, open label, single arm, multicentre study in patient with locally advanced rectal cancer who receive standard concomitant CT/RT therapy (825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks) followed by durvalumab (1500 mg Q4W for 3 administrations). Surgery is performed after 10-12 weeks from neoadjuvant therapy. The primary endpoint is the proportion of pCRs after at least 1 cycle of durvalumab; secondary endpoints are the proportion of clinical complete remissions (cCRs) after at least 1 cycle of durvalumab, the proportion of adverse and serious adverse events (NCI CTCAE v5.0). The sample size has been estimated by using the optimal Simon’s two-stage design assuming a null pCR proportion of 0.15 and an alternative pCR percentage of 0.30 (alpha = 0.05, power = 0.80). If more than 4 pCRs were observed in the first 19 enrolled patients, 36 additional patients were to be accrued for a total of 55 evaluable patients. The null hypothesis is rejected if ≥ 13 pCRs are observed in 55 patients. Results: Between November 2019 and August 2021, 60 patients were accrued, of which 55 were evaluable for study objectives. Fifty-two of 55 treated patients received all 3 infusions of durvalumab. After treatment, a clinical response percentage of 81.8% was observed; 3 patients had progression of disease due to local and/or metastases before surgical intervention. Eighteen patients achieved complete pathological response (32.7%), confirmed by central revision. Near complete regression, moderate and minimal regression were observed in 14 (25.5%), 9 (16.4%) and 11 (20.0%) patients respectively. Regarding toxicity, 23 patients (41.8%) had adverse events (AEs) related to durvalumab treatment. Two patients (1.8%) discontinued durvalumab for toxicity. Grade 3 AEs occurred in 4 (7.3%) patients (diarrhea, skin toxicity, transaminase increase, lipase increase and pancolitis). No Grade 4 toxicity was observed. In 20 patients (36.4%) G1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypo-thyroidism), dermatologic toxicity (skin rash) and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). Conclusions: This study met its primary endpoint showing a promising activity of neoadjuvant chemo-radiotherapy plus durvalumab in terms of pCR rate and a safe toxicity profile. Clinical trial information: NCT04083365.

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

“…All 13 protocols of the clinical studies considered radiotherapy always in conjunction with chemotherapy; 7 of 13 trials scheduled the immunotherapy after the induction of radiotherapy, [ 27 – 33 ] with four study protocols prescribing it concurrently, [ 34 – 37 ] one scheduling it before, [ 38 ] and one administering it either before or after SCRT. [ 39 ] Seven trials implemented PD-1 inhibitor therapy [ 27 , 28 , 35 – 39 ] and six used a PD-L1 agent, [ 29 – 34 ] with most (8/13) reporting results on MSS LARC. [ 27 , 28 , 32 – 34 , 36 , 37 , 39 ] In those, the pCR ranged from 22.2% to 66.6%, with most of the trials (5/8) using a PD-1 inhibitor.…”

“…A similar pCR was reported in the PANDORA trial (32.7%), albeit with capecitabine and LCRT. [ 29 ] In the PANDORA and R-IMMUNE trials, the comparison is less challenging; both studies have a similar number of patients (19 and 26, respectively) and prescribe PD-L1 inhibitors (durvalumab and atezolizumab, respectively); however, PANDORA reported higher pCR rates than R-IMMUNE (32.7% and 24%, respectively). [ 29 , 30 ] Neither of those trials reported on the microsatellite status of the patients.…”

“…[ 29 ] In the PANDORA and R-IMMUNE trials, the comparison is less challenging; both studies have a similar number of patients (19 and 26, respectively) and prescribe PD-L1 inhibitors (durvalumab and atezolizumab, respectively); however, PANDORA reported higher pCR rates than R-IMMUNE (32.7% and 24%, respectively). [ 29 , 30 ] Neither of those trials reported on the microsatellite status of the patients. With a similar setup but with a higher number of patients ( n = 45) and a specific focus on MSS disease, the NSABP FR-2 trial finds a similar pCR rate as R-IMMUNE (22.2% vs 24%) with the PD-L1 agent durvalumab.…”

“…Four trials have already published results in journal articles and are presented first in this review, [ 27 , 28 , 36 , 39 ] followed by the studies that showcased their results in the form of abstracts in international conferences. [ 29 – 35 , 37 , 38 ] A summary of the studies can be found in Table 1 .…”

“…The phase II PANDORA trial (NCT04083365) investigated the addition of a PD-L1 inhibitor, durvalumab, after CRT. [ 29 ] The patients received LCRT with 50.4 Gy for 5 days per week for 5 weeks with concurrent capecitabine (825 mg/m 2 orally twice daily) followed by durvalumab (1500 mg IV) 1 week post CRT every 4 weeks for three cycles. Surgery was performed 10–12 weeks post CRT induction.…”