Phase II study of preoperative (PREOP) chemoradiotherapy (CTRT) plus avelumab (AVE) in patients (PTS) with locally advanced rectal cancer (LARC): The AVANA study.

Abstract

3511 Background: Preop CTRT is considered the standard of care in the management of LARC. RT can induce antigen release from a low neoantigen-burden tumor (such as a mismatch repair proficient colorectal cancer) and activate dendritic cells leading to a CD8+ T lymphocyte-mediated anticancer immune response. In LARC patients, neoadjuvant CTRT increases PD-L1 expression in tumor cells, strongly suggesting a neoadjuvant combinatory strategy with RT and PD-1/PD-L1 pathway blockade. Based on such considerations, we have designed the AVANA study to investigate the role of Ave in combination with preop CTRT in LARC. Methods: This is an Italian multi-center, phase II study. Pts with resectable LARC, defined by the presence of at least one of the following features: cN+, cT4, high risk cT3, received standard preop CTRT (capecitabine 825 mg/sqm/bid 5 days/week+ 50.4 Gy in 28 fractions over 5.5 weeks) plus 6 cycles of Ave 10 mg/Kg every 2 weeks. Surgery with total mesorectal excision was performed at 8-10 weeks after the end of CTRT. The primary end-point was the pCR rate, defined as complete histological regression with no available tumor cells ypT0N0. Secondary end-points were R0 resection rate, tumor downstaging, local recurrence, sphincter preservation rate, progression-free survival, overall survival, safety profile, and the evaluation of exploratory predictive and/or prognostic biomarkers. Assuming as null hypothesis p0 a pCR rate of 15%, a significance level of 5% (one-side), and a power of 80%, a sample size of 101 pts was needed to detect an absolute increment of 10% in pCR rate (from 15% to 25%). The experimental regimen is considered for further studies if, in at least 22 pts, we observe a pCR. Results: From April 2019 to November 2020, a total of 101 resectable LARC pts were enrolled in 10 Italian Centers. The median age was 63 years (23-82), 62 (61.4%) pts were male, 93 (92%) had ECOG PS 0. At baseline, 94 (93%) and 16 (16%) pts had cN+ and cT4 LARC, respectively. All pts completed the induction phase. Out of 96 pts evaluable for pathological response, 22 (23%) pts achieved a pCR and 59 (61.5%) pts a major pathological response (a central review is ongoing). At this time, microsatellite status is available only in 39 pts, of which only one was instable. The rate of grade 3-4 non-immune and immune-related adverse events was 8% and 4%, respectively. Avelumab was early interrupted in 9 pts out 101, mainly due to toxicity. Conclusions: The combination of preop CTRT plus Ave showed a promising activity and a feasible safety profile. According to our statistical considerations, the experimental regimen will be considered for further studies. Updated results will be presented during the Congress. Sponsored by GONO and partially supported by Merck. EUDRACT 2017-003582-10. Clinical trial information: NCT03854799.

Neoadjuvant Immunotherapy for MSI-H/dMMR Locally Advanced Colorectal Cancer: New Strategies and Unveiled Opportunities

“…The AVANA study is a multicenter phase II study that is examining the efficacy of nCRT combined with avelumab (anti-PD-L1 antibody) for treatment of LARC ( 44 ). The results suggest that nCRT can induce the antigen release of low neoantigen burden tumors (such as mismatched CRC) and activate dendritic cells, leading to a CD8+ T lymphocyte-mediated anticancer immune response.…”

The Evolving Landscape of Immunotherapy in Locally Advanced Rectal Cancer Patients

“…This evidence was followed by the randomized phase-2 PICC trial, where 34 dMMR/MSI-H cT3-T4 or N+ CRC patients were randomized 1:1 to receive 6 cycles of the anti-PD1 toripalimab ± the COX-2 inhibitor celecoxib, and 88% and 65% pCR were observed in the combination and mono-immunotherapy arms, respectively [ 20 ]. Post-hoc analyses of the phase-2 single arm VOLTAGE-A and AVANA trials, assessing the efficacy of the anti-PD1 nivolumab and avelumab plus neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC), showed a 60% and 50% pCR rate in the dMMR/MSI-H subgroup, respectively [ 10 , 11 ]. Nonetheless, these findings have been considered strictly preliminary, due to the limited number of dMMR/MSI-H patients enrolled in both studies (five in the VOLTAGE and two in the AVANA trials) [ 10 , 11 ].…”

“…Post-hoc analyses of the phase-2 single arm VOLTAGE-A and AVANA trials, assessing the efficacy of the anti-PD1 nivolumab and avelumab plus neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC), showed a 60% and 50% pCR rate in the dMMR/MSI-H subgroup, respectively [ 10 , 11 ]. Nonetheless, these findings have been considered strictly preliminary, due to the limited number of dMMR/MSI-H patients enrolled in both studies (five in the VOLTAGE and two in the AVANA trials) [ 10 , 11 ].…”

“…In the pMMR/MSI-L population of the AVANA trial ( n = 60), concomitant CRT and avelumab elicited major pathological responses (MPR) in 69% of patients (pCR: 8%) [ 10 ]. In the pMMR/MSI-L cohort of the VOLTAGE-A trial ( n = 37), CRT followed by nivolumab resulted in MPR in 38% of patients (pCR: 30%) [ 11 ].…”

“…These advances in immunotherapy in the metastatic setting were not matched with parallel progresses in the earlier stages, where surgery ± adjuvant chemotherapy or neoadjuvant (chemo)radiotherapy remain the mainstay approaches in localized rectal cancer, respectively [ 7 , 8 ]. However, in recent years some efforts have been made to incorporate ICIs in the multidimensional management of localized rectal cancer, with promising findings from ICI administration in pMMR/MSI-L patients and striking clinical responses and organ preservation rate in dMMR/MSI-H patients treated with the anti-PD1 dostarlimab [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Drawing from these considerations, we here discuss the major findings of immunotherapy in patients with localized rectal cancer.…”