Eric Deutsch, MD, PhD, Professor and Chair of Radiation Oncology at Gustave Roussy, Villejuif, France, commended the speakers for conducting trials whose results he found “very interesting.”
The Averectal trial involved a short course of radiation with modified FOLFOX-6 (oxaliplatin, fluorouracil [5-FU], leucovorin) and avelumab given preoperatively, followed by surgery 3 to 4 weeks later.1 The pathologic complete response rate was 37.5%, with 67.5% achieving a major pathologic response. Response seemed to correlate with the Immunoscore, which is based on CD3+ and CD8+ density in the tumor; however, other studies have also found the Immunoscore to predict response to conventional chemoradiation therapy. “This suggests that profiles of sensitivity to avelumab plus FOLFOX after a short course of radiation may not differ from profiles of tumors responding to chemoradiation alone,” said Dr. Deutsch.
Eric Deutsch, MD, PhD
The AVANA trial involved conventional chemoradiation plus avelumab followed by surgery 8 to 10 weeks later.2 Its pathologic complete response rate was 23%, with 60% of patients achieving a major pathologic response. “Interestingly,” Dr. Deutsch noted, response did not appear to be linked to microsatellite instability status.
Comparing Outcomes With Other Trials
It is important to compare those outcomes with what has been achieved without PD-1/PD-L1 inhibitors in recent total neoadjuvant therapy trials, Dr. Deutsch said. For instance, RAPIDO involved a short course of radiation therapy followed by an oxaliplatin-based regimen, then surgery; 28.4% of patients had a complete pathologic response.3 In PRODIGE 23, modified FOLFIRINOX (5-FU, leucovorin, irinotecan, oxaliplatin) was given before chemoradiotherapy with long-course radiation, followed by surgery and 3 months of adjuvant chemotherapy; 27.8% of patients achieved a complete pathologic response.4
“Therefore, what we see here with avelumab, at least with low-dose radiotherapy, is that the complete pathologic response rate is not that different,” he commented.
Furthermore, in a study by Sauer et al, for patients who underwent upfront surgery without prior treatment, 18% of patients who had clinical stage T3 and/or N+ disease were ultimately classified as having T1–2 N0 tumors.5 This suggests that in a nonrandomized study, major pathologic response rates may be overestimated, “and it’s important to take this into account,” maintained Dr. Deutsch.
‘An Exit to the Death Valley of New Drugs Plus Radiotherapy’
“At a glance, these two trials are novel and very interesting, addressing an important question: Can we really improve outcomes of preoperative chemoradiation in rectal cancer using a PD-1/PD-L1 inhibitor? The major question is whether there is an effect also on distant disease and survival…. We don’t know whether, at the end of the day, we impact only pathologic complete response and local control or also survival, and it’s too early to say,” Dr. Deutsch said. “This has to be evaluated furtherer in a randomized trial, taking into account progression-free survival and overall survival as endpoints.”
“What’s really striking to me at this stage,” he concluded, “is that, in rectal cancer, we probably have found an ‘exit to the death valley of new drugs plus radiotherapy.’ So far, [conventional] drugs have either led to toxicity and surgical complications or have lacked efficacy. Here, we have promising compounds for which there’s a trend toward increasing pathologic complete responses, at least with short-course radiotherapy, with no toxicity observed or negative impact on surgery.”
DISCLOSURE: Dr. Deutsch has received honoraria from AstraZeneca/MedImmune, Boehringer Ingelheim, and Roche/Genentech; has served as a consultant or advisor to Merck Serono; has served as an institutional consultant or advisor to AstraZeneca/MedImmune; has received institutional research funding from AstraZeneca/MedImmune, Boehringer Ingelheim, and Roche; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca/MedImmune.
1. Shamseddine A, Zeidan YH, Bouferraa Y, et al: Oncodistinct study #5: Efficacy and safety of neoadjuvant short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma: Averectal study. ESMO World Gastrointestinal Cancer Congress 2021. Abstract SO-30. Presented July 1, 2021.
2. Salvatore L, Bensi M, Corallo S, et al: Phase II study of preoperative chemoradiotherapy plus avelumab in patients with locally advanced rectal cancer: The AVANA Study. ESMO World Gastrointestinal Cancer Congress 2021. Abstract O-12. Presented July 1, 2021.
3. Hospers G, Bahadoer RR, Dijkstra EA, et al: Short-course radiotherapy followed by chemotherapy before total mesorectal excision in locally advanced rectal cancer, the randomized RAPIDO trial. ASCO20 Virtual Scientific Program. Abstract 4006. Presented May 30, 2020.
4. Conroy T, Lamfichekh N, Etienne P-L, et al: Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: Final results of PRODIGE 23 phase III trial, a UNICANCER GI trial. ASCO20 Virtual Scientific Program. Abstract 4007. Presented May 30, 2020.
5. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004.
In the treatment of newly diagnosed locally advanced rectal cancer, two phase II studies evaluating the addition of the PD-L1 inhibitor avelumab to chemoradiotherapy showed promising rates of pathologic complete response, major pathologic response, and tumor downstaging. The study investigators...