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Chemoimmunotherapy in the context of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer
Background
Colorectal cancer is the third most common and the fourth most deadly cancer worldwide, with a high mortality rate in advanced-stage disease. Current standard therapy includes neoadjuvant chemoradiation or short-course radiation followed by total mesorectal excision (TME) and adjuvant chemotherapy. Recently, the RAPIDO and Prodigee23 phase III randomized trials examined the role of total neoadjuvant therapy (TNT) in rectal cancer and both reported a 28% pathologic complete response (pCR) and improvement in disease free survival (DFS). In addition, immunotherapy, specifically PDL-1 inhibitors, has shown promising clinical benefits when used in treating different types of cancers. In the context of TNT strategy, this study aims to assess the efficacy and safety profile of the combination of radiation therapy with chemoimmunotherapy, in treating patients with locally advanced rectal adenocarcinoma (NCT03503630).
Methods
This is an open-label, single-arm multicenter and stage-2 phase II study investigating the pCR and safety of using short course radiation therapy (25 Gy in 5 fractions), followed by 6 cycles of mFOLFOX-6 plus avelumab (10 mg/kg), followed by TME, in patients with locally advanced, potentially resectable rectal adenocarcinoma. Patients were followed for 3 years survival post-surgery. The primary endpoint is to assess the percentage of patients who achieved pCR, while the secondary endpoints are the DFS at 3 years, tumor regression grade (TRG), and frequency and severity of different adverse events (AE) related to avelumab.
Results
44 patients were accrued from 2018 to 2020, of which 40 patients received at least one treatment cycle and underwent TME for analysis. 14(35%) were females and 26(65%) were males. The median age is 58.5 years (min 31–max 74). As for the outcomes, 15(37.5%) patients achieved pCR/TRG=0 (no viable tumor cells), 12(30%) had near-complete response/TRG=1 ( 50% viable tumor cells). Patients with pCR had a mean immunoscore (IS) of 68 +/-22 SD as opposed to a mean IS of 53 +/-22 SD in 25(62.5%) patients without pCR (p-value=0.049). The 3 years DFS is 85% and only 6(15%) out of the 40 patients had recurrence. Moving on, 291 AEs were reported (16 hematologic vs 275 non-hematologic), out of which 15 were related to avelumab, 22 to surgery and 35 to immunologic causes. 43(14.7%) were serious adverse events (SAE) of which 4(9%) were grade 1 SAEs, 8(19%) grade 2, 25(58%) grade 3, 5(12%) grade 4 and 1(2%) grade 5. Of the grade 3-5 SAEs, none were related to avelumab as 11 were due to TME, 3 to post-ileostomy closure and 17 were miscellaneous. Moreover, 27(87%) of SAEs resolved without sequalae and 1(3%) is treatment-unrelated that resulted in death from cardiopulmonary arrest. We will report on quality of life (QoL) in a later submission pending data completion.
Conclusions
In the context of TNT, chemoimmunotherapy may play a role in certain patient categories, especially in those with initial high immunoscore to achieve higher pathologic complete response. Further studies with rectal preservation strategy are needed.
Clinical trial identification
Clinicaltrials.gov; NCT03503630 https://clinicaltrials.gov/ct2/show/NCT03503630.
Legal entity responsible for the study
The author.
Funding
This research was financially supported by Merck (CrossRef Funder ID: 10.13039/100009945), as part of an alliance between Merck and Pfizer.
Disclosures
D. Mukherji: Honoraria (self): Merck Serono, MSD, BMS; Research grant / Funding (institution): Merck Serono, Astellas, BMS. All other authors have declared no conflicts of interest.
