595P - The DUREC trial: Durvalumab plus total neoadjuvant therapy in locally advanced rectal cancer - a multicenter, single-arm, phase II study (GEMCAD-1703)

Background

Total neoadjuvant therapy (TNT) is a new standard of care for locally advanced rectal cancer (LARC). However, the activity of immunotherapy in combination with chemoradiotherapy (CRT) in microsatellite-stable (MSS) rectal cancer has been limited. We explored the efficacy and safety of TNT in combination with the anti-PD-L1 durvalumab (D) in LARC pts with MSS rectal adenocarcinoma.

Methods

The DUREC study is a multicenter, single-arm, phase II trial that recruited pts with stage II and III MSS rectal adenocarcinoma with MRI-defined high-risk T3 (extramural vascular invasion (EMVI), >5mm of perirectal fat infiltration, mesorectal fascia involvement), T4, N2, or distal third tumors (T3/4). Pts received 6 cycles of FOLFOX with D at 1500 mg q4W, followed by CRT with capecitabine and D, continuing D until surgery. The first 6 pts underwent a safety run-in phase. Primary endpoint was pathological complete response (pCR) rate. Assuming a minimum efficacy for pCR of 16% and an optimum of 30%, with an α error of 0.1 and a β error of 0.1 (90% power), the study aimed to recruit 58 pts.

Results

61 pts were enrolled (median age, 61.3 years; 70% male). Clinical staging was T3/T4 tumors (78/22%), N2 (53%), and 60% had EMVI positivity. Mean number of administered cycles of mFOLFOX6 and durvalumab were 5.8 and 6.2, respectively, with 41 patients (67.2%) receiving 7 cycles of durvalumab before surgery. Among the 56 (92%) pts who underwent surgery, 22 (39%) achieved a pCR and 18 (32%) achieved a major response (71% of major pathological responses). pCR rate for the intention-to-treat population was 36% (95% CI 24.2%-49.4%). Reasons for not performing surgery were metastatic disease progression during therapy (n=3), toxicity (n=1) and major protocol deviation (n=1). Eight pts (13%) had treatment-related serious adverse events, with diarrhea being the most common (3.3%).

Conclusions

The DUREC trial is the first prospective clinical study evaluating the combination of immunotherapy throughout the TNT process for treating MSS LARC. The study met its primary endpoint, demonstrating promising activity and safety, and deserving further development in a phase III study.

Clinical trial identification

EudraCT 2018-004835-56.

Editorial acknowledgement

Legal entity responsible for the study

Spanish Group of Digestive Cancer (GEMCAD).

Funding

MedImmune/AstraZeneca.

Disclosure

J. Capdevila Castillon: Financial Interests, Personal, Invited Speaker: Novartis, Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono; Financial Interests, Personal, Advisory Board: Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono, Esteve, ITM; Financial Interests, Personal, Research Grant: Novartis, Pfizer, Bayer, AstraZeneca, Advanced Accelerator Applications, Eisa. V. Alonso: Financial Interests, Personal, Advisory Board: Sanofi, Amgen, Servier, Novartis; Financial Interests, Personal, Other, Travel/Accommodation expenses: F. Hoffmann-La Roche Ltd, Merck. I. Macias Declara: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, MSD. M. Melian: Financial Interests, Personal, Advisory Role: Merck, Servier; Financial Interests, Personal, Speaker, Consultant, Advisor: Merck, Servier, Amgen, Bayer; Financial Interests, Personal, Other, Travel/accommodation expenses: Roche, Amgen, Merck, Servier. J. Gallego Plazas: Financial Interests, Personal, Advisory Board: AAA, Amgen, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Lilly, Merck, MSD, Pierre Fabre, Roche, Servier; Financial Interests, Personal, Invited Speaker: AAA, Amgen, Bayer, Bristol Myers Squibb, Ipsen, Lilly, Merck, MSD, Novartis, Servier; Financial Interests, Personal, Other, Educational: Amgen, Ipsen, Merck, Novartis, Pierre Fabre, Roche; Financial Interests, Institutional, Funding: Astellas, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Servier; Non-Financial Interests, Member of Board of Directors: Spanish Society Medical Oncology, Spanish Group Of Neuroendocrine an Endocrine Tumours; Non-Financial Interests, Project Lead: Agamenon-Seom Registry of Esophagohastric Cancer. R. Vera: Financial Interests, Personal, Advisory Board: Roche, Amgen, Sanofi; Financial Interests, Personal, Invited Speaker: Merck, Bayer, Eisai, Servier; Financial Interests, Personal, Other, Program Coordinator: Lilly. J. Maurel: Financial Interests, Personal, Advisory Board: Advance Medical, Roche, Cancer Expert Now, Sirtex, Pierre Fabre, Shire, AstraZeneca, Bayer, Sanofi, Merck/MSD; Financial Interests, Institutional, Funding: Amgen, Merck, Incyte, Roche; Financial Interests, Institutional, Coordinating PI: Merck, Guardant; Non-Financial Interests, , Leadership Role: GEMCAD (Grupo Español Multidisciplinar en Cancer Digestivo). J. Hernando: Financial Interests, Personal, Advisory Board: Eisai, Ipsen, Novartis, AAA, Angelini, Pfizer, Roche. A. Garcia Alvarez: Financial Interests, Personal, Advisory Board: ADACAP (Novartis); Other, Expenses (Travel, Congress inscription): Advanz, Eisai, Ipsen, ADACAP (Novartis). E. Polo: Financial Interests, Personal, Advisory Role: Merck, Amgen, Servier; Financial Interests, Personal, Training: Merck, Ipsen, Amgen, Servier. E. Espin: Financial Interests, Personal, Other, Proctor: Intuitive/Abex. G. Villacampa Javierre: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabre, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. F. Losa: Financial Interests, Institutional, Research Grant, Insitutional research funding: F. Hoffmann-La Roche Ltd, Amgen; Financial Interests, Institutional, Research Grant, Institutional research funding: Merck; Financial Interests, Personal, Other, Travel/Accommodation expenses: F. Hoffmann-La Roche Ltd, Merck; Financial Interests, Personal, Advisory Board: F. Hoffmann-La Roche Ltd, Amgen, Merck, Sanofi, Servier; Financial Interests, Personal, Speaker’s Bureau: F. Hoffmann-La Roche Ltd, Sanofi; Financial Interests, Personal, Expert Testimony: F. Hoffmann-La Roche Ltd, Sanofi; Financial Interests, Personal, Funding, Research funding: Support for writing assistance: F. Hoffmann-La Roche Ltd. All other authors have declared no conflicts of interest.