Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial
(1) Porcari S (2) Ciccarese C (3) Heidrich V (4) Rondinella D (5) Quaranta G (6) Severino A (7) Arduini D (8) Buti S (9) Fornarini G (10) Primi F (11) Stumbo L (12) Giannarelli D (13) Giudice GC (14) Damassi A (15) Giron Berros JR (16) Pun_och_ M (17) Barbazuk TB (18) Piccinno G (19) Pinto F (20) Armanini F (21) Asnicar F (22) Schinzari G (23) Derosa L (24) Kroemer G (25) Sanguinetti M (26) Masucci L (27) Gasbarrini A (28) Tortora G (29) Cammarota G (30) Zitvogel L (31) Segata N (32) Iacovelli R (33) Ianiro G
Three clinical trials investigating methods to improve immune checkpoint blockade (ICB) were recently published. Duttagupta, Messaoudene et al. investigated the addition of healthy donor FMT to ICB protocols for NSCLC and melanoma, while Porcari et al. investigated the addition of FMT from patients who had a complete response to ICB to standard-of-care treatment with anti-PD-1 and a VEGFR TKI in patients with metastatic RCC. Finally, Kendra et al. investigated neoadjuvant use of anti-PD-1 in patients with resectable desmoplastic melanoma.
(1) Porcari S (2) Ciccarese C (3) Heidrich V (4) Rondinella D (5) Quaranta G (6) Severino A (7) Arduini D (8) Buti S (9) Fornarini G (10) Primi F (11) Stumbo L (12) Giannarelli D (13) Giudice GC (14) Damassi A (15) Giron Berros JR (16) Pun_och_ M (17) Barbazuk TB (18) Piccinno G (19) Pinto F (20) Armanini F (21) Asnicar F (22) Schinzari G (23) Derosa L (24) Kroemer G (25) Sanguinetti M (26) Masucci L (27) Gasbarrini A (28) Tortora G (29) Cammarota G (30) Zitvogel L (31) Segata N (32) Iacovelli R (33) Ianiro G
Three clinical trials investigating methods to improve immune checkpoint blockade (ICB) were recently published. Duttagupta, Messaoudene et al. investigated the addition of healthy donor FMT to ICB protocols for NSCLC and melanoma, while Porcari et al. investigated the addition of FMT from patients who had a complete response to ICB to standard-of-care treatment with anti-PD-1 and a VEGFR TKI in patients with metastatic RCC. Finally, Kendra et al. investigated neoadjuvant use of anti-PD-1 in patients with resectable desmoplastic melanoma.
ABSTRACT: Renal cell carcinoma (RCC) is a common malignancy with limited durable responses to first-line immune checkpoint inhibitor (ICI)-based therapies. Emerging evidence implicates the gut microbiome in modulating ICI efficacy. In the investigator-initiated, randomized, double-blind placebo-controlled phase 2a TACITO trial, we evaluated whether fecal microbiota transplantation (FMT) from complete ICI responders enhances clinical outcomes in treatment-naive patients with metastatic RCC (mRCC) receiving pembrolizumab + axitinib. The primary endpoint was the rate of patients free from disease progression at 12 months after randomization (12-month progression-free survival (PFS)). Secondary endpoints were median PFS and median overall survival, objective response rate (ORR), safety and microbiome changes, after randomization. Forty-five patients randomly received donor FMT (d-FMT) or placebo FMT (p-FMT). Although the primary endpoint was not met (70% versus 41% for d-FMT versus p-FMT, respectively, P = 0.053), the secondary endpoint of median PFS was significantly longer with d-FMT (24.0 months in the d-FMT arm versus 9.0 months in the p-FMT arm; hazard ratio = 0.50, P = 0.035). The ORR was 52% of patients in the d-FMT arm and 32% of patients receiving placebo. Microbiome analysis confirmed donor strain engraftment and increased α-diversity and larger microbiome shifts (β-diversity) compared with baseline composition in the d-FMT treatment group. Acquisition or loss of specific strains, but not total engraftment, was associated with the primary endpoint. Our findings support the safety and potential efficacy of selected donor FMT to enhance ICI-based treatment in mRCC, which deserves further investigations. ClinicalTrials.gov identifier: NCT04758507 .
Author Info:
(1) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences
, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (2) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (3) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (4) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (5) Department of Laboratory and Hematology Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. (6) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (7) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (8) Department of Medicine and Surgery, University of Parma, Parma, Italy. (9) UO Oncologia Medica 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy. (10) Medical Oncology, Central Hospital of Belcolle, Viterbo, Italy. (11) Department of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico di Roma, Rome, Italy. (12) Facility di Epidemiologia e Biostatistica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. (13) Department of Medicine and Surgery, University of Parma, Parma, Italy. (14) UO Oncologia Medica 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy. (15) Medical Oncology, Central Hospital of Belcolle, Viterbo, Italy. (16) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (17) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (18) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (19) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (20) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (21) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (22) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (23) Gustave Roussy Cancer Campus, ClinicObiome, Villejuif, France. Universit Paris-Saclay, _le-de-France, France. Institut National de la Sant et de la Recherche Mdicale (INSERM) U1015, Equipe Labellise-Ligue Nationale contre le Cancer, Villejuif, France. (24) Universit Paris Cit, Sorbonne Universit, Inserm, Centre de Recherche des Cordeliers, Paris, France. Universit Paris-Saclay, INSERM US23 / CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. Institut du Cancer Paris CARPEM, Department of Biology, Hpital Europen Georges Pompidou, AP-HP, Paris, France. Centre de Recherche des Cordeliers, Equipe labellise par la Ligue contre le cancer, Institut Universitaire de France, Paris, France. (25) Department of Laboratory and Hematology Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Universit Cattolica del Sacro Cuore, Rome, Italy. (26) Department of Laboratory and Hematology Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Universit Cattolica del Sacro Cuore, Rome, Italy. (27) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (28) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (29) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy, Rome, Italy. (30) Gustave Roussy Cancer Campus, ClinicObiome, Villejuif, France. Universit Paris-Saclay, _le-de-France, France. Institut National de la Sant et de la Recherche Mdicale (INSERM) U1015, Equipe Labellise-Ligue Nationale contre le Cancer, Villejuif, France. (31) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (32) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore Facolt di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (33) Department of Translational Medicine and Surgery, Universit Cattolica del Sacro Cuore Facolt di Medicina e Chirurgia, Rome, Italy. gianluca.ianiro@unicatt.it. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. gianluca.ianiro@unicatt.it.
