scholarly journals 348 A phase 2 umbrella study of retifanlimab (INCMGA00012) alone or in combination with other therapies in patients with advanced or metastatic endometrial cancer (POD1UM-204, GOG 3038, ENGOT-en12/NOGGO)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A374-A374
Author(s):  
Brian Slomovitz ◽  
Bradley Monk ◽  
Katherine Moxley ◽  
Nadeem Ghali ◽  
Justyna Fronczek Sokol ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Endometrial Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Clinical Activity ◽  
Phase 2 ◽  
Monotherapy Group ◽  
Open Label ◽  
Group A

BackgroundManagement of advanced endometrial cancer after failure with platinum therapy remains a challenge. Tumors characterized by DNA repair abnormalities are associated with high numbers of neoantigens; immunotherapy is promising in this setting as demonstrated in studies with checkpoint inhibitors (CPI). 1–6 Overcoming emerging resistance to CPI through novel combinations is a focus of research. Retifanlimab is an investigational humanized immunoglobulin G4 monoclonal antibody against programmed cell death 1 (PD 1). In POD1UM-101, retifanlimab monotherapy demonstrated acceptable tolerability and durable clinical benefit in multiple advanced tumor types, including pretreated endometrial cancer.7 POD1UM-204 is designed to further investigate efficacy and safety of retifanlimab alone or in combination with other immunotherapy or targeted agents in patients with advanced/metastatic endometrial cancer.MethodsPOD1UM-204 is a phase 2, multicenter, nonrandomized, open-label, umbrella study in women =18 years of age, with histologically confirmed diagnosis of advanced/metastatic endometrial cancer that has progressed on or after platinum-based chemotherapy. Patients must have an ECOG performance status =1, at least 1 measurable tumor lesion by Response Evaluation Criteria in Solid Tumors v1.1, and provide tumor tissue at baseline.Approximately 220 patients will be enrolled into 4 treatment groups: Group A–patients with MSI-H (microsatellite instability high) endometrial cancer and no prior CPI therapy (up to 100 patients) receiving retifanlimab monotherapy; Group B–patients with dMMR (deficient DNA mismatch repair) or POLE (DNA polymerase epsilon) endometrial cancer and no prior CPI therapy (up to 40 patients) receiving retifanlimab monotherapy; Group C–patients with unselected endometrial cancer and regardless of prior CPI treatment (up to 40 patients) receiving retifanlimab plus epacadostat (indoleamine 2,3-dioxygenase inhibitor); and Group D–patients with endometrial cancer and activating fibroblast growth factor receptor (FGFR1, 2 or 3) mutations or alterations outside of the kinase domain and regardless of prior CPI treatment (up to 40 patients) receiving retifanlimab plus pemigatinib (FGFR1, 2, 3 inhibitor) (figure 1). Patients can receive up to 26 treatment cycles if they continue to derive benefit and have not met criteria for withdrawal.The primary study objective is evaluating retifanlimab monotherapy antitumor activity (objective response rate [ORR] determined by independent central review [ICR]) in Group A. Secondary study objectives include assessing additional efficacy measures (duration of response, disease control rate and progression-free survival by ICR, and overall survival) in Group A; determining clinical activity (ORR by the investigator) in Groups B, C and D; and evaluating safety and tolerability of retifanlimab.Abstract 348 Figure 1POD1UM-204 study designResultsN/AConclusionsN/AAcknowledgementsThis study is sponsored by Incyte Corporation (Wilmington, DE).Trial RegistrationClinicalTrials. gov Identifier: NCT04463771; EudraCT 2020-000496-20Ethics ApprovalThe study was approved by institutional review boards or independent ethics committees of participating institutions.ConsentN/AReferencesMittica G, Ghisoni E, Giannone G, et al. Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity. Oncotarget 2017;8:90532–544.Di Tucci C, Capone C, Galati G, et al. Immunotherapy in endometrial cancer: new scenarios on the horizon. J Gynecol Oncol 2019;30:e46.Brooks R, Fleming G, Lastra R, et al. Current recommendations and recent progress in endometrial cancer. CA Cancer J Clin 2019;69:258–79.Makker V, Rasco D, Vogelzang N, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2019;20:711–8.Marabelle A, Le D, Ascierto P, et al. Efficacy of Pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 2020;38:1–10.Oaknin, A, Duska L, Sullivan R, et al. Preliminary safety, efficacy, and pharmacokinetic/pharmacodynamic characterization from GARNET, a phase I/II clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-h and MSS endometrial cancer. Gynecol Oncol 2019;154(suppl 1):17 [Abstract 33].Mehnert JM, Joshua AM, Lakhani N, et al. First-in-human phase 1 study of INCMGA00012 in patients with advanced solid tumors: interim results of the cohort expansion phase. J Immunother Cancer 2018;6(suppl 1):115 [Abstract P669].

Dostarlimab in the treatment of recurrent or primary advanced endometrial cancer

2020 ◽  
Author(s):  
Lawrence Kasherman ◽  
Soha Ahrari ◽  
Stephanie Lheureux
Keyword(s):  
Endometrial Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Dna Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Dna Mismatch ◽  
Tumor Subtypes

Immune checkpoint inhibitors have demonstrated significant clinical activity across various tumor subtypes; however, their utility in gynecologic malignancies has thus far proven modest. Since the identification of a molecular subclassification system for endometrial cancer (EC), research in immune checkpoint inhibitor therapies has been focusing on certain subgroups predictive for response, particularly microsatellite instability hypermutated/DNA mismatch repair-deficient subtype. Dostarlimab, a PD-1 inhibitor, has demonstrated preliminary evidence of clinical activity and acceptable safety profile in patients with across recurrent EC, particularly microsatellite instability-hypermutated/DNA mismatch repair deficient EC. This review outlines existing data for the efficacy and safety of dostarlimab in recurrent or advanced-stage EC.

A phase 2 trial of CRS-207 and pembrolizumab in adults with recurrence of metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinomas.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS200-TPS200
Author(s):  
Ronan Joseph Kelly ◽  
Thomas Adam Abrams ◽  
Daniel V.T. Catenacci ◽  
Zev A. Wainberg ◽  
Bruce Shih-Li Lin ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Clinical Activity ◽  
Cell Mediated Immunity ◽  
Specific Cell ◽  
Phase 2 ◽  
Open Label ◽  
Mesothelin Expression

TPS200 Background: CRS-207 is a live, attenuated, double-deleted Listeria monocytogenes (LADD) strain with a mesothelin expression cassette inserted. CRS-207 has a well-established, manageable toxicity profile and can elicit mesothelin-specific cell-mediated immunity. Clinical activity of CRS-207 has been shown in a separate Phase 1 trial of mesothelioma. In gastroesophageal (GE) cancers, mesothelin expression is estimated between 30% – 50% and has been correlated with poor prognosis. Preclinical models suggest the combination of LADD-based immunotherapeutics and a PD1 inhibitor may induce more sustained anti-tumor responses than either LADD or PD1 inhibitor monotherapy. GE cancers are responsive to PD1 inhibitors in a subset of patients; this trial proposes to evaluate the efficacy of CRS-207 combined with pembrolizumab in patients with relapsed GE cancer, and to correlate clinical activity with mesothelin expression level. Methods: This Phase 2, open-label, single-arm, multicenter clinical study (NCT 03122548) will enroll approximately 79 subjects at 20 sites. Adults with histologically-confirmed, advanced gastric, GEJ, or esophageal adenocarcinomas are eligible. Subjects must have received 1 or 2 prior treatment regimens, which must have included a platinum and a fluoropyrimidine. Subjects must have disease progression with measurable tumors. A pre-treatment biopsy of either the primary tumor or metastatic site is required prior to dosing. Subjects with prior exposure to checkpoint inhibitors or other immunotherapies are excluded. From cycle 1 to 4 during the treatment and evaluation period, pembrolizumab (IV 200 mg) and CRS-207 (IV 1 x 109 CFU) are both administered in 3-week cycles. Afterward, pembrolizumab will be administered once every 3 weeks; CRS-207 will be given once every 6 weeks. CT scans will be performed every 6 weeks to monitor disease status. The primary endpoint is objective response rate defined by RECIST 1.1. Clinical trial information: NCT03122548.

Phase I/II study to evaluate systemic durvalumab + intraperitoneal (IP) ONCOS-102 in patients with peritoneal disease who have epithelial ovarian (OC) or metastatic colorectal cancer (CRC): Interim phase I clinical and translational results.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3017-3017
Author(s):  
Dmitriy Zamarin ◽  
Kunle Odunsi ◽  
Brian M. Slomovitz ◽  
Linda R. Duska ◽  
John J. Nemunaitis ◽  
...  
Keyword(s):  
Phase I ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Oncolytic Viruses ◽  
Clinical Activity ◽  
Phase 2 ◽  
Open Label ◽  
Peritoneal Disease ◽  
Macrophage Colony ◽  
End Stage

3017 Background: Metastasis to the peritoneal cavity is associated with end-stage disease in many cancers, including OC and CRC, both of which exhibit poor responses to checkpoint inhibitors. Locoregional treatment with oncolytic viruses may be used to improve the efficacy of checkpoint inhibitors at both treated and distant tumor sites. This study evaluates the combination of IP-administered ONCOS-102, an oncolytic adenovirus encoding for granulocyte macrophage colony stimulating factor (GMCSF), with systemic durvalumab, an anti PD-L1 antibody, in patients with peritoneal disease who have histologically confirmed OC or metastatic CRC and have failed prior standard therapies. Methods: This ongoing Phase 1/2, open-label study (NCT02963831) evaluates safety and antitumor/biologic activity of durvalumab (1500 mg IV, every 4 weeks x 12) + ONCOS-102 (IP, weekly x 6); cyclophosphamide is given pre first ONCOS-102 dose. Phase 1 uses a 3+3 design to evaluate the ONCOS-102 dose (1 or 3 x 1011 VP) to be given with durvalumab. Phase 2 evaluates the activity of the combination using Simon’s 2-stage MINIMAX design. Safety, response rate by RECIST 1.1, and immunological effects in tumors were evaluated for Phase 1; the current abstract reports on the phase 1 results. Results: Enrollment opened 7 Sep 2017; data cutoff, 1 Nov 2019. There were 17 patients treated in Phase 1: 8 CRC, 9 ovarian; 94% female; median age, 56 [37-77] years; ECOG PS0, 47%; ECOG PS1, 53%. There were no DLTs. Grade 3 treatment-related AEs included hypokalemia (n = 2); anemia, myocarditis, increased GGT, and influenza like illness (n = 1 each). There were 4 deaths due to PD. One patient had durable confirmed partial response and remains on treatment > 1 year; 4 patients had stable disease as best overall response. Two patients remained on treatment at data cutoff. Analysis of pre- and on-treatment tumor biopsies revealed changes in the tumor-infiltrating immune cells and PD-L1 expression, including an increase in tumor-infiltrating CD8 T cells in 5 of 11 evaluable patients. Conclusions: Combination of durvalumab and IP ONCOS-102 was safe, and no DLTs were observed. Preliminary analyses demonstrate evidence of biologic and clinical activity. Phase 2 enrollment is ongoing. Clinical trial information: NCT02963831 .

scholarly journals Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer

2021 ◽  
Vol 22 (8) ◽  
Author(s):  
Federica Pecci ◽  
Luca Cantini ◽  
Alessandro Bittoni ◽  
Edoardo Lenci ◽  
Alessio Lupi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Cancer Progression ◽  
Checkpoint Inhibitors ◽  
Tnm Classification ◽  
Standard Of Care ◽  
First Line Therapy ◽  
Combination Strategies ◽  
The Impact

Opinion statementAdvanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An “immunoscore,” based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

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