Retifanlimab Shows Promising Antitumor Activity in Advanced Endometrial Cancer

Retifanlimab (INCMGA 0012) demonstrated encouraging antitumor activity with favorable tolerability in patients with recurrent microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) endometrial cancer, according to data from the phase 1 POD1UM-101 trial (NCT03059823), presented during the 2021 SITC Annual Meeting.¹

At a median follow-up of 8.4 months (range, 1.9-28.3), the confirmed objective response rate (ORR) per RECIST v1.1 criteria was 43.4% (n = 33/76; 95% CI, 32.1%-55.3%); this was comprised of 11 complete responses (14.5%), and 22 partial responses (PRs; 28.9%). Moreover, 32.9% (n = 25) of patients achieved stable disease, and 21.1% (n = 16) experienced disease progression.

The median duration of response (DOR) achieved with retifanlimab had not yet been reached; 75.8% (n = 25) of patients experienced a DOR of 6 months or longer. The disease control rate was 76.3% (95% CI, 65.2%-85.3%). Additionally, the median progression-free survival (PFS) was 11.0 months (95% CI, 5.6–not evaluable [NE]) with the agent, and the median overall survival (OS) was NE (95% CI, 19.3-NE).

“These findings support further clinical investigation of retifanlimab, either alone or in combination therapy, in patients with endometrial cancer,” Dominique Berton-Rigaud, MD, of Service de Cancérologie médicale, ICO Centre René Gauducheau, Saint-Herblain, France, and colleagues, wrote in a poster presentation on the data.

Limited treatment options are available to patients with recurrent or metastatic endometrial cancer. Moreover, the prognosis for this patient population is poor, with a 5-year survival rate of approximately 17.0%. Approximately 25.0% of endometrial cancers are MSI-H or dMMR. Because these tumors are characterized by abnormalities in DNA repair and associated with high numbers of neoantigens, immunotherapy approaches with PD-1 inhibitors represent a promising option.^2-4

An investigational humanized immunoglobulin G4 monoclonal antibody against human PD-1, retifanlimab, is under evaluation in the ongoing, first-in-human POD1UM-101 study. The agent demonstrated acceptable tolerability and durable clinical activity in patients with multiple advanced tumor types, including in those with pretreated endometrial cancer. Data from a preplanned interim analysis of the trial showed that the agent had promising activity specifically in patients with recurrent MSI-H or dMMR endometrial cancer.^5-9

In the analysis featured in the poster, investigators shared the results regarding the safety and clinical activity of retifanlimab in patients with MSI-H or dMMR recurrent endometrial cancer, which was cohort H of the POD1UM-101 study.

The trial enrolled patients who were at least 18 years of age with histologically proven, unresectable recurrent endometrial cancer that was MSI-H or dMMR based on local testing. Patients had to have measurable disease per RECIST v1.1 criteria and have progressed on, or following, 1 to 5 prior systemic treatments. Moreover, patients had to have an ECOG performance status of 0 or 1, and adequate liver and renal laboratory parameters. Tumor specimen collection for retrospective central confirmation of MSI-H/dMMR status and testing for PD-L1 expression was required.

Those with symptomatic or untreated central nervous system metastases, or who had received previous treatment with an immune checkpoint inhibitor were not eligible to participate. Other exclusion criteria included those with clinically significant cardiovascular, gastrointestinal, or pulmonary conditions; those who had received systemic corticosteroids or immunosuppressant drugs within 14 days before study drug initiation; those with a history of suspected autoimmune disease; and known positive human immunodeficiency status or active hepatitis B or C infection.

Patients enrolled to cohort H of the study received retifanlimab at a dose of 500 mg every 4 weeks. Patients will undergo 2 years of follow-up.

The primary end point of the study was safety and tolerability and secondary end points included ORR, DOR, PFS, OS.

Among the 76 patients enrolled, the median age was 67 years (range, 49-88); the majority where White (73.7%) and had an ECOG performance status of 1 (59.2%). Moreover, most patients had metastatic disease (88.2%), visceral metastases (80.3%), and a histology of endometrioid carcinoma (92.1%). Moreover, 72.4% had a PD-L1 expression of less than 1%.

Notably, 98.7% of patients received prior systemic treatment in any disease setting, and 96.1% received prior systemic therapy for advanced disease. Moreover, 65.8% received 1 prior line, 22.4% received 2 prior lines, and 7.9% received 3 or more prior lines. Additionally, 71.1% of patients previously received radiotherapy and 89.5% previously underwent surgery.

At a data cutoff on July 6, 2021, 76 patients had received at least 1 dose of retifanlimab, with 2 (2.6%) completing treatment, and 30 (39.5%) remaining on treatment. Forty-four patients (57.9%) discontinued treatment, primarily due to radiographic disease progression (38.2%) and adverse effects (AEs; 11.8%). Other reasons for discontinuation included clinical progression (2.6%), death (2.6%), patient withdrawal (1.3%), or another reason (1.3%).

Patients received a median of 0 (range, 1-26) infusions of retifanlimab at 500 mg every 4 weeks, and the median duration of treatment was 7.4 months (range, 0.03-23.0). Sixty-four percent of patients (n = 14/22) who achieved a confirmed PR with retifanlimab experienced a tumor size reduction of more than 70%. Twenty-nine of 33 responders remain on treatment.

Moreover, 6 patients had sustained response after stopping treatment. The DORs per independent review committee from the time of treatment discontinuation ranged from 3.0 to 24.9 months in these patients.

In terms of safety, 74 patients (97.4%) experienced at least 1 treatment-related AE (TRAE), and grade 3 or higher TRAEs we reported in 11 patients (14.5%). Immune-related AEs that led to study drug discontinuation were reported in 4 patients (5.3%), and included autoimmune hepatitis (n = 1), hepatitis (n = 1), myositis (n = 1), and polymyalgia rheumatica (n = 1).

Serious AEs were reported in 39.5% of patients, and 5.3% were serious TRAEs. Additionally, 11.8% of AEs led to drug discontinuation, 27.6% led to drug interruption, and 2.6% led to death.

The most common TRAEs of any grade were fatigue (18.4%), pruritus (15.8%), diarrhea (14.5%), asthenia (14.5%), rash (10.5%), arthralgia (9.2%), hypothyroidism (9.2%), hyperthyroidism (7.9%), decreased appetite (6.6%), and rash pruritic (5.3%). The most common grade 3 or higher TRAEs were diarrhea (1.3%), and rash (1.3%).

Potential immune-related treatment-emergent toxicities (TEAEs) of any grade were experienced by 38.2% of patients; these effects were grade 3 or higher in 9.2% of patients. The most common potential immune-related TEAEs included hyperthyroidism (10.5%), skin reactions (10.5%), hypothyroidism (9.2%), hepatitis (3.9%), pneumonitis (3.9%), and acute kidney injury (2.6%). The most common grade 3 or higher immune-related toxicities were hepatitis (2.6%), acute kidney injury (2.6%), skin reactions (1.3%), and pneumonitis (1.3%).

References

1. Berton D, Pautier P, Lorusso D, et al. Retifanlimab (INCMGA00012) in patients with recurrent MSI-H or dMMR endometrial cancer: results from the PODIUM-101 study. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 956.
2. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. doi: 10.3322/caac.21654
3. Lorenzi M, Amonkar M, Zhang J, et al. Epidemiology of microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) in solid tumors: a structured literature review. J Oncol. 2020. doi:10.1155/2020/1807929
4. Nebot-Bral L, Brandao D, Verlingue L, et al. Hypermutated tumours in the era of immunotherapy: The paradigm of personalised medicine. Eur J Cancer. 2017;84:290-303. doi:10.1016/j.ejca.2017.07.026
5. La Motte-Mohs R, et al. J ImmunoTher Cancer. 2017;5;87. Abstract P33.
6. Menhert 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. Presented at: 2018 SITC Annual Meeting; November 7-11, 2018; Washington DC. Abstract P669.
7. Berton D, Vergote I, Pautier P, et al. A phase 1 study of retifanlimab (INCMGA00012), a PD-1 inhibitor, in patients with advanced solid tumors: preliminary results in recurrent MSI-high or DMMR endometrial cancer (POD1UM101). J Immunother Cancer. 2020;8(3):A1–A559.
8. Menhert JM, Paz-Ares L, Pikiel J, et al. A phase 1 study of INCMGA00012, a PD-1 Inhibitor, in patients with advanced solid tumors: preliminary results for patients with advanced cervical cancer (POD1UM-101). Presented at: 2019 SITC Annual Meeting; November 6-10, 2019; Washington DC. Abstract P349.
9. Maio M, Schenker M, Medioni J, et al. Phase 2 study of retifanlimab (INCMGA00012) in patients (pts) with selected solid tumors (POD1UM-203). J Clin Oncol. 2021;39(15):2571-2571. doi: 10.1200/JCO.2021.39.15_suppl.2571