Tislelizumab a potential treatment alternative for gynaecologic MSI-H/dMMR tumours

The humanized IgG4 monoclonal antibody tislelizumab was clinically active in women with gynaecologic microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) solid tumours, and was generally well-tolerated with no new safety signals, according to a subgroup analysis of the phase II RATIONALE 209 study presented at SGO 2022.

Evidence shows that MSI-H/dMMR may be a strong predictive biomarker for immunotherapy. [Cancer Commun 2018;38:6] “This is of particular interest in tumour types such as endometrial cancer, in which the incidence of MSI-H/dMMR has been reported to be nearly 30 percent,” said study author Dr Dong Wang from the Chongqing University Cancer Hospital, Chongqing, China, and colleagues.

The team thus sought to evaluate the activity of tislelizumab in 17 participants (median age 55 years) with gynaecologic tumours (endometrial, cervical, and ovarian cancer [n=15, 1, and 1, respectively]) from the overall RATIONALE 209 cohort (n=80) of adults with locally advanced unresectable or metastatic MSI-H/dMMR solid tumours. Participants have either received or refused prior cancer therapy regimens for advanced or metastatic disease, had ≥1 measurable lesion, and no prior checkpoint inhibitor treatment. They were given tislelizumab 200 mg IV Q3W.

All 17 participants had undergone prior anticancer procedure or surgery with curative intent. Sixteen had received prior anticancer therapy, of whom six received prior chemoradiation.

Objective response rate was 53 percent (p<0.0001), including three complete responses in women with endometrial cancer. Median time to response was 9.1 weeks and disease control rate was 60 percent.

Median overall survival and progression-free survival were not reached. Median duration of response was also not reached, but responses went on for up to 15 months in women with endometrial cancer, 16 months among those with cervical cancer, and about 2 years in women with ovarian cancer.

“Most patients experienced a reduction in tumour lesion diameter during the trial,” said Wang.

All women experienced ≥1 treatment-emergent adverse events (TEAEs), with 10 reporting grade ≥3 TEAEs (the most common being urinary tract infection). Seven patients had immune-mediated TEAEs. Only one TEAE led to treatment discontinuation.

Tislelizumab has high affinity and binding specificity for PD-1 engineered to minimize Fcγ receptor binding on macrophages, thereby abrogating antibody-dependent cellular phagocytosis. [Ann Oncol 2018;29:v27-v28; J Clin Oncol 2018;36:TPS3112]

The current findings add to existing literature reflecting the benefit of tislelizumab monotherapy in individuals with solid tumours, including MSI-H/dMMR tumours. [J Immunother Cancer 2020;8:e000437; J Immunother Cancer 2020;8:e000453; Cancer Sci 2021;112:305-313; Cancer Res 2021;81;(13_Suppl):Abs CT039] MSI-H/dMMR tumours share common histopathologic characteristics that may render them susceptible to immune checkpoint inhibitors such as anti-PD-1/PD-L1 monoclonal antibodies. [Clin Cancer Res 2016;22:813-820; Cancer Discov 2015;5:43-51; Cell Rep 2016;15:857-865]

The results also reinforce the primary results of the study, which reflected the benefit of tislelizumab in this patient setting in terms of objective response rate compared against historical control rates. [J Clin Oncol 2021;39;(15_suppl):2569]

“[Taken together, our] data support tislelizumab as a potential new treatment option for patients with gynaecological MSI-H/dMMR tumours,” said Wang and colleagues. “Further investigation with a larger population is warranted to confirm the clinical benefit of tislelizumab in these patients.”