The addition of toripalimab-tpzi (Loqtorzi) to concurrent chemoradiotherapy (CCRT) led to an overall response rate (ORR) of 100% (95% CI, 85.9%-100%) in patients with locally advanced cervical cancer, according to data from a phase 1b trial (NCT04368273); however, the aggravation of radiation-related adverse effects (rAEs) and incidence of serious immune-related AEs (irAEs) warrant further investigation into immune checkpoint inhibitor and CCRT combinations in this setting.1

Findings published in BMC Cancer showed that at a median follow-up of 27.3 months (range, 22.0-46.1), patients (n = 30) achieved a 3-month complete response (CR) rate of 90% (95% CI, 72.3%-97.4%) and a 3-month partial response (PR) rate of 10% (95% CI, 2.6%-27.7%). Overall, best responses comprised CR at 96% (95% CI, 80.9%-99.8%) and PR at 3% (95% CI, 0.17%-19%). The lone patient with a best response of PR experienced parametrial recurrence at 9.9 months. The median time to response was 0.9 months (range, 0.8-3.4), and the median duration of response was 25.7 months (range, 8.2-45.1).

Regarding safety, all patients experienced at least 1 treatment-related AE (TRAE), and the rate of grade 3 or higher TRAEs was 80%. Additionally, rAEs were reported in 37% of patients, although all were grade 1 or 2. Late rAEs occurred in 66.7% of patients. Furthermore, irAEs of grade 1 or 2 occurred in 30% of patients. One patient (3%) experienced a grade 3 or higher irAE (immune-related hemophagocytic lymphohistiocytosis [HLH]), which was fatal.

“First-line toripalimab plus CCRT demonstrated promising antitumor activity in patients with locally advanced cervical cancer. However, high rate of irAEs, fatal HLH, and late rAEs necessitate careful consideration,” lead study author Ping Jiang, MD, of the Department of Radiation Oncology at Peking University Third Hospital in Beijing, China, and colleagues wrote in a publication of the data. “Despite remarkable efficacy, the rate of grade 3 [or higher] TRAEs was as high as 80%, including a fatal irAE, suggesting that stringent patient selection, optimization of treatment cycles, and the incorporation of a control arm in future studies are imperative to clearly define the risk-benefit ratio.”

What Was the Value of Investigating Toripalimab Plus CCRT in Locally Advanced Cervical Cancer?

Although past studies, such as the phase 3 KEYNOTE-826 trial (NCT03635567), demonstrated the benefit of adding immune checkpoint inhibition to chemotherapy for the first-line treatment of patients with recurrent or metastatic cervical cancer,2 there have been conflicting data regarding the use of immune checkpoint inhibitors plus CCRT in the context of locally advanced cervical cancer.1

In the phase 3 KEYNOTE-A18 trial (NCT04221945), the addition of pembrolizumab (Keytruda) to CCRT led to improvements in 36-month progression-free survival (PFS) and overall survival (OS) rates in patients with locally advanced cervical cancer.3 However, data from the phase 3 CALLA trial (NCT03830866) showed that patients treated with durvalumab (Imfinzi) plus CCRT did not experienced a PFS benefit vs those given CCRT alone.4

Thusly, investigators of the phase 1b trial conducted in China sought to further evaluate the use of an immune checkpoint inhibitor/CCRT combination in patients with locally advanced cervical cancer, along with assessing the safety and efficacy of toripalimab in this patient population.1

How Was the Phase 1b Trial Designed?

The single-arm, phase 1b trial enrolled patients 18 to 75 years of age with human papillomavirus–positive, histologically confirmed, stage IB3 to IVA cervical cancer per FIGO 2018 criteria. Patients were required to have at least 1 measurable lesion per MRI, an ECOG performance status of 0 to 2, a life expectancy of at least 3 months, and adequate organ and bone marrow function.

All patients received pelvic external beam radiation therapy (EBRT) at 50.4 Gy in 28 fractions, and those with positive lymph nodes were administered a simultaneous integrated boost of 10 Gy in 5 fractions. Additionally, high dose rate brachytherapy was given at a total dose ranging from 30 to 36 Gy in 5 or 6 fractions 1 month after the start of EBRT.

As patients received EBRT, they were also given cisplatin at 40 mg/m² once per week for 4 to 6 weeks, and toripalimab was administered at 240 mg biweekly for 4 total doses. After CCRT, patients received paclitaxel at 260 mg/m² and cisplatin at 40 mg/m² for 2 to 4 cycles, as indicated. Patients with residual local disease per pelvic MRI at 1 month after treatment received consolidation chemotherapy. Notably, patients who achieved a CR on MRI received 5 fractions of intracavitary brachytherapy, and those with residual disease received 6 fractions. Patients discontinued treatment in the event of unacceptable toxicity, pregnancy, disease progression, or withdrawal of consent. No dose modifications were allowed during the study.

The incidence and severity of AEs during treatment and up to 3 months after treatment served as the trial’s primary end point. Secondary end points included 3-month ORR and PFS.

Enrolled patients had a median age of 58.5 years (range, 23-71), and 97% of patients were Han Chinese. The majority of patients were menopausal (77%), had an ECOG performance status of 1 (83%), had squamous cell carcinoma (93%), had N1 lymph node status (53%), and had a tumor diameter of 5 cm or less (83%).

What Were the Additional Efficacy and Safety Data From the Phase 1b Trial?

Findings also showed that 4 patients experienced disease recurrence. Along with the 1 patient who had a best response of PR and a parametrial recurrence, distant metastases were reported in 3 patients who achieved CR. Recurrence times ranged from 9.2 months to 38.8 months. The median PFS was not reached, and the 2-year PFS rate was 90% (95% CI, 72.2%-96.7%). Patients also experienced a 2-year local recurrence–free survival rate of 96.7% (95% CI, 78.6%-99.5%).

Regarding safety, the most common any-grade TRAEs included leukopenia (100%), anemia (100%), and nausea (90%). The most common grade 3 or higher TRAEs were leukopenia (63%), lymphopenia (37%), and anemia (27%). TRAEs did not lead to any treatment interruptions or discontinuation, study termination, or death, other than the 1 patient who experienced immune-related HLH.

The most frequently reported early rAEs included proctitis (23%), cystitis (17%), vagina hemorrhage (17%), dermatitis (13.3%), and mucous membrane reaction (10%). Common late rAEs comprised rectal hemorrhage (53.3% at grade 2), hematuria (10% at grade 2), and peripheral sensory neuropathy (13.3% at grade 1).

Grade 1/2 irAEs included chromatosis (17%), rash (7%), pruritus (7%), hypothyroidism (7%), and adrenal insufficiency (7%).

ReferencesJiang P, Wei S, Li C, et al. Safety and efficacy of toripalimab plus concurrent chemoradiotherapy for locally advanced cervical cancer: a single-arm, phase Ib trial. BMC Cancer. 2025;25(1):1566. doi:10.1186/s12885-025-15059-yColombo N, Dubot C, Lorusso D, et al. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385(20):1856-1867. doi:10.1056/NEJMoa2112435Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet. 2024;403(10434):1341-1350. doi:10.1016/S0140-6736(24)00317-9Monk BJ, Toita T, Wu X, et al. Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(12):1334-1348. doi:10.1016/S1470-2045(23)00479-5