Preliminary Data Show Responses With Toripalimab Plus Bevacizumab/Chemotherapy in Patients With Refractory, Recurrent, or Metastatic Cervical Cancer

Alexander Melamed, MD

Treatment with toripalimab, bevacizumab (Avastin), and platinum-based chemotherapy led to responses among patients with refractory, recurrent or metastatic cervical cancer, according to preliminary data from a phase 2 trial (NCT04973904). Findings were presented at the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.¹

Findings showed that patients in the intention-to-treat (ITT) population (n = 22) experienced an investigator-assessed objective response rate (ORR) of 77.3% (95% CI, 54.6%-92.2%), with all responders achieving a partial response. Additionally, 18.2% of patients had stable disease, and 4.5% had progressive disease. The disease control rate (DCR) was 95.5% (95% CI, 77.2%-99.9%), the median duration of response was not reached, and the median time to response was 1.5 months (95% CI, 1.4-1.6).

“Toripalimab administered with bevacizumab and platinum-based chemotherapy shows a promising response rate and DCR among patients with refractory, recurrent and metastatic cervical cancer and appears to be tolerable,” said Alexander Melamed, MD, who presented the data on behalf of lead study author Peng Peng, MD, and colleagues.

Peng is a member of the Department of Obstetrics and Gynecology at Peking Union Medical College Hospital and the Chinese Academy of Medical Sciences at Peking Union Medical College in Beijing, China. Melamed is a gynecologic oncologist in the Department of Gynecologic Oncology at Massachusetts General Hospital in Boston.

The National Comprehensive Cancer Network guidelines include the combination of pembrolizumab (Keytruda) plus chemotherapy with or without bevacizumab as a preferred regimen for the first-line treatment of PD-L1–positive recurrent or metastatic cervical cancer.² That regimen was approved by the FDA in October 2021 for the treatment of patients with persistent, recurrent or metastatic cervical cancer whose tumors have a PD-L1 combined positive score of 1 or higher.³

The PD-1 inhibitor toripalimab is approved in 6 indications in China.¹ “Previous studies have suggested the addition of [toripalimab] to chemoradiotherapy [has shown] promising efficacy and manageable toxicity in refractory, recurrent and metastatic cervical cancer,” Melamed said.

The single-arm, open-label, phase 2 trial enrolled patients with histologically confirmed refractory, recurrent or metastatic cervical cancer who received no prior systemic treatment for recurrent/metastatic disease. Patients must have been unable to undergo radical treatment with surgery and/or radiotherapy. They also needed to have at least 1 measurable lesion per RECIST v1.1 criteria and an ECOG performance status of 0 or 1.

All patients were treated with 240 mg of toripalimab, 7.5 mg/kg of bevacizumab, and platinum-based chemotherapy once every 3 weeks for 6 cycles. Chemotherapy consisted of 175 mg/m2 of paclitaxel plus 50 mg/m2 of cisplatin or area under the curve 5 of carboplatin. After 6 cycles, patients received maintenance with 240 mg of toripalimab plus 7.5 mg/kg of bevacizumab once every 3 weeks for 12 months, or until disease progression or unacceptable toxicity occurred.

ORR served as the trial’s primary end point. Secondary end points included DCR, progression-free survival, overall survival, and safety.

The null hypothesis was an ORR of less than 50%, based on the response rates for bevacizumab plus chemotherapy in patients with recurrent/metastatic cervical cancer. The alternative hypothesis was an ORR of more than 75%. Stage 1 of the trial planned to enroll 14 patients, and if more than 7 experienced a response, the trial advanced to stage 2, where 9 more patients would be enrolled.

As of the December 23, 2022, data cutoff, 24 patients were enrolled, although the 24th patient was enrolled outside the planned trial sample, based on her wishes. The 22 patients in the ITT population received at least 1 assessment per RECIST v1.1 criteria.

Among the 24 patients treated, the median age was 54.5 years (range, 33-75). International Federation of Gynecology and Obstetrics (FIGO) staging at diagnosis included IA (4.2%), IB (33.3%), IIB (12.5%), IIIB (8.3%), IIIC (29.2%), and IVB (12.5%). Additionally, 79.2% of patients had squamous cell carcinoma, and 20.8% had adenocarcinoma.

Prior systemic treatment included surgery plus chemotherapy and radiotherapy (41.7%), chemoradiotherapy or radiotherapy (33.3%), surgery (12.5%), or none (12.5%). Twenty-five percent of patients had only local recurrence, 45.8% had only distant metastasis, and 29.2% had both local recurrence and distant metastasis.

As of data cutoff, 54.2% of the 24 patients were in ongoing treatment, and 1 patient (4.2%) completed treatment per trial protocol. Reasons for treatment discontinuation included disease progression (20.8%), adverse effects (AEs; 8.3%), protocol deviation (8.3%), and death (4.2%). The median duration of treatment was 5.3 months (range, 0-12).

Regarding safety among all 24 evaluable patients, 87.5% experienced at least 1 any-grade treatment-related adverse effect (TRAE), and grade 3 or higher TRAEs occurred in 54.2% of patients. Notably, 8.3% of patients discontinued treatment due to a TRAE, and 1 patient (4.2%) died due to a TRAE. Additionally, 20.8% of patients experienced a serious adverse effect (AE).

“There was 1 death from acute heart failure, which may have been related to the treatment,” Melamed said.

The most common any-grade TRAEs included neutropenia (58.3%), leukopenia (54.2%), anemia (37.5%), increased alanine transaminase (25%), nausea (12.5%), thrombocytopenia (8.3%), increased creatinine (8.3%), and rectovaginal fistula (8.3%). Any-grade vomiting, proteinuria, increased blood pressure, sudden deafness, acute kidney injury, and numbness all occurred in 1 patient each (4.2%).

The most common grade 3 or higher TRAEs included neutropenia (41.7%), leukopenia (16.7%), and rectovaginal fistula (8.3%). Grade 3 or higher increased blood pressure, sudden deafness, acute kidney injury, and numbness were reported in 1 patient each.

Immune-related AEs (irAEs) of any grade were reported in 54.2% of patients; however, no grade 3 or higher irAEs occurred. The most common any-grade irAEs consisted of increased adrenocorticotropic hormone (33.3%), increased serum cortisol (29.2%), thyroid dysfunction (29.2%), and rash (8.3%).

Editor’s note: Dr Melamed reported consulting for AstraZeneca. Dr Peng did not report any financial disclosures.

References

1. Peng P, Yao H, Liu D, et al. Toripalimab combined with bevacizumab and chemotherapy for refractory, recurrent or metastatic cervical cancer: preliminary results of a single-arm, open-label, phase II trial. Presented at: 2023 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 25-28, 2023; Tampa, FL.
2. NCCN clinical practice guidelines in oncology (NCCN guidelines®): cervical cancer. January 6, 2023. Accessed March 27, 2023. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf
3. FDA approves pembrolizumab combination for the first-line treatment of cervical cancer. News release. FDA. October 13, 2021. Accessed March 27, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/