The current outlook for patients with persistent, recurrent, or metastatic cervical cancer is poor, with a five-year survival rate of 17%. In 2014, Avastin (bevacizumab) was approved in combination with standard-of-care chemotherapy as a first-line (1L) therapeutic, based on an improvement in overall survival (OS) from 13.3 months to 16.8 months (GOG 240 Phase III trial). Despite this advancement, nearly all patients relapse after 1L therapy. Available second-line and later (2L+) treatment options are poor and are characterised by low response rates, making this an area of high unmet need.
In 2018, Keytruda (pembrolizumab), an anti-PD-1 monoclonal antibody, was granted FDA accelerated approval as a 2L therapeutic for patients with PD-L1 positive tumours. The KEYNOTE 158 trial reported an overall response rate (ORR) of 14.3%. The median duration of response (DOR) was not reached, with 75% of responses ongoing at >9 months. The durability of the responses observed makes checkpoint inhibition an exciting therapeutic area. In June 2021, Merck and Co announced that the Phase III trial (KEYNOTE 826) of Keytruda in combination with chemotherapy with or without Avastin for the 1L treatment of cervical cancer (irrespective of PD-L1 expression) had met its primary endpoints of OS and progression-free survival (PFS) and would be submitted for regulatory review. Keytruda is likely to move into 1L therapy in the emerging treatment landscape. Libtayo (cemiplimab), developed by Sanofi and Regeneron, will challenge Keytruda in the 2L, with the EMPOWER-Cervical 1 Phase III trial stopped early due to positive results. A median OS of 12.0 months with Libtayo, compared to 8.5 months with physician’s choice of chemotherapy and a 16% ORR with a median DOR of 16 months was reported. The FDA has also granted priority review to the BLA for AGEN2034 (balstilimab), a further anti-PD-1 monoclonal antibody developed by Agenus, on the basis of a Phase II trial. There are additional PD-1 and PD-L1 monoclonal antibodies in late-stage clinical trials as 1L and 2L treatments, including AiRuiKa (camrelizumab), Tecentriq (atezolizumab), BCD-100 (prolgolimab), HLX 10 (serplulimab) and QL1604. AK104, a bispecific PD-1/CTLA-4 antibody developed by Akeso Biopharma, is currently being evaluated in a Phase III trial in China and in a Phase II trial in the US and other countries for 1L and 2L treatment.
The low response rate to checkpoint inhibitors in cervical cancer patients leaves a significant unmet need in this disease setting. Tisotumab Vedotin is a novel tissue factor (TF)-targeting antibody-drug conjugate (ADC), which has been co-developed by Seagen and Genmab for the treatment of solid tumours, including cervical cancer. The innovaTV 204 Phase II trial involving 102 patients with previously treated disease reported a 24% ORR, with 7% CR and 17% PR rates. The median DOR was 8.3 months. TF expression level did not show a statistically significant association with an investigator-assessed best-confirmed response, making it a promising therapeutic option for patients irrespective of target antigen expression level. Based on the Phase II data, the FDA has accepted and granted priority review to a BLA for Tisotumab Vedotin, with an approval decision set to be announced in October 2021.
Another exciting and novel therapeutic in the pipeline for cervical cancer is the autologous tumour infiltrating lymphocyte (TIL) infusion Lifileucel, developed by Iovance. Preparation of the Lifileucel infusion involves the harvesting of a patient’s TILs, which are expanded ex-vivo and infused back into the patient following lymphodepletion. The FDA has granted breakthrough designation to Lifileucel based on interim results from the Phase II innovaTIL-04 trial, which showed an impressive ORR of 44% in the 27 treated patients, including three complete responses. 83% of patients had maintained this response at a median follow-up period of 7.4 months and median DOR had not been reached.
The current chemotherapy-dominated landscape of cervical cancer treatment is set to change to include multiple different drug classes. The licensing of checkpoint inhibitors, a novel ADC and a TIL product would transform the outlook for patients diagnosed with persistent, recurrent or metastatic cervical cancer, with these agents demonstrating durable patient responses.