Immune Checkpoint Inhibitors Change Treatment Landscape for Metastatic Cervical Cancer

Cervical cancer is the fourth most common cancer for women worldwide, with an estimated 13,000 cases diagnosed and 4000 deaths recorded each year.¹ Human papillomavirus (HPV) remains the most prominent risk factor for cervical cancer. Screenings, including Papanicolaou tests and HPV tests, and preventive HPV vaccines can reduce the incidence of cervical cancer. However, limited access to these prevention measures due to health disparities can increase the rate of cervical cancer in underserved patient populations.^1,2

The current first-line therapy for patients with recurrent or metastatic cervical cancer includes platinum-based chemotherapy or paclitaxel with or without bevacizumab (Avastin; Genentech, Inc), a therapy approved in 2014 because it showed an overall survival (OS) benefit when added to chemotherapy.¹ In the trial (NCT00803062) that led to the approval, the median OS was 6.5 months to 13.3 months for chemotherapy-only regimens and 16.9 months with the addition of bevacizumab.3 Until 2021, bevacizumab was the most recent FDA-approved drug for recurrent or metastatic cervical cancer.

However, in 2021, pembrolizumab (Keytruda; Merck & Co, Inc), a PD-1 inhibitor, was approved for this disease state. Additionally, 2 other PD-1 inhibitors, cemiplimab-rwlc (Libtayo; Regeneron Pharmaceuticals, Inc) and nivolumab (Opdivo; Bristol Myers Squibb), have also demonstrated efficacy in this patient population, although they have not yet been FDA approved to treat recurrent or metastatic cervical cancer.

PD-1 inhibitors, such as pembrolizumab, cemiplimab, and nivolumab, work by binding to the PD-1 receptor and blocking its interactions with PD-L1 and PD-L2, releasing PD-1 pathway–mediated inhibition of antitumor immune response. To date, 3 key trials have investigated PD-1 inhibitors for the treatment of cervical cancer.

In the phase 3 KEYNOTE-826 trial (NCT03635567), 617 patients without prior systemic chemotherapy treatment with PD-L1–positive metastatic cervical cancer were randomly assigned to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy with or without bevacizumab, the latter of which was at the investigator’s discretion. With a median follow-up of 22 months, progression-free survival (PFS) was 10.4 months in the pembrolizumab group and 8.2 months in the placebo group (HR, 0.62; 95% CI, 0.50-0.77; P < .001). Additionally, OS at 24 months was 53% in the pembrolizumab group and 41.7% in the placebo group (HR, 0.64; 95% CI, 0.50-0.81; P < .001).

Furthermore, in a subgroup analysis of the KEYNOTE-826 trial results, defined by the addition of bevacizumab (yes or no), histology (squamous or nonsquamous), platinum use (carboplatin or cisplatin), and prior chemoradiation therapy (yes or no), similar benefits with the addition of pembrolizumab were seen across all subgroups, which demonstrate a meaningful benefit to the broader patient population. The most common grade 3 or higher adverse events (AEs) were anemia (30.3% in the pembrolizumab group and 26.9% in the placebo group) and neutropenia (12.4% and 9.7%, respectively).⁴ Thus, the addition of pembrolizumab did not exacerbate known AEs of chemotherapy or bevacizumab and vice versa. Immune-related AEs occurred in 33.9% of patients receiving pembrolizumab and 15.2% in the placebo group. Because of pembrolizumab’s efficacy and safety profile, its addition to chemotherapy with or without bevacizumab has been added as first-line treatment for advanced metastatic cervical cancer with tumors expressing PD-L1.^1,4

In another phase 3 trial (NCT03257267), 608 patients (regardless of PD-L1 status) who had received prior bevacizumab and paclitaxel therapy were randomly assigned to receive cemiplimab 350 mg every 3 weeks or investigator’s choice of single-agent chemotherapy. With a median follow-up period of 18.2 months, OS was significantly longer with cemiplimab compared with singleagent chemotherapy (12.0 vs 8.5 months; 95% CI, 0.56-0.84; 2-sided P < .001). Further, PFS was also significantly longer in the cemiplimab group (HR, 0.75; 95% CI, 0.63-0.89; 2-sided P < .001), with the most common grade 3 or higher AEs noted as anemia (12% in the cemiplimab group and 26.9% in the controlled group), urinary tract infection (5% and 2.8%, respectively), and neutropenia (1.0% and 9.0%, respectively).⁵ Based on these trial results, cemiplimab appears to be a well-tolerated therapy and can be used in patients regardless of PD-L1 expression status.

In a phase 2 trial (NCT02257528), 26 patients, regardless of PD-L1 status, with recurrent or metastatic disease with 2 or fewer prior systemic therapies received nivolumab 240 mg every 2 weeks. The estimated PFS and OS at 6 months were 16.0% and 78.4%, respectively.⁶ The trial results showed that treating this patient population with nivolumab as a single agent demonstrated promising antitumor activity with an acceptable safety profile.

Lastly, tisotumab vedotin-tftv (Tivdak; Seagen Inc) is a novel antibody-drug conjugate that was approved for cervical cancer in 2021. It is directed against tissue factor, which is a protein that is highly prevalent in cervical cancer. Upon internalization, monomethyl auristatin E is released, resulting in cell cycle arrest and apoptotic cell death.^7,8

In a phase 2, open-label, multicenter trial (NCT03438396), 101 patients with recurrent or metastatic cervical cancer received 2 mg/kg (maximum 200 mg) of tisotumab vedotin-tftv intravenously once every 3 weeks. With a median follow-up of 10 months, an objective response rate was achieved in 24% of patients, with 7% achieving complete response and 17% achieving partial response. The median duration of response was 8.3 months. Treatment-related AEs at grade 3 or higher included neutropenia (3%), fatigue (2%), ulcerative keratitis (2%), and peripheral neuropathy (2%).^7,8

Additionally, because tisotumab vedotin-tftv has been associated with ocular toxicity, referral to an ophthalmologist is required for a baseline eye examination prior to each treatment and as clinically indicated.⁸ Topical eye drops are required, including vasoconstrictor eye drops to be used immediately prior to each infusion, corticosteroid eye drops to be used prior and continued after for 72 hours following each infusion, and lubricating eye drops to be used throughout treatment and for 30 days after the last dose. Additionally, patients must avoid eye irritants and wearing contact lenses throughout treatment. The involvement of eye care may pose as an additional barrier to underserved patients because of limited access to resources and the additive costs associated with medications and ophthalmologist visits.

With the addition of immune checkpoint inhibitors, the treatment paradigm for metastatic cervical cancer has changed. For patients who are PD-L1 positive, optimal sequencing of subsequent treatments for recurrent cervical cancer is unknown because these patients may be receiving a 4-drug regimen including bevacizumab and pembrolizumab up front. Because the clinical trials previously discussed all excluded patients who have previously received a PD-1 inhibitor, ongoing research can demonstrate whether this patient population is expected to benefit from immune checkpoint therapy.

In the cemiplimab and nivolumab trials, patients were enrolled regardless of PD-L1 status, and for those patients who are microsatellite instability high and mismatch repair deficient, pembrolizumab is still an option. Regardless of PD-L1 status, tisotumab vedotin-tftv is a new second-line option for cervical cancer, ushering in antibody-drug conjugates for the treatment of gynecologic malignancies.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Cervical cancer, version 01. 2022. Accessed September 4, 2022. https:// www.nccn.org/professionals/physician_gls/cervical.pdf

2. Zhang S, Xu H, Zhang L, Qiao Y. Cervical cancer: epidemiology, risk factors and screening. Chin J Cancer Res. 2020;32(6):720-728. doi:10.21147/j.issn.1000-9604.2020.06.05

3. Tewari KS, Sill MW, Long HJ III, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370(8):734-743. Published correction appears in N Engl J Med. 2017;377(7):702.

4. Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385(20):1856-1867. doi:10.1056/NEJMoa2112435

5. Tewari KS, Monk BJ, Vergote I, et al; Investigators for GOG Protocol 3016 and ENGOT Protocol En-Cx9. Survival with cemiplimab in recurrent cervical cancer. N Engl J Med. 2022;386(6):544-555. doi:10.1056/NEJMoa2112187

6. Santin AD, Deng W, Frumovitz M, et al. Phase II evaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002). Gynecol Oncol. 2020;157(1):161-166. doi:10.1016/j.ygyno.2019.12.034

7. Coleman RL, Lorusso D, Gennigens C, et al; innovaTV 202/GOG-3023/ENGOT-cx6 Collaborators. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(5):609-619. doi:10.1016/S1470-2045(21)00056-5

8. Tisotumab vedotin-tftv. Package insert. Seagen Inc; 2021. Accessed September 4, 2022. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2021/761208Orig1s000lbledt.pdf

About the Authors

Fendi Jan, PharmD, is a postgraduate year 2 oncology pharmacy resident in the Department of Pharmacy at University of Washington Medicine and in the Department of Pharmacy at Fred Hutchinson Cancer Center in Seattle, Washington.

Amy Indorf, PharmD, BCOP, is a clinical pharmacy specialist in the Department of Pharmacy at Fred Hutchinson Cancer Center and in the Department of Pharmacy at University of Washington Medicine.

Allison Kupsh, PharmD, is a clinical pharmacy specialist in the Department of Pharmacy at University of Washington Medicine and in the Department of Pharmacy at Fred Hutchinson Cancer Center.