Cervical Cancer Awareness Month: Trials Assess New Immunotherapies

Margarett C. Ellison, MD, MHA, FACS, FACOG

On January 26, 2010, Congress passed House Resolution recognizing January as Cervical Health Awareness Month.¹ The incidence of cervical cancer has decreased in the United States due to interventions such as Papanicolaou screening and Human Papilloma Virus (HPV) vaccination over the past 43 years from 15 to 7.7 per 100,000 women. The American Cancer Society predicts 14,100 new cases and 4280 deaths due to cervical cancer in 2022.² Therefore, the need to treat this largely preventable and curable disease still exists beyond surgery, chemotherapy, and radiation therapy modalities.

Most cervical cancers are caused by HPV subtypes 16 and 18, and virally-mediated cervical cancer can present viral antigens to T cells and initiate HPV-specific immune responses. Because of this, immunotherapy has been explored as a treatment paradigm.³ PD-1 and PD-L1 have been utilized as immune response biomarkers as their upregulation has been reported in cervical cancer.⁴ The last 2 years have shown considerable promise in selecting several targeted therapies to treat advanced, persistent, and recurrent cervical cancer.

The KEYNOTE-826 Clinical Trial

KEYNOTE-826 (NCT03635567) was a multicenter, randomized, double-blind, placebo-controlled trial, which examined pembrolizumab (Keytruda) with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (Avastin).⁵ The study enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy irrespective of PD-L1 expression status. They were randomized 1:1 to 1 of 2 treatment groups: pembrolizumab at 200 mg plus chemotherapy with or without bevacizumab versus placebo plus chemotherapy with or without bevacizumab. Pembrolizumab was continued until disease progression, unacceptable toxicity, or up to 2 years of treatment.

The main efficacy end point measures were overall survival (OS) and progression-free survival (PFS) assessed by the investigator using RECIST v1.1 criteria. Additional outcome measures were objective response rate (ORR) and duration of response (DOR). For patients with tumors expressing PD-L1 (combined positive score [CPS] ≥1, n = 548), the median OS was not reached (NR) in the pembrolizumab arm and was 16.3 months in the placebo arm (HR, 0.64; 95% CI, 0.50-0.81; 1-sided P = .0001). The median PFS was 10.4 months (95% CI, 9.7-12.3) in the pembrolizumab arm and 8.2 months (95% CI, 6.3-8.5) in the placebo arm (HR, 0.62; 95% CI, 0.50-0.77; 1-sided P < .001). The ORR was 68.1% and 50.2% with median DOR of 18.0 and 10.4 months in the pembrolizumab and placebo arms, respectively.⁵

On October 13, 2021, the FDA approved pembrolizumab in combination with chemotherapy, with or without bevacizumab, for patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1), as determined by an FDA-approved test.⁶

The innovaTV 204 Clinical Trial

Results of the innovaTV 204 study (NCT03438396) published in Lancet Oncology in 2021 opened to door to FDA approval for another targeted option for metastatic or recurrent cervical cancer with disease progression on or after chemotherapy, tisotumab vedotin-tftv (Tivdak).^7,8 This drug is a tissue factor-directed antibody and microtubule inhibitor conjugate. The innovaTV 204 trial evaluated 101 patients with recurrent or metastatic cervical cancer who had received no more than 2 prior systemic regimens in the recurrent or metastatic setting in an open-label, multicenter, single-arm clinical trial.⁷ About two-thirds of patients had received bevacizumab as part of initial systemic therapy. Patients received tisotumab vedotin-tftv at 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity. End points were ORR as assessed by an independent review committee (IRC) using RECIST v1.1 criteria and DOR.

The ORR was 24% (95% CI, 16%-33%) with a median response duration of 8.3 months (95% CI, 4.2-NR). The most common adverse events (AEs) included anemia, lymphocytopenia, neutropenia, fatigue, nausea, peripheral neuropathy, alopecia, epistaxis, conjunctival AEs, hemorrhage, creatinine increased, dry eye, prothrombin international normalized ratio increased, activated partial thromboplastin time prolonged, diarrhea, and rash. Importantly, product labeling includes a boxed warning for ocular toxicity. The recommended dose is 2 mg/kg (up to a maximum of 200 mg for patients ≥100 kg) given as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.⁸

The EMPOWER-Cervical 1 Clinical Trial

This year also the FDA accepted for priority review PD-1 inhibitor cemiplimab-rwlc (Libtayo) to treat patients with recurrent or metastatic cervical cancer whose disease progressed on or after first-line platinum chemotherapy after the phase 3 EMPOWER-Cervical 1 study (NCT03257267) was closed early at interim analysis due to positive results.⁹ The multicenter open-label trial randomized 608 patients 1:1 to PD-1 cemiplimab versus investigator’s choice single-agent chemotherapy. Patients with recurrent or metastatic cervical cancer were enrolled after first-line therapy with platinum-based chemotherapy. End points were OS, PFS, ORR, quality of life, and safety.

At the interim analysis, OS (12.0 vs 8.5 months), PFS, and ORR favored cemiplimab. The most common AEs of any grade for cemiplimab versus chemotherapy were anemia (25% vs 45%), nausea (18% vs 33%), and vomiting (16% vs 23%). Discontinuation due to AEs occurred in 8% of patients receiving cemiplimab and 5% receiving chemotherapy.⁹ The target action date for the FDA decision is January 30, 2022.¹⁰

_References:

_{1. H.Res.1011 - Recognizing the importance of cervical health and of detecting cervical cancer during its earliest stages and supporting the goals and ideals of Cervical Health Awareness Month. Congress. Accessed January 18, 2022. https://bit.ly/3rrRqgm}

_{2. Cervix. American Cancer Society. Accessed January 18, 2022. https://bit.ly/3IgMWQe}

_{3. Otter SJ, Chatterjee J, Stewart AN, Michael A. The role of biomarkers for the prediction of response to checkpoint immunotherapy and the rationale for the use of checkpoint immunotherapy in cervical cancer. Clin Onco (R Coll Radiol). 2019;31(12):834-843. doi:10.1016/j.clon.2019.07.003}

_{4. Heeren AM, Punt S, Bleeker MC, et al. Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix. Mod Pathol. 2016:29(7):753-763. doi:10.1038/modpathol.2016.64}

_{5. 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}

_{6. FDA approves pembrolizumab combination for the first-line treatment of cervical cancer. FDA. Published October 13, 2021. Accessed January 18, 2022. https://bit.ly/3fAYlhE}

_{7. Coleman RL, Lorusso D, Gennigens C, et al; innovaTV 204/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. FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. FDA. Updated September 21, 2021. Accessed January 18, 2022. https://bit.ly/3GFwNUl}

_{9. Tewari KS, Monk BJ, Vergote I, et al. VP4-2021: EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9: Interim analysis of phase III trial of cemiplimab vs. investigator's choice (IC) chemotherapy (chemo) in recurrent/metastatic (R/M) cervical carcinoma. Ann Onc. 2021;32(7):P940-941. https://doi.org/10.1016/j.annonc.2021.04.009}

_{10. FDA accepts Libtayo (cemiplimab-rwlc) for priority review for advanced cervical cancer. News Release. Regeneron Pharmaceuticals, Inc. September 28, 2021. Accessed October 4, 2021. https://prn.to/3osRTPv}