CE / CME
Pharmacists: 1.25 contact hours (0.125 CEUs)
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Nurses: 1.25 Nursing contact hours
Released: May 13, 2022
Expiration: May 12, 2023
Ritu Salani, MD, MBA:
It’s been long stablished that cervical cancer is predominantly driven by human papillomavirus (HPV) infection, which can potentially lead to tumorigenesis over the course of many years. The most effective strategies, currently, against cervical cancer are prevention with HPV vaccination or early detection of preneoplastic lesions.38,39
Ritu Salani, MD, MBA:
I would like to discuss important developments that have occurred in cervical cancer treatment over the past few decades. This schematic provides a comprehensive overview of treatment options for all stages of cervical cancer, including cervical dysplasia, early disease, locally advanced disease, and metastatic disease.40-42
The 2 most recent additions to the treatment landscape for advanced/metastatic cervical cancer were adding pembrolizumab to platinum-based CT in patients with metastatic, PD-L1–positive cervical disease, driven by results from KEYNOTE-826,27 and the approval of tisotumab vedotin as second-line therapy in patients with recurrent or metastatic cervical cancer with disease progression on or after CT, based on the results from the single-arm phase II innovaTV 204/GOG 3023 study.43
But first, I will briefly discuss the role of immunotherapy as second-line treatment in cervical cancer, as well as other exciting agents in development.
Ritu Salani, MD, MBA:
KEYNOTE-158 is an ongoing phase II basket trial of single-agent pembrolizumab in multiple solid tumors, including cervical cancer (estimated N = 1595).44 In 2018, results from KEYNOTE-158 showing improved responses in patients with PD-L1–positive cervical cancer resulted in FDA accelerated approval of single-agent pembrolizumab in this setting.27
Ritu Salani, MD, MBA:
At SGO 2021, Chung and colleagues45 presented updated results from the KEYNOTE-158 cervical cancer cohort with a median of 36.9 months of follow-up.45 The ORR in patients with PD-L1 positivity was 14.3% vs 0% in the PD-L1–negative group, although 3 patients achieved SD in this subset.
In patients who responded, the median time to response was fairly short at 2.3 months (range: 1.6-17.6 months).
Ritu Salani, MD, MBA:
The updated PFS and OS results show that at 2 years, 12.9% remained progression free, and 23.7% were alive, suggesting single-agent immunotherapy does make a difference for these patients who have previously failed frontline CT.
Ritu Salani, MD, MBA:
The highly encouraging phase II results in previously treated patients led to the ongoing phase III KEYNOTE-826 study of pembrolizumab plus CT vs placebo plus CT, both with or without bevacizumab (N = 548). The coprimary endpoints are OS and PFS.
Important to note that results from this phase III trial led to FDA approval of pembrolizumab in combination with CT with or without bevacizumab, for patients with persistent recurrent or metastatic cervical cancer whose tumors express PD-L1 (combined positive score CPS ≥1), as determined by an FDA-approved test
Ritu Salani, MD, MBA:
Although the PFS results in the PD-L1–positive and the larger ITT group were positive to result in FDA approval (median: 10.4 months for both groups vs 8.2 months for placebo), it’s important to note that nearly all (approximately 90%) of patients in this study were PD-L1–positive; the PD-L1–negative population was very limited.
Ritu Salani, MD, MBA:
Similarly, the addition of pembrolizumab to CT (with or without bevacizumab) improved OS in both the ITT population (HR: 0.67) and the majority subset with PD-L1 CPS ≥1.
Ritu Salani, MD, MBA:
The ORR and DoR rate also were significantly improved with the addition of pembrolizumab to CT compared with placebo. As with PFS and OS, the benefit was evident across subgroups. In the all-comer population, the ORR in the pembrolizumab arm was 65.9% (68.1% with PD-L1 CPS ≥1) vs 50.8% with placebo. The median DoR in all comers and in the PD-L1 CPS ≥1 population was 18.0 months vs 10.4 months with placebo.
Ritu Salani, MD, MBA:
It is reassuring that the AE profile from the KEYNOTE-826 study showed no new safety signals with the addition of pembrolizumab to CT, regardless of bevacizumab. This regimen was very well tolerated, and although all-cause grade 3 toxicities occurred in many patients in the pembrolizumab arm (82%), the rate of discontinuation of any treatment was 37.5%. Of importance, only 5.9% of patients in the pembrolizumab arm discontinued all treatment, which is comparable with the placebo arm.
In my practice, I have seen patients tolerate this regimen very well. However, it is important to note that when toxicities occur, management depends on which agent is causing the specific toxicity (eg, taxanes cause neuropathy). In this study, the incorporation of pembrolizumab showed a benefit, so if a patient has a toxicity related to bevacizumab or other agents, then continuing pembrolizumab and dropping the other agent(s) is a reasonable strategy. For patients who have hypertension, wound healing issues, or fistulas, holding or discontinuing bevacizumab while continuing pembrolizumab improved outcomes in this study.
Eva Y. Pan, PharmD, BCOP:
This is a hopeful time in the management of cervical cancer with the recent approval of immunotherapy in combination with CT for the frontline setting. However, pembrolizumab plus CT, with or without bevacizumab is one of the more challenging regimens used to treat gynecologic cancers.
With regard to pembrolizumab, it is very important for pharmacists to educate nurses and patients about identifying and monitoring irAEs and to assist healthcare professionals in managing the irAEs. Pharmacists should review patients’ complete list of medications to identify whether patients with baseline steroid use are good candidates for long-term treatment with immunotherapy. This is because steroid doses higher than prednisone 10 mg (eg, above physiologic dose) potentially could interfere with immunotherapy.
In KEYNOTE-826, pembrolizumab treatment could be continued for up to 35 cycles after the CT portion was completed. One option that may be more convenient for patients is to switch from pembrolizumab every 3 weeks to a dose of 400 mg every 6 weeks.
In patients receiving bevacizumab, it is important to monitor blood pressure and urine protein. For example, bevacizumab administration should be temporarily suspended if 24-hour urine protein levels are >2 g and resumed when levels are <2 g. Treatment discontinuation is recommended in cases of nephrotic syndrome (24-hour urine protein >3.5 g).46 Moreover, if patients are about to undergo surgery, bevacizumab should be withheld for 4 weeks. Bowel perforation can be a risk of bevacizumab and is associated with bowel obstruction.
Pharmacists can help determine optimal dose reductions for the CT portion of this regimen, based on AEs including myelosuppression. Pharmacists also should evaluate the need for growth factor support, if indicated, and help with the insurance approval if it is an issue. Pharmacists then also should evaluate for the use of other supportive medications, for example, duloxetine for neuropathy or olanzapine for nausea and vomiting.
Ritu Salani, MD, MBA:
In addition to immunotherapies, targeted agents are now becoming an option in cervical cancer. Tisotumab vedotin is an FDA-approved ADC directed to tissue factor and covalently linked to the microtubule-disrupting agent MMAE via a protease-cleavable linker.47,48 Tissue factor is highly expressed in cervical cancers, which makes this ADC an appealing strategy. Tisotumab vedotin can kill malignant cells through various mechanisms, including direct cytotoxicity from the linked payload, bystander-cell killing effect, immunogenic cell death, and both antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.49
Ritu Salani, MD, MBA:
The ongoing innovaTV 204 trial is a single-arm phase II study evaluating tisotumab vedotin in 102 patients with recurrent or metastatic cervical cancer.43 All patients had progressed on at least 2 prior systemic CT regimens (including bevacizumab if they were eligible). The primary endpoint for the study is ORR.
Results from innovaTV 204 with encouraging responses resulted in the FDA approval of tisotumab vedotin for recurrent or metastatic cervical cancer with disease progression on or after CT.50
Ritu Salani, MD, MBA:
At the data cutoff, the ORR was 24% with CRs in 7% of patients and PRs in 17%. In addition, almost 50% of patients achieved SD, which is an impressive response in a population with no curative therapies. The median DoR was 8.3 months.
Ritu Salani, MD, MBA:
As expected, new agents bring new toxicities, and tisotumab vedotin is no exception. This study was designed to assess ocular toxicity, bleeding, and peripheral neuropathy associated with the ADC.
Ocular toxicities were seen in 54% of patients, but fortunately these toxicities were primarily grade 1/2 with only 2% of patients experiencing grade 3 ocular toxicities. Ocular toxicities were generally successfully resolved with an eye care plan. It is important to use this strategy when incorporating tisotumab vedotin into the treatment plan for cervical cancer. Tisotumab vedotin should be used in conjunction with eye cooling packs and eye drops to help mitigate the eye toxicity; it also is critical to advise patients receiving tisotumab vedotin to follow the eye care plan recommendations, which are outlined in the package insert. The main risk is having a patient discontinuing treatment with an active agent because of a preventable toxicity. Although 39% of patients experienced bleeding, nearly all (34%) was grade 1. Likewise, 33% of patients developed peripheral neuropathy (from the MMAE), but only 7% was grade 3—which was the most common grade 3 event in this report.
I have treated a limited number of patients with tisotumab vedotin since its recent approval. A patient I treated did not have preexisting neuropathy but later developed mild neuropathy. Neuropathy can be a very challenging toxicity to manage; it can affect patients’ daily activities, and if physicians are not highly alert to this risk, there is a chance the patient may need to stop an otherwise effective drug. Although neuropathy cannot be managed with an alternative dosing strategy, patients who have severe toxicity with first-line taxane-based therapy are at a higher risk in my experience. Before starting tisotumab vedotin, these patients should be prepared to use recommended strategies to help reduce the risk for developing peripheral neuropathy (eg, gabapentin, acupuncture).51 In my practice, we have used cold packs to help minimize eye toxicity from tisotumab vedotin, and it may be reasonable to consider using cold packs for fingertips or toes to minimize peripheral neuropathy toxicity. However, this has not yet been studied in a randomized trial and remains anecdotal.
Eva Y. Pan, PharmD, BCOP:
Tisotumab vedotin represents an exciting new option in the management of relapsed, recurrent cervical cancer.50 However, as previously mentioned, it is associated with ocular toxicity risk and requires labor-intensive supportive care to maximize its therapeutic benefit for patients. As a result, it is important to educate both nurses and patients on how to mitigate the risk and manage ocular AEs. Prior to each tisotumab vedotin infusion, patients need to see an eye specialist (ophthalmologist/optometrist) to assess for any changes in their vision. Patients also should be counseled to avoid contact lenses and anything that could cause eye irritation throughout treatment with tisotumab vedotin.
Corticosteroid and vasoconstrictor eye drops should be administered prior to tisotumab vedotin infusion. About 10 minutes before the infusion, nurses should apply cold packs to cover the patients’ eyes after administering the vasoconstrictor eye drops, the cold packs should be replaced as needed during the infusion and kept in place for approximately 20 minutes after the infusion. The reason for the cold packs and vasoconstrictor drops is to reduce the flow of tisotumab vedotin into the eye during infusion and thereby mitigate the ocular toxicity with this agent. The manufacturer’s website provides multiple resources to manage ocular AEs associated with tisotumab vedotin, including an eyecare guide for patients and an eyedrop tracker.
After tisotumab vedotin infusion, patients should self-administer corticosteroid eyedrops twice throughout the remainder of the infusion day and then 3 times a day for 2-3 days after the infusion with the steroid. Lubricating eyedrops should be administered throughout all of the cycles of treatment and for 30 days after the last dose. Patients need to be counseled to monitor closely for new or worsening ocular signs or symptoms, including redness, dry eye, itchy eye, and blepharitis, and then promptly contact their eyecare provider if any of these occur. Patients also may need additional reminders to continue to avoid contact lenses and potential eye irritants for the duration of treatment.
Ritu Salani, MD, MBA:
Important trials are underway that will continue to improve outcomes for patients with recurrent or metastatic cervical cancer. Early results from the III EMPOWER-CERVICAL 1 study evaluating cemiplimab, an anti–PD-1 monoclonal antibody, vs CT in patients with metastatic cervical cancer resistant to platinum-based CT and ≥1 previous therapy showed encouraging responses (50% vs 19%) and survival data (median PFS: 2.8 vs 2.9 months; median OS: 12.0 vs 8.5 months). Moreover, safety data suggested that cemiplimab was well tolerated, and patients’ quality of life was better than for those receiving CT.52
Despite encouraging survival and safety data, including in patients who had unknown/negative PD‑L1 expression or CPS status, the biologics license application for cemiplimab as a second-line treatment of advanced cervical cancer was voluntarily withdrawn by the study sponsor after discussions with the FDA. Promising data from early-phase clinical trials also have suggested benefit from nivolumab monotherapy (CheckMate 358),53 balstilimab (a PD-1 inhibitor) with or without zalifrelimab (a CTLA-4 inhibitor),54 and lifileucel (tumor-infiltrating lymphocytes).55
Ritu Salani, MD, MBA:
As of Spring 2022, there are several ongoing phase III studies of new approaches to recurrent or metastatic cervical cancer that I would like to highlight.
BEATcc is evaluating the addition of the PD-L1 inhibitor atezolizumab to bevacizumab in combination with CT (N = 404) (NCT03556839). Primary endpoints are PFS and OS. This study is similar to KEYNOTE 826, except that bevacizumab is mandated here.
CALLA is a study of chemoradiation with or without the PD-L1 inhibitor durvalumab in patients with high-risk locally advanced or metastatic cervical cancer (N = 770) (NCT03830866). Preliminary results, reported in a press release, suggested no significant PFS benefit (primary endpoint) for the addition of durvalumab to chemoradiation. I hope to see more details soon, but at this time, it’s a disappointing result.
KEYNOTE-A18 is a phase III study evaluating the addition of pembrolizumab to chemoradiation in patients with high-risk locally advanced cervical cancer (estimated N = 980) (NCT04221945). The primary endpoint is PFS and OS. Healthcare professionals should consider offering this study to eligible patients with cervical cancer, as it is ongoing and actively recruiting.
A phase II clinical study is currently evaluating cemiplimab together with an anti-HPV16 vaccine in patients with HPV16-positive recurrent/metastatic cervical cancer who experienced progression on/after first-line therapy (estimated N = 105) (NCT04646005). The primary endpoint is ORR at 3 years.
Lastly, the phase II STAR trial is evaluating the combination of PARP inhibitor niraparib and PD-1 inhibitor dostarlimab in patients with recurrent or progressive cervical cancers with measurable disease per RECIST v1.1 (estimated N = 66) (NCT04068753). The primary endpoint is response (CR or PR) at 1 year.
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