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Professor and Division Director
OB/GYN and Gynecologic Oncology
University of California, Los Angeles
Los Angeles, California
Ritu Salani, MD, MBA, has disclosed that she has received consulting fees from Arcus, Genentech, GlaxoSmithKline, Instil Bio, Merck, and Seagen; research support from Regeneron.
For many years, there was a dearth of available treatment options for women with cervical cancer. Until very recently, surgery plus chemoradiotherapy and platinum-based chemotherapy (CT) with or without bevacizumab remained the standard first-line treatment for women with locally advanced or metastatic cervical cancer.
Recent FDA Approvals in Cervical Cancers
In October 2021, new FDA approvals expanded our treatment options for women with advanced cervical cancer. Studies like KEYNOTE-826, evaluating the addition of pembrolizumab to platinum-based CT with or without bevacizumab vs platinum-based CT with or without bevacizumab in persistent, recurrent, or metastatic cervical cancer and no previous systemic therapy, and the phase II study of tisotumab vedotin, an antibody–drug conjugate targeting tissue factor, in women with recurrent or metastatic cervical cancer with disease progression on or after platinum-based CT, led to approvals in the frontline and second-line settings, respectively. These approvals already have changed the treatment paradigm for our patients with cervical cancer.
Bringing New Therapies Into Clinical Practice
Since October 2021, the frontline therapy I have been implementing for my patients with PD‑L1–positive disease or a combined positive score of ≥1 has been pembrolizumab plus platinum-based CT and bevacizumab as in the KEYNOTE-826 trial. If patients do not have PD‑L1–positive disease or a combined positive score ≥1, then I recommend platinum-based CT and bevacizumab alone. Of course, there may be contraindications to using pembrolizumab, particularly in patients with autoimmune disease. Fortunately, this scenario has been infrequent in my practice. Another concern with the quadruplet regimen in KEYNOTE-826 is that bevacizumab may increase the risk for fistulas, hypertension, or kidney disease and this might be limiting. If those are concerns, using platinum-based CT plus pembrolizumab alone would be a very reasonable option and approximately 30% of patients in that study did not receive bevacizumab.
It was unclear what to do if a patient progressed while receiving pembrolizumab in the frontline setting, particularly because we have just recently begun to use pembrolizumab upfront for advanced cervical cancer. Currently, there is no evidence to suggest that rechallenge with a checkpoint inhibitor after progression on pembrolizumab therapy in frontline would be appropriate. In patients with progression after platinum-based CT alone and no previous pembrolizumab, we can use checkpoint inhibitors in second-line if patients have PD‑L1–positive disease (pembrolizumab or nivolumab) and/or mismatch repair–deficient (pembrolizumab or dostarlimab) status.
Recent approvals have also expanded nonimmunotherapy options in the second line. In September 2021, tisotumab vedotin received the FDA’s accelerated approval as a second-line treatment for patients with recurrent or metastatic cervical cancer and disease progression on or after CT regardless of a biomarker. Thus, tisotumab vedotin has become the second-line therapy of choice for patients with progression on pembrolizumab plus platinum-based CT in frontline treatment or if their tumor lacks an actionable biomarker. In the phase II innovaTV 204 study of tisotumab vedotin, the overall response rate (ORR) was 24%, median duration of response was approximately 8 months (95% CI: 4.2-not reached), and overall survival was 12 months. Although these are steps in the right direction, therapies that can improve on survival outcomes are sorely needed.
Managing Adverse Events With Novel Agents
Managing toxicities in patients receiving second-line tisotumab vedotin therapy is critical. Patients receiving tisotumab vedotin require careful adverse event (AE) monitoring, including eye examinations prior to every visit, adherence to an eye-care plan (eg, corticosteroid and vasoconstrictor eye drops, cold packs, and lubricating eye drops), and additional self-care measures to reduce the likelihood of ocular AEs. These can be a significant barrier to adherence for patients because some of them already may have limited ability to get to their treatment appointments. Nevertheless, tisotumab vedotin has been shown to be a more effective option compared with historical CT, but it does require additional effort from both healthcare professionals and patients.
Ongoing Trials of Interest
There are several trials for which we hope to see data at upcoming gynecologic cancer conferences. Some of the most exciting trials are exploring the role of immunotherapy in patients with locally advanced disease; they include the phase III CALLA trial of chemoradiotherapy with or without durvalumab and the phase III KEYNOTE‑A18 trial of chemoradiotherapy with or without pembrolizumab.
For patients who are not good candidates for tisotumab vedotin as a second-line therapy, there are several trials that can be considered. The 2-arm, noncomparative phase II study of balstilimab (anti–PD-1) plus zalifrelimab (anti–CTLA-4) exhibited a promising ORR (~15% to 20%) in patients with recurrent or metastatic cervical cancer who relapsed after previous platinum-based therapy (NCT03495882). A biologics license application for accelerated approval of single-agent balstilimab was previously submitted to the FDA, but it was withdrawn. Hypothetically, the addition of an anti–CTLA-4 combination may be able to overcome biomarker-negative expression and augment antitumor potency. Another ongoing trial of interest is the phase I/II trial of bintrafusp alfa, a bifunctional fusion protein that comprises TGF-βRII (TGF-β trap) fused to a human monoclonal antibody blocking PD-L1. In patients with heavily pretreated recurrent cervical cancer, bintrafusp alfa achieved an ORR of 28.2%. Finally, the phase II SKYSCRAPER-04 trial is evaluating the safety and efficacy of combining tiragolumab, a TIGIT inhibitor, and atezolizumab rather than atezolizumab alone as a second-line therapy in patients with metastatic and/or recurrent PD-L1–positive cervical cancer.
Cellular therapy holds great promise for the treatment of recurrent, metastatic, or persistent cervical cancer. Lifileucel, which is an autologous tumor-infiltrating lymphocyte (LN-145), has been in development for a few years, and so far, we have seen a promising ORR of 44%. This treatment can be resource intensive, but it might be a potentially good option for some of our patients.
Another trial of interest was the phase 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. Despite encouraging survival data including in patients who had unknown/negative PD‑L1 expression or combined positive score 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. I think that although response rates were lower in PD‑L1–negative population, they were equivalent to CT alone. Moreover, safety data suggested that cemiplimab was well tolerated, and patients’ quality of life was better than for those receiving CT. I think it’s disappointing that the application was withdrawn for an active agent that may be another option for patients.
I think one of the key challenges this patient population faces to adopt new treatments is a limited availability of resources. Illustrative examples include patients who lack reliable transportation to and from their appointments or whose ability to manage the AEs associated with treatment given their circumstances are less than ideal. The patients I see have limited access to key resources due to their socioeconomic status, personal restraints, or other limitations or barriers. However, treatments are administered every 3 weeks, and once we identify the most appropriate treatment for our patients, we are able to help them identify financial assistance programs and transportation assistance or to accommodate some of their needs based on their unique situation. Within the UCLA health system, we also have different sites that we can leverage to have patients receive treatment closer to their homes. Safety is always a consideration, and we are all extra vigilant about a 4-drug regimen in this patient population. However, we were pleasantly reassured by the safety profile of the addition of pembrolizumab to the platinum-based CT, which has been well tolerated with minimal new AEs. Although very rare, we do have to monitor for immunotherapy-related AEs.
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