By Monica Avila, MD, MPH
Gynecologic Oncologist at Moffitt Cancer Center
Cervical cancer is the fourth most common cancer worldwide, now surpassing 600,000 cases and 300,000 deaths per year. However, only 10% of cases are in first-world countries because of vaccination and secondary prevention methods. In the United States, 13,960 new cases of invasive cervical cancer will be diagnosed each year. Of these, about 4,310 women will die from cervical cancer.
Frontline Treatment of Cervical Cancer
In 2014, a practice-changing study came out of the Gynecologic Oncology Group Foundation, also known as the GOG 240, evaluating the addition of VEGF inhibitor Bevacizumab to the standard of care chemotherapy with either Cis/Taxol or Top/Taxol including 70% of patients with recurrent and 17% of patients with advanced disease. Of these, three-fourths of the patients had seen prior platinum.
The addition of Bevacizumab proved to be the great equalizer with a 60% survival rate at one year mark. These patients were treated with a 30% reduction in hazard irrespective of chemo doublet given when Bevacizumab was added for both progression-free survival (FS) and overall survival (OS). This extended the median OS from one year to approximately 18 months.
Subgroup analyses revealed treatment benefit with Bevacizumab was also observed regardless of age, performance status, race, squamous histologic type, status with respect to prior platinum exposure, recurrent or persistent disease, and pelvic location of the target lesion.
In 2021, the standard of care changed again with the incorporation of immunotherapy into the triplet previously studied in GOG 240. The Anti PD1 Pembrolizumab was added to chemotherapy plus Bevacizumab and randomized in a 1:1 fashion. The usage of Bevacizumab was equivalent between the two groups. Over 80% of the patients had chronic pain syndrome (CPS) or a combined positive score of PDL1 availability greater than one. CPS > or equal to 1 then became the standard cut-off for qualifying for immunotherapy in the front-line setting per the FDA guidelines.
In the intent-to-treat (ITT) population, there was a 33% reduction in hazard in favor of the treatment intervention. This was statistically significant only in patients with CPS >1 and there was no difference in hazard when stratified between CPS >1 or CPS scores greater than 10.
Treatment for Recurrent Cervical Cancer
Beyond the use of concurrent chemotherapy, Bevacizumab, and immunotherapy: Keynote 28 explored single agent Pembrolizumab in the recurrent setting in PD1 positive tumors with 42% noting a hx of prior Bevacizumab exposure. Surprisingly, the single agent immunotherapy saw only a response rate of 17% when dosed at 10mg/kg for two years with only a median duration of response of five months. This was in patients with at least one prior line of therapy and all responses were partial responses.
Novel Therapeutics: Antibody Drug Conjugates (ADC) and Cell Therapy
Antibody Drug Conjugates (ADC)
- Tisotumab Vedotin is an Antibody-Drug Conjugate (ADC) where antibodies that engage tissue factor protein (TF) on human cervical cancer cells attach and via a linker deliver a cytotoxic payload of a microtubule disrupting agent called Monomethyl auristatin E (MMAE).
- InnovaTV 204: Phase 2 of Tisotumab Vedotin
This ADC was explored in recurrent or metastatic cervical cancer patients who received less than two prior lines at 2mg/kg IV q3wks with the primary endpoint of objective response rate and secondary objectives including OS. Primarily these tumors were squamous with 96% of patients positive for membrane TF expression but enrollment was TF agnostic. Sixty-four percent of these patients had seen Bevacizumab in the past which is not surprising as it is the frontline standard of care.
The objective response rate for Tidvak was higher than single agent IO at 24%. You can see a 70% saw reduction in disease volume, and this became the first ADC approved for gynecologic malignancies. Currently, a combination of therapies of this ADC with either chemotherapy or Pembrolizumab is being explored in the GOG 3024. It is FDA-approved as a single agent in the recurrent setting regardless of TF expression.
Tumor Infiltrating Lymphocytes (LN-145)
- A phase 2 study is currently open for patient accrual at Moffitt Cancer Center. A multicenter study is set to evaluate the efficacy and safety using autologous Tumor Infiltrating Lymphocytes (LN-145) in patients with recurrent, metastatic, or persistent cervical carcinoma (18959). The principal investigator for this study is Dr. Robert Wenham. This study is currently open and is accruing patients.
The purpose of this study is to find out if an investigational product called LN-145 (a patient's own immune cells called tumor-infiltrating lymphocytes (TILs)) is safe, tolerable, and effective in participants with recurrent and/or metastatic cervical cancer. The cells are extracted from a patient’s tumor, grown in a lab, and reinfused. LN-145 is an investigational drug and has not been approved by the Food and Drug Administration (FDA). Other drugs are used in this study, although they may be approved for other conditions and may be considered investigational in this study.
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