FDA Approves KEYTRUDA® for Cervical Cancer

SUMMARY: The FDA on June 12, 2018, approved KEYTRUDA® (Pembrolizumab) for patients with recurrent or metastatic Cervical cancer with disease progression on or after chemotherapy, whose tumors express PD-L1 (Combined Positive Score-CPS, of 1 or more) as determined by an FDA-approved test. The American Cancer Society estimates that for Cervical cancer in the US for 2018, about 13,240 new cases of invasive Cervical cancer will be diagnosed and about 4,170 women will die of the disease. Cervical pre-cancers are diagnosed far more often than invasive Cervical cancer. Cervical cancer is most frequently diagnosed in women between the ages of 35 and 44 and in the US. Hispanic women are most likely to get Cervical cancer, followed by African-Americans, Asians and Pacific Islanders, and whites.

Approximately 5% of new diagnoses of Cervical cancer accounts for stage IV disease. However, metastatic disease develops in 15-60% of women, usually within the first two years of completing primary treatment. A select group of women with locally recurrent or limited metastatic disease may be potentially cured with surgical resection or radiotherapy. This however may not be feasible in the majority of cases. Patients with recurrent and metastatic Cervical cancer have a poor prognosis, with limited systemic treatment options. There is currently no consensus on the standard of care for second-line systemic treatment of recurrent or metastatic Cervical cancer, and as such represents a significant unmet clinical need.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

The FDA approval was based on KEYNOTE-158 study, which is a multicenter, non-randomized, open-label, multi-cohort phase II basket study trial, investigating the antitumor activity of KEYTRUDA® in 11 different advanced cancer types, who had progressed on standard-of-care therapy. Basket Trial by definition allows the testing of one drug on a single mutation in a variety of tumor types, at the same time, thereby potentially increasing the number of patients who are eligible to receive certain drugs. KEYTRUDA® was investigated in 98 patients with recurrent or metastatic Cervical cancer, enrolled in a single cohort of the KEYNOTE- 158 trial.

Key eligibility criteria for this cohort included patients with histologically or cytologically confirmed advanced Cervical cancer who had progressed on or intolerant to one or more lines of standard therapy and had tumor sample available for biomarker analysis. Patients were treated with KEYTRUDA® 200 mg IV every 3 weeks until documented disease progression or unacceptable toxicity..PD-L1 positivity, defined as a Combined Positive Score (CPS) of 1 or more, was evaluated retrospectively by ImmunoHistoChemistry (IHC) using the PD-L1 IHC 22C3 pharmDx Kit. Median age was 46 years and 77 patients (79%) of enrolled patients had PD-L1 positive tumors. Primary endpoint was Objective Response Rate (ORR) assessed by independent central review. Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) and safety.

With a median follow up time of 11.7 months, the ORR in the 77 PD-L1 positive patients was 14.3% including 2.6% Complete Responses and 11.7% Partial Responses. The estimated median response duration was not reached, 91% had response duration of 6 months or more, and no responses were observed in patients whose tumors did not have PD-L1 expression (CPS less than 1). The most common adverse reactions in at least 10% of patients were fatigue, fever, nausea, vomiting, diarrhea/colitis, abdominal pain, constipation, hypothyroidism, and dyspnea. KEYTRUDA® was discontinued due to adverse reactions in 8% of patients.

It was concluded that KEYTRUDA® is the first anti-PD-1 therapy approved for the treatment of advanced Cervical cancer, providing an important new second-line option for certain patients with this disease, with durable antitumor activity and manageable toxicity profile. Pembrolizumab treatment of advanced cervical cancer: Updated results from the phase 2 KEYNOTE-158 study. Chung HC, Schellens JH, Delord J, et al. J Clin Oncol 36, 2018 (suppl; abstr 5522)