Nivolumab monotherapy demonstrated promising activity in a small number of patients with recurrent or metastatic cervical, vaginal, and vulvar cancer.
R. Wendel Naumann, MD
Nivolumab (Opdivo) monotherapy demonstrated promising activity in a small number of patients with recurrent or metastatic cervical, vaginal, and vulvar cancer, according to results of the gynecologic cancer cohort of the phase I/II CheckMate-358 trial (NCT02488759).
The objective response rate (ORR) was 26.3% (95% CI, 9.1-51.2) in the cervical cancer arm (n = 19) and 20.0% (95% CI, 0.5-71.6) in the vaginal/vulvar cancer arm (n = 5). At a median follow-up of 19.2 months, the median duration of response (DOR) was not reached in the cervical arm, and was 5.0 months in the vaginal/vulvar arm.
"This trial showed a 26.3% response rate which is higher than has been reported with immunotherapy before. In addition, the compete response rate was 15.8%," wrote study investigator R. Wendel Naumann, MD, gynecologic oncologist, Levine Cancer Institute, Atrium Health, said in a statement to OncLive.
In June 2018, the FDA granted pembrolizumab (Keytruda) an accelerated approval for patients with advanced, PD-L1—positive cervical cancer that has progressed on or after chemotherapy; the decision was based on data from the phase II KEYNOTE-158 trial, in which the PD-1 inhibitor elicited an ORR of 14.3% in this patient population.
However, there remains no established standard of care for patients with recurrent or metastatic cervical cancer, or vaginal and vulvar cancers, owing to limited responses and lack of robust trial data, respectively.
In the multicenter, open-label, multicohort phase I/II CheckMate-358 trial, nivolumab alone and in combination was evaluated in patients with virus-associated solid tumors in the neoadjuvant or recurrent and metastatic settings. In this analysis, 24 patients with cervical, vaginal, or vulvar carcinoma received nivolumab alone.
Patients had a median age of 51 years in the cervical cancer cohort and 59 years in the vaginal/vulvar cohort. The majority of patients presented with stage IV disease at the time of enrollment and received ≥1 prior line of systemic therapy for metastatic disease.
Investigator-assessed ORR served as the primary endpoint of the trial. Secondary endpoints included DOR, overall survival (OS), and progression-free survival (PFS). Safety and patient-reported outcomes (PROs) were included as exploratory endpoints.
Women ≥18 years of age with an ECOG performance status of 0 or 1, a histologically confirmed diagnosis of squamous cell carcinoma of the cervix, vagina, or vulva who received ≤2 prior systemic therapies for metastatic disease were eligible for enrollment. HPV-negativity, active brain or leptomeningeal metastases, secondary malignancy within the prior 3 years, or contraindication to immunotherapy served as exclusion criteria for the trial.
Patients received 240 mg of nivolumab intravenously every 2 weeks for a maximum of 2 years, or until disease progression or unacceptable toxicity. The median duration of treatment was 5.6 months in the cervical cancer cohort and 6.7 months in the vaginal/vulvar cancer cohort.
The disease-control rate was 68.4% (95% CI, 43.4-87.4) in the cervical cancer group and 80.0% (95% CI, 28.4%-99.5%) in the vaginal/vulvar cancer cohorts. Median OS was 21.9 months (95% CI, 15.1—not reached) in the cervical cancer group. At 12 and 24 months, 77.5% (95% CI, 50.5%-91.0%) and 49.8% (95% CI, 23.6%-71.3%) of patients were still alive in the cervical cancer group. Median PFS was 5.1 months in the cervical cancer group.
"In this very poor [prognostic] group of patients, we showed a median survival of 21.9 months, which is better than what is seen with chemotherapy in the first-line metastatic setting," wrote Naumann.
In the vulvar/vaginal cancer group, the median PFS and OS could not be calculated due to its small size. However, 40.0% and 20.0% of patients in the vaginal/vulvar cancer group were still alive at 12 and 18 months, respectively. At 6 months, 40.0% of patients remained progression free.
Patients in the cervical group underwent PD-L1 testing, but PD-L1 status was not found to have a statistically significant impact on responses.
“This study also included 37.5% of patients who were PD-L1 negative, and we observed a response in a patient with vulvar cancer,” Naumann said in his statement.
Regarding safety, most treatment-related adverse events (TRAEs) were grade 1/2. Three cases of grade 3/4 TRAEs were reported in the cervical group, one of which was pneumonitis and resulted in treatment discontinuation. The most common all-grade TRAEs were gastrointestinal (21.1%) and skin reactions (21.1%) in the cervical cancer group and skin-related and endocrine reactions (20.0%) in the vaginal/vulvar cancer group.
PROs for the cervical cancer cohort were assessed with the EORTC QLQ-C30 and EQ-5D questionnaire and revealed stable scores of physical functioning, emotional functioning, and social functioning at week 9 compared with baseline. Though, a clinically meaningful rise in pain, constipation, and fatigue was reported. Moreover, patients indicated a worsening in nausea and vomiting, dyspnea, insomnia, appetite loss, diarrhea, and financial difficulties. Due to the small numbers, PRO data were not reported in the vaginal/vulvar cancer cohort.
Data regarding the combination arm of nivolumab and ipilimumab (Yervoy) in recurrent and metastatic cervical cancer were presented at the 2019 ESMO Congress.2 Patients were randomized to receive 3 mg/kg of nivolumab every 2 weeks and 1 mg/kg of ipilimumab every 6 weeks (n = 45; arm 1), or 3 mg/kg of ipilimumab and 1 mg/kg of nivolumab for 3, 4-week cycles followed by 240 mg of nivolumab every 2 weeks (n = 46; arm 2). Treatment was continued until progression or unacceptable toxicity for a maximum of 1 year.
The majority of patients in both arms had received prior platinum and bevacizumab (Avastin). Patients who did not receive prior systemic therapy had a favorable response to the combination, irrespective of dosing schedule. In arm 1, the ORR was 31.6% and 23.1% in patients with prior systemic therapy and without, respectively. In arm 2, the ORR was 45.8% and 36.4% in patients with prior systemic therapy and without, respectively. Notably, patients with PD-L1 ≥1% had a higher ORR than those with PD-L1 <1%, irrespective of dosing schedule and prior systemic therapy.
In arm 1, patients who did not receive prior systemic therapy experienced a significantly prolonged median PFS of 10.2 months compared with those who did. At 1 year, 52.6% of patients who had not been exposed to prior systemic therapy were alive versus 17.9% of patients who had been. In arm 2, prior exposure to systemic therapy did not have a significant impact on median PFS. Additionally, 43.5% and 38.1% of patients who had received prior systemic therapy and who had not, respectively, were alive at 1 year.
Responses also appeared to be durable in patients who had not received prior systemic therapy. The 1-year OS rates in arm 1 were 83.5% in patients who hadn't received prior systemic therapy and 37.5% in patients who had. In arm 2, the 1-year OS rates were 78.0% and 84.7%, respectively.
No new safety signals were reported in either arm. Though, there was a higher incidence of gastrointestinal treatment-related adverse events leading to treatment discontinuation in arm 2 than arm 1. Given the continued demonstration of safety and efficacy, the trial will continue to enroll patients for further evaluation of nivolumab alone and in combination with ipilimumab in patients with recurrent and metastatic gynecologic cancers.