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With few chemotherapy options available for patients with cervical cancer, R. Wendel Naumann, MD, said that immunotherapy represents an attractive treatment option in the landscape.
R. Wendel Naumann, MD
With few chemotherapy options available for patients with cervical cancer, R. Wendel Naumann, MD, said during the 2020 SGO Winter Meeting that immunotherapy represents an attractive treatment option in the landscape.
Naumann, professor and director of minimally invasive surgery in gynecologic oncology with Levine Cancer Institute, Carolinas Medical Center, Atrium Health, noted that chemotherapy has proven to be largely ineffective in this disease.
An analysis of 3 Gynecologic Oncology Group studies that included 428 women who received standard cisplatin-based combination chemotherapy for advanced or recurrent cervical carcinoma showed that, even in low-risk patients, the objective response rate (ORR) is 43%, along with a median progression-free survival (PFS) of 7 months and a median overall survival (OS) of 12 months.1 Furthermore, there is no evidence that chemotherapy improves OS compared with best supportive care for recurrent disease, Naumann said.
He explained that immunotherapy makes sense in cervical cancer—a virally induced tumor that should be highly angiogenic. Virus-induced cancers generally make good targets for immunotherapy because viral proteins are strong immune stimulants.
In light of the “dismal” results with chemotherapy, Naumann called immunotherapy “an exciting option.”
“One of the things tumors have to do is evade apoptosis,” he said. “We know that the immune response is important, particularly for these virally induced cancers.”
In the KEYNOTE-158 trial, investigators evaluated pembrolizumab (Keytruda) for patients with patients with advanced cervical squamous cell cancer (n = 98). Patients received 200 mg of pembrolizumab every 3 weeks for 24 months or until withdrawal of consent, confirmed radiographic progression, unacceptable toxicity, or investigator decision.2 Eighty-four percent of patients were found to be positive for PD-L1.
Results showed that the ORR was 12.2% (95% CI, 6.5-20.4) with 3 complete responses and 9 partial responses. Overall, the median PFS was 2.1 months (95% CI, 2.0-2.1) and the median OS of 9.4 months (95% CI, 7.7-13.1).
All 12 responses were in patients with PD-L1—positive tumors, for an ORR of 14.6% (95% CI, 7.8-24.2). The median OS was 11.1 months (95% CI, 9.1-14.1) in the PD-L1–positive population.
Based on these preliminary data, the FDA granted an accelerated approval in June 2018 to pembrolizumab for the treatment of patients with advanced cervical cancer who have disease progression on or after chemotherapy, whose tumors express PD-L1 (combined positive score ≥1).
Despite this advance, there is no established standard of care for patients with recurrent or metastatic cervical cancer due to limited responses. Furthermore, vaginal and vulvar cancers are rare, and few clinical trials include these patient populations; therefore, there is a lack of robust trial data regarding these patients.
Investigators in the phase I/II CheckMate-358 trial sought to provide clinical evidence showing the value of nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in patients with recurrent or metastatic cervical, vaginal, and vulvar cancer.
In the nivolumab-alone cohort, 24 patients received 10 mg of intravenous nivolumab 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.
In the cervical cancer cohort (n = 19), 37.5% of patients had PD-L1—negative tumors and 42% had undergone ≥2 lines of systemic therapy.
The ORR was 26.3% (95% CI, 9.1-51.2) in the cervical cancer arm and 20.0% (95% CI, 0.5-71.6) in the vaginal/vulvar cancer arm (n = 5).3 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 cancer arm.
The median PFS in the cervical cancer group was 5.1 months (95% CI, 1.9-9.1) with a median OS of 21.9 months (95% CI, 15.1-not reached). Because of the small number of patients in the vaginal/vulvar cancer cohort, the median PFS and OS were not calculated.
“We saw several durable, long lasting responses,” Naumann said. “We saw 1 response in the vulvar carcinoma group and another that was close—we only had 5 patients in that cohort.”
Naumann et al presented findings of the CheckMate-358 trial looking at the combination of nivolumab and ipilimumab in patients with recurrent and metastatic cervical cancer at the 2019 ESMO Congress.4 Patients were randomized to 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 three 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 ≤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.
The ORR in arm 1 was 23.1% in patients who received prior systemic therapy and 31.6% in those who did not have prior treatment. The ORR was more robust in arm 2, with an ORR of 36.4% in patients with prior systemic therapy and 45.8% for those without.
Patients with PD-L1 ≥1% had a higher ORR than those with PD-L1 <1% at 30.4% versus 24.0%, respectively, irrespective of dosing schedules and prior systemic therapy.
Patients in arm 1 who did not receive prior systemic therapy had a 10.2-month advantage in median PFS compared with those who had prior treatment at 13.8 months and 3.6 months, respectively. The 1-year PFS rates in these groups were 52.6% and 17.9%, respectively.
In arm 2, prior exposure to systemic therapy did not have a significant impact on median PFS; the median PFS was 8.5 months in the treatment-naïve group and 5.8 months in the previously treated cohort. Additionally, 43.5% of patients who had received prior systemic therapy were alive at 1 year versus 38.1% of patients who had not.
In the “excellent” OS results, Naumann said that in arm 1, the median OS was not reached in those who did not receive prior treatment compared with 10.3 months for those who had received therapy. The 1-year OS rates were 83.5% and 37.5%, respectively.
Additionally, in arm 2, the median OS was not reached for those who hadn’t received prior systemic therapy and the 1-year OS rate was 78.0%. The median OS was 25.4 months and the 1-year OS rate was 84.7% for those who received prior systemic therapy.
“Ipilimumab increases the response at the point of antigen presentation,” Naumann said. “If you have a virus that’s able to evade the immune system, that’s probably really important, so that’s why this combination is exciting.”