Nivolumab alone or in combination with ipilimumab produced encouraging responses that were maintained over time in patients with recurrent or metastatic cervical cancer.
Ana Oaknin, MD, PhD
Nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) produced encouraging responses that were maintained over time in patients with recurrent or metastatic cervical cancer, according to updated findings from the phase 1/2 CheckMate-358 trial (NCT02488759).1
At a minimum follow-up of 24 months, the investigator-assessed objective response rate (ORR) was 26% (95% CI, 9%-51%) with nivolumab alone (n = 19), 31% (95% CI, 18%-47%) with 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab (n = 45; N3+I1), and 38% (95% CI, 29%-48%) with 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab (n = 112; N1+I3).
“These data indicate that chemotherapy-free immunotherapy with nivolumab alone or in combination with ipilimumab can provide durable tumor regression with manageable toxicity in patients with recurrent/metastatic cervical cancer, regardless of tumor PD-L1 expression,” Ana Oaknin, MD, PhD, lead study author and head of the Gynaecological Tumour Unit at the Vall d’Hebron Institute of Oncology in Barcelona, Spain, said in a presentation of the data at the 2022 ESMO Congress.
In earlier findings, nivolumab demonstrated clinically meaningful antitumor activity as a single agent and in the N3I1 and N1I3 dosing schedules, with ORRs of 26%, 27%, and 41%, respectively.2,3
To be eligible for enrollment, patients had to have histologically confirmed, recurrent/metastatic squamous cell carcinoma of the cervix and have received no more than 2 prior therapies for recurrent/metastatic disease. They were also required to have at least 1 target lesion, an ECOG performance status of 0 or 1, and positive or unknown human papillomavirus status.
Patients were treated with 1 of 3 regimens: 240 mg of nivolumab every 2 weeks (n = 19); 3 mg/kg of nivolumab every 2 weeks plus 1 mg/kg of ipilimumab every 6 weeks (n = 45; N3+I1); or 1 mg/kg of nivolumab every 2 weeks plus 3 mg/kg of ipilimumab every 3 weeks for 4 cycles followed by 240 mg of nivolumab every 2 weeks (n = 45; N1+I3).
Based on an early efficacy signal in the N1+I3 arm, the study protocol was amended in July 2018 to include an N1+I3 expansion arm, in which 44 patients received 1 mg/kg of nivolumab and 3 mg/kg of ipilimumab in the first line and 23 patients received the combination in the second line.
Treatment was continued until disease progression or maximum of 24 months, unacceptable toxicity, or withdrawal of consent.
Imaging assessments were performed every 8 weeks for the first year of treatment and every 12 weeks thereafter.
The primary end point is investigator-assessed ORR. Secondary end points include duration of response (DOR), investigator-assessed progression-free survival (PFS), and overall survival (OS).
Baseline characteristics indicated that most patients were enrolled in Europe, had a PD-L1 expression of at least 1%, and received prior radiotherapy. Notably, 21%, 40%, and 64% of patients in the nivolumab, N3+I1, and N1+I3 arms, respectively, did not receive any prior systemic therapy in the metastatic setting.
Further findings indicated that N3+I1 and N1+I3 led to an “expectedly” higher ORR in the first line compared with the second line, at 39% (95% CI, 17%-64%) vs 26% (95% CI, 11%-46%) and 41% (95% CI, 29%-53%) vs 35% (95% CI, 21%-51%), respectively.
“N1+I3 showed a higher response rate than N3+I1 in the first- and second- or later-line setting,” Oaknin added.
The median DOR was not reached (NR; 95% CI, 35.3-NR) with nivolumab alone, 24.4 months (95% CI, 8.7-NR) with N3+I1, and 34.1 months (95% CI, 11.5-NR) with N1+I3.
Additionally, the median PFS was 5.1 months (95% CI, 1.9-9.1), 3.8 months (95% CI, 2.1-10.3), and 5.8 months (95% CI, 3.8-9.3) with nivolumab, N3+N1, and N1+N3, respectively.
The minimum follow-up for OS was 67.4 months, 36.9 months, and 17.9 months for the nivolumab, N3+I1, and N1+I3 arms, respectively. The median OS was 21.6 months (95% CI, 8.3-46.9), 15.2 months (95% CI, 9.0-36.2), and 20.9 months (95% CI, 14.4-32.8), respectively.
The 1- and 2-year OS rates with nivolumab alone were 73% (95% CI, 46%-88%) and 43% (95% CI, 20%-64%), respectively. With N3+I1, the 1- and 2-year OS rates were 54% (95% CI, 38%-68%) and 37% (95% CI, 23%-51%), respectively. N1+I3 led to 1- and 2-year OS rates of 69% (95% CI, 60%-77%) and 48% (95% CI, 38%-57%), respectively.
“Durable responses were observed regardless of tumor PD-L1 status across all treatment arms, [although] fewer responses [were] seen in patients with PD-L1 <1% treated with nivolumab monotherapy compared with patients with PD-L1 <1% treated with nivolumab and ipilimumab,” Oaknin said.
Regarding safety, no new signals were identified, and the frequency of adverse effects (AEs) was higher with N1+I3 vs either N3+I1 or nivolumab alone.
Specifically, treatment-related AEs (TRAEs) were highest with N1+I3 (any grade, 88%; grade 3/4, 46%), followed by N3+I1 (any grade, 80%; grade 3/4, 29%), and nivolumab alone (any grade, 63%; grade 3/4, 21%).
Similarly, TRAEs leading to discontinuation were highest with N1+I3 (any grade, 24%; grade 3/4, 19%), followed by N3+I1 (any grade, 18%; grade 3/4, 9%), and nivolumab alone (any grade, 11%; grade 3/4, 5%).
Regarding nonendocrine immune-mediated AEs, hepatitis and diarrhea/colitis did not occur in any patients in the nivolumab alone arm compared with the N3+I1 (hepatitis: grade 3/4, 7%; diarrhea/colitis: any grade, 4%; grade 3/4, 2%) and N1+I3 (hepatitis: any grade, 18%; grade 3/4, 16%; diarrhea/colitis: any grade, 16%; grade 3/4, 5%) arms.
“Safety profiles seen in this study were similar to those reported in previous clinical trials,” Oaknin concluded.