Nivolumab Plus Ipilimumab Shows Durable Clinical Activity in Cervical Cancer

Ana Oaknin, MD

Ana Oaknin, MD

In the CheckMate-358 study, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) showed durable clinical activity in patients with recurrent or metastatic cervical cancer, regardless of tumor PD-L1 expression.

The study tested 2 different regimens combining nivolumab and ipilimumab, and showed that the efficacy of the combination was superior in patients without prior systemic therapy versus with systemic therapy for recurrent/metastatic (R/M) disease, reported Ana Oaknin, MD, at the 2019 ESMO Congress.

“Very provocatively, across both regimens, efficacy was better in patients without prior systemic therapy,” said Oaknin, from Vall d’Hebron University Hospital, Barcelona, Spain. “Additionally, responses were durable; at a median follow-up of more than 10 months, the median duration of response was not reached for either regimen in patients without prior systemic therapy.”

Given the limited treatment options for patients with R/M cervical cancer “these data with nivolumab plus ipilimumab are of strong clinical interest and warrant further investigation in this patient population,” said Oaknin.

A total of 91 patients with histologically confirmed squamous cell carcinoma of the cervix and who received 2 or fewer prior systemic therapies for R/M disease were randomized 1:1 to either nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks (nivo3 + ipi1) or nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg, given every 3 weeks for 4 doses followed by nivolumab at 240 mg every 2 weeks (nivo1 + ipi3).

At the time of data lock, the median follow-up was 10.7 months in the nivo3 + ipi1 arm and 13.9 months in the nivo1 + ipi3 arm. In the nivo3 + ipi1 arm, median progression-free survival (PFS) was 13.8 months (95% CI, 2.1-not reached) in the patients not previously treated with systemic therapy for R/M disease and 3.6 months (95% CI, 1.9-5.1) in those with previous systemic therapy for R/M disease. At 6 months, the probability of PFS was 57.9% and 26.9% in the 2 groups, respectively, and at 12 months, these percentages were 52.6% and 17.9%, respectively.

In the nivo1 + ipi3 arm, the median PFS was 8.5. months (95% CI, 3.7-not reached) in the patients with no prior systemic therapy for R/M disease and 5.8 months (95% CI, 3.5-17.2) in those who had received prior systemic therapy for R/M disease. The probability of PFS at 6 months was 60.9% in those with no prior systemic therapy for R/M disease and 47.6% in those with prior systemic therapy, and at 12 months, these percentages were 43.5% and 38.1%, respectively.

“The overall survival curves were really striking,” said Oaknin. Median overall survival (OS) was not reached in the nivo3 + ipi1 group that had no prior systemic therapy for R/M disease and 10.3 months in those with prior systemic treatment for R/M disease. The corresponding median OS values in the nivo1 + ipi3 arm were not reached and 25.4 months, respectively.

Cervical cancer is the fourth most common cancer in women worldwide, with more than 99% of cases associated with human papilloma virus (HPV) infection. Currently, the standard of care for R/M disease without prior systemic therapy is the combination of cisplatin, paclitaxel, and bevacizumab. Median overall survival with this combination in the R/M setting is <17 months. &ldquo;Unfortunately, for those patients who progress on chemotherapy and bevacizumab, treatment options are very limited,&rdquo; said Oaknin.

The PD-1 inhibitor pembrolizumab (Keytruda) is approved by the FDA for the treatment of R/M cervical cancer&nbsp;post-chemotherapy, but its approval is limited to those patients whose tumors express PD-L1 (combined positive score &ge;1). Upregulation of PD-1 and PD-L1 expression has been reported in cervical cancer, which suggests that this tumor type is likely to respond to PD-1/PD-L1-based therapy. CTLA-4 is another inhibitory checkpoint that plays a key role in regulating adaptive immunity, offering the possibility of response to agents that target this protein receptor.

CheckMate-358 is an ongoing phase I/II study that is investigating nivolumab-based therapies in virus-associated cancers, regardless of tumor cell PD-L1 expression. Patients enrolled were positive for HPV or their HPV status was unknown. An ECOG performance status of 0 or 1 was required for entry. Treatment continued until toxicity, disease progression, or a maximum of 24 months. Patients were followed with imaging every 8 weeks for 1 year and then every 12 weeks.

Baseline characteristics were well-balanced between the 2 arms. The vast majority enrolled had metastatic disease and 82.2% (nivo3 + ipi1) and 73.9% (nivo1 + ipi3) were evaluable for PD-L1 expression. Some 62.2% in the nivo3 + ipi1 arm and 67.6% in the nivo1 + ipi3 arm had PD-L1 expression &ge;1%. More than 80% in each arm had received prior platinum therapy and radiation therapy. Some 42.2% in the nivo3 + ipi1 arm and 52.2% in the nivo1 + ipi3 arm had not received systemic therapy in the R/M setting.

In the nivo3 + ipi1 arm, the objective response rate was 31.6% in those patients who received no prior systemic therapy for R/M disease and 23.1% in those with prior systemic therapy for R/M. The corresponding ORR percentages in the nivo1 + ipi3 arm were 45.8% and 36.4%, respectively. A complete response was observed in 4 patients in each treatment arm. Eight patients in the nivo3 + ipi1 arm and 15 in the nivo1 + ipi3 arm had a partial response. The median duration of response had not been reached in patients treated in the first-line setting for metastatic disease in both arms.

In the nivo3 + ipi1 arm, the ORRs were 30.8% (no prior systemic treatment for R/M disease) and 40.0% (prior systemic treatment) in those with PD-L1 tumor expression &ge;1%, and 33.3% and 9.1%, respectively, in those with PD-L1 expression <1%. In the nivo1 + ipi3 arm, the ORRs were 36.4% and 16.7%, respectively, in the PD-L1—positive patients, and 0% and 57.1%, respectively, in those with PD-L1 expression <1%.

There was a higher incidence of treatment-related adverse events (AEs) leading to treatment discontinuation in the nivo1 + ipi3 arm compared with nivo3 + ipi1 (32.6% vs 17.8%), as well as a higher rate of treatment-related serious AEs leading to discontinuation (21.7% vs 6.7%).

There was a higher incidence of treatment-related gastrointestinal events in the nivo1 + ipi3 arm compared with nivo3 + ipi1 (56.5% vs 35.6%) &ldquo;and this could be due to the higher ipilimumab dose,&rdquo; said Oaknin.

CheckMate-358 is continuing to enroll patients with R/M cervical cancer.

Reference:

Naumann RW, Oaknin A, Meyer T, et al. Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: Results from CheckMate 358. Presented at 2019 ESMO Congress; September 27-October 2, 2019; Barcelona, Spain. Abstract LBA62.