Research has shown that patients with para-aortic lymph node metastasis, human papillomavirus-18, and those with certain histocompatibility genes in their cervical tumors also have a poor prognosis. Preclinical research suggests, however, that immune checkpoint blockade with radiation can enhance immune-mediated activity in patients who have up to stage IV disease.
Jyoti S. Mayadev, MD
For the curative-intent treatment of locally advanced cervical cancer, there is a 20-year-old guidance from the National Institutes of Health, recommending chemotherapy plus radiotherapy.1However, this combination is not curative for patients with stage III or IV disease. Research has shown that patients with para-aortic lymph node metastasis, human papillomavirus (HPV)-18, and those with certain histocompatibility genes in their cervical tumors also have a poor prognosis. Preclinical research suggests, however, that immune checkpoint blockade with radiation can enhance immune-mediated activity in patients who have up to stage IV disease.2
The phase I study of sequential ipilimumab (Yervoy) after chemoradiotherapy as a curative-intent treatment of patients with node-positive cervical cancer included 34 female patients with stage Ib2 to VI cervical cancer with positive pelvic lymph nodes, para-aortic lymph nodes, or both.
The primary end point of the study was safety and the secondary end points were overall survival (OS) and progression-free survival (PFS). Exploratory end points were also assessed, and they included, HPV genotype, HLA allele status, and PD-1 expression, which were measured in peripheral blood.
At the time of data cutoff, 21 patients had been treated with at least 2 cycles of ipilimumab. Among patients who received at least 2 cycles of treatment, the 12-month OS rate was 90% and the PFS rate was 81%.
Eighty-six percent of patients received 4 cycles of ipilimumab (n = 18) and 14% completed 4 cycles of treatment with ipilimumab (n = 3), and no patients required a dose reduction. There were no dose-limiting toxicities (DLTs) observed among the 3 patients who received ipilimumab 3 mg/kg every 3 weeks or in the 5 patients who received ipilimumab 10 mg/kg every 3 weeks. Based on this level of tolerability, 10 mg/kg was set as the maximum tolerated dose (MTD) of ipilimumab in the study. More than 15% of patients (2 out of 13) experienced lipase increase (grade 3) and dermatitis (grade 3) DLTs. These adverse events (AEs) occurred during cycle 2 of treatment and were considered self-limiting with no further complications. Self-limiting decreased absolute neutrophil count occurred in 1 patient, which caused a delay in starting cycle 4.
Most common AEs observed were diarrhea (grade 1 or 2), dermatitis, and endocrinopathies. One case of abdominal pain (grade 3) and cognitive disturbance (grade 3) each was reported. This patient underwent an MRI of the brain after receiving the first cycle of ipilimumab 3 mg/kg. This case was resolved within 1 week.
The most common grade 3/4 adverse event was a decrease in lymphocyte count. No grade 4 or 5 AEs were observed with the lower dose of ipilimumab at the median follow-up of 14.8 months.
Treatment with ipilimumab led to an increase in PD-L1 expression on CD4+ and CD8+ T cells. For CD4+ T cells, the median expression was 8.3 (95% CI, 24.8-44.4) compared with the median after chemoradiotherapy (29.1; 95% CI, 22.7-43.5) and at baseline 10.0 (95% CI, 7.8-27.3,P<.001). For CD8+ T cells, the median PD-L1 expression was 17.5% (95% CI, 16.8-29.3) after treatment with ipilimumab compared with 20.1; (95% CI, 17.1-29.3) after CRT and 9.9 (95% CI, 8.5-18.2, P<.01) at baseline. This increase in PD-L1 expression did not correlate with survival outcomes.
According to cervical swab samples, which were collected from all patients prior to treatment, 95% of patients were HPV-positive with one patient sample deemed inconclusive. The genotype tests showed that 52% of the patients were positive for HPV-16 (n = 11), 14% had HPV-18 (n = 3), and 34% had another high-risk HPV type. Of the HPV-positive patients, 1 patient was confirmed as having more than 1 genotype and 2 patients had low-risk genotypes.
At baseline, the HLA-A0201 allele status of each patient was determined. Thirty-eight percent of patients carried the HLA-A0201 allele (n = 8). The study investigators also performed an analysis of how HPV and HLA genotypes correlate to PFS and OS. This analysis showed that 3 PFS events occurred in each of the high-risk genotypes, which led investigators to conclude that there was no difference in PFS across genotypes. The analysis also showed no difference in OS, as 2 OS events occurred in all 3 genotypes.
Patients in the study were screened with positron-emission tomography and computed tomography and computed tomography of the chest, abdomen, and pelvis before enrollment. The study enrolled those with Gynecologic Oncology Group performance status of 0 to 1, an absolute neutrophil count ≥1,500/mcl, platelets ≥100,000/mcl, creatinine ≤institutional upper limit normal (ULN), bilirubin ≤1.5×ULN, serum glutamic oxaloacetic transaminase and alanine aminotransferase ≤2.5×ULN, alkaline phosphatase ≤2.5×ULN, and grade 1 or lower neuropathy.
The study excluded individuals who had prior pelvic or abdominal radiation, cytotoxic chemotherapy, previous therapy of any kind for this malignancy or any pelvic or abdominal radiation for any prior malignancy, those with a history of other invasive malignancies, except those who had non-melanoma skin cancer, and those who received prior treatment with ipilimumab, anti-programmed cell death (PD) 1 antibody, cluster of differentiation (CD)137 agonist or other immune-activating therapy. Individuals with certain infections and diseases that may have interfered with treatment were also excluded.
The investigators of the study consider the small percentage of patients with disease progression and the increase in PD-L1 expression following curative-intent treatment with ipilimumab to be a correlation with outcomes. A new study (NCT03738228), evaluating atezolizumab (Tecentriq) before and/or with chemoradiotherapy in this patient population has been launched to further evaluate the benefit of immune checkpoint blockade as a curative-intent treatment for patients with cervical cancer.
“This trial is of paramount importance to understand the safety and feasibility when immunotherapy is added to the standard of care chemoradiation in locally advanced cervical cancer. We need to have more studies and investigations that will help to identify therapeutic targets to improve outcomes in this node-positive patient population,” Jyoti S. Mayadev, MD, associate professor of Radiation Medicine and Applied Sciences, director of Gynecologic Brachytherapy and chief of Gynecology Oncology Radiation Services at UC San Diego Health and lead study author toldTargeted Oncologywhen asked about the implications of this research for the treatment landscape of cervical cancer.