Immunotherapy Makes Modest Strides in Cervical Cancer

Bradley J. Monk, MD

Bradley J. Monk, MD

The landscape for treatment of gynecologic cancer has changed since 2014, especially with the approval of bevacizumab (Avastin) for patients with advanced cervical cancer and then for patients with platinum-resistant recurrent ovarian cancer, according to Bradley J. Monk, MD. However, better therapeutic strategies and better biomarkers are needed in the realm of gynecologic cancers, he said during a recent webinar about meeting unmet clinical needs in cervical cancer.

Hosted by Physicians’ Education Resource® and moderated by Monk, the webinar addressed the rationale for and use of immunotherapy in the treatment of patients with cervical cancer. Panelists included Shannon N. Westin, MD, MPH, and Linda R. Duska, MD, MPH.

Rationale for Immunotherapy in Cervical Cancer

Westin, an associate professor and director of early drug development in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center in Houston, said that human papillomavirus (HPV) is the most common cause of cervical cancer.

Two oncoproteins of the HPV-16 genome, one of the most common strains associated with cervical cancer, inhibit the function of tumor suppressor products p53 and retinoblastoma protein, she said. However, she suggested that this knowledge has not yet yielded any therapeutic opportunities.

The US Preventive Services Task Force (USPSTF) recently updated their screening guidelines for cervical cancer to include the high-risk HPV test as an alternative to Pap smear testing every 3 years for women aged 30 to 65 years who are at average risk of cervical cancer.¹The USPSTF noted that all women between ages 21 and 65 are at risk of developing cervical cancer due to the potential of exposure to high-risk HPV types. Importantly, this change in the guidelines acknowledged the benefit of HPV testing alone, which can accurately detect HPV types 16 and 18.

Investigators have so far been unsuccessful in finding targetable oncogenic drivers for treating cervical cancer. “We’ve struggled with the identification of oncogenes that are potentially driving these [cervical] tumors,” Westin commented.

However, researchers have noted elevations of abnormalities in immune response pathways, such as the IFNG pathway. Additionally, PD-L1 expression has been identified in some cervical cancers, with a higher proportion noted in squamous cell cancers compared with the adenocarcinoma histology, demonstrating a rationale for PD-1/PD-L1 checkpoint inhibition in cervical cancer.²

Current Immunotherapy Data

Thus far, data from clinical trials of 2 PD-1 checkpoint inhibitors have been released, showing modest benefits for patients with advanced cervical cancer; the findings were originally presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting. A third anti—PD-1 therapy, cemiplimab, is being investigated in patients with recurrent or metastatic platinum-refractory cervical cancer in an ongoing phase III clinical trial comparing it with investigator’s choice of chemotherapy (NCT03257267).

“A data set from a single-arm trial caught us off guard a little bit, because this relatively small study led to an FDA approval,” said Monk, a professor and director of the Division of Gynecologic Oncology at Creighton University School of Medicine, University of Arizona College of Medicine, and medical director of gynecologic oncology research, US Oncology Network.

KEYNOTE-158 is an ongoing multicohort phase II trial of pembrolizumab (Keytruda) in patients with advanced solid tumors (NCT02628067). In preliminary data presented at the 2017 ASCO meeting, among the first 82 patients enrolled in the advanced cervical squamous cell cancer cohort, the objective response rate (ORR) was 12% (95% CI, 6%-21%), which consisted of 3 complete and 7 partial responses, all of which were ongoing at data cutoff.³

“This was kind of our first awareness that there was some activity of checkpoint inhibitors in recurrent cervical cancer,” Monk noted.

Pembrolizumab was approved on June 12, 2018, for the treatment of patients with advanced PD-L1—positive cervical cancer with disease progression on or after chemotherapy based on further data from the KEYNOTE-158 trial.

Among 77 patients with PD-L1—positive cervical cancer, which was defined as combined positive score (CPS) of ≥1 as measured by an FDA-approved test, the ORR was 14.3% (95% CI, 7.4%-24.1%).⁴All patients had received ≥1 prior chemotherapy regimen in the metastatic setting. At 6 months follow-up, 91% of responses were ongoing. The median duration of response was not reached.

Common grade 3/4 adverse events (AEs) included urinary tract infections, hemorrhage, musculoskeletal pain, fatigue, and infections, and serious AEs included anemia, fistula, hemorrhage, and infections. Discontinuations due to AEs occurred in 8% of patients.

“In ovarian cancer we might not accept 14%, because we have other medicines, but in this [cervical cancer] patient population, this exceeds the bar,” commented Duska, professor of Obstetrics and Gynecology at the University of Virginia School of Medicine in Charlottesville. “In addition to that, the drug is relatively well tolerated, it’s easy to give, it has few side effects, patients did very well with it, and the length of response was very meaningful. These women don’t have a lot of other choices. I think this is a very viable option for patients who find themselves in this clinical situation.”

The multicohort phase I/II CheckMate 358 study is looking at nivolumab (Opdivo) and nivolumab-based combination therapy in patients with virus-associated tumors, including a cohort of patients with recurrent or metastatic cervical, vaginal, and vulvar cancers. The cohort included 24 patients, including 19 with cervical cancer, who had received up to 2 prior treatment regimens for recurrent or metastatic disease.

The ORR was 20.8% overall and 26.3% in the patients with cervical cancer.⁵It was higher in treatment-naïve patients at 28.6% compared with 17.6% in previously treated patients, which Monk called “quite provocative.” The overall median progression-free survival was 5.5 months.

Treatment-related AEs occurred in 70.8% of patients and were most commonly diarrhea, fatigue, arthralgia, and decreased appetite.

Need to Know When Treating Patients With Immunotherapy

Duska explained the significance of the CPS biomarker in the pembrolizumab approval. CPS relates to the combined score for PD-L1 expression in tumor-associated immune cells, as calculated by the number of PD-L1—positive cells divided by the total number of tumor cells multiplied by 100. The CPS, as tested by the PD-L1 IHC 22C3 companion diagnostic, helps identify those patients with a score of ≥1 who are more likely to respond to pembrolizumab.

In an analysis of the CPS for evaluation of PD-L1 expression in solid tumors, the scoring method identified 9 out of 11 responders and was found to be reproducible when scored by pathologists.⁶

“TPS [tumor proportion score] and CPS allow us to quantify that PD-L1 testing in a meaningful way that we can then apply to choosing therapies,” Duska said, adding that that the CPS is different from the TPS—patients could have a negative TPS but a positive CPS. Additionally, she noted, in-house pathologists can learn to test for CPS so that the samples do not need to be sent out.

Duska and Westin emphasized the importance of educating both patients and the overall medical community to be aware of and help manage potential immune-related AEs (irAEs). “Early identification and early intervention [are] the [keys] to managing these immune-related adverse events and preventing a tragic complication,” Westin said. Awareness leads to better recognition of irAEs, so they can quickly be brought to the oncologist’s attention and managed, avoiding the need for hospitalization.

For example, in the case of pneumonitis, Westin suggested that patients should alert their oncologists to any signs of shortness of breast, chest pain, or new or worsening cough. The physician can then rule out other causes with radiographic imaging and other tests. If the pneumonitis is grade ≥2, the therapy should be held, the patient should be treated with oral corticosteroids and empiric antibiotics, and a pulmonary consult should be considered for a bronchoscopy. In addition, the checkpoint inhibitor therapy should be permanently discontinued if the irAE is higher than grade 3 or recurrent grade 2.

The most common irAE from treatment with a checkpoint inhibitor is colitis, which can occur in 20% to 30% of patients and is grade 3/4 in 1% to 2%. Although there are several potential causes of irAEs, an increased level of inflammatory cytokines could cause damage leading to colitis, Westin said.

“Immunotherapy has changed the face of all cancers in the past decade. It’s not a slam dunk yet for cervix cancer; we need to have better biomarkers. We do the best we can [with what we have],” Duska concluded.

References:

1. Curry SJ, Krist AH, Owens DK, et al; US Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement.JAMA. 2018;320(7):674-686. doi: 10.1001/jama.2018.10897.
2. Heeren AM, Punt S, Bleeker MC, et al. Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix.Mod Pathol.2016;29(7):753-763. doi: 10.1038/modpathol.2016.64.
3. Schellens JHM, Marabelle A, Zeigenfuss S, et al. Pembrolizumab for previously treated advanced cervical squamous cell cancer: preliminary results from the phase 2 KEYNOTE-158 study.J Clin Oncol.2017;35(suppl; abstr 5514). meetinglibrary.asco.org/record/145853/abstract.
4. Keytruda (pembrolizumab) [prescribing information]. Whitehouse Station, NJ; Merck & Co., Inc., 2018. merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed September 24, 2018
5. Hollebecque A, Meyer T, Moore KN, et al. An open-label, multicohort, phase I/II study of nivolumab in patients with virus-associated tumors (CheckMate 358): efficacy and safety in recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers.J Clin Oncol.2017;35(suppl; abstr 5504). meetinglibrary.asco.org/record/152783/abstract.
6. Kulangara K, Hanks DA, Waldroup S, et al. Development of the combined positive score (CPS) for the evaluation of PD-L1 in solid tumors with the immunohistochemistry assay PD-L1 IHC 22C3 pharmDx.J Clin Oncol.2017;35(suppl 15; abstr e14589). doi: 10.1200/JCO.2017.35.15_suppl.e14589.
7. Opdivo (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2018. packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed September 24, 2018.