Recent Drug Approvals in Gynecologic Oncology: A Statement from SGO’s Communications and Clinical Practice Committees (July, 2018)

Recently, the Food and Drug Administration (FDA) approved two targeted therapies for patients with gynecologic malignancies, pembrolizumab (Keytruda) for cervical cancer and bevacizumab (Avastin) for ovarian cancer. With these exciting developments in gynecologic cancer care, we detail the specifics of these approvals, including supporting data and clinical considerations.

Pembrolizumab for advanced cervical cancer

On June 12, 2018, the FDA approved the immunomodulatory agent, pembrolizumab (Keytruda), for patients with recurrent or metastatic cervical cancer whose tumors express programmed death-ligand 1 (PD-L1) and have progressed on or following chemotherapy.

This approval is based on the results of the KEYNOTE-158 trial, a multi-institutional, open-label and non-randomized trial investigating the efficacy of pembrolizumab in multiple advanced solid tumor cohorts, including cervical cancer. Primary efficacy outcomes assessed included objective response rate (ORR) and response duration. The ORR in the 77 patients with PD-L1 positive cervical cancers was 14.3% (95% CI: 7.4, 24.1), including 2.6% complete responses and 11.7% partial responses. The estimated median response duration based on the 11 patients exhibiting a response by independent review was not reached (range 4.1, 18.6+ months); 91% had a response duration of at least 6 months.

Confirmation of PD-L1 expression in the tumor by an FDA-approved test is required. PD-L1 IHC 22C3 pharmDx is an FDA-approved companion diagnostic test. Only patients with a combined positive score (CPS) of ?1 are eligible for pembrolizumab as no responses were observed in patients whose tumors did not express PD-L1. The recommended dose of pembrolizumab is 200mg (flat dose) administered as an intravenous infusion over 30-minutes once every 3 weeks. There are no dose reductions.

The Society of Gynecologic Oncology (SGO) strongly encourages all oncologists who plan to prescribe pembrolizumab become familiar with the unique side-effect profile of this agent including the diagnosis and management of specific immune-related toxicities. Immune-related adverse events include pneumonitis, thyroiditis, adrenal failure, hypophysitis, colitis, skin rashes and hepatitis. It is essential to counsel patients and clinical staff carefully regarding these risks. In general, treatment is withheld for grade 2 and 3 toxicities and steroids may be required. Treatment is permanently discontinued for grade 3 pneumonitis, nephritis, persistent grade 2 or 3 adverse reactions that do not recover to grade ?1 and grade 4 skin reactions (see full prescribing information here). Involving consultants familiar with immune toxicities is important in the care of these patients. Long term follow-up with an oncologist is also important as some of these adverse events may arise many months later, even after discontinuation of the drug. Careful review of the patient’s medical history to rule out pre-existing autoimmune conditions is critical prior to considering immunotherapy. In the cervical cancer cohort of the KEYNOTE-158 trial, 8% of patients discontinued treatment due to adverse reaction and serious adverse reaction occurred in 39% of patients which included anemia (7%), fistula (4.1%), hemorrhage (4.1%) and infection (4.1%). Most common adverse reactions, occurring in at least 10% of patients, included fatigue, pain, diarrhea/colitis, nausea, vomiting, constipation, infection, rash, hypothyroidism, headache and dyspnea. A thorough discussion with patients must include the risks and potential benefits of treatment, and the potential for serious, long-term treatment-related complications.

The SGO acknowledges this as an exciting development as it provides an additional treatment option for women with PD-L1 positive recurrent or metastatic cervical cancer for whom effective treatment options are limited, and yet there are unique toxicities that providers should be familiar with and patient should be counseled appropriately prior to starting treatment.

Bevacizumab for advanced stage ovarian cancer

The FDA granted approval on June 13, 2018, for bevacizumab (Avastin) in combination with intravenous carboplatin and paclitaxel, followed by bevacizumab as a single agent for the treatment of advanced stage epithelial ovarian, fallopian tube or primary peritoneal cancer following initial cytoreductive surgery.

The FDA’s approval of bevacizumab for this clinical indication is based upon data from the phase III GOG-0218 trial, in which women with stage III or IV epithelial ovarian, fallopian tube or peritoneal cancer were randomized following their initial cytoreductive surgery to receive intravenous carboplatin and paclitaxel alone, in combination with bevacizumab, or in combination with bevacizumab followed by up to 16 cycles of bevacizumab as a single agent. Bevacizumab was administered at a dose of 15 mg/kg intravenously. Originally reported in 2010, women who received bevacizumab in combination with chemotherapy and continued with bevacizumab maintenance therapy had a median progression-free survival (PFS) of 14.1 months compared to 10.3 months in women who received chemotherapy alone. When the data were censored for women whose progression was marked by an increase in CA125 alone, the PFS for bevacizumab in combination with chemotherapy followed by single-agent bevacizumab was 18.2 months compared to 12.8 months in the control group of bevacizumab with chemotherapy without single-agent bevacizumab. Notably, no statistically significant improvement in overall survival was found for those who received bevacizumab.

The SGO commends the investigators for this important contribution and recognizes that FDA approval of bevacizumab in the front-line setting of ovarian cancer will likely improve access to this drug for patients who may derive benefit. The SGO also notes that the recent FDA approval does not negate the results of other landmark clinical trials that have contributed to evidence-based best practices for the treatment of newly diagnosed advanced ovarian cancer, including options of carboplatin with dose-dense taxol and IV/IP chemotherapy.

Potential candidates for bevacizumab should be selected based upon their individual clinical scenario and counseled appropriately for shared decision making regarding the risks and benefits of adding bevacizumab to their platinum-based systemic therapy. The SGO specifically recommends consideration of the following when counseling patients regarding the role of bevacizumab in their treatment options.

Patients with poor prognostic factors (and no contraindications) are most likely to benefit

• While no overall survival advantage was detected for bevacizumab in GOG-0218, the study was not powered for this secondary endpoint. ICON-7 compared women with ovarian cancer of all stages who received carboplatin and paclitaxel alone with women who received chemotherapy with bevacizumab (7.5mg/kg) in combination followed by 12 additional cycles of single-agent bevacizumab. This study was powered to detect a difference in overall survival which was not significantly different for the study population as a whole; however, in a subset of women with poor prognostic factors (stage IV disease, inoperable or suboptimally debulked stage III disease), the addition of bevacizumab improved PFS (16.0 months compared to 10.5 months) as well as an improvement in restricted mean survival (39.3 months compared to 34.5 months).
• A subset analysis of GOG-0218 suggested that patients with ascites may have additional benefit in PFS and OS with the inclusion of bevacizumab.

Contraindications/Other Considerations

• Patients undergoing intraperitoneal/intravenous chemotherapy with cisplatin and paclitaxel following optimal cytoreduction should not receive bevacizumab in combination with their chemotherapy because of the high rate of grade 3 toxicities seen in GOG 252.
• Caution must be used in incorporating bevacizumab into neoadjuvant chemotherapy regimens due to toxicities related to surgery. The National Comprehensive Cancer Network (NCCN) recommends withholding bevacizumab for at least 6 weeks prior to interval cytoreductive surgery.
• Providers and patients must be aware of the toxicities unique to bevacizumab including thromboembolism, gastrointestinal perforations, hypertension and delayed wound healing.

Shared decision making with patients

• Counseling should include a discussion of a patient’s goals and priorities for her treatment. The improvement in PFS is approximately 4 months with an additional 11 months of treatment.
• Bevacizumab adds additional potential toxicities and increased cost to platinum-based chemotherapy. An OS benefit was not demonstrated with the addition of bevacizumab. Patients with certain high risk factors may differentially experience the improvement in PFS with the addition of bevacizumab.

Future treatment considerations

• Patients who receive bevacizumab in the upfront setting may still benefit from receiving additional treatment, including bevacizumab, for recurrent ovarian cancer.

Additional Information

N Engl J Med. 2011 Dec 29;365(26):2473-83. DOI: 10.1056/NEJMoa1104390.

Incorporation of bevacizumab in the primary treatment of ovarian cancer. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX; Gynecologic Oncology Group.

J Clin Oncol 35, no. 15_suppl (May 20 2017) 5514-5514. DOI: 10.1200/JCO.2017.35.15_suppl.5514. Pembrolizumab for previously treated advanced cervical squamous cell cancer: Preliminary results from the phase 2 KEYNOTE-158 study. Schellens JHM, Marabelle A, Zeigenfuss S, Ding J, Knowles Pruitt S, Chung HC.