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IMPORTANCE: The KEYNOTE-826 randomized clinical trial showed statistically significant and clinically meaningful survival benefits with the addition of pembrolizumab to chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer. Treatment effects in patient subgroups of the study population are unknown. OBJECTIVE: To assess efficacy outcomes in patient subgroups of KEYNOTE-826. DESIGN, SETTING, AND PARTICIPANTS: Exploratory subgroup analyses were conducted in a global, phase 3, randomized, double-blind, placebo-controlled clinical trial. Participants included women with persistent, recurrent, or metastatic adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma of the cervix that had not been treated with systemic chemotherapy and was not amenable to curative treatment. This subanalysis was conducted from November 20, 2018, to May 3, 2021. INTERVENTIONS: Pembrolizumab, 200 mg, every 3 weeks or placebo for up to 35 cycles plus chemotherapy (paclitaxel, 175 mg/m2, plus cisplatin, 50 mg/m2, or carboplatin AUC 5 [area under the free carboplatin plasma concentration vs time curve]) with or without bevacizumab, 15 mg/kg. MAIN OUTCOMES AND MEASURES: Overall survival (OS) and progression-free survival (PFS) by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 in subgroups defined by use of bevacizumab (yes or no), choice of platinum (carboplatin or cisplatin), prior chemoradiotherapy (CRT) exposure only (yes or no), and histologic type (squamous or nonsquamous) in patients with programmed cell death ligand 1–positive tumors (defined as a combined positive score [CPS] ≥1) and in the intention-to-treat population. RESULTS: A total of 617 patients (median age, 51 years; range, 22-82 years) were enrolled in the trial. In the CPS greater than or equal to 1 population, hazard ratios (HRs) for OS favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.62; 95% CI, 0.45-0.87) and without bevacizumab (HR, 0.67; 95% CI, 0.47-0.96), use of carboplatin (HR, 0.65; 95% CI, 0.50-0.85) and cisplatin (HR, 0.53; 95% CI, 0.27-1.04), with prior CRT only (HR, 0.56; 95% CI, 0.39-0.81) and without prior CRT only (HR, 0.72; 95% CI, 0.52-1.00), and squamous (HR, 0.60; 95% CI, 0.46-0.79) and nonsquamous (HR, 0.70; 95% CI, 0.41-1.20) histologic type. In the intention-to-treat population, HRs for OS also favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.63; 95% CI, 0.47-0.87) and without bevacizumab (HR, 0.74; 95% CI, 0.53-1.04), use of carboplatin (HR, 0.69; 95% CI, 0.54-0.89) or cisplatin (HR, 0.59; 95% CI, 0.32-1.09), with prior CRT only (HR, 0.64; 95% CI, 0.45-0.91) and without prior CRT only (HR, 0.71; 95% CI, 0.53-0.97), and squamous (HR, 0.61; 95% CI, 0.47-0.80) and nonsquamous (HR, 0.76; 95% CI, 0.47-1.23) histologic type. Similar to OS, the addition of pembrolizumab prolonged PFS across all subgroups in the CPS greater than or equal to 1 and intention-to-treat populations. CONCLUSIONS AND RELEVANCE: The findings of this trial suggest that adding pembrolizumab to chemotherapy with or without bevacizumab improved OS across subgroups of patients with persistent, recurrent, or metastatic cervical cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03635567

(Abstracted from N Engl J Med2022;386(6):544–555)Despite widespread implementation of cervical cancer screening and prevention programs including cytologic assessment and high-risk human papillomavirus DNA detection as well as effective vaccines, the incidence of cervical cancer remains high. Treatment varies based on stage and grade and involves a combination of surgery, platinum-based chemotherapy, bevacizumab, chemoradiation, and intracavitary brachytherapy.

Objective: Fully humanized monoclonal antibodies have revolutionized the treatment of many solid tumors, including ovarian, lung, colorectal, and breast cancer. Among the most widely used monoclonal antibodies in clinical oncology are cetuximab, trastuzumab, rituximab, and bevacizumab. Methods: This is a review article focusing on the drug patents for cetuximab, trastuzumab, rituximab, and bevacizumab. Results: These four monoclonal antibodies are used in both first and second line treatment regimens for multiple common malignancies. With recent patent expirations, pharmaceutical companies involved in biosimilar manufacture are looking to establish ownership over these financial monopolies. Conclusion: This article will review these four notable monoclonal antibodies, their role in clinical oncology, and the drug patents that are nearing expiration. There are currently only two biosimilars approved in the United States: the trastuzumab biosimilar trastuzumab-dkst (Ogivri) and the bevacizumab biosimilar bevacizumab-awwb (Mvasi). In Europe, SB3, a trastuzumab biosimilar, is approved for use as well as two rituzimab biosimilars, truxima and rixathon.

ABSTRACTIntroduction: Though cervical cytology, HPV DNA testing, and pre-invasive disease management has significantly reduced the number of new diagnoses of cervical cancer, women with persistent oncogenic HPV infection are at significant risk for developing invasive cervical cancer. Early stage and locally advanced disease can be cured, but women with advanced or recurrent disease have a very poor prognosis. This underscores the need for different treatment strategies for advanced cervical cancer, the most promising of which are novel therapeutics that target the ability of HPV to overcome host immune tolerance.Areas covered: This review includes new therapies being investigated for the treatment of recurrent, metastatic or refractory cervical cancer, separated into broad categories of cellular and non-cellular based strategies.Expert opinion: Advanced and recurrent cervical cancer has a poor prognosis, prompting investigations into the development of strategies that will eradicate tumor and/or overcome host immunologic tolerance of disease. It is unknown whether it will be these strategies alone or a combination of treatment modalities that will ultimately provide the best outcomes; nevertheless, the new data are promising.

ABSTRACTIntroduction: Ovarian cancer is a disease with a propensity to recur despite dramatic responses to initial treatment, which typically consists of a combination of cytoreductive surgery and platinum-based chemotherapy. A maintenance therapy, which may prevent or delay relapse while not negatively impacting quality of life, is critical to improving outcomes.Areas covered: This review discusses the pharmacologic properties, clinical efficacy, and safety profile of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.Expert opinion: Following presentation of ENGOT-OV16/NOVA at the European Society for Medical Oncology (ESMO) 2016 Congress, niraparib became the first PARP inhibitor to receive full approval by the U.S. Food and Drug Administration (FDA) for the maintenance treatment of recurrent ovarian cancer, regardless of a patient’s germline or somatic mutational status. This approval has had a sweeping impact on treatment strategies, moving the indication for a PARP inhibitor earlier in the treatment course and greatly expanding the population of patients who may benefit from this class of drugs. Active clinical trials suggest that new indications and novel treatment combinations are eagerly sought.

Objectives To evaluate outcomes and cost-effectiveness of targeted therapy sequencing for metastatic and recurrent cervical cancer.Method Models were simulated based on phase II and III trials on bevacizumab (bev) from GOG-240, cemiplimab (cemi) from GOG 3016, pembrolizumab (pembro) from KEYNOTE-826, and tisotumab vedotin (tiso) from GOG 3023. Costs were based on IBM Micromedex RED BOOK™ and company listed costs.Results For [chemo + bev → chemo], total cost was $125,918.04, with median overall survival (mOS) of 21.8 months, and cost-effectiveness ratio (CER) of $119,835.79. For [chemo + bev → cemi], total cost was $187,562.99 with mOS of 28.5 months and CER of $162,039.16. For [chemo + bev + pembro → chemo], total cost was $319,963.78 with mOS 32.9 months and CER of $249,930.10. For [chemo + bev + pembro → tiso], total cost was $455,204.45, with mOS 36.5 months and CER of $320,072.99.Conclusion The combination of immunotherapies and biologics have significantly increased overall survival, but with associated higher costs, primarily related to drug costs.

(Abstracted from Obstet Gynecol2022;139:157–162)Ovarian cancer represents a disproportionate amount of mortality associated with gynecologic malignancies, with more than 13,940 deaths annually. Two factors that significantly contribute to this are the phenomenon that most women are diagnosed at an advanced stage, and most develop recurrent and chemoresistant disease.

On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events.

(Abstracted from J Clin Oncol2019;37:1380–1390)The Gynecologic Oncology Group (GOG) protocol 172 demonstrated a median survival of 127.6 months with an intraperitoneal (IP) chemotherapy regimen compared with 82 months with an intravenous (IV) cisplatin-based chemotherapy regimen in women with stage 3 ovarian cancer and surgically resected disease. These findings represented an advancement in IP chemotherapy efficacy in ovarian cancer, although several phase 1 studies have concurrently found significant toxicity secondary to IP chemotherapy.

ABSTRACTIntroduction: Advanced melanoma is a devastating disease that has propelled research in therapeutics beyond chemotherapy and radiotherapy. Being highly immunogenic, melanoma is a model tumor for immunotherapy and has highlighted the therapeutic potential of the immune checkpoint inhibitors.Areas covered: This review discusses the pharmacologic properties, clinical efficacy, and safety profile of pembrolizumab, an IgG4-kappa humanized monoclonal antibody against the programmed cell death protein 1 (PD-1) receptor, for the treatment of unresectable or metastatic melanoma.Expert opinion: Pembrolizumab was the first PD-1 inhibitor to be approved by the U.S. Food and Drug Administration (FDA). Remarkably, this accelerated approval for the treatment of advanced, heavily pretreated melanoma was based on response rates alone from a phase I trial. As anticipated, pembrolizumab confirmed a survival advantage in phase II and III trials and has led the way for the study of other drugs that share its mechanism of action. Defining disease and patient characteristics associated with a response remains amongst the most pressing priorities.

(Abstracted from N Engl J Med2021;385:1856–1867)Platinum-based chemotherapy plus bevacizumab and paclitaxel is the standard first-line therapy for persistent, recurrent, or metastatic cervical cancer. The phase 2 KEYNOTE-158 trial found evidence of a response to pembrolizumab among patients with programmed death ligand-1 (PD-L1) positive cervical cancer.

Ovarian cancer continues to present a significant health challenge with little progress being made over the past two decades in reducing the incidence and mortality. More recently, novel therapeutics have emerged as a potential way of improving outcomes for women with advanced ovarian cancer who harbor mutations in genes involved in homologous recombination (HR), most notably BRCA1 and BRCA2. In the United States, Olaparib, a PARP inhibitor, has been recently approved for ovarian cancer patients treated with three or more lines of prior chemotherapy who harbor germline mutations in BRCA1 or BRCA2. As a caveat to Olaparib’s FDA approval, BRACAnalysis CDx®was approved as a companion diagnostic test for women with ovarian cancer to determine their BRCA1/2 mutation status and eligibility for treatment. This review article will provide essential background information on hereditary breast and ovarian cancer (HBOC), describe the therapeutic mechanism of PARP inhibitors, and will chronicle the current and emerging homologous recombination deficiency (HRD) assays and their associated patents.

In gynecologic oncology, surgical and adjuvant therapy rely heavily on correct pathologic diagnosis. Thus, in-house review of outside pathologic slides and specimens has become routine within large tertiary referral centers. We sought to determine the impact of outside pathologic slide review on gynecologic oncology patient care and treatment. Gynecologic oncology cases between January 2007 and January 2012 were evaluated. Clinical information was gathered from comprehensive chart reviews and reports created after multidisciplinary treatment planning conferences. Discrepancies in diagnosis were identified as major if they resulted in a treatment alteration and minor if they did not impact care. Data were analyzed using descriptive statistics and the Fisher exact test. A total of 279 cases were identified and reviewed as part of the study—126 (45.2) biopsycytology specimens and 153 (54.8) surgical excision specimens. Minor discrepancies were noted in 25 reviewed cases (9) and major discrepancies in 19 cases (6.8). Among those patients in whom management was changed based on specialized pathologic review, 50 underwent additional surgery, 16 had their surgical plan modified, and 16 received adjuvant treatment or had their adjuvant treatment modified. In 235 cases (84.2), institutional rereview of the outside slidesspecimens did not result in a change in diagnosis. Diagnostic discrepancies were evenly distributed across all primary sites evaluated. The cost of outside pathologic review was estimated at 2,936 US dollars per change in diagnosis. Mandatory slide review in gynecologic oncology is important and results in diagnostic changes in approximately 16 of cases, with 43 of those changes impacting treatment.

Following publication of five pivotal randomized trials of concurrent chemo-irradiation for patients with locally advanced cervical cancer (ie, International Federation of Gynecology and Oncology (FIGO] stages IB2–IVA) in 1999 and 2000, the National Cancer Institute issued a Clinical Alert advising that concurrent chemotherapy (typically, single-agent cisplatin) be incorporated into the treatment program of women scheduled to receive definitive pelvic radiotherapy. Although the adoption of this new standard has improved overall survival and decreased the recurrence rate by 50%, for those patients who do relapse, the prognosis is very poor and, ultimately, therapy in this setting is palliative in nature. The Gynecologic Oncology Group (GOG) has now completed eight randomized trials for metastatic and recurrent cervical cancer, all of which have studied cisplatin-based regimens. The eighth trial (protocol 204) compared four cisplatin-based doublets containing paclitaxel, topotecan, vinorelbine, or gemcitabine. Because the vast majority of patients are now expected to receive cisplatin “up front” as part of primary therapy with pelvic radiation, there are concerns for the development of drug-resistant clones in recurrences both inside and outside of the radiation field. The GOG has recently reported the results from a phase II trial evaluating the anti-vascular agent, bevacizumab, in women who were eligible for second-line or third-line therapy for metastatic and/or recurrent disease (protocol 227C). It becomes imperative that we continue to evaluate novel regimens for this disease.

(Abstracted from N Engl J Med2019;381:1929–1939)The National Comprehensive Cancer Network recommends secondary cytoreduction for ovarian cancer patients with recurrent disease who have received no treatment for a period of 6 months following a complete response from prior chemotherapy. Retrospective reviews and meta-analyses have shown the most benefit from this operation in those with platinum-sensitive disease and those with little or no postoperative residual disease.

Because primary carcinoma of the vagina comprises less than 2% of all gynecologic malignancies, the reported experience in the treatment of large numbers of patients is available only from a few major centers and most often encompasses a variety of differences in treatment selection and technique. The objective of this study was to assess the long term results of an interstitial iridium-192 afterloading implant technique using the Syed-Neblett dedicated vaginal plastic template. Patients who were treated from 1976 to 1997 were examined retrospectively. Seventy-one patients underwent interstitial implantation with (n = 61 patients) or without external beam radiotherapy. The median age was 59 years (range, 16–86 years). Patients were staged according to the International Federation of Gynecology and Obstetrics system and included Stage I (n = 10 patients), Perez modification Stage IIA (n = 14 patients), Perez modification Stage IIB (n = 25 patients), Stage III (n = 15 patients), and Stage IV (n = 7 patients). Each implant delivered an approximately 20-gray (Gy) minimum tumor dose, with the total tumor dose reaching 80 Gy with integrated external beam radiotherapy. Local control was achieved in 53 patients (75%). The median follow-up was 66 months (range, 15–163 months), and the 2-year, 5-year, and 10-year actuarial disease free survival rates are 73%, 58%, and 58%, respectively. By stage, 5-year disease free survival rates included Stage I, 100% of patients; Stage IIA, 60% of patients; Stage IIB, 61% of patients; Stage III, 30% of patients; and Stage IV, 0% of patients. The factors disease stage and primary lesion size independently influenced the survival rates. Significant complications occurred in 9 patients (13%) and included necrosis (n = 4 patients), fistulae (n = 4 patients), and small bowel obstruction (n = 1 patient). Interstitial irradiation can effect local control in the majority of patients with primary carcinoma of the vagina with acceptable morbidity. Long term cure is demonstrable in patients with Stage I–III disease. Cancer 2001;91:758–70. © 2001 American Cancer Society.