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Purpose: Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease., Methods: This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control., Results: Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents., Conclusion: Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.

Purpose: To evaluate the addition of the humanized monoclonal antiprogrammed death ligand-1 (PD-L1) antibody, atezolizumab, to platinum-based chemotherapy and bevacizumab in newly diagnosed stage III or IV ovarian cancer (OC)., Methods: This multicenter placebo-controlled double-blind randomized phase III trial (ClinicalTrials.gov identifier: NCT03038100) enrolled patients with newly diagnosed untreated International Federation of Gynecology and Obstetrics (FIGO) stage III or IV OC who either had undergone primary cytoreductive surgery with macroscopic residual disease or were planned to receive neoadjuvant chemotherapy and interval surgery. Patients were stratified by FIGO stage, Eastern Cooperative Oncology Group performance status, tumor immune cell PD-L1 staining, and treatment strategy and randomly assigned 1:1 to receive 3-weekly cycles of atezolizumab 1,200 mg or placebo (day 1, cycles 1-22), with paclitaxel plus carboplatin (day 1, cycles 1-6) plus bevacizumab 15 mg/kg (day 1, cycles 2-22), omitting perioperative bevacizumab in neoadjuvant patients. The co-primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat and PD-L1-positive populations., Results: Between March 8, 2017, and March 26, 2019, 1,301 patients were enrolled. The median progression-free survival was 19.5 versus 18.4 months with atezolizumab versus placebo, respectively (hazard ratio, 0.92; 95% CI, 0.79 to 1.07; stratified log-rank P = .28), in the intention-to-treat population and 20.8 versus 18.5 months, respectively (hazard ratio, 0.80; 95% CI, 0.65 to 0.99; P = .038), in the PD-L1-positive population. The interim (immature) overall survival results showed no significant benefit from atezolizumab. The most common grade 3 or 4 adverse events were neutropenia (21% with atezolizumab v 21% with placebo), hypertension (18% v 20%, respectively), and anemia (12% v 12%)., Conclusion: Current evidence does not support the use of immune checkpoint inhibitors in newly diagnosed OC. Insight from this trial should inform further evaluation of immunotherapy in OC., Competing Interests: Kathleen N. MooreHonoraria: Research To Practice, Prime Oncology, Physicans' Education ResourceConsulting or Advisory Role: Genentech/Roche, Immunogen, AstraZeneca, Tesaro, VBL Therapeutics, Merck, Aravive, Pfizer/EMD Serono, Eisai, AbbVie, Vavotar Life Sciences, Mersana, Myriad GeneticsResearch Funding: PTC Therapeutics, Lilly, Merck, Tesaro, Genentech, Clovis Oncology, Lilly Foundation, Regeneron, Advaxis, Bristol-Myers Squibb, Verastem, Novartis Pharmaceuticals UK Ltd, AstraZeneca, Agenus, Takeda, Forty Seven, Stem CentRx, Immunogen, Bayer, Novogen, AbbVie/Stem CentRx Michael BookmanEmployment: The Permanente Medical GroupConsulting or Advisory Role: AstraZeneca, AbbVie, Immunogen, Genentech/Roche, Seattle Genetics, Aravive, Merck Sharp & Dohme Jalid SehouliHonoraria: AstraZeneca, Eisai, Clovis Oncology, Olympus Medical Systems, Johnson & Johnson, PharmaMar, Pfizer, Teva, Tesaro, MSD Oncology, GlaxoSmithKline, BayerConsulting or Advisory Role: AstraZeneca, Clovis Oncology, PharmaMar, Merck, Pfizer, Tesaro, MSD Oncology, Lilly, Novocure, Johnson & Johnson, Roche Diagnostics, Ingress Health, Riemser, Sobi, GlaxoSmithKline, NovartisResearch Funding: AstraZeneca, Clovis Oncology, Merck, Bayer, PharmaMar, Pfizer, Tesaro, MSD Oncology, RocheTravel, Accommodations, Expenses: AstraZeneca, Clovis Oncology, PharmaMar, Roche Pharma AG, Tesaro, MSD Oncology, Olympus Austin MillerUncompensated Relationships: Genentech Giovanni ScambiaConsulting or Advisory Role: Clovis Oncology, AstraZeneca, PharmaMar, Roche, TesaroSpeakers' Bureau: Clovis Oncology, MSD Johanna MäenpääHonoraria: GlaxoSmithKline, AstraZeneca, RocheConsulting or Advisory Role: GlaxoSmithKline, Eisai Europe, AstraZenecaTravel, Accommodations, Expenses: GlaxoSmithKline Lyndsay WillmottHonoraria: Clovis Oncology, AstraZeneca/Merck, Tesaro/GSK, Eisai, Genentech, GlaxoSmithKlineConsulting or Advisory Role: Tesaro/GSK, AstraZeneca/Merck, Clovis Oncology, Eisai, GenentechSpeakers' Bureau: Tesaro/GSK, AstraZeneca/Merck, Clovis Oncology Nicoletta ColomboHonoraria: Roche/Genentech, AstraZeneca, Tesaro, PharmaMar, GlaxoSmithKline, MSD Oncology, Clovis Oncology, Pfizer, Amgen, Immunogen, Novartis, Mersana, Eisai, Merck, Takeda, BiocadConsulting or Advisory Role: Roche/Genentech, PharmaMar, AstraZeneca, Clovis Oncology, Pfizer, MSD Oncology, Tesaro, BioCad, GlaxoSmithKline, Immunogen, Mersana, Eisai, Merck, Takeda, Biocad Michalis LiontosEmployment: Pfizer [I]Stock and Other Ownership Interests: Pfizer [I]Honoraria: MSD Oncology, Roche, Janssen, Sanofi, Bristol-Myers Squibb/Celgene, AstraZeneca, Ipsen, Astellas PharmaConsulting or Advisory Role: Amgen, GlaxoSmithKline, AstraZeneca, JanssenTravel, Accommodations, Expenses: Bayer, Pfizer, Roche, AstraZeneca Yolanda GarciaConsulting or Advisory Role: GlaxoSmithKline/Tesaro, Roche, AstraZenecaSpeakers' Bureau: AstraZenecaResearch Funding: Roche, AstraZenecaTravel, Accommodations, Expenses: GlaxoSmithKline/Tesaro, Roche Christopher J. DarusHonoraria: AstraZenecaConsulting or Advisory Role: AstraZeneca Carol AghajanianConsulting or Advisory Role: Mersana, Eisai, Roche, AbbVie, AstraZeneca/Merck, Roche/Genentech, Repare TherapeuticsResearch Funding: Genentech/Roche, AbbVie, Clovis Oncology, AstraZeneca Aikou OkamotoHonoraria: AstraZeneca Japan, MSD, Chugai Pharma, TakedaConsulting or Advisory Role: AstraZeneca Japan, Chugai PharmaSpeakers' Bureau: AstraZeneca JapanResearch Funding: Kissei Pharmaceutical, Meiji Holdings, Pfizer, Fuji Pharma, Taiho Pharmaceutical, Kaken Pharmaceutical, Chugai Pharma, Tsumura & Co, Daiichi Sankyo Co, Ltd, Shinnihonseiyaku, Mochida Pharmaceutical Co, Ltd, ASKA Pharmaceutical Co, Ltd, Takeda, Terumo Fan WuEmployment: RocheStock and Other Ownership Interests: Roche Luciana MolineroEmployment: GenentechStock and Other Ownership Interests: Roche/GenentechPatents, Royalties, Other Intellectual Property: P35974-US Patent Application Inventorship Vidya MaiyaEmployment: Roche/GenentechStock and Other Ownership Interests: Roche/GenentechTravel, Accommodations, Expenses: Roche/GenentechOther Relationship: Roche/Genentech Victor K. KhorEmployment: Genentech/RocheStock and Other Ownership Interests: Roche, Iovance Biotherapeutics Yvonne G. LinEmployment: Genentech/RocheStock and Other Ownership Interests: Genentech/RocheConsulting or Advisory Role: Venn Biosciences Corporation Sandro PignataHonoraria: AstraZeneca, Roche, PharmaMar, Tesaro, Pfizer, MSD, GlaxoSmithKline, Clovis OncologyConsulting or Advisory Role: AstraZeneca, Roche, PharmaMar, Pfizer, Tesaro, Clovis Oncology, GlaxoSmithKlineResearch Funding: Roche, AstraZeneca, MSD, PfizerNo other potential conflicts of interest were reported.

Purpose: Women with abnormal cervical cancer screening results are referred to colposcopy and biopsy for diagnosis of cervical cancer precursors (high-grade squamous intraepithelial lesions [HSILs]). Colposcopy with a single biopsy can miss identification of HSILs. No systematic study has quantified the improved detection of HSIL by taking multiple lesion-directed biopsies., Methods: The Biopsy Study was an observational study of 690 women referred to colposcopy after abnormal cervical cancer screening results. Up to four directed biopsies were taken from distinct acetowhite lesions and ranked by colposcopic impression. A nondirected biopsy of a normal-appearing area was added if fewer than four directed biopsies were taken. HSIL identified by any biopsy was the reference standard of disease used to evaluate the incremental yield and sensitivity of multiple biopsies., Results: In the overall population, sensitivities for detecting HSIL increased from 60.6% (95% CI, 54.8% to 66.6%) from a single biopsy to 85.6% (95% CI, 80.3% to 90.2%) after two biopsies and to 95.6% (95% CI, 91.3% to 99.2%) after three biopsies. A significant increase in sensitivity of multiple biopsies was observed in all subgroups. The highest increase in yield of HSIL was observed for women with a high-grade colposcopic impression, HSIL cytology, and human papillomavirus (HPV) type 16 positivity. Only 2% of all HSILs diagnosed in the participants were detected by biopsies of normal-appearing transformation zone., Conclusion: Collection of additional lesion-directed biopsies during colposcopy increased detection of histologic HSIL, regardless of patient characteristics. Taking additional biopsies when multiple lesions are present should become the standard practice of colposcopic biopsy., (© 2014 by American Society of Clinical Oncology.)

Purpose: To determine the safety of sentinel lymph node biopsy as a replacement for inguinal femoral lymphadenectomy in selected women with vulvar cancer., Patients and Methods: Eligible women had squamous cell carcinoma, at least 1-mm invasion, and tumor size ≥ 2 cm and ≤ 6 cm. The primary tumor was limited to the vulva, and there were no groin lymph nodes that were clinically suggestive of cancer. All women underwent intraoperative lymphatic mapping, sentinel lymph node biopsy, and inguinal femoral lymphadenectomy. Histologic ultra staging of the sentinel lymph node was prescribed., Results: In all, 452 women underwent the planned procedures, and 418 had at least one sentinel lymph node identified. There were 132 node-positive women, including 11 (8.3%) with false-negative nodes. Twenty-three percent of the true-positive patients were detected by immunohistochemical analysis of the sentinel lymph node. The sensitivity was 91.7% (90% lower confidence bound, 86.7%) and the false-negative predictive value (1-negative predictive value) was 3.7% (90% upper confidence bound, 6.1%). In women with tumor less than 4 cm, the false-negative predictive value was 2.0% (90% upper confidence bound, 4.5%)., Conclusion: Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva.

Purpose: Pertuzumab is a humanized monoclonal antibody that inhibits human epidermal growth factor receptor 2 (HER2) heterodimerization and has single-agent activity in recurrent epithelial ovarian cancer. The primary objective of this phase II study was to characterize the safety and estimate progression-free survival (PFS) of pertuzumab with gemcitabine in patients with platinum-resistant ovarian cancer., Patients and Methods: Patients with advanced, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received a maximum of one prior treatment for recurrent cancer were randomly assigned to gemcitabine plus either pertuzumab or placebo. Collection of archival tissue was mandatory to permit exploration of biomarkers that would predict benefit from pertuzumab in this setting., Results: One hundred thirty patients (65 per arm) were treated. Baseline characteristics were similar between arms. The adjusted hazard ratio (HR) for PFS was 0.66 (95% CI, 0.43 to 1.03; P = .07) in favor of gemcitabine + pertuzumab. The objective response rate was 13.8% in patients who received gemcitabine + pertuzumab compared with 4.6% in patients who received gemcitabine + placebo. In patients whose tumors had low HER3 mRNA expression (< median, n = 61), an increased treatment benefit was observed in the gemcitabine + pertuzumab arm compared with the gemcitabine alone arm (PFS HR = 0.32; 95% CI, 0.17 to 0.59; P = .0002). Grade 3 to 4 neutropenia, diarrhea, and back pain were increased in patients treated with gemcitabine + pertuzumab. Symptomatic congestive heart failure was reported in one patient in the gemcitabine + pertuzumab arm., Conclusion: Pertuzumab may add activity to gemcitabine for the treatment of platinum-resistant ovarian cancer. Low HER3 mRNA expression may predict pertuzumab clinical benefit and be a valuable prognostic marker.