Jason Konner

A Phase II Study of Fulvestrant plus Abemaciclib in Hormone Receptor–Positive Advanced or Recurrent Endometrial Cancer

Abstract Purpose: Inhibition of the cyclin D–cyclin-dependent kinase (CDK)4/6–INK4–retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer are suboptimal, perhaps due to genomic alterations that promote estrogen receptor–independent cyclin D1–CDK4/6 activation. We hypothesized that the addition of abemaciclib, a CDK4/6 kinase inhibitor, to antiestrogen therapy with fulvestrant would be an effective therapeutic strategy in patients with advanced or recurrent endometrial cancer. Patients and Methods: In this phase II study, patients with advanced or recurrent endometrial cancer received 150 mg of abemaciclib orally twice daily with 500 mg of fulvestrant intramuscularly monthly with a 2-week loading dose. Eligibility included estrogen receptor or progesterone receptor expression ≥1% by IHC, measurable disease, ≤2 prior lines of chemotherapy, and ≤1 prior lines of hormonal therapy. The primary endpoint was the objective response rate by RECIST v1.1. Results: Twenty-seven patients initiated therapy, and 25 were evaluable for efficacy. Eleven patients achieved partial response; 10 responses (91%) were in copy number–low/no specific molecular profile tumors, 1 response (9%) was in a microsatellite instability–high tumor, and no responses were observed in copy number–high/TP53abnormal tumors. The objective response rate was 44% (90% confidence interval, 27.0%–62.1%). The median duration of response was 15.6 months. The median progression-free survival was 9.0 months (90% confidence interval, 1.8–20.4). The most common grade ≥3 treatment-related adverse events were neutropenia (26%) and anemia (19%); no new safety signals were identified. Conclusions: The combination of abemaciclib and fulvestrant has promising activity with durable responses in advanced or recurrent endometrial cancer; a randomized trial is planned. See related commentary by Garg and Oza, p. 2073

Characteristics and survival of ovarian cancer patients treated with neoadjuvant chemotherapy but not undergoing interval debulking surgery

Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) confers similar outcomes as primary debulking surgery and chemotherapy. Little is known about patients who receive NACT but do not undergo debulking surgery. Our aim was to characterize these patients. We prospectively identified patients with newly diagnosed stage III/IV ovarian cancer treated with NACT from 7/1/15-12/1/17. Fisher exact and Wilcoxon rank-sum tests were used to compare clinical characteristics by surgical status. The Kaplan-Meier method was used to estimate survival outcomes. Log-rank test and Cox proportional hazards model were applied to assess the relationship of covariates to outcome, and time-dependent covariates were applied to variables collected after diagnosis. Of 224 women who received NACT, 162 (72%) underwent IDS and 62 (28%) did not undergo surgery. The non-surgical group was older (p<0.001), had higher Charlson comorbidity index (CCI; p<0.001), lower albumin levels (p=0.007), lower Karnofsky performance scores (p<0.001), and were more likely to have dose reductions in NACT (p<0.001). Reasons for no surgery included poor response to NACT (39%), death (15%), comorbidities (24%), patient preference (16%), and loss to follow-up (6%). The no surgery group had significantly worse overall survival (OS) than the surgery group (hazard ratio=3.34; 95% confidence interval=1.66-6.72; p<0.001), after adjustment for age, CCI, and dose reductions. A significant proportion of women treated with NACT do not undergo IDS, and these women are older, frailer, and have worse OS. More studies are needed to find optimal therapies to maximize outcomes in this high-risk, elderly population.

Spectrum ofBRAFMutations and Gene Rearrangements in Ovarian Serous Carcinoma

PURPOSELow-grade serous carcinoma (LGSC) is a rare type of ovarian cancer, which commonly arises from serous borderline tumor (SBT) and is characterized by frequent activating mutations in the mitogen-activated protein kinase pathway, including BRAF. The BRAFV600Emutation is associated with improved prognosis in SBT and LGSC, and responses to BRAF inhibitor therapy have been reported. We sought to characterize the clinicopathologic and molecular features of BRAF-driven tubo-ovarian and primary peritoneal serous tumors.METHODSRetrospective analysis of our institutional cohort of SBTs (n = 22), LGSCs (n = 119) and high-grade serous carcinomas (HGSCs, n = 1,290) subjected to targeted massively parallel sequencing was performed to identify cases with BRAF genetic alterations. Putative BRAF rearrangements were confirmed using targeted RNA sequencing and/or fluorescence in situ hybridization (FISH). BRAFV600Eoncoprotein expression was assessed by immunohistochemistry on selected cases.RESULTSBRAF somatic genetic alterations were identified in 29 of 1,431 (2%) serous tumors and included mutations (n = 24), gene rearrangements (n = 3), and amplification (n = 2). BRAF mutations were more frequent in SBTs (7 of 22; 32%) compared with LGSCs (11 of 119; 9%, P = .009) and HGSCs (6 of 1,290; 0.5%; P &lt; .0001, SBT/LGSC v HGSC). The BRAFV600Ehotspot mutation was most common (n = 16); however, other BRAF driver mutations were also detected (n = 8). BRAF mutations were often clonal or truncal in SBTs and LGSCs, but subclonal in most HGSCs. Pathogenic BRAF gene fusions were identified in LGSCs (n = 2) and HGSC (n = 1) and involved distinct fusion partners ( AGK, MKRN1, and AGAP3). Three patients with BRAF-mutant LGSC were treated with targeted mitogen-activated protein kinase inhibitors, one of whom was maintained on therapy for over 3 years with clinical benefit.CONCLUSIONRecognition of BRAF alterations beyond V600E mutation in LGSC may have clinical implications for appropriate targeted therapy selection.

Secondary Cytoreduction and Carboplatin Hyperthermic Intraperitoneal Chemotherapy for Platinum-Sensitive Recurrent Ovarian Cancer: An MSK Team Ovary Phase II Study

PURPOSEThe purpose of this phase II study was to evaluate hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin for recurrent ovarian cancer during secondary cytoreductive surgery.MATERIALS AND METHODSPatients were intraoperatively randomly assigned to carboplatin HIPEC (800 mg/m2for 90 minutes) or no HIPEC, followed by five or six cycles of postoperative IV carboplatin-based chemotherapy, respectively. Based on a binomial single-stage pick-the-winner design, an arm was considered winner if ≥ 17 of 49 patients were without disease progression at 24 months post-surgery. Secondary objectives included postoperative toxicity and HIPEC pharmacokinetics.RESULTSOf 98 patients, 49 (50%) received HIPEC. Complete gross resection was achieved in 82% of the HIPEC patients and 94% of the standard-arm patients. Bowel resection was performed in 37% of patients in the HIPEC arm compared with 65% in the standard ( P = .008). There was no perioperative mortality and no difference in use of ostomies, length of stay, or postoperative toxicity. At 24 months, eight patients (16.3%; 1-sided 90% CI, 9.7 to 100) were without progression or death in the HIPEC arm and 12 (24.5%; 1-sided 90% CI, 16.5 to 100) in the standard arm. With a medium follow-up of 39.5 months, 82 patients progressed and 37 died. The median progression-free survival in the HIPEC and standard arms were 12.3 and 15.7 months, respectively (hazard ratio, 1.54; 95% CI, 1 to 2.37; P = .05). There was no significant difference in median overall survival (52.5 v 59.7 months, respectively; hazard ratio, 1.39; 95% CI, 0.73 to 2.67; P = .31). These analyses were exploratory.CONCLUSIONHIPEC with carboplatin was well tolerated but did not result in superior clinical outcomes. This study does not support the use of HIPEC with carboplatin during secondary cytoreductive surgery for platinum-sensitive recurrent ovarian cancer.

Assessing the Genomic Landscape of Cervical Cancers: Clinical Opportunities and Therapeutic Targets

Abstract Purpose: Tumor genomic profiling is increasingly used to guide treatment strategy in patients with cancer. We integrated tumor genomic, clinical demographic, and treatment response data to assess how prospective tumor-normal sequencing impacted treatment selection in patients with cervical cancer. Experimental Design: Cervical cancers were prospectively analyzed using the MSK-IMPACT (Memorial Sloan Kettering Cancer Center – Integrated Mutation Profiling of Actionable Cancer Targets) next-generation sequencing panel. Clinical data, including histology, stage at diagnosis, treatment history, clinical trial enrollment and outcomes, date of last follow-up, and survival status were obtained from medical records. Results: A total of 177 patients with cervical cancer (squamous, 69; endocervical adenocarcinoma, 50; gastric type, 22; adenosquamous, 21; and other, 15) underwent MSK-IMPACT testing. The most prevalent genomic alterations were somatic mutations or amplifications in PIK3CA (25%), ERBB2 (12%), KMT2C (10%), and KMT2D (9%). Furthermore, 13% of patients had high tumor mutational burden (TMB &amp;gt;10 mut/Mb), 3 of which were also microsatellite instability–high (MSI-H). Thirty-seven percent of cases had at least one potentially actionable alteration designated as a level 3B mutational event according to the FDA-recognized OncoKB tumor mutation database and treatment classification system. A total of 30 patients (17%) were enrolled on a therapeutic clinical trial, including 18 (10%) who were matched with a study based on their MSK-IMPACT results. Twenty patients (11%) participated in an immune checkpoint inhibition study for metastatic disease; 2 remain progression free at &amp;gt;5 years follow-up. Conclusions: Tumor genomic profiling can facilitate the selection of targeted/immunotherapies, as well as clinical trial enrollment, for patients with cervical cancer.

Outcomes After Secondary Cytoreductive Surgery With or Without Carboplatin Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Followed by Systemic Combination Chemotherapy for Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

The purpose of this study is to see if the investigators can improve the treatment of this type of cancer. They want to find out what effects, good and/or bad, giving heated chemotherapy into the belly, known as hyperthermic intraperitoneal chemotherapy (HIPEC), has on the patient and this type of cancer. The goal of HIPEC is to expose any cancer left in the abdomen after surgery to high doses of chemotherapy. The chemotherapy is heated in the hope that this will make it easier for it to get into and kill the cancer cells. The drug used for HIPEC will be carboplatin, a Food and Drug Administration (FDA) approved drug for use in ovarian, fallopian tube or primary peritoneal cancer.