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Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028

Varga, Andrea; Piha-Paul, Sarina; Ott, Patrick A; Mehnert, Janice M; Berton-Rigaud, Dominique; Morosky, Anne; Yang, Ping; Ruman, Jane; Matei, Daniela
OBJECTIVE:To evaluate safety, tolerability, and antitumor activity of pembrolizumab monotherapy in patients with programmed death ligand 1 (PD-L1)-expressing advanced ovarian cancer enrolled in the multicohort, phase Ib KEYNOTE-028 trial. METHODS:Key inclusion criteria were age ≥18 years; advanced ovarian epithelial, fallopian tube, or primary peritoneal carcinoma; failure of previous therapy; and tumor PD-L1 positivity. Patients received pembrolizumab (10 mg/kg every 2 weeks) for ≤24 months or until disease progression/intolerable toxicity. Tumor response was assessed per RECIST v1.1 (investigator review). Adverse events (AEs) were graded using CTCAE version 4.0. Primary end point was confirmed objective response rate (ORR) per RECIST v1.1 (investigator review); data cutoff date was February 20, 2017. RESULTS:Twenty-six patients (median age, 57.5 years) with PD-L1-positive advanced metastatic ovarian cancer received pembrolizumab; 38.5% had metastatic disease, and 73.1% previously received ≥3 lines of therapy. Treatment-related AEs (TRAEs) occurred in 19 (73.1%) patients, most commonly arthralgia (19.2%), nausea (15.4%), and pruritus (15.4%). One grade 3 TRAE (increased plasma transaminase level) occurred. No deaths and no treatment discontinuations due to TRAEs occurred. After a median follow-up duration of 15.4 months, ORR was 11.5% (1 complete response, 2 partial responses); 7 patients (26.9%) achieved stable disease. Median progression-free and overall survival were 1.9 (95% CI, 1.8-3.5) and 13.8 (95% CI, 6.7-18.8) months, respectively. CONCLUSION:Pembrolizumab conferred durable antitumor activity with manageable safety and toxicity in patients with advanced PD-L1-positive ovarian cancer and is under further investigation in an ongoing phase II trial, KEYNOTE-100.
PMID: 30522700
ISSN: 1095-6859
CID: 4449222

Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN Solid Tumor trial

Keilholz, Ulrich; Mehnert, Janice M; Bauer, Sebastian; Bourgeois, Hugues; Patel, Manish R; Gravenor, Donald; Nemunaitis, John J; Taylor, Matthew H; Wyrwicz, Lucjan; Lee, Keun-Wook; Kasturi, Vijay; Chin, Kevin; von Heydebreck, Anja; Gulley, James L
BACKGROUND:We report phase 1b data from patients enrolled in the JAVELIN Solid Tumor clinical trial (NCT01772004) with unresectable stage IIIC or IV melanoma that had progressed after ≥1 line of therapy for metastatic disease. PATIENTS AND METHODS:Patients received avelumab (10 mg/kg)-a human anti-PD-L1 antibody. Assessments included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS:As of December 31, 2016, 51 patients were treated and followed for a median of 24.2 months (range, 16.1-31.5). Most patients had cutaneous (n = 28 [54.9%]) or ocular (n = 16 [31.4%]) melanoma and had received a median of 2 prior lines of therapy (range, 0-4), including ipilimumab (n = 26 [51.0%]). The confirmed ORR was 21.6% (95% CI, 11.3-35.3; complete response, 7.8%; partial response, 13.7%). The median duration of response was not estimable (95% CI, 2.6 months-not estimable). Median PFS and OS were 3.1 months (95% CI, 1.4-6.3) and 17.2 months (95% CI, 6.6-not estimable), respectively. Subgroup analyses suggested meaningful clinical activity (ORR [95% CI]) in patients with non-ocular melanoma (31.4% [16.9-49.3]), PD-L1-positive tumors (42.1% [20.3-66.5]), or prior ipilimumab therapy (30.8% [14.3-51.8]). Thirty-nine patients (76.5%) had a treatment-related adverse event (TRAE), most commonly infusion-related reaction (29.4%), fatigue (17.6%), and chills (11.8%); 4 patients (7.8%) had a grade 3 TRAE. Five patients (9.8%) had an immune-related TRAE (all were grade 1/2). No grade 4 TRAEs or treatment-related deaths were reported. CONCLUSION:Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in patients with previously treated metastatic melanoma. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01772004 .
PMCID:6335739
PMID: 30651126
ISSN: 2051-1426
CID: 4449262

Author Correction: Autophagy maintains tumour growth through circulating arginine

Poillet-Perez, Laura; Xie, Xiaoqi; Zhan, Le; Yang, Yang; Sharp, Daniel W; Hu, Zhixian Sherrie; Su, Xiaoyang; Maganti, Anurag; Jiang, Cherry; Lu, Wenyun; Zheng, Haiyan; Bosenberg, Marcus W; Mehnert, Janice M; Guo, Jessie Yanxiang; Lattime, Edmund; Rabinowitz, Joshua D; White, Eileen
In this Letter, 'released' should have been 'regulated' in the sentence starting: 'Deletion of Atg5 in the host similarly regulated circulating arginine and suppressed tumorigenesis...' This has been corrected online.
PMID: 30523330
ISSN: 1476-4687
CID: 4449232

Approaches to High-Risk Resected Stage II and III Melanoma

Yushak, Melinda; Mehnert, Janice; Luke, Jason; Poklepovic, Andrew
Over the last decade, several therapies, including both targeted and immune checkpoint inhibitors, have dramatically changed the treatment landscape for patients with metastatic melanoma. These same therapies are now being used in the adjuvant setting with the hope of delaying or preventing the development of metastatic disease. Although phase III trials have shown a clear benefit for patients with resected bulky nodal disease, treatment decisions for patients with earlier-stage (high-risk stage II and stage IIIA) melanoma in the adjuvant setting are less straightforward given the small number of patients studied so far. Among patients with stage IIIB and worse disease, both targeted and immune checkpoint inhibitors have shown benefit in recurrence-free survival. Although a head-to-head comparison has not been completed, patient and tumor characteristics can guide the optimal treatment of an individual.
PMID: 31099653
ISSN: 1548-8756
CID: 4449292

Clinical characterization of colitis arising from anti-PD-1 based therapy

Wang, Daniel Y; Mooradian, Meghan J; Kim, DaeWon; Shah, Neil J; Fenton, Sarah E; Conry, Robert M; Mehta, Rutika; Silk, Ann W; Zhou, Alice; Compton, Margaret L; Al-Rohil, Rami N; Lee, Sunyoung; Voorhees, Amber L; Ha, Lisa; McKee, Svetlana; Norrell, Jacqueline T; Mehnert, Janice; Puzanov, Igor; Sosman, Jeffrey A; Chandra, Sunandana; Gibney, Geoffrey T; Rapisuwon, Suthee; Eroglu, Zeynep; Sullivan, Ryan; Johnson, Douglas B
Colitis is a frequent, clinically-significant immune-related adverse event caused by anti-programmed death-1 (PD-1). The clinical features, timing, and management of colitis with anti-PD-1-based regimens are not well-characterized. Patients with advanced melanoma that received either anti-PD-1 monotherapy ("monotherapy") or combined with ipilimumab ("combination therapy") were screened from 8 academic medical centers, to identify those with clinically-relevant colitis (colitis requiring systemic steroids). Of 1261 patients who received anti-PD-1-based therapy, 109 experienced colitis. The incidence was 3.2% (30/937) and 24.4% (79/324) in the monotherapy and combination therapy cohorts, respectively. Patients with colitis from combination therapy had significantly earlier symptom onset (7.2 weeks vs 25.4 weeks, p < 0.0001), received higher steroid doses (median prednisone equivalent 1.5 mg/kg vs 1.0 mg/kg, p = 0.0015) and experienced longer steroid tapers (median 6.0 vs 4.0 weeks, p = 0.0065) compared to monotherapy. Infliximab use and steroid-dose escalation occurred more frequently in the combination therapy cohort compared to monotherapy. Nearly all patients had resolution of their symptoms although one patient died from complications. Anti-PD-1 associated colitis has a variable clinical presentation, and is more frequent and severe when associated with combination therapy. This variability in checkpoint-inhibitor associated colitis suggests that further optimization of treatment algorithms is needed.
PMCID:6287774
PMID: 30546965
ISSN: 2162-4011
CID: 4449242

Detection of Three Distinct Clonal Populations Using Circulating Cell Free DNA: A Cautionary Note on the Use of Liquid Biopsy

Riedlinger, Gregory M; Jalloul, Nahed; Poplin, Elizabeth; Mehnert, Janice M; Groisberg, Roman; Khiabanian, Hossein; Ganesan, Shridar
PMCID:6777732
PMID: 31588418
ISSN: 2473-4284
CID: 4449362

High-Dose Ipilimumab and High-Dose Interleukin-2 for Patients With Advanced Melanoma [Case Report]

Silk, Ann W; Kaufman, Howard L; Curti, Brendan; Mehnert, Janice M; Margolin, Kim; McDermott, David; Clark, Joseph; Newman, Jenna; Bommareddy, Praveen K; Denzin, Lisa; Najmi, Saltanat; Haider, Azra; Shih, Weichung; Kane, Michael P; Zloza, Andrew
High-dose ipilimumab (IPI) and high-dose interleukin-2 (IL-2) are approved agents for metastatic melanoma, but the efficacy and safety of the combination are unknown. The objective of this study was to evaluate the feasibility, safety, and efficacy of combination high-dose IPI and high-dose IL-2 in patients with histologically confirmed advanced unresectable stage III and IV melanoma. This Phase II, multicenter, open-label, single-arm trial was conducted in nine patients enrolled between 12/2014 and 12/2015. Subjects were treated with high-dose IPI 10 mg/kg intravenous (IV) every 3 weeks for four doses starting at week 1 and high-dose IL-2 (600,000 IU/kg IV bolus every 8 h for up to 14 doses) concurrently with IPI at weeks 4 and 7. After the first 12 weeks of combination therapy, maintenance IPI (10 mg/kg IV) monotherapy was administered every 12 weeks for up to 1 year. No patient had received prior PD-1 blockade, and only one received prior vemurafenib. Confirmed partial response was achieved in one (11%), stable disease in four (44%), and progressive disease in four (44%) of nine patients. Two patients achieved durable disease control of 44+ and 50+ months at the most recent follow-up without subsequent therapy. The median overall survival was not reached after a minimum 24 months of follow-up time. One-year and 2-year survival rates were 89 and 67%, respectively. Seven patients (78%) experienced grade 3 or 4 adverse events related to the study therapy, three of which were attributed to both agents. One patient discontinued the treatment due to liver and kidney toxicity. While toxicity was significant, all events were reversible, and there was no treatment-related mortality. In peripheral blood of patients with decreasing tumor burden, the ratio of the non-classical MHC-II proteins HLA-DM to HLA-DO increased 2-fold, raising the possibility of the ratio of HLA-DM:HLA-DO as a novel biomarker of response to treatment. Although the sample size was limited, combination therapy with high-dose IPI and high-dose IL-2 was feasible and associated with clinical benefit. IL-2-based compounds in combination with CTLA-4 blockade should be studied in advanced melanoma patients who fail to benefit from first-line PD-1 blockade. Clinical Trial Registration: ClinicalTrials.gov, NCT02203604. Registered 30 July 2014, https://clinicaltrials.gov/ct2/show/NCT02203604.
PMCID:6965158
PMID: 31998643
ISSN: 2234-943x
CID: 4449382

NCI9782: A phase 1 study of talazoparib in combination with carboplatin and paclitaxel in patients with advanced solid tumors. [Meeting Abstract]

Turk, Anita Ahmed; Leal, Ticiana; Chan, Nancy; Wesolowski, Robert; Spencer, Kristen Renee; Malhotra, Jyoti; Lang, Joshua Michael; McNeel, Douglas G.; O\Regan, Ruth; Mehnert, Janice M.; Eickhoff, Jens C.; Liu, Glenn; Wisinski, Kari Braun
ISI:000487345800734
ISSN: 0732-183x
CID: 5180722

Multicenter Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma

Hurwitz, Michael E; Markowski, Paul; Yao, Xiaopan; Deshpande, Hari; Patel, Jaymin; Mortazavi, Amir; Donadio, Alessia; Stein, Mark N; Kelly, William Kevin; Petrylak, Daniel Peter; Mehnert, Janice M
BACKGROUND:Sorafenib, an oral tyrosine kinase inhibitor, may enhance the antitumor activity of platinum-based chemotherapy in transitional-cell carcinoma. This study investigated the safety and clinical outcome of adding sorafenib to gemcitabine and carboplatin for patients with advanced transitional-cell carcinoma. PATIENTS AND METHODS:on days 1 and 8) and carboplatin (area under the curve of 5 on day 1) with sorafenib (400 mg 2 times a day on days 2-19 every 21 days) for 6 cycles. Subjects with stable disease or partial or complete response continued to receive sorafenib until disease progression. The primary end point was progression-free survival (PFS) at 5 months with a secondary end point of response (partial or complete). RESULTS:Seventeen subjects were enrolled. The median number of cycles of gemcitabine and carboplatin with sorafenib provided was 4.4. A total of 15, 5, and 8 subjects required reductions of gemcitabine, carboplatin, and sorafenib, respectively. Thirteen subjects (76%) required multiple dose reductions. Eleven subjects (65%) were free of progression at 5 months. The overall response rate was 54% (95% confidence interval [CI], 0.28-077), with 4 patients experiencing complete response (24%; 95% CI, 0.07-0.50) and 5 partial response (29%; 95% CI, 0.10-0.56); 7 subjects (41%) had stable disease. Median PFS was 9.5 months (95% CI, 0.43-1.26), and median overall survival was 25.2 months (95% CI, 0.96-5.65). One-year PFS was 31%, and 1-year overall survival was 72%. Eleven subjects (65%) discontinued treatment because of toxicity. There were no toxic deaths. CONCLUSION:Gemcitabine and carboplatin with sorafenib showed clinical activity in advanced TCC, with some prolonged progression-free intervals. However, gemcitabine and carboplatin with sorafenib was associated with significant toxicity, causing discontinuation of therapy in most patients.
PMID: 30177237
ISSN: 1938-0682
CID: 4449202

Autophagy maintains tumour growth through circulating arginine

Poillet-Perez, Laura; Xie, Xiaoqi; Zhan, Le; Yang, Yang; Sharp, Daniel W; Hu, Zhixian Sherrie; Su, Xiaoyang; Maganti, Anurag; Jiang, Cherry; Lu, Wenyun; Zheng, Haiyan; Bosenberg, Marcus W; Mehnert, Janice M; Guo, Jessie Yanxiang; Lattime, Edmund; Rabinowitz, Joshua D; White, Eileen
Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation1-5. Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect that manifests as starvation intolerance and gradual loss of white adipose tissue, liver glycogen and muscle mass1. Cancer cells also benefit from autophagy. Deletion of essential autophagy genes impairs the metabolism, proliferation, survival and malignancy of spontaneous tumours in models of autochthonous cancer6,7. Acute, systemic deletion of Atg7 or acute, systemic expression of a dominant-negative ATG4b in mice induces greater regression of KRAS-driven cancers than does tumour-specific autophagy deletion, which suggests that host autophagy promotes tumour growth1,8. Here we show that host-specific deletion of Atg7 impairs the growth of multiple allografted tumours, although not all tumour lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumour cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme arginase I (ARG1) in the circulation of Atg7-deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating ARG1, and reduced both serum arginine and tumour growth. Deletion of Atg5 in the host similarly regulated [corrected] circulating arginine and suppressed tumorigenesis, which demonstrates that this phenotype is specific to autophagy function rather than to deletion of Atg7. Dietary supplementation of Atg7-deficient hosts with arginine partially restored levels of circulating arginine and tumour growth. Thus, defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumour growth; this identifies a metabolic vulnerability of cancer.
PMID: 30429607
ISSN: 1476-4687
CID: 4449212