Anila Qureshi

Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma

BACKGROUND Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence‐free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. METHODS In this randomized, double‐blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence‐free survival in the intention‐to‐treat population. RESULTS At a minimum follow‐up of 18 months, the 12‐month rate of recurrence‐free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment‐related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. CONCLUSIONS Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence‐free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol‐Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906; Eudra‐CT number, 2014‐002351‐26.)

Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: A randomised, double-blind, multicentre, phase 3 trial

BACKGROUNDnA phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg.nnnMETHODSnThis randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189.nnnFINDINGSnBetween Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6-42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9-29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6-17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9-13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70-0·99; p=0·04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events.nnnINTERPRETATIONnIn patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment.nnnFUNDINGnBristol-Myers Squibb.

Severe toxicity following induction chemotherapy for acute myelogenous leukemia in a patient with Werner's syndrome

Werners syndrome is an autosomal recessive disorder resulting in premature aging. Most patients die in their fifth decade from malignancies or heart disease. The gene for Werners syndrome (WRN) encodes a recQ helicase. Cells from patients with Werners syndrome have increased sensitivity to DNA-damaging drugs in vitro. Here we present a patient with Werners syndrome who developed severe chemotherapy-induced toxicity during treatment for acute myelogenous leukemia. We propose that lack of WRN resulted in increased sensitivity of the patients cells to the toxicity of chemotherapy.

Abstract CT073: Immunomodulatory effects of nivolumab and ipilimumab in combination or nivolumab monotherapy in advanced melanoma patients: CheckMate 038

Introduction: Nivolumab and ipilimumab (NIVO+IPI) in combination was more efficacious than nivolumab (NIVO) alone in advanced melanoma patients (pts) in the phase 3 CheckMate 067 study (Larkin et al, NEJM. 2015). To elucidate the differential mechanisms of action of NIVO+IPI vs NIVO, we assessed biomarkers in pts with advanced melanoma treated with these agents in the CheckMate 038 study. Methods: IPI-naive pts without brain metastases from parts 1-3 of the phase 1b CA209-038 study (NCT01621490) who received NIVO+IPI Q3W (1 mg/kg+3 mg/kg, n=53) or NIVO alone Q2W (3 mg/kg, n=52) were included in the analysis. Tumor and peripheral immune markers were assessed (Table), and compared across treatment groups and by best overall response (BOR) per RECIST v1.1. Results: Increases in tumor-infiltrating CD8 T cells were observed with both NIVO+IPI and NIVO treatment, with greatest increases in NIVO+IPI pts with CR/PR or SD vs other BOR groups (Table). Increases in tumor PD-L1 expression were observed with both treatments, with 10-fold greater increases in pts with CR/PR to NIVO+IPI vs pts with PD/NE to NIVO+IPI or CR/PR to NIVO alone. Reductions in circulating MDSCs were observed with NIVO+IPI treatment across BOR groups, but only in pts with CR/PR in the NIVO-treated group. Increases in CXCL9, CXCL10 and IFN-gamma were observed irrespective of BOR in pts treated with both NIVO+IPI and NIVO alone, with the greatest increases with NIVO+IPI treatment. Conclusion: NIVO+IPI vs NIVO alone was associated with consistent reductions in MDSCs and greater increases in IFN-gamma signaling. Pts with CR/PR to NIVO+IPI had the greatest increases in CD8 T cells and PD-L1 expression, suggesting enhanced T-cell effector function. This may partly explain the higher ORR observed for NIVO+IPI vs NIVO alone in CheckMate 067. Further analyses will elucidate the differential immunomodulatory effects of NIVO+IPI in combination vs NIVO monotherapy in pts with advanced melanoma. Citation Format: Antoni Ribas, Salvador Martin-Algarra, Shailender Bhatia, Wen-Jen Hwu, Craig L. Slingluff, William H. Sharfman, F. Stephen Hodi, Walter J. Urba, Jason J. Luke, John B. Haanen, Margaret K. Callahan, Jedd D. Wolchok, Scott D. Chasalow, Petra Ross-Macdonald, Tina C. Young, Anila Qureshi, Christine E. Horak. Immunomodulatory effects of nivolumab and ipilimumab in combination or nivolumab monotherapy in advanced melanoma patients: CheckMate 038 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT073. doi:10.1158/1538-7445.AM2017-CT073

High-dose mitoxantrone-based induction therapy in newly diagnosed AML. Results of 171 patients treated at NYMC between 1991–2003

6610 Background: We developed a high dose mitoxantrone(M)-based induction regimen based on the steep dose-response curve for M.nnnMETHODSn171 newly dxd AML pts were rxd on 4 trials between 1991-2003. Study 1: Phase II study, age <60. Induction: M 80 mg/m2 x 1, ara-C (A) 3 gm/m2/d x 5, VP-16 (V) 150 mg/m2/d qod x 3. Consolidation: 5 mos A x 4d with M 20 mg/m2 mos 3 + 5, V 150 mg/m2 x 2 mos 4 + 6. Study 2: randomized study of high vs standard dose M with A in pts ≥ 60 yrs. Pts did not receive consolidation. Only pts with high dose M are included here. Study 3: Same as study 1 except pts received ATRA 45 mg/m2 x 3 doses. Pts < 60 received consolidation as in study 1. Pts ≥ 60 did not receive consolidation. Study 4: Pts ≥60 yrs, same as study 2 + temozolomide postremission therapy. In each study, pts with prior antecedent hematologic disorder (AHD) or secondary AML were included.nnnRESULTSnMedian age: 59 (21-88); M/F: 91/80; cytogenetics(SWOG): good:13%, intermediate:50%, poor:26%, indeterminate:5%, IM:6%; Prior AHD: 32% of pts.nnnRESPONSEnPts < 60 yrs: CR 79%, failure (F):18%, toxic death (TD):3%; Pts ≥60: CR 52%, F 34%, TD 14%. CR without AHD: 78%, with AHD: 44%. CR by cytogenetic group: good: 91%, int: 67%, poor: 50%, indeter: 63%. Median duration of response (DOR) is 24 mos (range 1-139+ mos) for pts < 60 yrs, and 8 mos (1-66+ mos) for pts ≥ 60. Overall survival (OS) is 19 mos (0-139+ mo) for pts < 60 and 7.6 mos (0-66+ mos) for pts ≥ 60 yrs. For pts without AHD < 60 yrs, median DOR is 38.9 mos and median OS is 24 mos.nnnCONCLUSIONSnHigh dose M-based therapy yields high response rates and high percentage of durable remissions even in poor risk patients, many of whom would not be eligible for typical US AML trials. No significant financial relationships to disclose.