Amanda Shreders

Prolonged Benefit from Ipilimumab Correlates with Improved Outcomes from Subsequent Pembrolizumab

Anti–PD-1 therapies are becoming first-line treatments for metastatic melanoma, but how prior immune therapy affects anti–PD-1 efficacy is unknown. Prior ipilimumab was found to predict response to anti–PD-1, which could help select patients for therapy. Patients with metastatic melanoma whose disease progresses on ipilimumab can clearly derive benefit from subsequent anti–programmed death-1 (PD-1). However, patients experience heterogeneous outcomes with ipilimumab, including rapid or delayed progression, and it is unclear whether patterns of ipilimumab progression influence subsequent clinical responses to anti–PD-1. We retrospectively reviewed data from 116 patients with metastatic melanoma who progressed on ipilimumab and were subsequently treated with pembrolizumab. The study objectives were to determine whether progression-free survival (PFS) with ipilimumab was associated with PFS, objective response rate (ORR), and clinical benefit rate (CBR; ORR + stable disease) with pembrolizumab. Patients with PFS ≥90 days after treatment with ipilimumab generally had superior outcomes with subsequent pembrolizumab treatment compared with patients with PFS <90 days (ORR, 49% vs. 35%, P = 0.12; CBR, 66% vs. 46%, P = 0.03). Patients with prolonged ipilimumab benefit (PFS ≥ 180 days) had excellent outcomes with pembrolizumab compared with rapid progressors (PFS < 45 days; ORR, 55% vs. 25%; CBR, 80% vs. 25%; median PFS, 249 vs. 50 days). Using logistic regression models, PFS with ipilimumab was independently correlated with response to pembrolizumab (odds ratio, 1.22; 95% CI, 1.02–1.51). This study shows that prolonged PFS with ipilimumab predicts excellent outcomes with subsequent pembrolizumab treatment, offering valuable prognostic information for clinicians. Cancer Immunol Res; 4(7); 569–73. ©2016 AACR.

Dexamethasone, rituximab and cyclophosphamide for relapsed and/or refractory and treatment-naïve patients with Waldenstrom macroglobulinemia

The management of Waldenström macroglobulinaemia (WM) relies predominantly on small trials, one of which has demonstrated activity of dexamethasone, rituximab and cyclophosphamide (DRC) in the frontline setting. We report on the efficacy of DRC, focusing on relapsed/refractory (R/R) patients. Ibrutinib, a recently approved agent in WM demonstrated limited activity in patients with MYD88WT genotype. Herein, we additionally report on the activity of DRC based on the MYD88L265P mutation status. Of 100 WM patients evaluated between January 2007 and December 2014 who received DRC, 50 had R/R WM. The overall response rate (ORR) was 87%. The median progression‐free survival (PFS) and time‐to‐next‐therapy (TTNT) were 32 (95% confidence interval [CI]: 15–51) and 50 (95% CI: 35–60) months, respectively. In the previously untreated cohort (n = 50), the ORR was 96%, and the median PFS and TTNT were 34 months (95% CI: 23–not reached [NR]) and NR (95% CI: 37–NR), respectively. Twenty‐five (86%) of 29 genotyped patients harbored MYD88L265P. The response rates and outcomes were independent of MYD88 mutation status. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Similar to the frontline setting, DRC is an effective and well‐tolerated salvage regimen for WM. In contrast to ibrutinib, DRC offers a less expensive, fixed‐duration option, with preliminary data suggesting efficacy independent of the patients’ MYD88 status.

Efficacy of immunotherapy for metastatic mucosal melanoma

Melanoma is a malignancy arising from melanocytes, and while the overwhelming majority of melanomas are cutaneous in nature, extra-cutaneous melanomas are also relatively common. Approximately between 0.8% and 3% of all melanomas arise from the mucosal membranes with approximately 50% arising from the nasal cavity, approximately 25% from the anorectal region and approximately 20% from the urogenital tract [1–7] Though cutaneous melanoma is more common in men and is more prevalent in coastal and southern regions, mucosal melanomas are more common in older women without a preferential geographic location [1–3]. While cutaneous melanoma is about 16-times more common in fair skin patients, mucosal melanoma is only twice as common in fair skin patients [3]. Additionally there are no known risk factors for mucosal melanoma unlike cutaneous melanoma which is related to ultraviolet light exposure [1–3]. The occult anatomic location of mucosal melanomas results in few patients diagnosed at an early stage as demonstrated by only 9% of cutaneous melanomas having nodal involvement at diagnosis compared with 21% of head and neck, 61% of anorectal and 23% of vulvovaginal melanoma [2]. Given that mucosal melanoma patients more frequently present at a higher stage, patients with mucosal melanoma have a worse 5-year overall survival (OS) compared with patients with cutaneous melanomas (25% for mucosal vs 81% for cutaneous) [2,6]. Despite having a common embryologic origin, cutaneous and mucosal melanomas are molecularly unique [1,4]. For example, while 40–50% of cutaneous melanomas harbor a BRAF mutation, only 10% of mucosal melanomas are BRAF mutant [2,3,6,8]. Conversely, mutations or amplifications in c-KIT are seen in approximately 25% of mucosal melanomas compared with approximately 5–10% seen in cutaneous melanomas [2–4,6,9]. While mucosal melanomas differ from cutaneous melanomas in risk factors, epidemiology and molecular mutations, treatment options for patients with metastatic mucosal melanoma are the same as those patients with metastatic cutaneous melanoma. Currently, immunotherapy provides the backbone for most patients with metastatic melanoma, yet it remains unclear if immunotherapy has the same efficacy in patients with mucosal melanoma as it does in patients with cutaneous melanoma. While there are no randomized, prospective trials specifically dedicated to assess the efficacy of immunotherapy in mucosal melanoma, there are multiple retrospective analyses involving immunotherapy in patients with metastatic mucosal melanoma. In this correspondence, we review the available data evaluating the efficacy of both ipilimumab and anti-PD1 agents in patients with m etastatic mucosal melanoma. Efficacy of immunotherapy for metastatic mucosal melanoma

Universal screening for depression in cancer patients and its impact on management patterns.

232 Background: Screening for distress in cancer patients (pts) is recommended by several national guidelines. High distress scores are associated with increased depression. We established universal depression screening and investigated its impact on cancer patient management. METHODS Patient Health Questionnaire (PHQ9) was administered to newly diagnosed cancer patients prior to receiving their first non-oral antineoplastic agent. Patient demographics, disease characteristics, chronic medication load, antidepressant use, treatment interruptions, weight change, referral and adherence to psychiatry were recorded. Pts with high (> 9) and low (< 4) PHQ9 scores were compared using Chi-square and Wilcoxon rank-sum tests. RESULTS Screening was performed in 1,190 consecutive pts over an 18 month period at Mayo Clinic. Responses were received from 1055 (89%) pts, of which 144 had high score (PHQ-H). These were compared with 99 randomly selected low score (PHQ-L) pts. The 243 pts (median age 65; range 18-92 years) in the final analysis included: 53.5% females, 90% Caucasians, 74% married and 77% living with others. Diagnosis was solid organ cancer in 81% and metastatic disease in 54% patients, and 13% were on antidepressants for preexisting depression. PHQ-H were more likely to be on antidepressants than PHQ-L (19% vs. 3%; p = 0.0002), be referred to psychiatry (69% vs. 12%; p < 0.0001), attend psychiatry appointment (45% vs. 12%; p < 0.0001) and require behavioral therapy (50% vs 8%; p = 0.0065). PHQ-H did not have a significantly increased antidepressant use, treatment interruptions (p = 0.5) or weight change (p = 0.4). Race, gender, chronic medication load, marital status, living situation, metastatic disease and type of cancer were not significantly different between PHQ-H and PHQ-L. CONCLUSIONS We implemented a universal depression screening and management plan for cancer pts and noted that previously being on antidepressants was associated with higher patient distress. Higher score led to more frequent behavioral therapy, possibly preventing non-compliance or need for increased psychotropic medications. Our model identifies cancer pts with depression and implements an effective management plan for their care.

Abstract 10: Concordance of BAP1, PBRM1, Ki-67, and TOPOIIa protein expression in primary clear cell renal cell carcinoma tumors and patient-matched metastatic tumors

Introduction: Efforts to improve clear cell renal cell carcinoma (ccRCC) mortality have focused primarily on evaluating prognostic biomarkers in primary tumors in order to identify indicators of response to treatment and targets for novel therapies. To date little attention has been paid to the status of these biomarkers in the more therapeutically-relevant metastatic tumor. Thus, we evaluated concordance of expression of four key prognostic ccRCC biomarkers (BAP1, PBRM1, Ki-67 and TOPOIIa) in a large cohort of patient-matched primary ccRCC and metastatic tumors. Methods: We identified 114 patients treated surgically for ccRCC between 1990 and 2005 who had synchronous (M1) or metachronous (M0) metastases, underwent metastasectomy for at least one metastatic lesion and had archived tissue available from the primary and at least one metastatic tumor. We performed IHC on all primary and metastatic tumors for BAP1, PBRM1, Ki-67, and TOPOIIa using previously-published protocols. BAP1 and PBRM1 expression was categorized as positive or negative and Ki-67 and TOPOIIa was quantified as the number of positive cells per mm2. For BAP1 and PBRM1, we calculated the concordance between patient-matched primary and metastatic tumors as the percentage of pairs where the primary and metastatic tumor had the same designation (i.e., positive or negative). For TOPOIIa and Ki-67, we assessed concordance using Spearman correlation coefficient. Analysis of variance was used to evaluate if concordance between primary-metastatic tumor pairs for TOPOIIa and Ki-67 was associated with metastatic site, metastatic timing (M0/M1), metastatic tumor grade, metastatic tumor necrosis, and metastatic tumor sarcomatoid differentiation. Results: There were a total of 161 patient-matched metastatic tumors available for the 114 patients: 78 patients had only a single metastasis while 36 patients had two or more metastases. While sites of metastases varied, pulmonary metastases were the most common (44% of all metastases). Loss of BAP1 expression was observed in19% of the primary ccRCC and 98.6% of the tumor pairs had concordant BAP1 status between the paired primary and metastatic tumors. Loss of PBRM1 was observed in 56% of the primary ccRCC tumors and 89.3% of tumor pairs showed concordant PBRM1 status. By comparison, median expression of Ki-67 was 65.0mm2 in the primary ccRCC tumors and the Pearson correlation with the patient-matched metastatic tumors was 0.43. The difference in Ki-67 expression between primary-metastatic tumor pairs was associated with necrosis in the metastatic tumor (p=0.014). Median expression of TOPOIIa was 2.6mm2 in the primary ccRCC tumors and the Pearson correlation with the patient-matched metastatic tumors was 0.25. The difference in TOPOIIa expression between primary-metastatic tumor pairs was associated with metastatic site (p=0.0006) and metastases to the heart were significantly different than pulmonary metastases (p Conclusion: We observed high concordance for loss of BAP1 and PBRM1 expression between primary ccRCC and metastatic tumors in the same patient. Conversely, we noted high discordance in protein expression of Ki-67 and TOPOIIa between patient-matched primary-metastatic tumor pairs. Moreover, this discordance varied by key pathological features. Our results suggest that using the status of a biomarker in primary ccRCC as a guide for the status in metastatic tumors is not always appropriate and needs to be evaluated on a marker-by-marker basis. Citation Format: Jeanette E. Eckel-Passow, Daniel J. Serie, John C. Cheville, Thai H. Ho, Sue M. Harrington, Tracy Hilton, Christine Lohse, Amanda Shreders, Payal Kapur, James Brugarolas, R Houston Thompson, Bradley C. Leibovich, Eugene D. Kwon, Richard W. Joseph, Alexander S. Parker. Concordance of BAP1, PBRM1, Ki-67, and TOPOIIa protein expression in primary clear cell renal cell carcinoma tumors and patient-matched metastatic tumors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 10.