Wang, Michael

Abstract Abstract 1954 Background: Carfilzomib (CFZ) is a novel, highly selective epoxyketone proteasome inhibitor that produces potent and sustained proteasome inhibition both in vitro and in vivo. CFZ appears to lack many of the off-target activities frequently associated with bortezomib (BTZ). This lack of off-target activity may account for observed differences in tolerability seen with CFZ including lack of significant neuropathy and minimal neutropenia and diarrhea. To date, single agent CFZ has been evaluated in Ph 1 and 2 studies in >600 patients, and the vast majority of patients treated had relapsed and/or refractory (R/R) MM. In these settings, CFZ has demonstrated durable single-agent activity and was well-tolerated in patients with advanced stage disease with co-morbidities including baseline neuropathy or renal insufficiency. Here we present the results of parallel safety analyses of patients from four Ph 1 and 2 studies with CFZ. Materials and Methods: The present safety analyses were based on data accumulated from patients enrolled in the following trials: PX-171-003 A0 (R/R MM), PX-171-003 A1 (R/R MM), PX-171-004 (relapsed MM), and PX-171-005 (R/R MM with varying degrees of renal function). In all studies, the treatment schedule was based on a 28-day cycle, dosing CFZ QDx2 each week for 3 weeks (Days 1, 2, 8, 9, 15, 16) with 12 days of rest. Doses of CFZ ranged from 15–20 mg/m2 in cycle 1 (005 [15 mg/m2], 003 A0 and A1, 004 [20 mg/m2]). In three studies CFZ was escalated to 27 mg/m2 after the first cycle, as tolerated (003- A1, 004-BTZ naïve subset and 005). In PX-171-005, low-dose dexamethasone was added in the majority of patients. Results: CFZ was well-tolerated by patients across the 4 studies analyzed. The most common treatment-emergent adverse events (AEs) included fatigue, anemia, nausea, dyspnea, and thrombocytopenia. Detailed descriptions of the incidence of treatment-related AEs (all Grades (G) in ≥25% of pts; ≥G3 in ≥5% of pts) across studies are presented in the table. Peripheral neuropathy (PN) occurred infrequently across all 4 studies (N= 517), with only 20 patients (3.9%) experiencing PN of any G and only 2 patients (0.4%) with G3 PN. Febrile neutropenia was likewise uncommon, occurring in only 3 patients (0.6%). Serious treatment emergent AEs (SAEs) occurring in ≥1% of patients and considered possibly/probably related to study drug across all 4 studies included: pneumonia (3.5%), congestive cardiac failure (2.5%), acute renal failure (1.7%), pyrexia (1.2%), and dyspnea (1%). Conclusions: Despite a substantial disease burden present in the patient populations described here, CFZ was well-tolerated by patients with MM across all studies examined. The excellent safety/tolerability profile of CFZ has permitted prolonged administration (in some cases over 24 mos of continuous therapy including extension study) with minimal dose modifications or discontinuations due to toxicity. The low levels of neuropathy seen with CFZ make this agent a potentially important treatment option for patients with pre-existing neuropathy from either underlying disease or prior neuropathic anti-myeloma therapy. Disclosures: Singhal: Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martin:Celgene: Honoraria; Onyx: Consultancy. Vij:Onyx: Honoraria. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotec: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. McCulloch:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Niesvizky:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding. Stewart:Millennium: Consultancy; Celgene: Honoraria. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

Abstract Lenalidomide (Len), an analog of thalidomide (thal) is a novel, oral, immunomodulatory agent that is effective against multiple myeloma (MM). In 2 prospective, randomized, double-blind, placebo-controlled Phase III trials. Len with dexamethasone (Dex) induced a significantly higher overall response rate (OR) and complete remission rate (CR), as well as longer time-to-progression (TTP) in comparison with Dex alone. This prospective analysis assessed whether prior thalidomide exposure might induce subsequent resistance to Len/Dex. We evaluated 704 patients (pts) from both trials (MM009, MM010) who had relapsed or refractory multiple myeloma, had not been resistant to Dex and were randomized to receive either oral Len (25 mg daily for 3 weeks every 4 weeks) plus Dex (40 mg on days 1–4, 9–12, 17–20 every 4 weeks for 4 cycles) or placebo plus Dex. Two hundred seventy four pts (39%) received prior thal, while 430 (61%) had not. The prior thal exposed pts and thal-naive pts were similar in regard to age, Beta-2-microglobulin, hemoglobin, serum M protein, albumin and history of previous transplantation. The frequency of deep venous thrombosis and pulmonary embolism (DVT/PE) with prior thal exposure was higher at 14% with Len/Dex than 4% with Dex alone (p < 0.01). However, the frequency of DVT/PE with no prior thal exposure was similar at 8% with Len/Dex to 6% with Dex alone (p = 0.49). In the prior thal pts, severe neuropathy occurred in 4% with Len/Dex, not significantly different from the 1% with Dex alone (p=0.2). The pooled data from all 704 pts showed that pts treated with Len/Dex, compared with those treated with Dex alone, had superior median Time-To-Progression (TTP) (48 vs 20 weeks) and OR (60% vs 22%, p <0.001). Similarly, among the subgroups exposed or not exposed to thal, Len/Dex was superior to Dex alone in OR and TTP. For the 126 patients who received prior thal, the OR with Len/Dex was significantly less (43%) among 54 Pts resistant to thal than that observed for 72 Pts who had been sensitive to thal (63%, p < 0.05). Multivariate analysis using Cox proportion hazards model indicated that after controlling for treatment (Len/Dex vs Dex) and baseline disease characteristics, independent and significant predictors of shorter TTP included prior thal exposure, duration of myeloma and number of prior therapies. Len in combination with Dex was more effective than Dex in patients with relapsed or refractory multiple myeloma despite prior thal exposure. Results with Len/Dex were superior for those not exposed to thal, suggesting some, but not complete, cross resistance between Len and thal. Len/Dex vs Dex with or without Prior Thal Thal (N=274) No Thal (N=430) LD D p LD D p Intent-to-Treat (n) 126 148 227 203 TTP (med. weeks) 36.9 19.9 <.001 61.3 20.4 <.001 OR (%) 54.0 14.9 <.001 63.4 27.6 <.001 PR (%) 42.1 12.8 <.001 32.2 23.2 <.05 NCR (%) 4.0 0.7 <.001 13.2 2.0 <.001 CR (%) 7.9 1.4 <.01 18.1 2.5 <.001

Abstract Abstract 3723 Background: Waldenström macroglobulinemia (WM), a lymphoproliferative disorder with marrow infiltration by lymphoplasmacytic lymphoma cells and production of monoclonal IgM, is characterized clinically by good initial responses to standard therapeutic approaches. However, a minority of patients achieve a complete remission, and most inevitably relapse, indicating a need for validation of new, targeted therapies. Notably, B-cell receptor signaling has been linked to clonal evolution in WM, and Spleen tyrosine kinase (Syk) is over-expressed in primary patient cells. Also, a recent phase I/II study of the Syk inhibitor fostamatinib in patients with a variety of non-Hodgkin lymphomas showed evidence of activity in three patients with WM. These findings supported our central hypothesis, which proposed that Syk could be a rational new target for therapy of WM, which we pursued first with pre-clinical studies. Methods: Studies of fostamatinib were performed using the WM cell line MWCL-1, and the IgM-producing cell line BWCM.1, as well as in primary cells from patients with WM, and in a novel murine xenograft model utilizing MWCL-1 cells. Results: Fostamatinib induced a time- and dose-dependent reduction in viability of MWCL-1 and BWCM.1 cells, with median inhibitory concentrations (IC50) that were in the physiologically relevant range of approximately 0.25 and 1 μM, respectively, at 3 days. Cell cycle analysis showed a decrease in cells at S-phase and at G2/M, while an increase was seen in cells in G1, and in the sub-G1fraction, suggesting induction of apoptosis. Consistent with the possibility that there was activation of type I programmed cell death, increased staining was seen in fostamatinb-treated cells with an antibody to Annexin V. Interestingly, evidence was seen of the induction of type II programmed cell death, or autophagy, as measured by an increase in cells staining with the lysotropic dye acridine orange. At the molecular level, fostamatinib blocked signaling through p44/42 mitogen-activated protein kinase (MAPK), MAPK kinase (MEK), protein kinase B/Akt, and Zeta-chain-associated protein kinase (ZAP)-70/Syk, as judged by a reduction in the phosphorylated forms of these intermediates by Western blotting. Notably, the viability of primary cells isolated from patients with WM was also reduced in association with blockade of p44/42 MAPK. Finally, a novel murine xenograft model was generated by injection of MWCL-1 cells into immunodeficient mice, which developed measurable tumors. When these were treated with fostamatinib, a delay in tumor growth was demonstrable. Conclusions: Targeting Syk with fostamatinib is an attractive strategy against pre-clinical models of WM both in vitro and in vivo. These findings lend further support for translation of fostamatinib to the clinic for patients with relapsed, and possibly even newly diagnosed WM. Disclosures: No relevant conflicts of interest to declare.

6592 Background: Sex, age and ECOG performance status (PS) may affect immune response and the efficacy of cancer immunotherapy with immune checkpoint inhibitors (ICI). We did a meta-analysis to assess the potential sex, age and ECOG PS differences of immunotherapy efficacy in advanced cancer. Methods: PubMed was searched up to January 15, 2019 for randomized controlled trials (RCT) comparing overall survival (OS) in patients with advanced cancer treated with ICI immunotherapy vs control therapy (without ICI). For sex difference analysis, pooled hazard ratio (HR) of death for men and women was calculated separately, and the heterogeneity between the two estimates was assessed using an interaction test by pooling study-specific interaction HR. Age ( < 65 vs ≥65) and ECOG PS (0 vs ≥1) difference was analyzed similarly. Subgroup analysis by cancer type and line of therapy (frontline vs subsequent) was explored. All analyses were done in Comprehensive Meta Analysis (v2) with random effects models. Results: Thirty phase 2/3 RCTs involving 17,728 patients were included. An OS benefit of immunotherapy was found for both men (HR 0.75, 95% confidence interval [CI] 0.69-0.81, P < 0.01) and women (HR 0.79, 95% CI 0.69-0.90, P < 0.01); for both younger ( < 65; HR 0.75, 95% CI 0.68-0.83, P < 0.01) and older (≥65; HR 0.76, 95% CI 0.69-0.83, P < 0.01) patients; and for both ECOG PS 0 (HR 0.78, 95% CI 0.69-0.89, P < 0.01) and PS ≥1 (HR 0.77, 95% CI 0.71-0.84, P < 0.01) patients. No significant difference of relative benefit from immunotherapy over control therapy was found in patients with different sex ( P = 0.283), age ( P = 0.906) or ECOG PS ( P = 0.783). In melanoma RCTs, compared with women (HR 0.77, 95% CI 0.64-0.94, P < 0.01), men (HR 0.56, 95% CI 0.42-0.76, P < 0.01) had more OS benefit from immunotherapy ( P = 0.037). No significant difference was found in other subgroup analyses by cancer types or line of therapy. Conclusions: Overall we found no evidence of association of sex, age, or ECOG PS with cancer immunotherapy efficacy. However, in melanoma, men might benefit more from immunotherapy than women.

Key Points KRd has a favorable benefit-risk profile compared with Rd, regardless of baseline cytogenetic risk status, in patients with relapsed MM. KRd improves but does not abrogate the poor prognosis associated with high-risk cytogenetics in patients with relapsed MM.

SummaryWhile proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme‐linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15–56 mg/m2), dose‐dependent inhibition of c20S and i20S chymotrypsin‐like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%]. A similar inhibition profile was observed in bone marrow–derived CD138+ tumour cells. Carfilzomib‐induced proteasome inhibition was durable, with minimal recovery in PBMCs after 24 h but near‐complete recovery between cycles. Importantly, the ProCISE assay can be used to quantify occupancy of individual c20S and i20S subunits. We observed a relationship between MM patient response (n = 29), carfilzomib dose and occupancy of multiple i20S subunits, where greater occupancy was associated with an increased likelihood of achieving a clinical response at higher doses. ProCISE represents a new tool for measuring proteasome inhibitor activity in clinical trials and relating drug action to patient outcomes.

Abstract Purpose: Waldenström macroglobulinemia (WMG) is a lymphoproliferative disorder characterized by good initial responses to standard therapeutics, but only a minority of patients achieve complete remissions, and most inevitably relapse, indicating a need for novel agents. B-cell receptor signaling has been linked to clonal evolution in WMG, and Spleen tyrosine kinase (Syk) is overexpressed in primary cells, suggesting that it could be a novel and rational target. Experimental Design: We studied the impact of the Syk inhibitor fostamatinib on BCWM.1 and MWCL-1 WMG-derived cell lines both in vitro and in vivo, as well as on primary patient cells. Results: In WMG-derived cell lines, fostamatinib induced a time- and dose-dependent reduction in viability, associated with activation of apoptosis. At the molecular level, fostamatinib reduced activation of Syk and Bruton's tyrosine kinase, and also downstream signaling through MAPK kinase (MEK), p44/42 MAPK, and protein kinase B/Akt. As a single agent, fostamatinib induced tumor growth delay in an in vivo model of WMG, and reduced viability of primary WMG cells, along with inhibition of p44/42 MAPK signaling. Finally, fostamatinib in combination with other agents, including dexamethasone, bortezomib, and rituximab, showed enhanced activity. Conclusions: Taken together, these data support the translation of approaches targeting Syk with fostamatinib to the clinic for patients with relapsed and possibly even newly diagnosed WMG. Clin Cancer Res; 21(11); 2538–45. ©2015 AACR.