Longer Duration Of Response Research Articles

MOR202 with low-dose dexamethasone (Dex) and in combination with pomalidomide/dex and lenalidomide/dex in relapsed or refractory multiple myeloma (RRMM): Interim analysis of a phase I/IIa dose-escalation study.

8024 Background: CD38 is a type II transmembrane glycoprotein expressed by MM cells. MOR202, a human IgG1 CD38 monoclonal antibody, has shown high single-agent activity in preclinical models of MM and synergy in combination with immunomodulatory drugs (IMiDs), lenalidomide (LEN) and pomalidomide (POM). Methods: This interim analysis of a multicenter phase I/IIa study reports safety and efficacy data from RRMM patient (pt) cohorts treated with clinically relevant doses of MOR202 (2-hour IV infusion; 4, 8 and 16 mg/kg q1w) + Dex (≤40 mg), or at 8 or 16 mg/kg q1w with an IMiD/Dex. Primary objectives were to evaluate the safety, maximum tolerated dose (MTD) and recommended phase II dose of MOR202. Results: As of January 2017, 79 pts had been treated, including 44 in clinically relevant cohorts: 18 received MOR202 + Dex, 15 MOR202 + LEN/Dex and 11 MOR202 + POM/Dex. Pts had received a median of 3, 2 and 3 prior treatment lines, respectively. The MTD of MOR202 was not reached. Combinations were generally well tolerated, with grade ≥3 adverse events (AEs) mainly hematological; 2 pts discontinued due to a MOR202-related AE (one grade 4 thrombocytopenia; one grade 3 acute kidney failure). Infusion-related reactions (all grade 1 or 2) were seen in only 3/44 (7%) pts, and mainly occurred during the first infusion. In the MOR202 + Dex cohort, 5/17 (29%) evaluable pts (receiving at least 1 cycle of treatment) had a response, including 3 with partial responses (PRs) and 2 with very good PRs (VGPRs). Responses were also seen in 11/13 (85%, 8 PRs, 3 VGPRs) evaluable pts in the MOR202 + LEN/Dex cohort and 5/9 (56%, 2 complete responses, 3 PRs) in the MOR202 + POM/Dex cohort. Longest response duration was 17 months (MOR202/Dex). Preliminary analysis showed preservation of high CD38 levels on MM cells under MOR202 therapy. Conclusions: In heavily pretreated pts with RRMM, a 2-hour infusion of MOR202 administered at up to 16 mg/kg with Dex or in combination with an IMiD/Dex, showed a favorable safety profile, including excellent infusion tolerability. Promising preliminary efficacy and long-lasting tumor control was seen. Clinical trial information: NCT01421186.

Open-label, multicentre safety study of vemurafenib in 3219 patients with BRAFV600 mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis

BackgroundThe orally available BRAF kinase inhibitor vemurafenib is an effective and tolerable treatment option for patients with metastatic melanoma harbouring BRAFV600 mutations. We assessed the safety of vemurafenib in a large population of patients with few alternative treatment options; we report updated 2-year safety. MethodsThis was an open-label, multicentre study of vemurafenib (960 mg bid) in patients with previously treated or untreated BRAF mutation-positive metastatic melanoma (cobas® 4800 BRAF V600 Mutation Test). The primary end-point was safety; efficacy end-points were secondary. An exploratory analysis was performed to assess safety outcomes in patients with long duration of response (DOR) (≥12 or ≥24 months). ResultsAfter a median follow-up of 32.2 months (95% CI, 31.1–33.2 months), 3079/3219 patients (96%) had discontinued treatment. Adverse events (AEs) were largely consistent with previous reports; the most common all-grade treatment-related AEs were arthralgia (37%), alopecia (25%) and hyperkeratosis (23%); the most common grade 3/4 treatment-related AEs were squamous cell carcinoma of the skin (8%) and keratoacanthoma (8%). In the exploratory analysis, patients with DOR ≥12 months (n = 287) or ≥24 months (n = 133) were more likely to experience grade 3/4 AEs than the overall population. No new specific safety signals were observed with longer vemurafenib exposure. ConclusionsAfter 2 years' follow-up, safety was maintained in this large group of patients with BRAFV600 mutation-positive metastatic melanoma who are more representative of routine clinical practice than typical clinical trial populations. These data suggest that long-term vemurafenib treatment is effective and tolerable without the development of new safety signals.

PD-1 and PD-L1 antibodies in cancer: current status and future directions.

Immunotherapy has moved to the center stage of cancer treatment with the recent success of trials in solid tumors with PD-1/PD-L1 axis blockade. Programmed death-1 or PD-1 is a checkpoint molecule on T cells that plays a vital role in limiting adaptive immune responses and preventing autoimmune and auto-inflammatory reactivity in the normal host. In cancer patients, PD-1 expression is very high on T cells in the tumor microenvironment, and PD-L1, its primary ligand, is variably expressed on tumor cells and antigen-presenting cells within tumors, providing a potent inhibitory influence within the tumor microenvironment. While PD-L1 expression on tumors is often regarded as a negative prognostic factor, it is clearly associated with a positive outcome for treatment with PD-1/PD-L1 blocking antibodies, and has been used to select patients for this therapy. Responses of long duration, a minority of patients with atypical responses in which progression may precede tumor shrinkage, and a pattern of autoimmune side effects often seen with this class of drugs characterize therapy with PD-1/PD-L1 blocking drugs. While excellent efficacy has been seen with a limited number of tumor types, most epithelial cancers do not show responses of long duration with these agents. In the current review, we will briefly summarize the scientific background data supporting the development of PD-1/PD-L1 blockade, and then describe the track record of these antibodies in multiple different histologies ranging from melanoma and lung cancer to less common tumor types as well as discuss biomarkers that may assist in patient selection.

A phase I/IIa Study of the CD38 Antibody MOR202 in Combination With Pomalidomide or Lenalidomide in Patients With Relapsed or Refractory Multiple Myeloma

A phase I/IIa Study of the CD38 Antibody MOR202 in Combination With Pomalidomide or Lenalidomide in Patients With Relapsed or Refractory Multiple Myeloma

A Phase I/IIa Study of the CD38 Antibody MOR202 Alone and in Combination with Pomalidomide or Lenalidomide in Patients with Relapsed or Refractory Multiple Myeloma

A Phase I/IIa Study of the CD38 Antibody MOR202 Alone and in Combination with Pomalidomide or Lenalidomide in Patients with Relapsed or Refractory Multiple Myeloma

Single-Agent MOR208 in Relapsed or Refractory (R-R) Non-Hodgkin's Lymphoma (NHL): Results from Diffuse Large B-Cell Lymphoma (DLBCL) and Indolent NHL Subgroups of a Phase IIa Study

Single-Agent MOR208 in Relapsed or Refractory (R-R) Non-Hodgkin's Lymphoma (NHL): Results from Diffuse Large B-Cell Lymphoma (DLBCL) and Indolent NHL Subgroups of a Phase IIa Study

Combination Treatment of Rituximab, Cyclophosphamide, and Dexamethasone for Warm Autoimmune Hemolytic Anemia

▪IntroductionWarm autoimmune hemolytic anemia (WAIHA) is an uncommon blood disorder characterized by autoantibody destruction of red blood cells. Although the initial response rate to corticosteroid therapy is 70-85%, less than 20% of patients are cured by corticosteroid therapy alone (Murphy and LoBuglio, 1976). Treatment options for refractory disiease include splenectomy, rituximab, immunosuppression, and cytotoxic therapy. The combined regimen of rituximab, cyclophosphamide and dexamethasone (RCD) has been reported to have significant efficacy in the treatment of WAIHA in patients with chronic lymphocytic leukemia (Gupta et al 2002; Kaufman et al 2009). Due to our experience of a poor response to single agent rituxumab, we treated a cohort of patients with primary and secondary WAIHA with RCD. We now report the outcomes of 19 patients treated with this regimen.MethodsBetween January 1, 2009 to August 1, 2016, a cohort of patients with primary and secondary WAIHA was treated with RCD at LAC-USC Medical Center, USC Norris Cancer Center, and Keck Hospital of USC. RCD was administered as follows: rituximab 375 mg/m2 IV D1, cyclophosphamide 750 mg/m2 D1 or D2, and dexamethasone 12 mg PO/IV D1-7. Treatment cycles were repeated at 3-to-4-week intervals until the best achievable response.Complete response (CR) was defined as hemoglobin (Hb) > 12 g/dL and normalization of hemolytic markers (reticulocyte count, LDH, and indirect bilirubin). If Hb was > 12 g/dL and there was mild elevation in the hemolytic markers attributable to comorbid conditions, this was also considered a CR. Partial response (PR) was defined as Hb ≥ 10 g/dL or > 2 g/dL increase in Hb.Results19 patients with WAIHA received RCD. The median number of cycles was 4 (range 2-7). Median age was 37 (range 21-77). 16 were female. 7 had secondary WAIHA (1 with Graves disease, 2 with systemic lupus erythematosus [SLE], 1 with rheumatoid arthritis [RA]-SLE overlap syndrome, 1 with RA-Sjogrens overlap syndrome, 1 with autoimmune hepatitis, and 1 with likely autoimmune lymphoproliferative syndrome (APLS). 12 had primary WAIHA. 2 patients had Evans syndrome. RCD was first line treatment in 6 patients. In pre-treated patients, the median number of prior treatments was 2 (range 1-7). All pre-treated patients had received steroids; 3 had received rituximab; 1 had splenectomy. Other prior treatments included mycophenolate, azathioprine, cyclosporine, intravenous immunoglobulin, alemtuzumab, and sirolimus.Overall response rate was 97% (18/19) (8 with CR, 10 with PR). Among those with CR, 4 had primary WAIHA and 6 had received prior treatment. Among those with PR, 7 had primary WAIHA and 5 had received prior treatment. 11 patients were placed on maintenance immunosuppression after completing RCD. Of the 7 patients who did not receive maintenance immunosuppression, the median duration of response was 8 months at the time of abstract submission. The longest duration of response was 22 months at the time of abstract submission.1 patient who had a CR, relapsed 2 years later and received additional RCD without response. 1 patient with Evans syndrome, hypogammaglobinemia, and possible ALPS had received 7 prior lines of treatment, including rituximab and splenectomy. This patient had a CR of WAIHA and ITP with RCD. During and after RCD, she was continued on sirolimus and mycophenolate.Cyclophosphamide was held for ≥ 1 cycle in 4 patients (1 due to patient refusal due to alopecia, 1 due to mouth pain, 1 due to scheduling issues, 1 due to unclear reason). 1 patient had dose-reduction of cyclophosphamide due to young age. There was 1 missed dose of rituximab due to patient non-adherence. Treatment delays occurred in 1 patient due to patient non-adherence.Toxicities included GI symptoms (2), headache (1), oral pain with dysphagia (1), flu-like symptoms (1) syncopal episode (1), hypersensitivity reaction to rituximab (2), aplastic anemia from viral infection (1), alopecia (1), hospitalization for cellulitis (1), and thrombocytopenia (2).ConclusionsRCD has a high overall response rate in the upfront and refractory treatment of patients with primary and secondary WAIHA with an acceptable toxicity profile. DisclosuresNo relevant conflicts of interest to declare.

A Phase II Study of the Combination of Lenalidomide and Rituximab in Patients with Treatment-NaïVe and Relapsed Chronic Lymphocytic Leukemia

Introduction. The combination of Lenalidomide (Len) and rituximab has been investigated in patients (pts) with treatment-naive (TN) and relapsed (R) CLL with an overall response rate (ORR) ranging between 66% and 85%. Fludarabine refractoriness and a median daily Len dose Methods. Pts were eligible for this study if they had treatment indications per IWCLL 2008 criteria, WHO PS ≤2 and adequate hepatic and renal function. Len was started on day 9 of cycle 1 at 10 mg orally and administered daily indefinitely. Rituximab, 375 mg/m2, was administered every 28 days for 12 cycles. Response was assessed at month 3, 6 and every 6 months thereafter. Pts in this study returned to our center at time of response assessment and were allowed to receive R infusion at their oncologist9s office. The primary end point of this study was ORR. Results. One-hundred-twenty pts (61 TN and 59 R) were enrolled between 1/2012 and 11/2014; 83 (69%) pts received their R infusion locally. Baseline pts characteristics are shown in the Table. The median number of cycles administered was 16 [1-54] in TN and 20 [1-59] in R pts. Fifty-five TN and 53 R pts were evaluable for response. Twelve pts discontinued therapy before the first response assessment [toxicity (8), loss to follow-up (3), and death (1)]. ORR was 73% in TN and 64% in R pts, CR/CRi rate was 35% in TN and 28% in R pts. MRD eradication was achieved in 16% of TN and 2% of R pts. Median time to response was 11 [8-14] and 6 [5-7] months in TN and R pts. Median response duration (RD) has not been reached for TN pts and was 37 (29-45) months for R pts; 28% of TN and 62% of R pts have progressed. Characteristics predictive of higher ORR were: B2M ≤ 4 mg/L in TN pts (85% vs 55%, p=0.03); age 60 mL/min in R pts; on MVA, only B2M maintained its association (84% vs 46%; OR 5, 95% CI 1.1-10; p=0.03). FISH and IGHV status did not predict ORR. Characteristics associated with longer RD were age ≤ 65 years (p=0.009) and non-complex karyotype (p=0.05) in TN pts; on MVA, only age maintained its association (not reached vs 33 months; HR 5; 95% CI 1-25.6; p=0.05); Treatment-associated G 3-4 toxicities occurred in 28% of TN and 30% of R pts. Most common toxicities were: infections (10% of TN and 22% of R pts), thromboembolic complications (6%, both groups), skin rash (6% in TN pts only), and tumor flare reaction 6% (TN pts only). Forty-three (70%) TN and 50 (85%) R pts have discontinued treatment, median time to failure (TTF) was 22 [16-28] and 34 [25-43] months, respectively. Reasons for interruption were: progression in 13 (30%) TN and 25 (50%) R pts, toxicity in 25 (57%) TN and 20 (40%) R pts, pt/physician choice in 3 (7%) TN and 4 (8%) R pts, and other cancers in 2 (5%) TN and 1(2%) R pt. Factors predictive of a longer median TTF were eGFR ≥ 60 mL/min in TN pts (23 months vs 7 months, p=0.05) and early Rai stage in R pts (41 vs 36 months, p=0.04). At a median follow-up of 34 [1-53+] months, 4 (7%) TN and 14 (24%) R pts died, with a 4-year OS of 90% and 70%, respectively. Factors associated with shorter median OS were advanced Rai stage in TN pts (75% vs 100%, p=0.02), and > 2 prior treatments in R pts (on MVA; 50% vs 90% 4-years OS; HR 5.2; 95% CI 1.3-21; p=0.02). When comparing pts treated at our center to those receiving R infusion in the community, no significant differences in ORR, G3-4 toxicity rate or OS were observed. Conclusions. In our experience, the combination of Len and R is able to induce responses in 73% of TN and in 64% of R pts. Pts age IGHV status. Similar results in terms of efficacy and toxicity were observed in pts treated at our center or managed in close cooperation with local providers. With the expanding number of active treatment options for pts with CLL, the identification of clinical and biological factors predictive of response is becoming increasingly important. Disclosures Thompson: Pharmacyclics: Consultancy, Honoraria. Jain: Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novartis: Consultancy, Honoraria; Infinity: Research Funding; Genentech: Research Funding; Servier: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Incyte: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding. Burger: Pharmacyclics: Research Funding. Wierda: Gilead: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Novartis: Research Funding; Genentech: Research Funding. Kantarjian: Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

Liposomal Irinotecan in the Treatment of Refractory Pancreatic Cancer.

Effective therapies against metastatic pancreatic cancer remain limited, and despite treatment, many will ultimately progress. Previously, few options were available for second line therapy in metastatic pancreatic cancer. Liposomal encapsulated irinotecan, in combination with leucovorin-modulated fluorouracil, was found to significantly increase overall survival in patients who have progressed after gemcitabine- based therapy in a large, international, randomized clinical trial (NAPOLI-1). We reviewed the background of systemic therapy for metastatic pancreatic cancer, examined putative mechanisms for the success of encapsulated drugs, and identified recent patent applications on the use of liposomal irinotecan in pancreatic cancer. The landmark NAPOLI-1 trial established a second-line option for those with metastatic pancreatic cancer refractory to gemcitabine chemotherapy, but effective therapies with long duration of response are still lacking. Alternative techniques targeting key driver genes in pancreatic cancer and novel methods of early detection and targeting drugs are currently being explored. How liposomal irinotecan can be integrated into chemotherapy regimens, including neoadjuvant or first line combinations, are currently being tested in clinical trials and covered by several new patent applications.

Grand Fir Nutrient Management in the Inland Northwestern USA

Grand fir (Abies grandis (Douglas ex D. Don) Lindley) is widely distributed in the moist forests of the Inland Northwest. It has high potential productivity, its growth being nearly equal to western white pine, the most productive species in the region. There are large standing volumes of grand fir in the region. Nutritionally, the species has higher foliage cation concentrations than associated conifers, especially potassium (K) and calcium (Ca). In contrast, it has lower nitrogen (N) foliage concentrations, which creates favorable nutrient balance on N-limited sites. Despite concentration differences, grand fir stores proportionally more nutrients per tree than associated species because of greater crown biomass. Although few fertilization trials have examined grand fir specifically, its response is inferred from its occurrence in many monitored mixed conifer stands. Fertilization trials including grand fir either as a major or minor component show that it has a strong diameter and height growth response ranging from 15% to 50% depending in part on site moisture availability and soil geology. Grand fir tends to have a longer response duration than other inland conifers. When executed concurrently with thinning, fertilization often increases the total response. Late rotation application of N provides solid investment returns in carefully selected stands. Although there are still challenges with the post-fertilization effects on tree mortality, grand fir will continue to be an important species with good economic values and beneficial responses to fertilization and nutrient management.

Abstract CT056: Preliminary safety, efficacy, and pharmacodynamics of a highly selective PI3Kδ inhibitor, INCB050465, in patients with previously treated B-cell malignancies

Abstract Background: PI3Kδ inhibitors have demonstrated efficacy in the treatment of B-cell malignancies, but off-target toxicity and/or the inability to achieve near-complete inhibition of the PI3Kδ pathway may affect the depth and duration of response. INCB050465 is a novel, potent, and selective PI3Kδ inhibitor (Shin et al. AACR 2015. Abstract 2671), with a differentiated profile for potency (whole blood IC50 = 10 nM), dose (<50 mg total daily dose), and preclinical safety (lack of hepatoxicity up to exposures that exceed IC90 coverage by >10-fold). An open-label phase 1 study was initiated to evaluate INCB050465 alone or in combination with other agents in patients with previously treated B-cell malignancies; preliminary results of the dose escalation of INCB050465 monotherapy are reported. Methods: Adult patients with B-cell malignancies who were refractory to or for whom available treatments had failed were eligible. Dose escalation was conducted with a 3 + 3 design after an initial single patient cohort. Patients were observed for 21 days before enrollment of the next cohort. Results: As of the data cutoff, 15 patients were enrolled and treated with INCB050465 at doses ranging from 5 to 30 mg once daily. The median age was 64 years and 47% were men. Patients received a median of 2 prior treatment regimens and the median time since initial diagnosis was 4.9 years. Disease subtypes included DLBCL (n = 6), CLL (n = 3), FL (n = 2), MZL (n = 2), MCL (n = 1), and HL (n = 1). Median exposure to INCB050465 was 15.4 weeks (range, 6.9 to 36.4+ weeks) and no patients required dose reduction. INCB050465 was well tolerated with no DLTs observed. Five patients discontinued treatment, 4 due to disease progression and 1 due to an adverse event (grade 2 exfoliative dermatitis). Ten grade 3 or greater treatment-emergent adverse events were seen in 6 patients: anemia (n = 2), bacteremia, Escherichia infection, hypotension, neutropenia, pneumonia, sepsis, syncope, and WBC count decreased (n = 1 each). To date, only grade 1 transaminase elevations have been observed. Responses were observed in DLBCL (3/6 patients), CLL (1/3), FL (2/2), MZL (2/2), and MCL (1/1). Clinical benefit was observed early in the course of treatment, and the longest duration of response was 27+ weeks. Terminal half-life and suppression of PI3Kδ signaling at trough support once daily dosing. Conclusions: INCB050465 monotherapy was generally well tolerated at all doses tested. Robust and durable signaling pathway inhibition was achieved at all doses and INCB050465 showed promising efficacy in FL, DLBCL, and other lymphomas, with a potentially favorable toxicity profile vs other PI3Kδ inhibitors. Enrollment in dose-escalation, combination therapy, and disease-specific cohorts is ongoing. Citation Format: Andres Forero-Torres, Michael S. Wertheim, Tycel J. Phillips, Martin E. Gutierrez, William J. Edenfield, Swamy Yeleswaram, Maureen Bleam, Li Zhou, Jennifer H. Pulini, Théa Faivre, Harry Miao, Matt Spear, Rod Ramchandren. Preliminary safety, efficacy, and pharmacodynamics of a highly selective PI3Kδ inhibitor, INCB050465, in patients with previously treated B-cell malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT056.

The influence of structural arrangement on long-duration blast response of annealed glazing

This paper investigates the influence of structural arrangement on long-duration blast loaded annealed glazing via variable thickness, area, aspect ratio and edge support conditions. Initially, the findings of eighteen full-scale air-blast trials employing 33 annealed glazing panels are reported where it is demonstrated that fracture mode and fragmentation are a strong function of edge supports. Rigidly clamped edges are shown to induce localised stress transmission, producing significant cracking and small fragments. In contrast, elastic edges are shown to produce large, angular fragments, demonstrating the importance of accurately modelling edge conditions when analysing fragment hazard. Quantification of peak centre panel deflection and breakage time is then presented where variable results indicate the influence of edge supports and aspect ratio to be dependent on proximity to the threshold area as a function of glazing thickness. An initial Applied Element Method (AEM) analysis is then employed to model the influence of structural arrangement on long-duration blast-loaded annealed glazing. AEM models are shown to reasonably predict glazing fragmentation behaviour, breakage time and peak panel deflection at the moment of breakage. Thus indicating AEM's potential suitability to provide a predictive capacity for annealed glazing response during long-duration blast.

Long-term complete response of antiandrogen withdrawal syndrome in a patient with metastatic prostate cancer: A case report

Antiandrogen withdrawal syndrome (AWS) is a well-established phenomenon in prostate cancer treated with combined androgen blockade (CAB). AWS is generally defined as subjective and/or objective improvement following discontinuation of an antiandrogen. However, the duration of the AWS response is usually limited. In addition, a complete response is quite rare. We herein present the case of a patient who achieved complete response from AWS, with the duration of this response lasting for >6 years. A 72-year-old man with metastatic prostate cancer received CAB with a luteinizing hormone-releasing hormone analog and bicalutamide. In addition, for local cancer control, external beam radiation therapy (70 Gy) to the prostate was performed. Subsequently, the serum prostate-specific antigen (PSA) level reached a nadir (undetectable level). Four years later, the patient's serum PSA level started to rise, and bicalutamide was discontinued to confirm AWS at a serum PSA level of 0.34 ng/ml. The PSA level immediately decreased again to an undetectable level (0.00 ng/ml), where it has been remained for 6 years. Bone scintigraphy and computed tomography scans have shown no evidence of bone or other metastases since the introduction of AWS. To the best of our knowledge, there have been no reports of such a long duration of complete response from AWS. Therefore, this phenomenon should always be considered, even in patients with advanced disease.

Comment on the American Society of Clinical Oncology Value Statement

Our concern is that the primary efficacy measures used in the article, such as median overall survival (OS) and progression-free survival (PFS), may not sufficiently summarize the true benefi to f some oncology drugs, especially immuno-oncology agents, and may not adequately address the issues that are foremost in the patient’s mind: What will this treatment mean for me? Will I live longer with an acceptable quality of life or will I not? The measures of median OS and PFS are established, validated benchmarks that provide important information about the impact of treating a large group of patients with a drug or therapeutic regimen. However, depending on the range of outcomes resulting from that treatment, the medians may not always convey the information that is most useful for patients who are deciding whether to invest in a costly course of therapy. Take, for example, the checkpoint inhibitor ipilimumab (BristolMyers Squibb, Princeton, NJ) in metastatic melanoma. The median OS in previously treated patients is approximately 10 months, with modest response rates in the range of 10% to 15%. 2 To be sure, a several-month improvement in OS was an important step forward in the treatment of this disease. But we believe that apatient is equally or even more likely to be interested in knowing that landmark analyses have shown that 18% to 20% of patients survive 5 years or more and that there is a plateau of survival past 3 years. Asking “Is it worth thousands of dollars for a 4-month increase in the OS of patients receiving this treatment?” is different from asking “Is it worth thousands of dollars to increase your chances of surviving 5 years from less than 10% to 18%?” Median survival differences are used to calculate a commonly used measure of value, which is the quality-adjusted life-year. Insurance providers, investigators, and public health agencies have been focused on OS and PFS medians because they have been shown to be excellent surrogates for the benefit of chemotherapeutic and targeted drugs when they are used in large patient populations. For individual patients, however, N is always one, and they may be better informed by focusing on the odds of increased survival instead of the statistical medians. There has been much discussion of achieving a“tail on the curve” of survivalwith immuno-oncology drugs, and recent published studies using the programmed death-1 antibodies pembrolizumab 3 and nivolumab 4 suggest that may indeed be the case. The assessment of variables like PFS and response rate for immune therapies is further complicated by the well-documented unconventional responses seen with these agents, with progression preceding regression and long duration of response in some cases. 5 We do not wish to argue that important measures like median OSandPFS andquality-adjusted life-years should bereplaced inall cases by assessing the benefit of a long-term survival plateau after treatment with an oncology drug or regimen. Rather, we wish to suggest that it be factored into how physicians present treatment options to their patients so that they can make the best-informed decision possible about the value of therapy for their cancer.

Searching for a Light at the End of the Tunnel? Beyond Hypomethylating Agents in Myelodysplastic Syndromes.

Hypomethylating agents (HMAs) are the mainstay treatment of patients with myelodysplastic syndromes. Hypomethylating agents remain the only treatment, other than allogeneic hematopoietic stem cell transplantation (AHSCT), that improves overall survival (OS) for patients with higher-risk myelodysplastic syndromes. It is crucial to maximize the benefit of HMAs by selecting the appropriate dosing and schedule and continuing therapy until clear evidence of lack of response or failure of therapy. Strategies to improve outcome with HMAs include identifying tools and biomarkers for better patient selection, namely the ability to identify those who achieve complete response (CR) or long duration of response, combination strategies with HMAs aim to improve response rate or its duration. The outcome of patients with myelodysplastic syndromes after HMA failure is poor for both patients with higher-risk and lower-risk disease and represents an unmet medical need. The best outcomes after HMA failure are reported with AHSCT or novel agents in clinical trials. This article discusses the maximizing benefit of HMAs, offers strategies to improve outcome with HMAs, and, finally, reviews selected novel agents in development after HMA failure.

Tight Junction Protein 1 Modulates Proteasome Capacity and Proteasome Inhibitor Sensitivity in Multiple Myeloma via EGFR/JAK1/STAT3 Signaling

Proteasome inhibitors have revolutionized outcomes in multiple myeloma, but they are used empirically, and primary and secondary resistance are emerging problems. We have identified TJP1 as a determinant of plasma cell proteasome inhibitor susceptibility. TJP1 suppressed expression of the catalytically active immunoproteasome subunits LMP7 and LMP2, decreased proteasome activity, and enhanced proteasome inhibitor sensitivity invitro and invivo. This occurred through TJP1-mediated suppression of EGFR/JAK1/STAT3 signaling, which modulated LMP7 and LMP2 levels. In the clinic, high TJP1 expression in patient myeloma cells was associated with a significantly higher likelihood of responding to bortezomib and a longer response duration, supporting the use of TJP1 as a biomarker to identify patients most likely to benefit from proteasome inhibitors.

Searching for a Light at the End of the Tunnel? Beyond Hypomethylating Agents in Myelodysplastic Syndromes

Hypomethylating agents (HMAs) are the mainstay treatment of patients with myelodysplastic syndromes. Hypomethylating agents remain the only treatment, other than allogeneic hematopoietic stem cell transplantation (AHSCT), that improves overall survival (OS) for patients with higher-risk myelodysplastic syndromes. It is crucial to maximize the benefit of HMAs by selecting the appropriate dosing and schedule and continuing therapy until clear evidence of lack of response or failure of therapy. Strategies to improve outcome with HMAs include identifying tools and biomarkers for better patient selection, namely the ability to identify those who achieve complete response (CR) or long duration of response, combination strategies with HMAs aim to improve response rate or its duration. The outcome of patients with myelodysplastic syndromes after HMA failure is poor for both patients with higher-risk and lower-risk disease and represents an unmet medical need. The best outcomes after HMA failure are reported with AHSCT or novel agents in clinical trials. This article discusses the maximizing benefit of HMAs, offers strategies to improve outcome with HMAs, and, finally, reviews selected novel agents in development after HMA failure.

Efficacy and Safety of Carfilzomib and Dexamethasone Vs Bortezomib and Dexamethasone in Patients with Relapsed Multiple Myeloma Based on Cytogenetic Risk Status: Subgroup Analysis from the Phase 3 Study Endeavor (NCT01568866)

Efficacy and Safety of Carfilzomib and Dexamethasone Vs Bortezomib and Dexamethasone in Patients with Relapsed Multiple Myeloma Based on Cytogenetic Risk Status: Subgroup Analysis from the Phase 3 Study Endeavor (NCT01568866)

Efficacy and Safety of Pegylated Interferon Alpha-2a in Patients with Essential Thrombocythemia and Polycythemia Vera: Results after a Median 7-Year Follow-up of a Phase 2 Study

Introduction: It has been previously reported that pegylated interferon alpha-2a can induce hematologic and molecular responses in patients with essential thrombocythemia "ET" and polycythemia vera "PV", but the follow up in these studies were relatively short.Objective: We present longer-term efficacy and safety results of a prospective phase II study of pegylated interferon alpha-2a in patients with ET and PV after a median follow up of 82.5 months (range, 8-107).Methods: Patients with a diagnosis of ET or PV, in a need of therapy, either newly diagnosed or previously treated, were eligible for this study. Median interferon starting dose of 180 mcg/week SQ (range, 450-90; 39% started on 90mcg/week) was modified in majority of the patients based on toxicity or lack of efficacy. Clinical and molecular responses were assessed every 3 to 6 months.Results: Among 83 enrolled patients (43 PV, 40 ET), 32 patients (39%) are still on study (but in 8 therapy is on hold: 5 due to toxicity, and 3 for financial reasons). Median age was 53 years (range, 19-78). Overall 37% of patients did not receive prior cytoreductive treatment. The overall median exposure to therapy was 87 months (range, 58-107) and was no different for patients still enrolled on the study and those who stopped study participation. Nine (28%) patients still on study are currently on a dose equal or higher than 90 mcg/week and 15 (47%) are on dose equal or smaller than 45mcg/week. JAK2 status or allele burden had no impact on achievement of response (clinical or molecular), time to response or duration of therapy. 55 of 59 (71%) JAK2V617F positive patients were evaluable for molecular response (Figure); 8 patients carried CARL mutation, 3 carried MPL and in 13 were triple negative. Median duration of hematologic and molecular response was 66 and 53 months, respectively; and directly correlated with treatment length and type of response (CMR had the longest duration of response). Overall yearly discontinuation rate were gradually decreasing for first 5 years, from 17% to 5%, and slowly increasing afterward to 10%. Of the 51 patients not on the study anymore, 27 (35% of the total) discontinued therapy primarily due to treatment toxicity. New late (≥24 months from start of therapy) G3/4 toxicity occurred in 17% of patients. Among patients in complete hematologic response treatment failure due to vascular adverse event or disease transformation was seen in 5 patients each. Three patients died on study (not related to therapy or disease), and 8 after stopping participation. Mean changes in allele burden over time in JAK2 positive patients are depicted in figure.Conclusions: Although pegylated interferon alpha-2a can induce significant hematologic and molecular responses; toxicity still limits its use over longer period of time and loss of response or transformation is encountered. TableResponseCharacteristicsFirst responseLast responseHem Resp, N. of patients (No), (%)CHR62 (76)25 (40)aPHR4 (5)1 (25)ORR66 (79)26 (39)aMol Resp, No, (%)CMR10 (18)9 (90)PMR20 (36)5 (25)*mMR5 (9)2 (40)ORR35 (74)16 (46)SafetyAny gradeGrade≥3Overall Adverse Events (AE), No, (%)any AE83 (100)57 (67)recurrent AE74 (89)13 (16)AE subtypes, No, (%)musculoskeletal73 (88)6 (8)neurological53 (64)2 (4)psychiatric38 (46)4 (11)gastrointestinal54 (65)11 (20)LFT elevation27 (33)5 (18)skin18 (22)2 (11)infection/fever26 (31)3 (12)respiratory23 (28)2 (9)cardiovascular13 (16)3 (23)metabolic16 (19)2 (13)neutropenia37 (45)21 (57)thrombocytopenia18 (22)a1 (6)anemia36 (43)1 (3)Autoimmune toxicity, No, (%)hepatitis1 (2.5)CNS vasculitis1 (2.5)lupus nephritis1 (2.3)Sjogren sy & dermatitis1 (2.5)Vascular AE (TEE/bleeding),Unprovoked6 (7)5 (83)No, (%)Provoked4 (5)3 (75)Disease transformation, No, (%)Myelofibrosis6 (7)AML1 (1)Safety over ≥24 months**Any gradeGrade≥3New AE, No (%)3th year10 (17)4 (40)4th year6 (11)4 (67)5th year5 (10)1 (20)≥ 6th year10 (24)1 (10)**Effective sample size for patients on therapy/year: Initial number of patients at risk at the beginning of period minus half of patients censored during that period*% calculated from 19 patientsastatistically significant differences by Fisher's exact testAbbr. CMR= complete molecular remission (undetectable JAK2 allele burden), PMR= partial molecular remission (>50% decrease in allele burden), mMR= minor molecular remission (20-49% decrease in allele burden) [Display omitted] DisclosuresOff Label Use: Pegylated Interferon alfa-2a used for patients with essential thrombocythemia and polycythemia vera. Cortes:Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

Reolysin Combined with Carfilzomib for Treatment of Relapsed Multiple Myeloma Patients

Introduction. The viral oncolytic agent, Reolysin (RV), is a promising novel therapeutic that selectively proliferates in myeloma cells. Our group conducted a phase 1 clinical trial of single agent RV in patients with relapsed and refractory multiple myeloma (MM), and reported that treatment was well tolerated and associated with prolonged disease stability in 25% of patients. Objective responses were not evident, likely because the viral RNA present in the myeloma cells was not producing infectious viral particles. Proteasome inhibitors can lead to myeloma cell death due to increased endoplasmic reticulum (ER) stress and induction of ER-stress related apoptosis (Kelly, Oncogene, 2012). We confirmed this effect preclinically with Carfilzomib (CFZ), and hypothesized that the addition of CFZ to RV would increase viral proliferation and MM cell death sufficiently to obtain objective response in patients with relapsed MM.Methods. For this pilot trial, patients were required to have relapsed myeloma with IMWG-defined measurable disease, ANC ≥ 1,000/uL, platelet count ≥ 50,000/uL, with no creatinine requirements. Cohorts of 6 patients each were planned. Cohort 1 included patients who were CFZ na•ve or had not progressed on a CFZ containing regimen. Intravenous CFZ (20 mg/m2 days 1 and 2 of cycle 1 and 27 mg/m2 thereafter), Reolysin (3 x 1010 TCID50/day), and dexamethasone (20 mg) were administered on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (Table 1). In situ based methodologies were used to examine the distribution of CD138, CD8, NK cells (CD117 and IL-22), CD 68, PD L1, reoviral capsid protein, and reoviral RNA in bone marrow biopsies performed prior to treatment on days 1 and 9 of cycle 1.Results. Seven patients have been enrolled, four are male, and all are Caucasian. Patients have a median age of 64, and have received on average 2.4 prior lines of therapy and 4.4 prior treatments. All patients were previously exposed to Revlimid and Velcade, and 4 patients were Velcade refractory. One patient was previously treated with CFZ but was deemed to be CFZ sensitive, one patient has dialysis-dependent CKD, and all but one patient had evidence of high-risk cytogenetics on CD138-selected FISH at the time of enrollment. 6/7 patients suffered myalgias and fever after the first two doses of Reolysin, but these symptoms did not recur in any subsequent doses. Treatment has been well tolerated in 5 patients, but 2 patients were removed from study after 2 doses of combination therapy, one for congestive heart failure, and the other for gastrointestinal bleed in the setting of grade 4 thrombocytopenia and an arteriovenous malformation. Due to these 2 DLTs, patient 7 was enrolled at dose level -1 (Carfilzomib 20 mg/m2 and Reolysin 3 x 109 TCID50/day on days 1, 2, 8, 9, 15, and 16 of a 28 day cycle). Within the first 14 days following the initiation of treatment, the mean decrease in platelets for the 7 evaluable patients was 79 (50 - 139), and this included grade 4 (N = 1), and asymptomatic grade 2 (N = 3), and grade 1 (N = 3) events. All patients have had a reduction of the monoclonal protein, 5 patients remain on study, and the longest duration of response is currently 8 cycles. Responses are VGPR (N = 2), PR (N = 3), MR (N = 1), and SD (N = 1) (Figure 1). Intracellular viral replication will be reported at the meeting.Conclusion. This 3-drug regimen is relatively well tolerated in heavily treated patients with relapsed MM. Most patients experience low grade fever and myalgias after the first two doses, and patients have evidence of thrombocytopenia in cycle 1. Combination treatment is associated with reduction of the monoclonal protein in all patients, and 86% (6/7) CFZ-sensitive patients have evidence of objective response.Table 1Combination treatment dose levelsDose levelDexamethasone (IVP)Carfilzomib (IVPB)Reolysin (IVPB)-120 mg/day20 mg/m2 /day3 x 109 TCID50/day1 (starting dose)20 mg/dayC1 Day 1 & 2 - 20 mg/m2 /dayC1 Day 8 & onward - 27 mg/m2 /day3 x 1010 TCID50/day [Display omitted] DisclosuresOff Label Use: Reolysin - oncolytic viral, anti-cancer agent.