scholarly journals Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma

Blood ◽  
2016 ◽  
Vol 127 (6) ◽  
pp. 681-695 ◽  
Author(s):  
Niels W. C. J. van de Donk ◽  
Philippe Moreau ◽  
Torben Plesner ◽  
Antonio Palumbo ◽  
Francesca Gay ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Plasma Cells ◽  
Blood Compatibility ◽  
Single Agent ◽  
Progression Free Survival ◽  
Complete Response ◽  
Therapeutic Antibody ◽  
Drug Discontinuation ◽  
Therapeutic Antibodies

AbstractImmunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies.

DREAMM-9: Phase III study of belantamab mafodotin plus VRd versus VRd alone in transplant-ineligible newly diagnosed multiple myeloma (TI NDMM).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS8556-TPS8556 ◽  
Author(s):  
Saad Zafar Usmani ◽  
Evangelos Terpos ◽  
Wojt Janowski ◽  
Hang Quach ◽  
Sarah West ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Phase Iii ◽  
Clinical Activity ◽  
Efficacy And Safety ◽  
Open Label

TPS8556 Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is the standard of care for transplant-eligible and TI NDMM, but relapse is usually inevitable. The median progression-free survival (PFS) is ~3 years for patients with TI NDMM, and with each relapse, the duration of response (DoR) diminishes, highlighting the need for novel, effective, targeted agents. Single-agent belantamab mafodotin is a first-in-class B-cell maturation antigen–binding, humanized, afucosylated, monoclonal immunoconjugate, showing deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma ( Lancet Oncol2020). Preclinical work suggests belantamab mafodotin plus bortezomib or lenalidomide enhances anti-myeloma activity. Therefore, studying clinical activity of belantamab mafodotin in combination with these agents is warranted. Methods: DREAMM-9 (NCT04091126) is a two-part, open-label study to determine efficacy and safety of single-agent belantamab mafodotin with VRd vs. VRd alone in patients with TI NDMM. Patients aged ≥18 years with ECOG status 0–2 and adequate organ system functions will be eligible. Part 1 (dose selection) will evaluate safety/tolerability of belantamab mafodotin with VRd administered by single (Day 1) or split dosing (Days 1 and 8) in ≤5 cohorts (n = 12/cohort): 1.9 mg/kg, 2.5 mg/kg split and single, and 3.4 mg/kg split and single. Six more patients may be added to cohort(s) most likely to be selected as recommended Phase III dose (RP3D). Dose-limiting toxicities and adverse events (AEs) will be assessed, and belantamab mafodotin RP3D determined through modified toxicity probability interval criteria. Part 2 (randomized Phase III) will determine efficacy and safety of belantamab mafodotin at RP3D with VRd vs. VRd alone (n = 750) in two arms randomized 1:1. Dual primary endpoints will be rate of minimal residual disease (MRD) negativity and PFS. Secondary endpoints will be response rates (overall response, complete response, very good partial response or better, sustained MRD negativity), DoR, time to progression, and overall survival. Safety assessment will include AEs, serious AEs and ocular findings. In both parts, belantamab mafodotin will be given with VRd for eight induction cycles and then with Rd for maintenance until disease progression or unacceptable toxicity. Funding: GlaxoSmithKline (209664). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04091126 .

scholarly journals Antibody Therapies for Multiple Myeloma

2021 ◽  
Author(s):  
Nikolaos Kanellias ◽  
Maria Gavriatopoulou ◽  
Evangelos Terpos
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Plasma Cells ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Check Point ◽  
Incurable Disease ◽  
Significant Prolongation ◽  
Significant Toxicity ◽  
Check Point Inhibitors

Multiple Myeloma (MM) is characterized by the abberant proliferation and expansion of plasma cells in the Bone marrow. Despite the broad use of proteasome inhibitors and IMiDs, Multiple Myeloma remains an incurable disease. The introduction of Monoclonal antibodies, along with bi-specific antibodies and check point inhibitors, has significantly enhanced the armamentarium of available therapeutic options in the relapsed setting. The incorporation of the above-mentioned novel agents in triplet or quadruplet therapeutic regimens has led to significant prolongation of overall survival (OS) and progression free survival (PFS), without adding significant toxicity. Anti-CD38 monoclonal antibodies has become the cornerstone of antimyeloma therapy in both the newly diagnosed and relapsed setting.

scholarly journals CD38 antibodies in multiple myeloma: back to the future

Blood ◽  
2018 ◽  
Vol 131 (1) ◽  
pp. 13-29 ◽  
Author(s):  
Niels W. C. J. van de Donk ◽  
Paul G. Richardson ◽  
Fabio Malavasi
Keyword(s):  
Multiple Myeloma ◽  
Blood Compatibility ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Proteasome Inhibitors ◽  
Suppressor Cells ◽  
Progression Free Survival ◽  
Hematologic Malignancies ◽  
Mechanisms Of Action ◽  
Immune Effector

CD38 is highly and uniformly expressed on multiple myeloma (MM) cells, and at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of nonhematopoietic origin. CD38 is a transmembrane glycoprotein with ectoenzymatic activity, and also functions as a receptor and adhesion molecule. Altogether, this has triggered the development of several CD38 antibodies including daratumumab (fully human), isatuximab (chimeric), and MOR202 (fully human). CD38 antibodies have pleiotropic mechanisms of action including Fc-dependent immune-effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD38+ immune-suppressor cells. CD38-targeting antibodies are generally well tolerated and induce partial response or better in ∼30% of heavily pretreated MM patients as monotherapy. Based on their distinct mechanisms of action, favorable toxicity profile, and single-agent activity, CD38 antibodies are attractive partners in combination regimens. Indeed, deep responses and prolonged progression-free survival can be achieved in relapsed/refractory MM patients when CD38 antibodies are combined with immunomodulatory agents or proteasome inhibitors. Infusion-related reactions, which typically occur during the first infusion, are the most frequent adverse events. Attention should also be paid to the interference of CD38 antibodies with certain laboratory assays, which may complicate response evaluation and blood compatibility testing. Several studies are currently examining the role of CD38-based therapies in newly diagnosed and high-risk smoldering MM. Furthermore, CD38 antibodies are currently also under investigation in other hematologic malignancies, including acute lymphoblastic leukemia, natural killer/T-cell lymphoma, and acute myeloid leukemia, as well as in solid tumors.

Final results from the phase Ib/II study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in patients with relapsed or progressive multiple myeloma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8529-8529 ◽  
Author(s):  
Michael Wang ◽  
Thomas Martin ◽  
William Bensinger ◽  
Melissa Alsina ◽  
David Samuel DiCapua Siegel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase 1 ◽  
Single Agent ◽  
Progression Free Survival ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Phase 2 ◽  
The Us ◽  
Duration Of Response ◽  
Grade 3

8529 Background: Carfilzomib (CFZ) is approved in the US as single-agent treatment for patients with multiple myeloma (MM) who have progressed after bortezomib (BTZ) and an IMiD and are refractory to last line of treatment. We previously reported interim data from PX-171-006 (NCT00603447), a Ph 1b/2 study of CRd in relapsed or progressive MM (Wang et al. ASCO 2011). Herein we report final results. Methods: Patients (1–3 prior treatments) received CRd in 28-day (D) cycles—CFZ IV on D1, 2, 8, 9, 15, 16, lenalidomide (LEN) PO D1–21, and dexamethasone (dex) wkly. In phase 1, CFZ (15–27 mg/m2) and LEN (10–25 mg) doses were escalated to determine the maximum tolerated dose (MTD) with a maximum planned dose (MPD) of CFZ 20 mg/m2 D1, 2 of Cycle 1 and 27 mg/m2 thereafter, LEN 25 mg/d, and dex 40 mg/wk, followed by phase 2 expansion at MTD/MPD. Endpoints included IMWG overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and safety. Results: A total of 84 patients were enrolled since June 2008. Overall, prior treatment included BTZ (77%/18% refractory) and LEN (70%/35% refractory); 20% had high-risk cytogenetics/FISH. MTD was not reached in Ph 1, supporting expansion at the MPD (n=52, 23% BTZ refractory and 42% LEN refractory). As of Nov 2012 (median follow-up 24.4 mo): ORR was 69% overall and 76.9% at MPD with very good partial response in 36.9% and 38.5% and stringent complete response in 3.6% and 3.8%, respectively; median DOR was 18.8 (95% CI 9.7–41.5) and 22.1 mo (95% CI 9.5–NE) respectively; median PFS was 11.8 (95% CI 7.6–20.7) and 15.4 mo (95% CI 7.9–NE), respectively. Seven responders at MPD pursued other therapy and were censored for PFS.A median of 8.5 (range 1−46) CFZ cycles were started; 4% required CFZ dose reductions; 15% discontinued CFZ due to adverse events (AEs). Grade 3/4 AEs were generally consistent with earlier studies in advanced MM that used similar doses of single-agent CFZ; grade 3/4 peripheral neuropathy was 1%. Conclusions: CRd was well tolerated, providing robust and durable responses in this pt population where 35% were LEN refractory. This combination is being further evaluated in several ongoing phase 2/3 trials. Clinical trial information: NCT00603447.

scholarly journals Monoclonal Antibodies versus Histone Deacetylase Inhibitors in Combination with Bortezomib or Lenalidomide plus Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma: An Indirect-Comparison Meta-Analysis of Randomized Controlled Trials

2018 ◽  
Vol 2018 ◽  
pp. 1-20 ◽  
Author(s):  
Yanhua Zheng ◽  
Hongyuan Shen ◽  
Li Xu ◽  
Juan Feng ◽  
Hailong Tang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Meta Analysis ◽  
Indirect Comparison ◽  
Progression Free Survival ◽  
Complete Response ◽  
Refractory Multiple Myeloma ◽  
Grade 3

During the past decades, agents with novel mechanisms of action, such as monoclonal antibodies (MAbs) and histone deacetylase inhibitors (HDACis) have been applied to treat relapsed or refractory multiple myeloma (RRMM). The treatment outcomes of MAbs versus HDACi in combination with bortezomib or lenalidomide plus dexamethasone remain unknown. We conducted this meta-analysis to compare indirectly the efficacy and safety of MAbs and HDACis in combination with bortezomib or lenalidomide plus dexamethasone. Six trials (eight articles) were included in the meta-analysis with 3270 RRMM patients enrolled. We synthesized hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS), risk ratios (RRs) for complete response (CR),very good partial response (VGPR), overall response (OR), progressive disease plus stable disease (PD + SD) and common at least grade 3 adverse events, and their corresponding 95%confidence intervals (95% CI). Treatment with MAbs in combination with bortezomib or lenalidomide plus dexamethasone resulted in longer PFS (HR 0.83, 95% CI: 0.66–0.98), fewer incidences of at least grade 3 thrombocytopenia (RR 0.35, 95% CI: 0.23–0.53), neutropenia (RR 0.70, 95% CI: 0.51–0.96), and sense of fatigue (RR 0.37, 95% CI: 0.17–0.82) than HDACis. The daratumumab plus bortezomib or lenalidomide and dexamethasone might significantly improve PFS in comparison with HDACis plus bortezomib or lenalidomide and dexamethasone (HR 0.55, 95% CI: 0.40–0.74). In conclusion, MAbs may be superior to HDACis in achieving longer PFS and may be better tolerated when in combination therapy with bortezomib or lenalidomide plus dexamethasone.

Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 772-778 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Progression Free Survival ◽  
Prior Treatment ◽  
Once Daily ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Treatment Regimens ◽  
Common Grade ◽  
Grade 3

Abstract Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.

scholarly journals Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma

2021 ◽  
Vol 9 (6) ◽  
pp. e002057
Author(s):  
Yousef Zakharia ◽  
Robert R McWilliams ◽  
Olivier Rixe ◽  
Joseph Drabick ◽  
Montaser F Shaheen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Advanced Melanoma ◽  
Free Survival ◽  
Programmed Death ◽  
Evaluable Population

BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

MASS-FIX versus standard methods to predict for PFS and OS among multiple myeloma patients participating on the STAMINA trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8009-8009
Author(s):  
Angela Dispenzieri ◽  
Amrita Y. Krishnan ◽  
Bonnie Arendt ◽  
Surendra Dasari ◽  
Yvonne Adeduni Efebera ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Multiple Testing ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Independent Effect ◽  
Next Generation ◽  
Different Response

8009 Background: Measuring response among patients with multiple myeloma is essential for the care of patients. Deeper responses have been associated with better progression free survival (PFS) and overall survival (OS). Serum (SIFE) and urine immunofixation are the currently used markers for biochemical documentation of CR after which marrow is tested for plasma cell clearance. Next generation flow cytometry and sequencing are used to document the presence of minimal residual disease (MRD). Mass spectrometry of blood by MALDI (Mass-Fix) is a new simple, inexpensive, sensitive, and specific means of detecting monoclonal immunoglobulins. To better test the hypothesis that Mass-Fix is superior to existing methodologies to predict for survival outcomes—especially SIFE-- samples from the STAMINA trial (NCT01109004), a trial comparing 3 transplant approaches among patients who have already received induction, were employed. Methods: Five-hundred and seventy-five patients were included. Samples from enrollment post-induction (post-I) and 1-year post enrollment (1YR) were tested when available. Four response parameters were assessed univariately: Mass-Fix, SIFE, complete response, and MRD by next generation flow cytometry. Mass spectrometry spectra were evaluated in a blinded fashion. Complete response was according to the 2006 International Myeloma Working Group criteria. Multivariate Cox proportional hazard models using stepwise regression were developed to explore the independent effect of the different response parameters on PFS and OS and interactions with other risk factors. Results: Of the 4 response measures, only MRD and Mass-Fix predicted for PFS and OS at multiple testing points on multivariate analyses (Table). Of the 4 post-I measurements, only MRD predicted for PFS; however, Mass-Fix was the only post-I measurement to predict for OS. Of all the 1-year measures, both 1YR Mass-Fix and 1YR MRD positivity predicted for inferior PFS and OS. In models including MRD and Mass-Fix, SIFE and CR were not prognostic for PFS or OS. Conclusions: Mass-Fix is a powerful means to track monoclonal proteins. The full utility of Mass-Fix was not exploited given the absence of a diagnostic sample and the fact that only serum (and not urine) was tested. Despite these limitations, it performed well at pre-induction and at 1 year. Mass-Fix provides a convenient and non-invasive means of predicting for myeloma outcomes. Clinical trial information: NCT01109004. [Table: see text]

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

2021 ◽  
pp. JCO.21.01045
Author(s):  
Pieter Sonneveld ◽  
Meletios A. Dimopoulos ◽  
Meral Beksac ◽  
Bronno van der Holt ◽  
Sara Aquino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Primary Study ◽  
Controlled Clinical Trial ◽  
Newly Diagnosed ◽  
Consolidation Treatment ◽  
Minimal Residual

PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

Single-arm phase II study of low-dose paclitaxel and pembrolizumab in platinum-refractory metastatic urothelial carcinoma (UC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 433-433
Author(s):  
Rhonda L. Bitting ◽  
Donald Charles Vile ◽  
Janet A. Tooze ◽  
Christopher Y. Thomas ◽  
Morgan Neve ◽  
...  
Keyword(s):  
Phase Ii ◽  
Low Dose ◽  
Immune Cell ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Intention To Treat ◽  
Definitive Therapy ◽  
Platinum Refractory

433 Background: Single agent checkpoint inhibition is effective in a small proportion of platinum-refractory UC patients but improvements are needed. UC is highly inflammatory, and low-dose chemotherapy may enhance the response to immunotherapy. We evaluated whether combination therapy with low-dose paclitaxel and pembrolizumab is more efficacious than single-agent pembrolizumab which had an objective response rate (ORR) of 21% in a similar patient population in the KEYNOTE-045 study. We also incorporated multiple novel biomarker studies to explore immune regulatory mechanisms in UC. Methods: This is a prospective, single-arm phase II trial (NCT02581982) of pembrolizumab combined with low-dose paclitaxel in patients with platinum-refractory metastatic UC. Key inclusion criteria included measurable progression of disease within 12 months of platinum therapy and ECOG ≤1. Patients received pembrolizumab 200mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21 day cycle for up to 8 cycles unless clinical or radiographic disease progression or unacceptable adverse events (AEs) were observed. Responding patients could remain on pembrolizumab maintenance for up to 2 years. The primary endpoint was ORR; key secondary endpoints included overall survival (OS), 6-month progression free survival (PFS), and safety. Results: Twenty-seven patients were treated between 4/2016 - 6/2020, with a median follow up of 9.9 months. At baseline, the median age was 68 years (range 49-80), with 81% men and 78% non-Hispanic white. The majority (59%) were ECOG 1. Twenty-one of 27 (78%) received prior definitive therapy: chemoradiation in 24% and surgery in 76%. The majority (78%) of patients received prior cisplatin. 70% progressed on a cisplatin-based regimen while 30% progressed on carboplatin-based regimen within 12 months of study entry. The ORR by intention to treat was 9 of 27 patients (33%) and in patients evaluable for response by imaging was 9 of 25 (36%), including 3 with complete response. Disease control rate in evaluable patients was 72%. Six-month PFS was 46.8% (95% CI: 27.2%, 64.2%) and median OS was 11.7 months (95% CI: 8.7 mo, NR). Common ≥ grade 2 AEs were anemia (44%), lymphopenia (37%), hyperglycemia (33%), and fatigue (33%). Possible treatment-related at least grade 3 or 4 AEs occurred in 56% of subjects, including 2 immune-mediated AEs (pneumonitis and nephritis) resulting in therapy cessation but a durable partial response. There were no grade 5 events. Conclusions: This study illustrates that the addition of low-dose paclitaxel to pembrolizumab improves outcomes in patients with platinum-refractory UC, relative to single-agent pembrolizumab. No unanticipated safety signals emerged. Exploratory analyses including PDL1 status, tumor mutational burden, and change in circulating microRNAs and in immune cell populations are ongoing. Clinical trial information: NCT02581982.

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