Duration Of Response Rate Research Articles

Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer.

PURPOSEGenetic rearrangements of the tyrosine receptor kinase ROS proto-oncogene 1 (ROS1) are oncogenic drivers in non-small-cell lung cancer (NSCLC). We report the results of an updated integrated analysis of three phase I or II clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2) of the ROS1 tyrosine kinase inhibitor, entrectinib, in ROS1 fusion–positive NSCLC.METHODSThe efficacy-evaluable population included adults with locally advanced or metastatic ROS1 fusion–positive NSCLC with or without CNS metastases who received entrectinib ≥ 600 mg orally once per day. Co-primary end points were objective response rate (ORR) assessed by blinded independent central review and duration of response (DoR). Secondary end points included progression-free survival (PFS), overall survival (OS), intracranial ORR, intracranial DoR, intracranial PFS, and safety.RESULTSIn total, 161 patients with a follow-up of ≥ 6 months were evaluable. The median treatment duration was 10.7 months (IQR, 6.4-17.7). The ORR was 67.1% (n = 108, 95% CI, 59.3 to 74.3), and responses were durable (12-month DoR rate, 63%, median DoR 15.7 months). The 12-month PFS rate was 55% (median PFS 15.7 months), and the 12-month OS rate was 81% (median OS not estimable). In 24 patients with measurable baseline CNS metastases by blinded independent central review, the intracranial ORR was 79.2% (n = 19; 95% CI, 57.9 to 92.9), the median intracranial PFS was 12.0 months (95% CI, 6.2 to 19.3), and the median intracranial DoR was 12.9 months (12-month rate, 55%). The safety profile in this updated analysis was similar to that reported in the primary analysis, and no new safety signals were found.CONCLUSIONEntrectinib continued to demonstrate a high level of clinical benefit for patients with ROS1 fusion–positive NSCLC, including patients with CNS metastases.

Is there any room for PD-1 inhibitors in combination with platinum-based chemotherapy as frontline treatment of extensive-stage small cell lung cancer? A systematic review and meta-analysis with indirect comparisons among subgroups and landmark survival analyses.

Background:The addition of PD-L1 inhibitors to platinum-based chemotherapy (CT) has newly received United States Food and Drug Administration (FDA) approval in extensive stage-small cell lung cancer (ES-SCLC). PD-1 agents similarly improved survival rates, even if not yet supported by international regulatory agencies. The current work aims to assess different efficacy and safety profiles among chemoimmunotherapy plus immuno-oncology (CT+IO) approaches according to different immune checkpoint inhibitor (ICI) subtypes.Material & Methods:We included in our meta-analysis six first-line randomised controlled trials (RCTs) comparing the association of single-agent ICI with CT versus CT alone in ES-SCLC. Pooled hazard ratios (HRs) and risk ratios (RRs) for progression-free survival (PFS), overall survival (OS), objective response rates (ORR), 12-month duration of response rate (DORR), disease control rate (DCR), treatment-related adverse events (TRAEs) and discontinuation rates (DRs) were obtained. Moreover, we performed indirect comparisons according to ICI subtypes, also among subgroups and landmark survival analyses.Results:Although no ORR benefit was observed, our results showed how CT+IO significantly improved DORR, resulting in improved PFS and OS with no differences in TRAEs; however, CT+IO led to a significant increase in DR. Interestingly, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1, the use of cisplatin, and the absence of brain metastases seem to be associated with a survival gain using CT+IO in ES-SCLC. Indirect comparisons suggested a slight advantage in favour of programmed cell death-1 (PD-1) and programmed death ligand 1 (PD-L1) over anti-CTLA-4 agents in terms of efficacy with no additional safety concerns. No further differences were observed between PD-1 and PD-L1 inhibitors among subgroups and landmark survival analyses with benefit trends towards anti-PD-1 in terms of DORR and DR.Conclusion:While confirming a survival advantage of CT+IO in selected patients, these results suggested the association of PD-1 inhibitors with CT as a viable option for novel therapeutic approaches in the frontline management of ES-SCLC. Further trials evaluating anti-CTLA-4 agents should be carefully studied in biomarker-selected patients.

Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma

AbstractTisagenlecleucel is a CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and adults with non-Hodgkin lymphoma (NHL). The initial experience with tisagenlecleucel in a real-world setting from a cellular therapy registry is presented here. As of January 2020, 511 patients were enrolled from 73 centers, and 410 patients had follow-up data reported (ALL, n = 255; NHL, n = 155), with a median follow-up of 13.4 and 11.9 months for ALL and NHL, respectively. Among patients with ALL, the initial complete remission (CR) rate was 85.5%. Twelve-month duration of response (DOR), event-free survival, and overall survival (OS) rates were 60.9%, 52.4%, and 77.2%, respectively. Among adults with NHL, the best overall response rate was 61.8%, including an initial CR rate of 39.5%. Six-month DOR, progression-free survival, and OS rates were 55.3%, 38.7%, and 70.7%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 11.6% and 7.5% of all patients, respectively. Similar outcomes were observed in patients with in-specification and out-of-specification products as a result of viability <80% (range, 61% to 79%). This first report of tisagenlecleucel in the real-world setting demonstrates outcomes with similar efficacy and improved safety compared with those seen in the pivotal trials.

Efficacy and Safety of Sabatolimab (MBG453) in Combination with Hypomethylating Agents (HMAs) in Patients with Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS): Updated Results from a Phase 1b Study

Efficacy and Safety of Sabatolimab (MBG453) in Combination with Hypomethylating Agents (HMAs) in Patients with Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS): Updated Results from a Phase 1b Study

Long-Term Subgroup Analyses from L-Mind, a Phase II Study of Tafasitamab (MOR208) Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Long-Term Subgroup Analyses from L-Mind, a Phase II Study of Tafasitamab (MOR208) Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Long-Term Safety and Efficacy of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Mantle Cell Lymphoma: A Multicenter, Open-Label, Phase II Study

Background: In spite of years of effort, Mantle Cell Lymphoma (MCL) remains a clinical challenge. The clinical significance of Bruton's Tyrosine Kinase (BTK) inhibitor has been validated with the approvals by FDA for the treatment of multiple subtypes of NHL including refractory and relapse (r/r) MCL. However, some serious adverse events (AEs) due to poor target selectivity (inhibition of EGFR, TEC, BMX and others), such as diarrhea, sever bleeding and atrial fibrillation, remain as challenges in clinic. Orelabrutinib is a novel, potent irreversible BTK inhibitor with high selectivity for BTK. Results of early clinical study showed that it has excellent safety/tolerability profiles and favorable pharmacokinetic/pharmacodynamic properties. Sustained ~100% BTK occupancy at 24 hours was achieved with once daily dosing regimen of 50 mg and above. In this presentation, we will report an updated analysis of orelabrutinib in Chinese patients with r/r MCL with minimum of 12 cycles of treatment. Aims: To evaluate the sustained efficacy and long-term safety of orelabrutinib in Chinese patients with r/r MCL. Methods: This is an open-label, multicenter, two stages, phase II study. The primary endpoint was objective response rate (ORR) assessed per Lugano criteria (2014). Safety and other efficacy (DOR, PFS, OS) evaluations were chosen as secondary endpoints. Results: A Total 106 patients, were enrolled in this study with median follow up time of 15.0 months. 79.2% of the patients were male and median age of 62.0 years old. Most patients were at advanced stage (73.6% were at stage IV and 20.8% were at stage III). According to per protocol analysis, 87 (87.9%) patients achieved ORR and 93.9% patients achieved disease control. The median duration of response (DOR) was not reached, the DOR rate at 12 months was 73.7%, as expected the median PFS and OS were not reached, the PFS and OS rates at 12-month were 70.8% and 88.7% respectively. Comparing to the results of previous analysis, the CR rate, by conventional CT method, increased to 27.4% and it was expected a higher rate of in depth response may occur with prolonged treatment. Further analysis showed orelabrutinib was efficacious in all subgroups (age, gender, status, stage, prior therapy, etc.). Orelabrutinib demonstrated excellent safety profile in r/r MCL patients. The frequently reported treatment related adverse events (TRAE) were primarily hematological toxicities including thrombocytopenia, neutropenia, leukopenia, and hypertension. The frequently reported grade 3 or higher AEs of any cause was thrombocytopenia . No treatment related ≥grade 3 GI and cardio toxicity, nor severe bleeding, were observed. Of the 106 patients, 32 experienced serious AEs; and 17 of them, mainly hematological toxicities and / or infections were treatment-related. Comparing to the safety data of median follow up of 10.5 months, there was only a mild increase of adverse events rate after extended treatments; the safety profiles were essentially the same. These results suggested that safety events primarily occurred during early treatment and it appeared less eventful with orelabrutinib continue treatment. Conclusion: Orelabrutinib showed continuous efficacious in treating patients with r/r MCL. In addition, orelabrutinib is safe and well tolerated with no treatment related grade 3 or higher diarrhea, atrial fibrillation/flutter or severe bleeding in this study. Results of prolong treatment expected to produce a higher rate of in depth response without altering its safety profiles support orelabrutinib being a better selection for BTKi therapy. The improved safety as a resulting of high target selectivity, and the convenience of daily dosing regimen provides orelabrutinib as preferred therapeutic choice for B cell malignancy. Disclosures Zhang: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.

A Phase 1b, Open-Label Study of Eftozanermin Alfa in Combination with Bortezomib and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Background Many patients (pts) with multiple myeloma (MM) will relapse after treatment or become refractory to all therapies currently available. For these pts, the prognosis is poor and there is a clear unmet need to identify agents with novel mechanisms of action. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway has a distinct role in the induction of apoptosis in tumor cells, and activating this pathway could represent an attractive therapeutic approach. Early generation TRAIL receptor agonists had minimal efficacy in pts with MM, which may be due to suboptimal TRAIL receptor clustering. Eftozanermin alfa (formerly ABBV-621) is a next-generation TRAIL receptor agonist specifically designed to optimize receptor clustering. The ongoing first-in-human study of eftozanermin alfa (NCT03082209) demonstrated a tolerable safety profile in pts with previously treated solid tumors and hematologic malignancies. Preclinical ex vivo and in vivo models of MM indicate combinatorial activity of eftozanermin alfa with proteasome inhibitors (PIs) resulting in enhanced efficacy. The addition of eftozanermin alfa to the well-established regimen of the PI bortezomib and dexamethasone may improve efficacy outcomes in pts with relapsed/refractory (R/R) MM. Study Design and Methods This is a phase 1b, open-label, nonrandomized, multicenter study enrolling pts (≥18 years, Eastern Cooperative Oncology Group score 0-1) with R/R MM. Approximately 40 pts are planned for enrollment. The primary objectives of the study are to determine the recommended phase 2 dose (RP2D) of eftozanermin alfa when given in combination with bortezomib and dexamethasone, and to assess the efficacy of this combination on the basis of overall response rate (ORR). Secondary objectives include assessing the safety and tolerability of eftozanermin alfa with bortezomib and dexamethasone and evaluating the rate of very good partial response (VGPR) or better, the duration of response (DOR), and pharmacokinetics (PK). Key inclusion criteria are pts with R/R MM who have received at least 3 but no more than 6 prior lines of therapy (including an immunomodulatory agent, a PI, and an anti-CD38 antibody) and have documented disease progression during or after the most recent therapy. Pts must also have measurable disease per standard International Myeloma Working Group (IMWG) criteria at baseline and adequate hematologic, hepatic, and renal function. Pts will be excluded if they have primary refractory disease, received bortezomib in the most recent prior therapy, or have peripheral neuropathy grade ≥2 or grade 1 with pain. The study consists of a screening period, a treatment period, and a follow-up period; dosing schedule details are presented in Figure. After screening, pts will receive eftozanermin alfa with bortezomib and dexamethasone until unacceptable toxicity, confirmed progressive disease, or other protocol-specified reasons for discontinuation are met. Treatment may continue for maximum 12 cycles. A safety lead-in will be performed to determine the RP2D of eftozanermin alfa when combined with bortezomib and dexamethasone. Dose escalation during the safety lead-in will be guided using a Bayesian optimal interval design with a target toxicity rate of 33%. The primary efficacy endpoint is the ORR, defined as the proportion of pts with partial response or better per IMWG criteria. Other efficacy endpoints include DOR, VGPR or better rate, and progression-free and overall survival. For all binary endpoints, the estimated proportion and associated 2-sided 90% Clopper-Pearson exact confidence intervals will be provided. The time-to-event endpoints will be summarized using the Kaplan-Meier method. Safety evaluations will include assessment of dose-limiting toxicities during cycle 1 of the safety lead-in, and monitoring of adverse events, vital signs, and clinical laboratory measures throughout the study. Samples for PK analysis, biomarker assessments, and assays for antidrug and neutralizing antidrug antibodies will be obtained at protocol-specified visits. Biomarker analyses may include evaluation of death receptor 4/5 expression, chromosomal abnormalities, and minimal residual disease status. Approximately 20 sites in 6 countries are planned to be involved in the study, which is anticipated to start in September 2020. Figure 1 Disclosures Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Polepally:AbbVie: Current Employment, Other: may hold stock or stock options.. Motwani:AbbVie: Current Employment, Current equity holder in publicly-traded company. Mu:AbbVie: Current Employment, Other: may hold stock or stock options.. Salman:AbbVie: Current Employment, Other: may hold stock or stock options.. Penugonda:AbbVie: Current Employment, Other: may hold stock or stock options.. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.

Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Long-Term Efficacy and Safety Results from a Phase 2 Study

Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Long-Term Efficacy and Safety Results from a Phase 2 Study

Abstract B26: EV-301: A phase 3 study evaluating enfortumab vedotin versus chemotherapy in patients with locally advanced or metastatic urothelial cancer (la/mUC) who have progressed on platinum-containing chemotherapy or anti-PD-(L)1 therapy

Abstract Background: Currently, there are no FDA-approved therapies for patients (pts) with la/mUC who have failed treatment with chemotherapy and immune checkpoint inhibitors, such as antibodies targeting PD-1 or PD-L1. Survival benefits with anti-PD-(L)1 therapy have not been consistently observed and objective response rates (ORR) in the second-line setting are ≤21%. Moreover, there are limited data on response to chemotherapy in pts who progressed on immune checkpoint inhibitors. Enfortumab vedotin (EV) is a fully humanized monoclonal antibody that delivers the microtubule-disrupting agent, monomethyl auristatin E, to tumors expressing Nectin-4. Nectin-4 has limited expression in normal tissue but is highly expressed in cancer cells, particularly UC. In a phase 1 study (EV-101; NCT02091999), EV 1.25 mg/kg was generally well tolerated and demonstrated a confirmed ORR of 43% with a duration of response (DoR) of 7.4 mo. Median overall survival (OS) was 12.3 mo and OS rate at 1 yr was 51.8%. Similar results were observed in a number of study subpopulations, including pts with prior anti-PD-(L)1 treatment and liver metastases at baseline. A pivotal phase 2 study of EV in pts with la/mUC with prior immune checkpoint inhibitor treatment (EV-201; NCT03219333) is ongoing, with enrollment into a cohort of pts with la/mUC previously treated with platinum and immune checkpoint inhibitor therapies now completed. Trial Design: EV-301 is a global, multicenter, open-label phase 3 trial (NCT03474107) enrolling ~550 adult pts with la/mUC with an ECOG score ≤1, who have received a prior platinum-containing chemotherapy and have experienced disease progression during or following treatment with anti-PD-(L)1 therapy. Patients will be randomized 1:1 to receive EV (1.25 mg/kg) administered IV on Days 1, 8, and 15 of each 28-day cycle (Arm A), or investigator choice of IV docetaxel, paclitaxel, or vinflunine (EU only) on Day 1 of each 21-day cycle (Arm B). Treatment with the study drug will continue until radiologic disease progression assessment, intolerance, or other discontinuation criterion is met. Radiologic assessments of tumor response status will be performed at baseline and every 8 weeks. The primary endpoint of EV-301 is to compare the OS of pts treated with EV with the OS of pts treated with chemotherapy alone; secondary endpoints include EV safety/tolerability profile, ORR, progression-free survival, DoR, and disease control rate assessment using RECIST v.1.1 criteria. Quality-of-life parameters and patient-reported outcomes will also be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire and EuroQoL 5-dimension 5-Level Questionnaire. Citation Format: Daniel Petrylak, Jonathan Rosenberg, Ignacio Duran, Yohann Loriot, Guru Sonpavde, Chunzhang Wu, Elaina Gartner, Amal Melhem- Bertrandt, Thomas Powles. EV-301: A phase 3 study evaluating enfortumab vedotin versus chemotherapy in patients with locally advanced or metastatic urothelial cancer (la/mUC) who have progressed on platinum-containing chemotherapy or anti-PD-(L)1 therapy [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B26.

KEYNOTE-013 4-year follow-up of pembrolizumab in classical Hodgkin lymphoma after brentuximab vedotin failure

AbstractThe KEYNOTE-013 study was conducted to evaluate pembrolizumab monotherapy in hematologic malignancies; classical Hodgkin lymphoma (cHL) was an independent expansion cohort. We present long-term results based on >4 years of median follow-up for the cHL cohort. The trial enrolled cHL patients who experienced relapse after, were ineligible for, or declined autologous stem cell transplantation and experienced progression with or did not respond to brentuximab vedotin. Patients received IV pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points were safety and complete response (CR) rate by central review. Enrolled patients (N = 31) had received a median of 5 therapies (range, 2 to 15). After a median follow-up of 52.8 months (range, 7.0 to 57.6 months), CR rate was 19%, and median duration of response (DOR) was not reached; 24-month and 36-month DOR rates were both 50% by the Kaplan-Meier method. Median overall survival was not reached; 36-month overall survival was 81%. Six patients (19%) experienced grade 3 treatment-related adverse events (AEs); there were no grade 4 or 5 treatment-related AEs. With long-term follow-up among a heavily pretreated cohort, pembrolizumab had a favorable safety profile; some patients maintained long-term response with pembrolizumab years after end of treatment. This trial was registered at www.clinicaltrials.gov as #NCT01953692.

Two-year follow-up of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, for second-line (2L) treatment of non-small cell lung cancer (NSCLC).

9558 Background: Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. Interim analysis of a global phase 1 study (NCT02517398) found an objective response rate (ORR) of 27.5% and a manageable safety profile in patients with NSCLC who received bintrafusp alfa 1200 mg in the 2L setting; median overall survival (OS) was not reached. Here we present the longest efficacy and safety follow-up in a cohort receiving bintrafusp alfa. Methods: Patients with advanced NSCLC unselected for PD-L1 expression level who progressed after first-line standard treatment (no prior immunotherapy) were randomized to receive bintrafusp alfa 500 or 1200 mg (n = 40 each) Q2W until disease progression, unacceptable toxicity or trial withdrawal. The primary objective was best overall response (BOR) per RECIST 1.1; secondary and exploratory objectives include safety and OS, respectively. Results: As of October 15, 2019, a total of 40 patients received bintrafusp alfa at the recommended phase 2 dose of 1200 mg Q2W for a median of 17 (range, 2-136) weeks, with a median follow-up of 128 weeks; 18 patients were still alive, 3 patients had an ongoing response, and 1 patient remained on treatment. Results for the 1200 mg dose cohort showed an ORR of 27.5%, and a median duration of response of 18 months. The 18- and 24-month progression-free survival and OS rates were 18.4% and 11.0%, and 49.7% and 39.7%, respectively. Duration of response rates at 18 and 24 months were 42.4% and 21.2%, respectively. Median OS in patients with positive (≥1%) PD-L1 expression was 21.7 months; 6 of 7 patients with high (≥80% with Ab clone 73-10, which is equivalent to ≥50% with 22C3) PD-L1 expression were still alive. The overall safety profile has remained consistent since the interim analysis, with no new safety signals or deaths and 1 additional treatment-related discontinuation (blood alkaline phosphatase increased). Conclusions: After two years of follow-up, bintrafusp alfa continues to show manageable safety with durable responses and encouraging long-term survival, especially in patients with high PD-L1 expression. A study evaluating bintrafusp alfa vs pembrolizumab as first-line treatment for NSCLC is ongoing in patients with high PD-L1 expression (NCT03631706). Clinical trial information: NCT02517398 .

Acalabrutinib in treatment-naïve chronic lymphocytic leukemia: Mature results from phase II study demonstrating durable remissions and long-term tolerability.

8024 Background: The next-generation Bruton tyrosine kinase inhibitor acalabrutinib was approved in patients (pts) with treatment-naïve (TN) and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) based on two complementary phase 3 studies, ELEVATE-TN and ASCEND. This report of ACE-CL-001 (NCT02029443), the first phase 2 study of acalabrutinib, provides the longest safety and efficacy follow-up to date in symptomatic TN CLL pts. Methods: Adults with TN CLL/SLL were eligible if they met iwCLL 2008 criteria for treatment, were inappropriate for/declined standard chemotherapy and had ECOG performance status 0–2. Pts received acalabrutinib 100 mg BID or 200 mg QD, later switching to 100 mg BID, until progressive disease (PD) or unacceptable toxicity. Primary endpoint was safety. Events of clinical interest (ECI) were based on combined AE terms for infections, bleeding events, hypertension, and second primary malignancies (SPM) excluding non-melanoma skin, and on a single AE term for atrial fibrillation. Additional endpoints included investigator-assessed overall response rate (ORR), duration of response (DOR), time to response (TTR), and event-free survival (EFS). Results: Ninety-nine pts (n = 62 100 mg BID; n = 37 200 mg QD), were treated [median age: 64 years, 47% Rai stage 3–4 disease, 10% del(17p), 62% unmutated IGHV]. At median follow-up of 53 months (range, 1–59), 85 (86%) pts remain on treatment; most discontinuations were due to AEs (n = 6) or PD (n = 3 [n = 1 Richter transformation]). Most common AEs (any grade) were diarrhea (52%), headache (45%), upper respiratory tract infection (44%), arthralgia (42%), and contusion (42%). All-grade and grade ≥3 ECIs included infection (84%, 15%), bleeding events (66%, 3%), and hypertension (22%, 11%). Atrial fibrillation (all grades) occurred in 5% of pts (incidence: 1% in years 1, 2, 4; 3% in year 3). SPMs excluding non-melanoma skin (all grades) occurred in 11%. Serious AEs were reported in 38% of pts; those in &gt; 2 pts were pneumonia (n = 4) and sepsis (n = 3). ORR was 97% (7% complete response; 90% partial response). Median TTR was 3.7 months (range, 2–22). Response rates were similar across high-risk groups. Median DOR and median EFS were not reached; 48-month DOR rate was 97% (95% CI, 90%–99%), and 48-month EFS rate was 90% (95% CI, 82%–94%). Conclusions: Long-term data from ACE-CL-001 further support the favorable results with acalabrutinib in phase 3 studies and demonstrate durable responses with no new long-term safety issues. Clinical trial information: NCT02029443 .

Subgroup Analyses from L-Mind, a Phase II Study of Tafasitamab (MOR208) Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Subgroup Analyses from L-Mind, a Phase II Study of Tafasitamab (MOR208) Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Safety, Tolerability and Efficacy of Orelabrutinib, Once a Day, to Treat Chinese Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Cell Leukemia

Bruton's Tyrosine Kinase (BTK) plays a critical role in B-cell receptor (BCR) signaling, which mediates B-cell proliferation, migration, and adhesion. As a therapeutic target, its clinical significance has been well established in multiple subtypes of non-Hodgkin's lymphoma (NHL). Orelabrutinib (ICP-022) is a novel, potent irreversible BTK inhibitor with much improved target selectivity in comparison to Ibrutinib and Acalabrunitib, which leads to improved safety profiles. With a proprietary formulation, Orelabrutinib achieves high bioavailability comparing to other BTK inhibitors. Results of Phase I study (another presentation on Orelabrutinib) demonstrated favorable pharmacokinetic and pharmacodynamic properties for Orelabrutinib. Sustained BTK occupancy at 24 hr was achieved with daily dosing regimen. In this presentation, we will report results from clinical study of Orelabrutinib in Chinese patients with r/r CLL/SLL. This is an open-label, multicenter, Phase II study with objectives to evaluate its safety, tolerability and efficacy following oral daily administration. The primary endpoint was objective response rate (ORR). The duration of response (DOR), progression-free survival (PFS) and safety were chosen as secondary endpoints. Response was assessed per 2008 IWCLL criteria with modification for PR with lymphocytosis (PR-L) (Cheson, Hallek 2012). This study is composed of two stages. The stage I was to assess the safety and tolerability of Orelabrutinib at 150 mg, QD in pts with r/r CLL/SLL, while the stage II was to evaluate its therapeutic benefits (N=80, 150 mg, QD). Total of 80 patients with r/r CLL (n=70)/SLL (n=10) were enrolled. As of 31 May 2019, 40 pts had completed six cycles of treatment (28 days/cycle). The Median follow-up was 6.3 months (range, 0.4-13.7 months). Safety: The most frequent (≥15%) any grade adverse events (AEs) of any cause were well characterized hematological toxicities: thrombocytopenia, neutropenia, and anemia; and respiratory system infections as well as purpura. No case of atrial fibrillation or secondary malignancy was reported. The most frequently (≥10%) reported ≥ Grade 3 AEs of any cause were neutropenia, thrombocytopenia, lung infection. Twenty-five pts experienced at least one serious AE. Of those, 13 were considered related to Orelabrutinib treatment, including platelet count decrease (3 pts), pneumonitis, pyrexia (2 pts each) and herpes zoster etc. (1 pt each). Efficacy: Of the 80 enrolled pts, seventy-eight pts were evaluable for response (by 31 of May 2019), the ORR was 88.5% (69/78). Among them, one patient was reported as CR, 39 pts were PR and 29 pts were PR-L. Stable disease was seen in 6/78 (7.7%). Total disease control rate is 96.2%. The median DOR was not reached, 6 months DOR rate was 89.8%. Subgroup analysis (age, disease stage, previous treatment, 17p deletion, 11q deletion, IGHV mutation) did not reveal significant differences. Conclusion: Orelabrutinib is safe and well tolerated. No significant adverse events like atrial fibrillation/flutter or secondary malignancies were reported. Orelabrutinib is efficacious to treat pts with r/r CLL/SLL. The improved safety, resulting from high target selectivity, and daily dosing regimen enable Orelabrutinib to be a valuable therapeutic choice both as monotherapy and likely in combination with other agents to treat B-cell malignancies. Disclosures Xu: Beijing InnoCare Pharma Tech Co., Ltd: Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Employment. Zhang:Beijing InnoCare Pharma Tech Co., Ltd: Employment. Zhu:Beijing InnoCare Pharma Tech Co., Ltd: Employment.

Abstract CT150: Phase II study of spartalizumab (PDR001) vs chemotherapy (CT) in patients with recurrent/metastatic nasopharyngeal cancer (NPC)

Abstract Background: There is currently no standard treatment for patients (pts) with platinum refractory, recurrent metastatic (R/M) NPC. Spartalizumab, a humanized anti-PD-1 IgG4 mAb, blocks interaction with PD-L1 and PD-L2. This is the first randomized phase II study to evaluate efficacy and safety of spartalizumab vs CT in NPC. Methods: This phase II open-label study recruited pts with non-keratinizing locally advanced R/M NPC who progressed on/after platinum-based CT and received up to 2 systemic therapies. Pts were randomized (2:1) to receive spartalizumab or CT, per investigator’s choice. Spartalizumab was dosed 400 mg every 4 weeks intravenously. Pts in CT arm could cross over to receive spartalizumab if progression confirmed by RECIST v1.1, based on independent central review. Primary endpoint was progression free survival (PFS); secondary endpoints were overall response rate (ORR), based on central review by RECIST v1.1, duration of response (DOR), overall survival, safety and pharmacokinetics. Correlation between efficacy and expression of immunologic biomarkers and immune-related genes was also studied. Results: In total, 76 pts in spartalizumab arm and 37 pts in CT arm were randomized (median age 51 years, ECOG performance status 0-2). As of Jan 31, 2018, 18/76 (23.7%) spartalizumab-treated pts, 8/37 (21.6%) CT-treated pts and 4/20 (20.0%) pts in crossover group were ongoing. Discontinuation rates were similar between arms, mainly due to progressive disease in spartalizumab arm (67.0%) and CT arm (68.0%). Median PFS (95% CI) was 1.9 mo (1.8;3.5) in spartalizumab arm vs 6.6 mo (3.7;9.2) in CT arm; primary endpoint was not met, with hazard ratio of 1.53 (95% CI 1.02;2.27). ORR (95% CI) was 18.4% (10.5;29.0) vs 32.4% (18.0;49.8) in spartalizumab vs CT arm, respectively, and 5.0% (0.1;24.9) in crossover group. ORR for pts treated with monotherapy CT was 19.2% (5/26) and for pts treated with CT doublet/triplet was 63.3% (7/11). The Kaplan-Meier estimate of DOR rate at 12 mo in responding spartalizumab-treated pts was 61.0% (95% CI 20.2;85.8). In CT arm, 11/12 pts either progressed or discontinued at 12 mo; at data cut-off, 1 pt remained responding for 3.61 mo. Safety profile of spartalizumab was largely consistent with results obtained from other spartalizumab single-agent studies. Overall, treatment-related grade 3/4 adverse events were reported in 18.4% of spartalizumab-treated pts and 40.5% of CT-treated pts. No treatment-related deaths occurred. RNA sequencing analyses of tumors revealed a correlation between response to spartalizumab and IFN-γ signature, TIM3 and LAG3 gene expression; this correlation was not observed in pts treated with CT. Conclusions: Spartalizumab was well tolerated and despite the study not reaching its primary endpoint, long-lasting tumor responses were observed in a subset of spartalizumab-treated pts with NPC. Biomarker analysis is ongoing. Citation Format: Darren Wan-Teck Lim, Hung-Ming Wang, Shau-Hsuan Li, Roger Ngan, Arunee Dechaphunkul, Li Zhang, Chia Jui Yen, Po Chung Chan, Somvilai Chakrabandhu, Brigette Ma, Suebpong Tanasanvimon, Victor Lee, Pei-Jen Lou, Zujun Li, Alexander Spira, Ammar Sukari, Joël Guigay, Steven McCune, Yongjian Sun, Sebastian Szpakowski, Yao Yao, Xueqiang Fan, Luigi Manenti, Caroline Even. Phase II study of spartalizumab (PDR001) vs chemotherapy (CT) in patients with recurrent/metastatic nasopharyngeal cancer (NPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT150.

Bacillus Calmette-Guerin (BCG) with or without pembrolizumab (pembro) for high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) that is persistent or recurrent following BCG induction: Phase III KEYNOTE-676 study.

TPS4591 Background: Intravesical instillation of BCG is standard of care for patients (pts) with HR NMIBC. However, many pts have persistent/recurrent HR NMIBC after BCG induction and are at increased risk for progression to muscle-invasive disease. Interim data from the phase 2 KEYNOTE-057 study has shown that the PD-1 inhibitor pembro had promising efficacy in HR NMIBC as monotherapy. KEYNOTE-676 (NCT03711032) is a randomized, comparator-controlled, phase 3 trial to evaluate efficacy and safety of pembro plus BCG in pts with persistent/recurrent HR NMIBC after BCG induction therapy. Methods: Pts are randomly assigned 1:1 to continue BCG therapy alone or receive BCG plus pembro 200 mg every 3 weeks. Treatment is stratified by carcinoma in situ (CIS) histology (presence/absence), PD-L1 combined positive score (≥10/˂10), and timing of NMIBC persistence/recurrence (0 to ≤6, ˃6 to ≤12, or ˃12 to ≤24 mo). Pts are eligible if they are ≥18 years of age with histologically confirmed persistent/recurrent HR NMIBC of the bladder after adequate BCG induction therapy, have undergone cystoscopy/transurethral resection of bladder tumor within 12 weeks before randomization, have no concurrent extravesical disease, and have an ECOG PS score of 0-2. Responses are assessed by cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1-2 and every 24 weeks for years 3-5 and by computed tomography urography every 18 months through year 5. Treatment will continue with pembro for up to 2 years and BCG for 3 years or until confirmed HR NMIBC persistence, recurrence, or disease progression, unacceptable toxicity, or pt/physician decision to withdraw. Primary end point is complete response rate in pts with CIS. Secondary end points are event-free survival (EFS), recurrence-free survival, overall survival, disease-specific survival, time to cystectomy, 12-month EFS rate in all pts, duration of response (DOR), 12-month DOR rate in pts with CR and safety and tolerability. Recruitment began in November 2018 and will continue until ~550 pts are enrolled. Clinical trial information: NCT03711032.

Acalabrutinib in Treatment-Naive (TN) Chronic Lymphocytic Leukemia (CLL): Updated Results from the Phase 1/2 ACE-CL-001 Study

Acalabrutinib in Treatment-Naive (TN) Chronic Lymphocytic Leukemia (CLL): Updated Results from the Phase 1/2 ACE-CL-001 Study

Avelumab in chemotherapy-refractory metastatic Merkel cell carcinoma: Subgroup analysis of efficacy.

80 Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. In a phase 2 trial in previously treated metastatic MCC (mMCC; JAVELIN Merkel 200, NCT02155647), avelumab, a fully human IgG1 anti–PD-L1 antibody, showed durable responses and a manageable safety profile, including confirmed objective response rate (ORR) of 31.8% (95.9% CI 21.9-43.1), 6-mo duration of response (DOR) rate estimate of 92%, and 6-mo progression-free survival (PFS) rate of 40% (95% CI 29-50). We report post-hoc subgroup analyses from this trial. Methods: Pts with mMCC and prior disease progression on chemotherapy received avelumab 10 mg/kg (1h IV) Q2W. Tumors were assessed every 6 wks (RECIST v1.1) by independent review. Kaplan-Meier method was used to estimate 6-mo DOR and PFS rate. Results: 88 pts were treated with avelumab and followed for ≥ 6 mos (data cutoff Mar 3, 2016). Responses occurred in all subgroups analyzed (Table). Trends of higher ORR and 6-mo PFS rates were seen in pts with fewer prior lines, lower disease burden (sum of target lesion diameters), or PD-L1+ tumors. 6-mo response durability was similar across evaluable subgroups. Conclusions: In post-hoc analyses, avelumab showed durable efficacy across subgroups. This trial is enrolling treatment-naive pts with mMCC to receive 1L avelumab. Clinical trial information: NCT02155647. [Table: see text]

Avelumab in patients with metastatic urothelial carcinoma: Pooled results from two cohorts of the phase 1b JAVELIN Solid Tumor trial.

330 Background: Avelumab is a fully human anti‒PD-L1 IgG1 antibody with promising efficacy and safety in patients (pts) with metastatic urothelial carcinoma (mUC). To further characterize the clinical activity of avelumab in mUC, we report a planned interim pooled analysis of 2 cohorts from a large phase 1b trial (NCT01772004). Methods: Pts with mUC progressed after platinum-based therapy or cisplatin-ineligible, and unselected for tumor PD-L1 expression, received avelumab 10 mg/kg (1 h IV) Q2W. Response was assessed every 6 wks by independent review per RECIST v1.1. Endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety (NCI CTCAE v4.0), and tumor PD-L1 expression (clone 73-10). Results: As of Mar 19, 2016, 241 pts received avelumab for a median of 8 wks (range 2-80); median follow-up was 7.3 mos (range 0-18.2). Primary tumor sites were upper tract (renal pelvis/ureter [23.7%]) and lower tract (bladder/urethra [76.3%]). 95.4% of pts had progressed on prior platinum therapy, and 63.4% had received ≥ 2 prior lines for advanced disease (range 0-6). In 153 pts with ≥ 6 mos follow-up, confirmed ORR was 17.6% (95% CI 12.0-24.6) with 9 complete responses and 18 partial responses; 24/27 (88.9%) were ongoing. Median DOR was not reached, and the 24-wk DOR rate was 92.0% (95% CI 71.6, 97.9). 36 pts had stable disease as best response (disease control rate 41.2%). Median PFS was 6.4 wks (95% CI 6.1-11.4), and median OS was 7.0 mos (95% CI 5.6-11.1). Based on a ≥ 5% PD-L1 staining cutoff in evaluable pts with PD-L1+ (n = 56) and PD-L1– (n = 75) tumors, ORR was 25.0% (95% CI 14.4-38.4) vs 14.7% (95% CI 7.6-24.7; p = 0.178). Treatment-related adverse events (TRAE) of any grade occurring in ≥ 10% of pts were infusion-related reaction (22.8%) and fatigue (12.0%). 7.5% had a grade ≥ 3 TRAE; fatigue (1.2%)/asthenia (0.8%) occurred in &gt; 1 pt. 28 pts (11.6%) had an immune-related TRAE (grade ≥ 3 in 2.5%). There was 1 treatment-related death (pneumonitis). Conclusions: Avelumab is well tolerated and shows promising clinical activity, including durable responses, in pts with mUC, regardless of tumor PD-L1 expression status. Follow-up is ongoing. Clinical trial information: NCT01772004.

Venetoclax (ABT-199/GDC-0199) Monotherapy Induces Deep Remissions, Including Complete Remission and Undetectable MRD, in Ultra-High Risk Relapsed/Refractory Chronic Lymphocytic Leukemia with 17p Deletion: Results of the Pivotal International Phase 2 Study

Venetoclax (ABT-199/GDC-0199) Monotherapy Induces Deep Remissions, Including Complete Remission and Undetectable MRD, in Ultra-High Risk Relapsed/Refractory Chronic Lymphocytic Leukemia with 17p Deletion: Results of the Pivotal International Phase 2 Study