Response Rate In Evaluable Patients Research Articles

Abstract PS15-03: Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: phase 1b cohort

Abstract Background: Vepdegestrant (ARV-471) is an oral PROTAC ER degrader. In a phase 1/2 study (NCT04072952), vepdegestrant monotherapy had a favorable safety profile and encouraging clinical activity, and showed robust ER degradation. The phase 1b cohort of this study is evaluating vepdegestrant in combination with the cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (palbo). In xenograft models, vepdegestrant plus palbo showed substantially greater tumor growth inhibition vs fulvestrant plus palbo, supporting investigation in patients with breast cancer. Methods: Eligible patients for the phase 1b combination cohort had ER+/HER2- locally advanced/metastatic breast cancer and had received ≥1 prior endocrine therapy and ≤2 chemotherapy regimens for advanced disease; prior CDK4/6 inhibitor treatment was permitted. Vepdegestrant was given orally once daily (QD) continuously at doses of 180 mg (n=2), 200 mg (n=21), 400 mg (n=3), or 500 mg (n=20); palbo 125 mg was given orally QD for 21 days followed by 7 days off treatment in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) in the first cycle and safety (adverse events [AEs] and laboratory abnormalities). Enrollment in these 4 dose levels is complete; we report data as of June 6, 2023. Results: Across 46 patients in the phase 1b cohort, 45 (97.8%) patients were female with a median age of 62.0 y (range: 29–78). Patients had received a median of 4 prior therapies (range: 1–11) in any setting, including 87.0% prior CDK4/6 inhibitors (78.3% prior palbo), 80.4% prior fulvestrant, and 76.1% prior chemotherapy (45.7% in the metastatic setting). There were no DLTs. Treatment-emergent AEs (TEAEs) leading to dose reductions or discontinuation of vepdegestrant occurred in 5 and 4 patients, respectively. TEAEs leading to dose reductions or discontinuation of palbo occurred in 34 and 8 patients, respectively. Grade 3/4 treatment-related AEs (TRAEs) to either vepdegestrant or palbo in ≥10% of patients were neutropenia (89.1%), decreased white blood cell count (15.2%), and decreased platelet count (10.9%); there were no grade 5 TRAEs and no patients had febrile neutropenia. The clinical benefit rate (rate of confirmed complete response, partial response, or stable disease ≥24 wks) in patients treated with vepdegestrant plus palbo was 63.0% (95% CI: 47.5–76.8). The objective response rate in evaluable patients with measurable disease at baseline (n=31) was 41.9% (95% CI: 24.5–60.9). Pharmacokinetics (PK) showed dose-dependent exposure for vepdegestrant, consistent with data for vepdegestrant administered as monotherapy; palbo exposure was similar across dose levels of vepdegestrant and modestly higher compared with historical palbo PK data. Circulating tumor DNA levels were evaluated in patients who received vepdegestrant 200 mg QD plus palbo and demonstrated substantial and sustained decreases in ESR1 mutant allele fraction across multiple treatment cycles. Conclusions: The combination of vepdegestrant plus palbo showed promising clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer who had received extensive prior treatment. The safety profile of vepdegestrant plus palbo was generally consistent with the known safety profiles of the 2 agents except for an increased occurrence of grade 3/4 neutropenia, which was readily managed with laboratory monitoring and dose reductions of palbo. There is an ongoing study lead-in to the global VERITAC-3 study (NCT05909397) that is evaluating 2 doses of palbo (100 mg and 75 mg) in combination with vepdegestrant 200 mg QD to determine the recommended phase 3 combination to compare with letrozole plus palbo as first-line treatment for ER+/HER2- advanced breast cancer. Citation Format: Erika Hamilton, Rinath Jeselsohn, Sara Hurvitz, Dejan Juric, Hyo Han, Melinda Telli, George Zahrah, Rita Nanda, Yuanyuan Zhang, Weiwei Tan, Elizabeth Duperret, Eric Zhi, Cecile Mather, Anne Schott. Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: phase 1b cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS15-03.

Palliative radiotherapy for painful non-bone lesions in patients with advanced cancer: a single center retrospective study

PurposeThis retrospective study aimed to assess the efficacy and safety of palliative radiotherapy for painful non-bone lesions in patients with advanced cancer.Materials and methodsWe enrolled patients with painful non-bone lesions who underwent conventional palliative radiotherapy between September 2018 and September 2022. The treatment targets included primary tumor lesions, lymph node metastases, non-bone hematogenous metastases, and other lesions. The primary endpoint was the overall pain response rate in evaluable patients, determined based on the International Consensus Pain Response Endpoint criteria. The secondary endpoints included overall survival, pain recurrence, and adverse events.ResultsOf the 420 screened patients, 142 received palliative radiotherapy for painful non-bone lesions, and 112 were evaluable. A pain response was achieved in 67 patients (60%) of the 112 evaluable patients within a median of 1.2 months. Among these patients, 25 exhibited complete response, 42 partial response, 18 indeterminate response, and 27 pain progression. The median survival time was 5.5 months, recorded at a median follow-up of 6.0 months, during which 67 patients died. Multivariate analysis identified poor performance status scores of 2–4, opioid use, and re-irradiation as independent factors associated with a reduced likelihood of achieving a pain response. Pain recurrence occurred in 18 patients over a median of 4.1 months. Seventeen patients had grade 1–2 adverse events, while none experienced grade 3 or higher toxicity.ConclusionPalliative radiotherapy can potentially be a safe and well-tolerated modality for managing painful non-bone lesions, with a low rate of adverse events.

Real-World Evaluation of Teclistamab for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction: Teclistamab (TEC) is a bispecific BCMA-CD3 directed T-cell antibody (BsAb), recently approved by EMA and FDA. Approval was based on the MajesTEC-1 study showing high overall response rates (≥PR in 63.0%) in heavily pretreated patients with relapsed multiple myeloma (RRMM). Few reports have described Real-World experience despite that TEC can induce unique side effects including cytokine release syndrome (CRS), neurotoxicity (ICANS) and a high incidence of infection (MajesTEC-1: incidence 76.4%; ≥Gr3: 44.8%). Thus, we performed a Real-World analysis of TEC therapy from 7 International Myeloma Foundation (IMF) associated MM academic centers. Methods: Patients treated with standard-of-care TEC were included. Data was collected until 7/28/2023. Results: 103 pts were included; median age 63 (range 33-91y); 15 pts. (14.5%) >75 yrs; 56.5% were male, 71.8% Caucasian, 11.6% Hispanic, and 12.6% Asian. Pts received a median of 6 PLT (range 1-16); 75% were triple-class-refractory (n=41/52 (79%), 30/85 (35%) had high-risk cytogenetics/FISH and 32/80 (40%) had 1q21 gain. At least 57/76 (75%) of pts would not have been eligible for MajesTEC-1 (mostly from prior BCMA (n=28 CAR-T, n=14 ADC; n=3 BsAb; n=5 CAR-T+ADC). 14 pts had CrCl <30ml/min with 2 on HD. Median number of hospital days was 8 (n= 72) but 31 patients were treated entirely as outpatients (Mayo clinic (MN, AZ, FL)). CRS was seen in 52 (50.4%) (all grade 1: except 6 Gr2, 1 Gr4), generally resolved within 24 hrs and was managed with tocilizumab alone (n= 27) or dex alone (n=9) or dex+toci (n=12). CRS was more common with inpatient (56.9%) vs outpatient (35.4%) TEC Rx. CrCl <30 ml, did not appear to alter the incidence or severity of CRS (50%; 1 Gr4). ICANS was infrequent (n=5; 4.85%), 1 pt with Gr 4-Sz requiring HD-steroids and TEC discontinuation). Infections were common, seen in 54 (52.4%) of patients, the majority were viral URI or CMV reactivation (n=26; 3 pts receiving CMV Rx, 1 pt with CMV organ disease). IVIG was given in 43/67 (64%) pts. The overall response rate for evaluable patients (n=82) was 63%; (sCR/CR 14; VGPR 23; PR 15; MR 2, SD 14; PD 14). In evaluable pts treated with prior BCMA (n=43), the ORR was 53% (sCR/CR 4; VGPR 14; PR 5; 1 MR; SD 10; PD 9). The most common reason for treatment discontinuation was PD (26.2%). 14 pts have died by the time of data cut-off (7/28/23), with the most common cause of death being disease progression. Conclusions: In this Real-World evaluation of TEC, a high ORR was seen, similar to the MajesTEC-1 study. Responses were rapid and are expected to deepen over time (median f/u 5m). CRS rates were similar to MajesTEC-1 and no new toxicity signal was noted. The rates of infection appear low but may be related to short follow-up. Details regarding the incidence and types of infection and the global use of IVIG will be described. With longer follow-up, additional efficacy/toxicity data will be presented.

Tetramodal therapy with transurethral resection followed by chemoradiation in combination with hyperthermia for muscle-invasive bladder cancer: early results of a multicenter phase IIB study

Background Transurethral resection of bladder tumor (TUR-BT) followed by chemoradiation (CRT) is a valid treatment option for patients with muscle-invasive bladder cancer (MIBC). This study aimed to investigate the efficacy of a tetramodal approach with additional regional hyperthermia (RHT). Methods Patients with stages T2–4 MIBC were recruited at two institutions. Treatment consisted of TUR-BT followed by radiotherapy at doses of 57–58.2 Gy with concurrent weekly platinum-based chemotherapy and weekly deep RHT (41–43 °C, 60 min) within two hours of radiotherapy. The primary endpoint was a complete response six weeks after the end of treatment. Further endpoints were cystectomy-free rate, progression-free survival (PFS), local recurrence-free survival (LRFS), overall survival (OS) and toxicity. Quality of life (QoL) was assessed at follow-up using the EORTC-QLQ-C30 and QLQ-BM30 questionnaires. Due to slow accrual, an interim analysis was performed after the first stage of the two-stage design. Results Altogether 27 patients were included in the first stage, of these 21 patients with a median age of 73 years were assessable. The complete response rate of evaluable patients six weeks after therapy was 93%. The 2-year cystectomy-free rate, PFS, LRFS and OS rates were 95%, 76%, 81% and 86%, respectively. Tetramodal treatment was well tolerated with acute and late G3–4 toxicities of 10% and 13%, respectively, and a tendency to improve symptom-related quality of life (QoL) one year after therapy. Conclusion Tetramodal therapy of T2–T4 MIBC is promising with excellent local response, moderate toxicity and good QoL. This study deserves continuation into the second stage.

A phase Ib/II study (IMMCO-1) of atezolizumab plus tivozanib in immunologically cold pancreatic, gallbladder, and biliary cancers.

TPS491 Background: Checkpoint inhibition (CPI) represents a significant advance in cancer care however it is not effective in the treatment of several immunologically cold tumors including pancreatic, gallbladder, and biliary cancers where checkpoint inhibitors have produced objective response rates of <5%. VEGF is thought to play a key role in modulating the anti-tumor immune response. Secreted by tumors, it leads to endothelial cell proliferation, vascular permeability, and vasodilation that together leads to the development of an abnormal vasculature with excessive permeability and poor blood flow, thus limiting immune surveillance. In addition, VEGF inhibits dendritic cell differentiation, limiting the presentation of tumor antigens to CD4 and CD8 T cells. Through the inhibition of VEGF, it may be possible to potentiate the effect of immune checkpoint blockade. Combined use of a VEGF tyrosine kinase inhibitor (TKI) and checkpoint inhibitor is already standard of care in advanced kidney, cervical and endometrial cancers. There has been suggestion that such a combination may have clinical activity in some microsatellite stable (MSS) GI malignancies. This signal seeking study aims to build upon those observations by incorporating a pan-VEGF axis inhibitor (tivozanib) with CPI. Methods: This is an open-label non-randomized phase Ib/II signal seeking basket study in multiple immunologically cold tumors. The co-primary endpoints are safety and efficacy of the combination of the VEGF-TKI tivozanib and CPI atezolizumab. Key eligibility criteria includes patients with MSS pancreatic, biliary (cholangiocarcinoma and gallbladder), well-differentiated grade 2 and 3 neuroendocrine tumors, ovarian and vulvar cancer, soft tissue sarcoma, castrate resistant prostate cancer, and HER2 positive hormone receptor negative breast cancer, that is metastatic and progressed on at least one line of therapy. Key exclusion criteria will include patients with known mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. The phase Ib portion will assess the safety profile of the combination of tivozanib and atezolizumab with a potential dose de-escalation of tivozanib using a 3+3 study design. Starting doses include tivozanib 1.34 mg per day for 21 days of each 28-day cycle and atezolizumab 1680 mg on day 1 of every 28-day cycle. The phase II portion will enroll up to 26 additional patients using the dose of tivozanib found to be safe in the Ib portion. Disease response assessments are every 12 weeks with CT Chest, Abdomen, and Pelvis via RECIST 1.1. Treatment will continue until progression or intolerance. This signal seeking study is looking to confirm the best objective response rate for evaluable patients increasing from <7% (null hypothesis) to 25% (one-sided alpha = 0.05; 80% power). Active enrollment continues. Clinical trial information: NCT05000294.

Venetoclax 400mg Combined with Bortezomib and Dexamethasone Is Efficacious and Feasible for Plasma Cell Dyscrasia

【Abstract】 Objective: To investigate the efficacy and safety of BCL-2 inhibitor Venetoclax (Ven) 400mg combined with bortezomib and dexamethasone in plasma cell dyscrasia with t(11,14). Methods: The data of twenty patients with plasma cell dyscrasia with t (11;14) were retrospectively analyzed.The majority of patients received Venetoclax 400mg combined with bortezomib and dexamethasone. The baseline clinical information, treatment efficacy and adverse effects after Ven-based regimen. Results: Seventeen multiple myeloma patients, two light-chain amyloidosis and one primary plasma cell leukemia (pPCL) patients were studied. Among seventeen MM patients, the median follow-up was 9.0 (0.5-27) months and the median treatment cycles was 4 (1-12);fourteen patients have been evaluated for response rate. The overall response rate for evaluable patients (ORR) was 85.7%, among that one patient (7.1%) achieved CR, four patients (28.6%) achieved VGPR and 7 (50%) achieved PR. The median progression-free survival (PFS) was11.0 months (95%CI 2.1-19.9); the median Overall survival (OS) was 14.0 months (95%CI 6.9-21.1). Two amyloidosis patients achieved VGPR and PR respectively, while one pPCL patient achieved CR. The most common grade 3 or worse treatment-emergent adverse events were thrombocytopenia (15%), infection (10%), neutropenia (5%), diarrhea (5%) and peripheral neuropathy (5%). There was no treatment-related death. Conclusion Ven (400mg) combined with bortezomib and dexamethasone is feasible, tolerated and efficacious in plasma cell dyscrasia.【Key words】Plasma cell dyscrasia; Venetoclax; Efficacy; Safety DisclosuresNo relevant conflicts of interest to declare.

Preliminary Clinical Response Data from a Phase 1b Study of Mavorixafor in Combination with Ibrutinib in Patients with Waldenström's Macroglobulinemia with MYD88 and CXCR4 Mutations

Preliminary Clinical Response Data from a Phase 1b Study of Mavorixafor in Combination with Ibrutinib in Patients with Waldenström's Macroglobulinemia with MYD88 and CXCR4 Mutations

Isatuximab Rescue for Inadequate Response to Lenalidomide and Dexamethasone in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma: Interim Analysis of the Phase II Iril Study of the Australian Myeloma Research Consortium (AMaRC 18-02)

Isatuximab Rescue for Inadequate Response to Lenalidomide and Dexamethasone in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma: Interim Analysis of the Phase II Iril Study of the Australian Myeloma Research Consortium (AMaRC 18-02)

Phase 2 Trial of Pomalidomide, Ixazomib and Dexamethasone in Patients with Multiple Myeloma with Extramedullary Disease or Plasma Cell Leukemia

Background: Multiple myeloma is typically characterized by clonal expansion of malignant plasma cells within the bone marrow compartment. Presence of extramedullary disease (EMD) either in the form of soft tissue plasmacytoma or circulating plasma cells can be seen at diagnosis but is more common in the relapsed and refractory patients. Presence of EMD is typically associated with a poor prognosis, both in the newly diagnosed and relapsed setting, but trials designed specifically for patients with EMD are sparse. Treatment of EMD can be challenging and the responses even when seen are often short lasting, highlighting the need for developing specific treatment approaches aimed at these patients. Based on initial trials suggesting activity of pomalidomide in the setting of EMD and the increased tissue distribution with the oral proteasome inhibitor ixazomib, we designed this trial to examine if the all oral combination of ixazomib, pomalidomide and dexamethasone can be effective in the setting of EMD. Patients and Methods: Patients with previously treated multiple myeloma, with adequate hematologic and organ function were enrolled if there was evidence, at study entry, of EMD defined as one or more plasmacytomas, outside the bone marrow that were non-contiguous with a bone lesion and had a single diameter of ≥2 cm OR as plasma cell leukemia, with circulating plasma cells > 5% of peripheral blood leukocytes or at least 0.5 X 109/L or 200 cells/150000 events by flowcytometry. Patients were treated on 28-day cycles, with ixazomib 4 mg on days 1, 8, and 15 along with pomalidomide 4 mg PO daily on days 1-21 and dexamethasone 40 milligrams weekly until disease progression or unacceptable toxicity. The goals of the study were to determine confirmed response rate (≥ PR), toxicities of this combination, differential response rates and progression-free survival (PFS). Confirmed response rate, differential response rates and PFS were estimated using Duffy and Santner approach, exact binomial distributions and Kaplan Meier curves, respectively. The study was designed to accrue 30 patients. Results: This study was designed to enroll up to 30 patients but was closed after enrolling 17 patients due to slow accrual. The baseline characteristics are as indicated in Table 1. Eleven patients were enrolled with an extramedullary plasmacytoma while the remaining six patients had plasma cell leukemia. Median number of lines of prior therapy was 3 (range: 1, 7). Overall, 10 (58.8%) patients had progressive disease and 11 (64.7%) patients have died, median (range) follow-up for the live patients is 22.2 (2.1, 37.9) months. Patients were treated for a median of 2 (range 1-34) cycles. A grade 3+ AE, at least possibly attributed, was seen in 53%. Grade 3+, at least possibly related, hematologic toxicity was noted in 41%, with 29% experiencing grade 3+ neutropenia. Notable grade 3+ non-hematologic toxicities (regardless of attribution), with >10% incidence rate were anemia, hypoxia, infections and lung infection. The confirmed response rate in evaluable patients was 35% (1 CRs and 5 PRs), with a 90% CI of 6% - 37%. While 33% (4/12; 95% CI: 1-8%) of patients reported a biochemical response, 40% (2/5; 95% CI: 0-4%) of patients reported an extramedullary response. The median PFS was 4.5 (95% CI: 2-11.8) months. Conclusions: The combination of ixazomib, pomalidomide and dexamethasone resulted in disease response in a third of this group of high-risk patients with EMD; however, the responses were not very durable, with a median PFS of only 4.5 months. The trial highlights the feasibility of doing clinical trials specifically targeted towards this high-risk patient population. Future trials should explore combinations of novel agents, including monoclonal antibodies through multicenter collaborative efforts. Disclosures Kansagra: Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics: Other: Advisory Board. Witzig:Spectrum: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; AbbVie: Consultancy; MorphSys: Consultancy; Celgene: Consultancy, Research Funding. Kumar:Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genecentrix: Consultancy; Carsgen: Other, Research Funding; Cellectar: Other; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Adaptive Biotechnologies: Consultancy; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Sanofi: Research Funding; Tenebio: Other, Research Funding.

A phase I trial a FR alpha targeted thymidylate synthase inhibitor CT900 exploring four schedules of treatment in expansion cohorts of patients with high-grade serous ovarian cancer.

6043 Background: CT900 (BTG945/ONX-0801) is a novel small molecule that binds to folate receptor alpha (FRα), is internalized and causes cytotoxicity by thymidylate synthase inhibition. Methods: The aims of the expansion cohorts were to determine toxicity, response rates and correlation of the response to FRα expression in patients with HGSOC (NCT02360345). Four expansion cohorts were studied which included: schedule A (6 mg/m2/q every 2 weeks), schedule B (12 mg/m2/q every 2 weeks), schedule C (12 mg/m2/q every 2 weeks with 12 mg dexamethasone IV and 8 mg of dexamethasone for 2 days) and schedule D (12 mg/m2/q every 3 weeks). Response rates were assessed by RECIST V1.1 and GCIG CA125 response criteria. Patients who were withdrawn for reasons other than toxicity within 8 weeks (cohorts A, B, C) and 12 weeks (cohort D) were not assessable for efficacy. FRα expression was quantified using immunohistochemistry. Results: A total of 67 patients were treated in the 4 cohorts (14, 25, 15 and 13 for cohorts A, B, C and D). The median age was 62 (IQR 57 - 68) and the median lines of previous treatment was 5 (range 1 to 13). A majority of patients were platinum resistant. The most common toxicities across all expansion cohorts were: fatigue (51%), nausea (36%), anemia (27%), fever (25%), AST elevation (21%), most of which were grade 1 - 2. Toxicity of special interest included radiological changes of pneumonitis and was 15% in all cohorts (7%, 16%, 27% and 8% in cohorts A, B, C and D, respectively). These changes were grade 1 - 2 in all but one case. RECIST response rates in evaluable patients across the different cohorts were: A 1/8 (13%), B 6/21 (29%), C 5/12 (42%) and D 2/12 (17%). FRα expression in archival tumor tissue was measured in 59/67 patients. Expression was found to be high/medium in 43/59 (73%), low in 7/59 (12%) and negative/very low in 9/59 (15%). In patients with high/medium FRα expression, the RECIST response rates in different cohorts were: A 0/9 (0%), B 6/16 (38%), C 4/12 (33%) and D 1/6 (17%). The CA125 response rate in all patients within cohort B was 13/25 (52%) and 10/16 (63%) in patients with high/medium FRα expression. Conclusions: CT900 has shown clinical activity in patients with heavily pre-treated platinum-resistant, high/medium FRα expressing HGSOC. Based on toxicity and efficacy, the schedule of 12 mg/m2/q2 weekly (schedule B) is the recommended phase II dose for further evaluation in patients with relapsed high/medium FRα expressing HGSOC. Clinical trial information: NCT02360345.

Characterization of Viral Epitopes and the HLA Restriction That Govern Anti-Adenoviral Response to Viral Specific T-Lymphocyte Therapy in a Pediatric Cohort

<h3>Introduction</h3> Adenoviral (AdV) infections are common after HSCT and are a major cause of complications. Antiviral medications are frequently ineffective and toxic. At CCHMC, viral specific T cells (VST) from 3^rd party donors are generated by pulsing peripheral blood mononuclear cells (PBMCs) with viral peptide pools (pepmix). The choice of VST product for each patient is based on pre-clinical evidence of anti-AdV activity and the degree of HLA match as the viral epitopes and HLA restriction driving this response remain poorly understood. <h3>Objective</h3> The focus of this study is to characterize the HLA restriction of the AdV response in our VST bank. <h3>Methods</h3> Epitope prediction for AdV hexon and penton was done with free software (HLA restrictor 1.2 and IEDB) in conjunction with published data. 20 9mer to 15mer peptides were synthesized. VSTs were pulsed with peptides based on the HLA haplotype of the product and activity was evaluated using FACS for intracellular interferon gamma (IFNg). Post-infusion analysis was performed using peptide pulsed PBMC followed by IFNg ELISpot. HLA restriction was confirmed using co-culture of VST with a set of mouse fibroblasts expressing a single HLA allele (SALs) loaded with AdV pepmix. <h3>Results</h3> We have characterized 93 VST products and identified that 60/93 (65%) products have AdV activity <i>in vitro</i>. 20 patients have received VST for AdV with a 75% response rate in evaluable patients. A response against at least one AdV peptide has been demonstrated in 12/13 assessed products (4 of which have been infused into patients), and a polyclonal response was seen in 6/12 products (Fig 1). PBMC from 4 VST recipients were probed with the same AdV peptides that had stimulated a response in their respective VST products. In 3/4 recipients there was a response to the same peptides post-infusion as observed in the VST product, confirming <i>in vivo</i> activity (Fig 2). To discern HLA restriction, AdV pepmix was loaded onto class II HLA SALs and then co-cultured with 4 VST products expressing those same class II alleles. Anti-ADV activity was identified for specific class II HLA for all products, confirming the antiviral response in each product is restricted differentially for distinct HLA alleles. In retrospective analysis of one case, a patient with poor clinical response was found to have received a product restricted largely through DRB1*03:01, which was not a site of HLA match, rather than at the matched site of DRB1*04:01 (Fig 3). <h3>Conclusions</h3> Robust methods can be used to characterize the viral epitopes driving anti-AdV activity of VST products and the subsequent HLA restriction of that response. Response is frequently polyclonal and to some degree restricted through HLA class II antigens. While our sample is small, we propose that prospective adoption of these methods, especially the use of SALs as an initial screen, may allow for more precise VST product selection with improved response rates.

Safety and Efficacy of Combined Ruxolitinib and Thalidomide in Patients with Myelofibrosis: A Phase II Study

Safety and Efficacy of Combined Ruxolitinib and Thalidomide in Patients with Myelofibrosis: A Phase II Study

P14.45 Primary diffuse large B-cell CNS lymphoma over 80 years: an analysis of 110 patients from the french Oculo-Cerebral Lymphoma (LOC) network

Abstract BACKGROUND in large unselected series, the median age of Primary CNS Lymphoma (PCNSL) patients (pts) is about 70 years. In one USA cancer registry study for PCNSL patients older than 65 years, 14% of them are older than 80 years. Data on clinical characteristics, therapeutical management, toxicity of treatment and outcome of these very elderly pts are limited. MATERIAL AND METHODS we reviewed PCNSL pts aged of 80 years or older included in the database of the French Oculo-Cerebral lymphoma (LOC) network. From January 2011, this network prospectively recorded all newly diagnosed PCNSL from 22 regional expert centers in France. RESULTS 110 pts with a DLBCL PCNSL aged of 80 years or older were diagnosed between January 2011 and January 2018 representing 8% of pts available in the LOC database. The clinical characteristics were as follows: 63% of females; median age: 83y (80–92); performance status (PS) ≥3, 55% of pts. Median creatinine clearance (CKD.EPI) was 70ml/min. Treatment was initiated either by a neuro-oncology or a hematology team in 35% and 65% of cases, respectively. First line treatment was high-dose (HD) methotrexate (MTX) based chemotherapy (CT) in 85 pts (77%), other chemotherapy regimen in 13 pts (12%) and palliative care in 12 pts (11%). Interestingly, no difference of distribution for the main clinical and biological characteristics was observed between these three groups. After first-line induction chemotherapy, response rate for evaluable patients (n=85) were as follows: 37% of complete response, 9% of partial response, 54% of stable or progressive disease. Rituximab was used in combination with CT in 53/98 treated pts (54%). For toxicity, among the 351 infusions performed for the 85 pts who received MTX-based CT, grade 3–4 toxicities were: 46% of any events, 15% of infection, 13% of cytopenia, 11% of acute renal failure and 8% of elevated liver enzymes. 13% of pts presented toxic death. Median progression free survival (PFS) and overall survival (OS) were 5 months and 8 months, respectively. Pts treated with MTX-based CT had a significantly prolonged PFS and OS. In the univariate analysis performed for the 85 pts treated with MTX-based CT, no initial clinical and biological influenced PFS or OS. Intravenous rituximab used in first line therapy significantly improved PFS and OS. CONCLUSION in this large series of consecutive PCNSL pts aged of 80y or over prospectively recorded in a national database, we showed that the prognosis remains poor with major toxicity under conventional treatment. No clinical predictor of survival was highlighted in our series. Patients initially treated with MTX-based CT in combination with rituximab had an improved outcome. The development of target and innovative therapies is needed for this category of patients representing 8% of all PCNSL in the database of the LOC network.​

Primary Diffuse Large B-Cell CNS Lymphoma over 80 Years: An Analysis of 110 Patients from the French Oculo-Cerebral Lymphoma (LOC) Network

Introduction: in large unselected series, the median age of Primary CNS Lymphoma (PCNSL) patients (pts) is about 70 years. In one USA cancer registry study for PCNSL patients (pts) older than 65 years, 14% of them are older than 80 years. Data on clinical characteristics, therapeutical management, toxicity of treatment and outcome of these very elderly pts are limited.Methods: We reviewed PCNSL pts aged of 80 years or older included in the database of the French Oculo-Cerebral lymphoma (LOC) network. From January 2011, this network prospectively recorded all newly diagnosed PCNSL from 22 regional expert centers in France. For this study, 110 PCNSL pts with a histological diagnosis of diffuse large B-cell lymphoma (DLBCL) aged of 80 years or older were analyzed. All medical records were reviewed for clinical and biological characteristics, modality of treatment and supportive care, toxicities and outcome.Results: 110 pts with a DLBCL PCNSL aged of 80 years or older were diagnosed between January 2011 and January 2018 representing 8% of pts available in the LOC database. The clinical characteristics were as follows: 63% of females; median age: 83y (80-92); performance status (PS) according to EORTC scale: 1, 24% of pts, 2, 21% of pts, 3-4, 55% of pts. 23.6% of pts had a CIRS-G grade 3 or 4 in at least one category and 40.9% had a cumulative CIRS-G score more than 6. Diagnosis procedure was biopsy (87%), tumor resection (5%), vitrectomy (4%), CSF cytology (4%). At diagnosis, 9/68 (13%) of evaluable pts had ocular involvement, 13/61 (21%) cerebrospinal (CSF) involvement, 79/110 (72%) involvement of the deep structures of the brain and 35/86 (41%) had elevated LDH level. Median creatinine clearance (CKD.EPI) was 70ml/min (min: 24, max: 102). Treatment was initiated either by a neuro-oncology or a hematology team in 35% and 65% of cases, respectively. Median delay between first symptoms and treatment was 60 days. First line treatment was high-dose (HD) methotrexate (MTX) based chemotherapy (CT) in 85 pts (77%), other chemotherapy regimen in 13 pts (12%) and palliative care in 12 pts (11%). Median number of CT cycles was 3 (1-11) with a median dose of MTX of 3g/m2 (0.5-5.0). Interestingly, no difference of distribution for the main clinical and biological characteristics (median age, PS, symptoms, tumor localization, albumin level, creatinine clearance) was observed between these three groups. Rituximab was used in combination with CT in 53/98 treated pts (54%). After first-line induction chemotherapy, response rate for evaluable patients (n=85) were as follows: 37% of complete response, 9% of partial response, 54% of stable or progressive disease. Finally, 27 pts (32%) received consolidation treatment with high-dose cytarabine after MTX-based CT. For toxicity, among the 351 infusions performed for the 85 pts who received MTX-based CT, grade 3-4 toxicities were: 46% of any events, 15% of infection, 13% of cytopenia, 10.5% of acute renal failure and 8% of elevated liver enzymes. 13% of pts presented toxic death. Median progression free survival (PFS) and overall survival (OS) were 3.9 months and 7 months, respectively. Pts treated with MTX-based CT had a significantly prolonged PFS and OS as compared to patients treated without MTX or with palliative care (Figure 1A, 1B). In the univariate analysis performed for the 85 pts treated with MTX-based CT, no initial clinical and biological characteristics (age, PS, type of symptoms, CIRS-G, tumor localization, LDH level, albumin level, hemoglobin level, lymphocyte count, creatinine clearance) influenced PFS or OS. The initial dose of MTX did not influence outcome but intravenous rituximab used in first line therapy significantly improved PFS and OS (Figure 1C, 1D).Conclusions: to the best of our knowledge, this is the largest series of consecutive PCNSL pts aged of 80y or over prospectively recorded in a national database. This study showed that the prognosis remains poor with major toxicity under conventional treatment. No clinical predictor of survival was highlighted in our series but patients initially treated with MTX-based CT in combination with rituximab had an improved outcome. The development of target and innovative therapies is needed for this category of patients representing 8% of all PCNSL in the database of the LOC network. [Display omitted] DisclosuresHouot:Celgene: Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Novartis: Honoraria.

Strontium-89 Chloride Delivery for Painful Bone Metastasis in Patients with History of Previous Radiation

Re-irradiation of previously irradiated site must be done with careful consideration to minimizing dose to organs at risk. In particular, re-irradiation of the spine carries significant morbidity due to risk of myelitis. Strontium-89 chloride (Sr-89) is widely used for treatment of painful bone metastasis. The purpose of this study is to evaluate pain response and safety of Sr-89 administration for painful bone metastasis in the setting of prior radiation. After institutional review board approval, records of patients who received Sr-89 injection for painful bone metastasis in previously irradiated sites were retrospectively reviewed. Patients with follow-up of less than 1 month were excluded from analysis. Efficacy of pain control was evaluated with the verbal rating scale (VRS), documentation of the analgesic dose employing the World Health Organization (WHO) pain relief ladder. Adverse events were measured using CTCAE v4.0. Twenty-three patients met study inclusion criteria, of which 12 were male and 11 were female. Median age at treatment was 69 years (50-83). Primary sites were lung (n=11), prostate (n=3), breast (n=2), uterine cervix (n=2), kidney (n=1), and other (n=4). Median follow-up was 8 (1-49) months. Twelve patients treated with SR-89 had prior history of palliative radiation therapy for bone metastasis. The remainder had received radiation for non-bony metastasis as follows: concurrent chemo-radiotherapy (CCRT) for lung cancer (n=7), post-operative radiotherapy to regional lymph nodes of breast cancer (n=1), pre-operative CCRT for rectal cancer (n=1), radical CCRT for cervical cancer (n=1), and radiotherapy to tumor bed for recurrent prostate cancer (n=1). Prior to administration of Sr-89, the VRS grade of 0/1/2/3 was n=1/5/12/5, respectively. Analgesic score 0/1/2/3/4/5/6 was n=3/9/2/4/3/1/1, respectively. After administration of Sr-89, VRS grade didn’t change in 3 patients, and improved in 20; 17 occurred after 1 month, 2 after 2 months, and 1 after 3 months. Analgesic score didn’t change in 15 but improved in 8 patients; 4 after 1 month, 2 after 2 months, 2 after 3 months. In two patients neither the VRS nor the analgesic score improved and in two patients the VRS improved but the analgesic score increased, hence difficult to evaluate efficacy of SR-89. This made the response rate of evaluable patients 90.1%. Flare phenomenon was observed in 3 patients, but all were controlled with analgesic and improved within one week. No grade 2 or worse adverse events was observed. Administration of strontium-89 chloride to patients with painful bone metastasis at previously irradiated sites is an effective and safe treatment options for palliation of symptoms at the end of life.

Impact of exon 19 versus exon 21 EGFR-activating mutation on outcomes with upfront pemetrexed-carboplatin chemotherapy.

BackgroundEGFR mutation subtype is a recognised factor impacting outcomes of patients receiving oral tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Evidence for the effect of this factor on outcomes in patients receiving pemetrexed is limited.MethodsWe completed a study comparing pemetrexed–platinum combination versus oral TKI in EGFR mutation-positive patients in lung cancer. We analysed the impact of EGFR mutation subtype, specifically, exon 19 and 21 on the PFS and OS of patients treated with pemetrexed (500 mg/m2 on day 1) and carboplatin (AUC 5 on day 1) as first-line therapy. Patients underwent axial imaging for response assessment on D42, D84, D126 and subsequently every two months till progression. Patients post-progression were treated with gefitinib.ResultsFifty-one patients (36%) had exon 21 mutation, while 92 patients (64%) had exon 19 mutation. Response rates in evaluable patients was 47.7% in exon 19 patients (41 patients, n = 86) and 42.9 % in exon 21 patients (18 patients, n = 42). There was a significant increase in median overall survival for patients with exon 19 mutations (24.5 months, 95% CI: 21.3–27.7 months ) over the exon 21-mutated patients (18.1 months, 95% Cl: 13.5–22.6 months, p = 0.002). This differential impact was due to second-line gefitinib having a differential outcome on these mutations.ConclusionPemetrexed-based chemotherapy does not have a differential impact on exon 19- or exon 21-mutated patients. However, second-line treatment with gefitinib has a favourable response and outcome in exon 19-mutated patients.

Efficacy of Second-Line Pemetrexed-Carboplatin in EGFR-Activating Mutation-Positive NSCLC: Does Exon 19 Deletion Differ from Exon 21 Mutation?

Background It is unknown whether the outcomes of second-line pemetrexed-carboplatin chemotherapy administered after progression on gefitinib are dependent on type of EGFR mutation present at baseline. Method Adult non-small-cell lung cancer patients, with exon 19 deletion or exon 21 L858R mutation, who progressed on gefitinib and received pemetrexed-carboplatin chemotherapy were selected for this analysis. Result 55 patients received pemetrexed-carboplatin as second-line treatment. Response rates in evaluable patients were 39.3% in exon 19 patients (n = 28) and 33.3% in exon 21 patients (n = 15) (p = 0.752, Fisher's exact 2-sided p value). The median PFS in exon 19 and 21 cohorts was 5.900 months (95% CI: 4.274–7.526) and 4.767 months (95% CI: 1.374–8.159), respectively. The median overall survival in exon 19 patients was (11.8 months, 95% CI: 9.916–13.684 months) significantly better than that seen in exon 21 mutation patients (6.2 months, 95% CI: 4.215–8.118 months, p = 0.024) on univariate analysis; however, on multivariate analysis, this association was not confirmed (HR = 0.361, 95% CI: 0.090–1.439, p = 0.149). Conclusion Exon 19 deletion has no impact on PFS and OS in EGFR-mutated patients treated with second-line pemetrexed-carboplatin.

Clinical factors associated with AR-V7 detection in ARMOR3-SV, a randomized trial of galeterone (Gal) vs enzalutamide (Enz) in men with AR-V7+ metastatic castration-resistant prostate cancer (mCRPC).

5005 Background: Presence of the AR-V7 splice variant may predict resistance to Enz and abiraterone in men with mCRPC. Gal is an oral agent that disrupts AR signaling via AR degradation, CYP17 lyase inhibition, and AR antagonism. ARMOR3-SV was designed to test the hypothesis that in mCRPC patients with AR-V7+ CTCs, Gal could improve radiographic progression-free survival (rPFS) versus Enz. Methods: In this randomized, open-label, multicenter phase 3 study (NCT02438007), men with treatment-naïve mCRPC were screened for CTC-specific AR-V7 (Qiagen), and AR-V7+ men were randomized 1:1 to Gal or Enz. rPFS (by independent blinded central review) was the primary endpoint. Planned sample size was 148, with 120 rPFS events to achieve 90% power to detect a hazard ratio of ≤0.55. Results: 953 patients were screened globally for AR-V7 from Sept 2015 through study closure; 73 men (8%; 95% CI 6-10%) were AR-V7+, 250 (26%) AR-V7–, and 630 (66%) had no CTCs/AR present (unevaluable). AR-V7 detection was associated with higher PSA levels ( &gt; vs &lt; median; P &lt; 0.01), more bone metastases ( &gt; 20 vs 11-20 vs 6-10 vs 0-5; P &lt; 0.01), presence of M1 disease at diagnosis (dx) (yes vs no; P = 0.04), shorter time from dx to screening ( &lt; vs &gt; median; P &lt; 0.01), higher ECOG (≥1 vs 0; P = 0.02), prior antiandrogen use (yes vs no; P &lt; 0.01) and prior docetaxel use (yes vs no; P &lt; 0.01). Among the AR-V7+ men, 38 were randomized (19 Gal, 19 Enz), 31 screen failed, and 4 were discontinued from screening at study halt. Baseline characteristics were balanced. On the recommendation of the DSMB, the study was closed early as it was unlikely to meet its primary endpoint. At the time of the study closure, in the Gal and Enz arms respectively, median time on therapy was 2.0 vs 2.8 mo, median time to PSA progression (PCWG1) was 3.9 vs 3.8 mo, PSA50 response rates in evaluable patients were 2/16 (13%) and 8/19 (42%), and there were no new safety signals. Conclusions: In treatment-naïve mCRPC patients, AR-V7 detection is more common in men with higher disease burden and portends a poor prognosis. Novel study designs and alternative treatment approaches are urgently needed for AR-V7+ mCRPC patients. Clinical trial information: NCT02438007.

P3.02b-055 Impact of Pemetrexed Chemotherapy in Exon 19 or Exon 21 Mutated NSCLC: Topic: EGFR Clinical

EGFR mutation subtype is being increasingly recognized as factor impacting outcome of patients receiving oral TKI in non-small cell lung cancer. Data for the effect of this factor on the outcome in patients receiving chemotherapy is limited. We have the post hoc analysis of the study at our center to answer this question. We completed a study comparing pemetrexed with platinum vs. oral TKI in EGFR mutation positive patients in lung cancer. We analyzed the impact of EGFR mutation subtype, exon 19 and 21 on the PFS and OS of patients treated with pemetrexed (500mg/m2 on day 1) and carboplatin (AUC 5 on day 1) as first line therapy every 21 days. Patients underwent axial imaging for response assessment on D42, D84, D126 and subsequently every 2 months till progression. Responding or stable patients were treated until progression or unacceptable toxicity (post 6 cycles, patients were offered maintenance pemetrexed every 21 days). 143 patients received pemetrexed based therapy as first line treatment for stage III/IV NSCLC in the chemotherapy arm. 51 patients (36%) had exon 21 mutation while 92 patients (64%) had exon 19 mutation. Response rates in evaluable patients was 47.7% in exon 19 patients (41 patients, n=86) and 42.9 % in exon 21 patients (18 patients, n=42). There was a differential impact of EGFR mutation on PFS (p=0.028, HR=1.787, 95% CI 1.066- 2.998) in favor of exon 19 mutation. They also had a significant increase in median overall survival (24.5 months, 95% CI 21.3-27.7 months ) over the exon 21 mutated patients (18.1 months,95% Cl 13.5-22.6 months, p=0.002). In this study, EGFR exon 19 mutation had a differential impact on both PFS and OS in Indian patients of advanced-stage NSCLC treated with chemotherapy.

A Matched-Pair Analysis of EPOCH Versus CHOP As Frontline Therapy for Nodal Peripheral T-Cell Lymphoma, Excluding ALK-Positive Anaplastic T-Cell Lymphoma: A Multicenter Experience in Thailand

BACKGROUNDNodal peripheral T-cell lymphomas (PTCLs), except ALK-positive anaplastic large cell lymphoma (ALCL) have inferior outcomes compared with their B-cell counterparts. CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone) is considered the standard therapy despite consistent results showing its ineffectiveness. The addition of etoposide (E) to chemotherapy showed encouraging results in selected subgroups of patients. We performed a matched-pair analysis comparing the efficacy of EPOCH to CHOP for untreated patients with nodal PTCLs, excluding ALK-positive ALCL.PATIENTS AND METHODSAccording to the Thai Lymphoma Study Group uniform treatment project, 58 patients with nodal PTCLs including angioimmunoblastic lymphoma, ALK-negative ALCL and PTCL, not otherwise specified received conventional EPOCH regimen as frontline therapy between January 2009 and December 2015. These patients were matched to 58 patients receiving CHOP (1:1) in multicenter registry of lymphoma in Thailand between 2007-2014 by center, International Prognostic Index (IPI) and age. Patients who underwent upfront autologous stem cell transplantation (ASCT) were censored at the time of transplantation.RESULTSThe baseline characteristics were well balanced between the two groups except a higher proportion of patients with ALK-negative ALCL in EPOCH group (24.1% vs 5.2%) (Table 1). The median cycle of chemotherapy was 6 (range, 1-8) in both groups. Four patients (6.9%) underwent upfront ASCT after EPOCH induction. The overall response rate for evaluable patients were 75.4% (complete response [CR] 57%) and 58% (CR 39%) in EPOCH and CHOP groups, respectively (P<0.0001). With a median follow up of 26 months, 4-year progression free survival (PFS) were 45.8% and 26.7% in EPOCH and CHOP group, respectively (P=0.022) (Figure 1). Projected overall survival (OS) at 4 years were 50.9% and 28.7% for EPOCH- and CHOP-treated patients, respectively (P=0.001) (Figure 2). By multivariate analysis, chemotherapy regimen was the only factor independently predicting PFS (Hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.04-3.19, P=0.034) and OS (HR 2.26, 95% CI 1.28-3.97, P=0.005).CONCLUSIONEPOCH provided superior outcomes than CHOP regimen as frontline therapy for patients with nodal PTCLS, excluding ALK-positive ALCL. The promising efficacy of EPOCH warrants further evaluation in prospective randomized controlled study. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.