Prior Lines Of Systemic Therapy Research Articles

Abstract PS4-25: Comprehensive genomic analysis reveals molecular correlates of response to immune checkpoint inhibitors (ICI) in metastatic triple-negative breast cancer (mTNBC)

Abstract Background: Genomic mechanisms associated with response to ICI in mTNBC are largely unknown. The aim of this work is to assess the genomic and immune profiles of mTNBC samples collected from patients (pts) treated with ICI. Methods: We identified 31 women with mTNBC treated with ICI (pembrolizumab, n=6, NCT02447003; atezolizumab, n=4, NCT01375842; nivolumab + cabozantinib, n = 6, NCT03316586; pembrolizumab + eribulin, n=8, NCT02513472; atezolizumab + nab-paclitaxel, n=7, NCT01633970) who had tumor tissue or blood available for sequencing obtained before and after ICI. Clinical benefit (CB), here defined as any objective response or stable disease (SD) for > 24 weeks, was observed in 20 pts (65%). An extraordinary responder was defined as having CB ≥ 2 yrs; 5 pts were considered extraordinary responders (range 26-60months). Whole exome sequencing (WES) was done on each tumor and on germline DNA from blood (23 pts had successful WES performed on samples collected before ICI; 5 of these had WES on samples taken after disease progression). RNA sequencing (RNAseq) was successfully performed in 18 of the tumors with WES performed on samples before ICI; and 3 of these had RNAseq on samples taken after disease progression. 18 pts had tumors assessed by multiplex immunofluorescence (mIF) panels encompassing CD4, CD8, PD-1, PD-L1, and cytokeratin on samples collected before ICI. WES, deep targeted panel and low coverage whole genome sequencing were performed on serially collected plasma samples from 22 pts to evaluate tumor fraction and specific mutations. The association between biomarkers and clinical benefit to ICI was assessed. Results: 21 of 31 pts (67%) had received ≥1 prior lines of systemic therapy in the metastatic setting before starting ICI. Among the most frequently mutated genes at baseline are: TP53 (57%); PIK3CA (18%); DNAH5, MYH8 (both 13%); KMT2C, AKT1, LAMA2 (all 9%). Pts with CB had a higher tumor mutational burden (TMB) than pts with no CB (p=0.018). Differential expression analysis of RNAseq data revealed an upregulation of several immune-related genes in pts with CB, indicating increased immune infiltration in that group. Gene set enrichment analysis of this expression data using hallmark and canonical pathway gene sets from MSigDB (nominal p-val < 0.05) showed that, compared to samples from pts without CB, extraordinary responders had elevated transcriptional signatures of several cancer-related pathways associated with cell survival, proliferation and metabolism, as well as genes associated with increased immune infiltration and upregulation of inflammatory response programs. The mIF showed that the tumor microenvironment (TME) of pts with CB were enriched in Cytokeratin-negative/PD-L1-positive cells compared to those without CB (p=0.014). Expression of CD4, CD8 and PD-1 was not significantly different between pts with and without CB. Genomic analysis of circulating tumor DNA, and tumor evolutionary analysis for pts with both pre- and post-ICI samples (acquired resistance) will be presented. Conclusions: Clinical benefit to ICI in mTNBC was associated with upregulation of immune-related pathways, enrichment of non-tumoral PD-L1-positive cells in TME, and high TMB. Citation Format: Romualdo Barroso-Sousa, Juliet Forman, Zachary T. Weber, Katherine Collier, Katrina Z. Kao, Edward T. Richardson, III, Tanya Keenan, Ofir Cohen, Michael P. Manos, Ryan C. Brennick, Patrick Ott, F. Steve Hodi, Deborah A. Dillon, Nancy U. Lin, Eliezer E. Van Allen, Scott Rodig, Eric P. Winer, Elizabeth A. Mittendorf, Catherine J. Wu, Daniel Stover, Nikhil Wagle, Sachet Shukla, Sara Tolaney. Comprehensive genomic analysis reveals molecular correlates of response to immune checkpoint inhibitors (ICI) in metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-25.

Phase I study of BI 754091 plus BI 754111 in Asian patients with gastric/gastroesophageal junction or esophageal cancer.

212 Background: Dual blockade of immune checkpoint molecules, PD-1 and LAG-3, has been proposed to restore T-cell function and thus enhance antitumor responses. This Phase I trial evaluated BI 754091 (anti-PD-1) with BI 754111 (anti-LAG-3) antibodies in Asian pts with advanced solid tumors (NCT03433898). Here, we present results from pts with anti-PD-(L)1 inhibitor-naïve gastric/gastroesophageal junction or esophageal cancer (Cohorts A and B). Methods: In Parts 1 and 2 (dose escalation), the recommended dose for the combination was determined as BI 754091 240 mg + BI 754111 600 mg IV Q3W. In Part 3, the combination was assessed in expansion cohorts including pts with gastric/gastroesophageal junction cancer (Cohort A) and esophageal cancer (Cohort B). Eligible pts had received ≥1 line of prior systemic therapy but no prior anti-PD-(L)1 therapy. The primary endpoint in Part 3 was objective response (OR; confirmed complete response or partial response [PR]) per RECIST 1.1. Results: In Cohort A/B, 36/37 pts were treated:26/31 (72/84%) male, median age 60/63 years. Patients were enrolled in Taiwan (1/7 pts, 3/19%), Japan (12/27 pts, 33/73%) or Korea (23/3 pts, 64/8%). The median number of regimens of prior systemic therapy was 2/2 (Cohorts A/B, range: 1–6/1–4). All pts in Cohort B had squamous cell carcinoma. At the time of analysis, pts in Cohort A/B had undergone a median of 84/73 days on treatment (range: 31–346/8–325), from the start of treatment until the date of snapshot, death or discontinuation. Confirmed OR (PR) was observed in 4/7 pts in Cohorts A/B; overall response rate (ORR) was 11% and 19%. Stable disease (SD) was observed in 10/8 (28/22%) pts in Cohorts A/B and overall disease control rate was 39/41%. In Cohorts A/B, adverse events (AEs) and treatment-related AEs were experienced by 30/34 (83/92%) and 12/22 (33/59%) pts, respectively. The most commonly reported AEs were pyrexia (25/19%), decreased appetite (17/19%), increased aspartate aminotransferase (11/14%), anemia (11/11%) and nausea (6/14%). In Cohort A/B, 9/15 (25/41%) pts experienced immune-related AEs, most commonly rash in Cohort A (4 pts; 11%) and hyperthyroidism in Cohort B (4 pts; 11%). In Cohorts A/B, 2/6 (6/16%) patients experienced AEs leading to discontinuation of treatment. Conclusions: Treatment was well tolerated and preliminary antitumor activity was seen. Addition of LAG3 did not improve ORR beyond that expected for an anti-PD-1 monotherapy in gastric and esophageal cancer without patient selection. Clinical trial information: NCT03433898. [Table: see text]

Real-world assessment of response to anti-programmed cell death 1 therapy in advanced cutaneous squamous cell carcinoma

Real-world assessment of response to anti-programmed cell death 1 therapy in advanced cutaneous squamous cell carcinoma

Novel risk scoring system for metastatic renal cell carcinoma patients treated with cabozantinib

BackgroundCabozantinib is an effective treatment for metastatic renal cell carcinoma (mRCC). The international mRCC database consortium (IMDC) criteria is the gold standard for risk stratification in mRCC. We created a risk scoring system specific for mRCC patients treated with cabozantinib. MethodsWe conducted a retrospective review of 87 patients with mRCC treated with cabozantinib at Winship Cancer Institute from 2015 to 2019. Overall survival (OS) and progression free survival (PFS) were used to measure clinical outcomes. Upon variable selection in multivariable analysis (MVA), elevated baseline monocyte-to-lymphocyte ratio (MLR), sarcomatoid histologic component, ECOG PS > 1, and absence of bone metastases were each assigned 1 point. A three-group risk scoring system was then created: low (score=0–1), intermediate (score=2), and high risk (score=3–4). The Cox proportional hazard model and Kaplan-Meier method were used for survival analyses. ResultsThe median age was 62 years-old and the majority were males (71%) with clear-cell RCC (75%). Most (67%) received at least 1 prior line of systemic therapy. High risk and intermediate risk pts had significantly shorter OS (high risk HR: 13.84, p<0.001; intermediate risk HR: 3.50, p = 0.004) and PFS (high risk HR: 7.31, p<0.001; intermediate risk HR: 1.87, p = 0.053) compared to low risk patients in MVA. ConclusionsRCC patients treated with cabozantinib may benefit from specific risk stratification criteria using RCC histology, ECOG PS, sites of metastatic disease, and MLR. These variables are easily accessible in the clinical setting and may be helpful to determine which mRCC patients may benefit from treatment with cabozantinib.

Pharmacological characteristics and clinical study results of Pemigatinib (Pemazyre® Tablets), a selective fibroblast growth factor receptor (FGFR) inhibitor

Pemigatinib (Pemazyre® Tablets 4.5 mg) is a novel fibroblast growth factor receptor (FGFR) inhibitor, created by Incyte Corporation. The product was approved in March 2021 and was launched in June 2021 for the treatment of patients with locally advanced or metastatic biliary tract cancer (BTC) with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that has progressed after at least one prior line of systemic therapy. Pemigatinib was shown to selectively inhibit kinase activity of FGFR1～3 (IC50; 0.39～1.2 nM). In cultured cells, pemigatinib inhibited the phosphorylation of FGFR1 and its downstream signals, ERK1/2 and STAT5 in a concentration-dependent manner. Pemigatinib also potently inhibited the growth of various types of cell lines with FGFR 1～3 gene alteration. Pemigatinib was shown to induce concentration-dependent tumor regression in a tumor xenograft model mice in which tumor tissue sections from patients with cholangiocarcinoma (CCA) harboring FGFR2 gene fusions were transplanted. Pemigatinib was well tolerated in Japanese and overseas Phase1 studies (INCB 54828-101 and 202). In the global phase2 study (INCB 54828-202) conducted in CCA patients with FGFR2 gene fusions or rearrangements, significant improvement in the overall response rate was observed. Although several adverse reactions were observed which was based on the mechanism of action of pemigatinib, the safety profile and management of the adverse reactions were favorable. Pemigatinib is expected to contribute to second-line drug treatment after failure of standard therapies in biliary tract cancer.

A Phase 1b Study to Evaluate the Safety and Efficacy of Durvalumab in Combination With Tremelimumab or Danvatirsen in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

BackgroundDespite recent advances, outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) remain poor. Immune checkpoint inhibitors have shown limited efficacy in this setting, but combinations with novel agents may enhance benefit. Combination therapy with durvalumab, an anti–programmed death ligand 1 (PD-L1) antibody, and danvatirsen (AZD9150; an antisense oligonucleotide inhibiting signal transducer and activator of transcription 3 [STAT3]) or tremelimumab (an anti–cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4] antibody) may augment endogenous antitumor activity. Patients and MethodsIn this phase 1b dose escalation and dose expansion study, we evaluated durvalumab 20 mg/kg every 4 weeks plus either tremelimumab 1 mg/kg every 4 weeks or danvatirsen 2 or 3 mg/kg (administered on days 1, 3, 5, 8, 15, and 22, then every week). Treatment continued until disease progression. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. ResultsAs of April 4, 2019, 32 patients were enrolled and treated, receiving a median of 2 prior lines of systemic therapy. Treatment-related adverse events occurred in 21 patients (65.6%), most commonly alanine aminotransferase/aspartate aminotransferase increased (grade 1-3), anemia (grade 1-3), and fatigue (grade 1). The overall objective response rate was 6.3%, with 2 partial responses. Median time to response was 11.0 weeks (range, 7.7-14.3 weeks). Median progression-free survival was 7.4 weeks (range, 0.1-31.4 weeks), and median overall survival was 28.0 weeks (range, 1.9-115.4 weeks). ConclusionThe primary endpoint was met, with durvalumab plus tremelimumab/danvatirsen generally well tolerated in patients with relapsed/refractory DLBCL; however, antitumor activity was limited.

A Phase 2, Open-Label, Multicenter Study of Tazemetostat in Combination with Rituximab for the Treatment of Relapsed or Refractory Follicular Lymphoma

Background: Patients with follicular lymphoma (FL) who do not achieve a response after 2 or more prior lines of systemic therapy have a poor prognosis when treated with salvage chemotherapy alone or PI3K inhibitors. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that supports germinal center (GC) formation and suspends differentiation during B-cell development by silencing genes that limit proliferation and promote exit from the GC. Throughout the pathogenesis of FL, EZH2 plays a consistent underlying role in maintaining the GC and B-cell proliferation, regardless of the oncogenic drivers. Dysregulation of EZH2 or gain-of-function mutations in EZH2 can lead to accumulation of malignant B cells and may contribute to the development of FL. Tazemetostat, a first-in-class oral EZH2 inhibitor, recently gained approval by the US Food and Drug Administration in patients with relapsed or refractory (R/R) FL after demonstrating single-agent, antitumor activity in patients with mutant (MT) or wild-type (WT) EZH2 R/R FL. Here we examine the efficacy and safety of tazemetostat in combination with rituximab for the treatment of R/R FL. Study Design and Methods: This trial is a phase 2, single-arm, open-label, multicenter study of tazemetostat in combination with rituximab in patients with R/R FL who have received at least 2 prior lines of systemic therapy, including an anti-CD20-based regimen. Patients eligible for inclusion are aged ≥18 years with grade 1 to 3A FL who have met Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria to receive treatment, have an Eastern Cooperative Oncology Group (ECOG) score ≤2, have &amp;gt;5.0 x 109/L circulating malignant cells, and have not received any prior treatment with EZH2 inhibitors. Patients with transformed FL, a history of clinically significant gastrointestinal conditions, or any uncontrolled illness are excluded from this study. EZH2 mutation testing will be performed during patient screening. Patients will receive tazemetostat 800 mg by mouth twice daily beginning on cycle 1 day 1 for continuous 28-day cycles until the end of cycle 24, for a total of 24 months of therapy. Patients will also receive rituximab 375 mg/m2 intravenously (IV) on cycle 1 day 1, then 375 mg/m2 IV or 1400 mg subcutaneously on days 8, 15, and 22 of cycle 1, and on day 1 of cycles 3, 4, 5, and 6, for a total of 8 doses of rituximab. The primary endpoint is the objective response rate (ORR; the proportion of patients with complete or partial response) in patients with WT EZH2. Key secondary endpoints include median progression free survival (PFS) in patients with WT EZH2; median PFS in all patients, regardless of mutational status; ORR in patients with MT EZH2; efficacy outcomes in rituximab-refractory patients; and incidence of adverse events. Efficacy and safety analyses will be performed on all patients who receive ≥1 dose of study drug. The evaluation of ORR will be based on Lugano 2014 response criteria and will be presented with corresponding 2-sided Clopper-Pearson 95% confidence intervals. The Kaplan-Meier method will be used to estimate PFS. Survival follow-up will be done following the study treatment period every 6 months for 2 years or until disease progression or death for all patients who complete the 24 months of tazemetostat therapy. Disclosures Patel: Adaptive Biotechnologies, AstraZeneca, Pharmacyclics, Janssen, Genentech, Celgene/BMS, BeiGene, Kite: Consultancy. Pagel:Gilead, Pharmacyclics LLC, an AbbVie Company, and AstraZeneca: Consultancy.

REGN5458, a BCMA x CD3 Bispecific Monoclonal Antibody, Induces Deep and Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

REGN5458, a BCMA x CD3 Bispecific Monoclonal Antibody, Induces Deep and Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Ibrutinib before Apheresis May Improve Tisagenlecleucel Manufacturing in Relapsed/Refractory Adult Diffuse Large B-Cell Lymphoma: Initial Results from a Phase 1b Study

Ibrutinib before Apheresis May Improve Tisagenlecleucel Manufacturing in Relapsed/Refractory Adult Diffuse Large B-Cell Lymphoma: Initial Results from a Phase 1b Study

A Phase I Trial Assessing the Feasibility of Romidepsin Combined with Brentuximab Vedotin for Patients Requiring Systemic Therapy for Cutaneous T-Cell Lymphoma

A Phase I Trial Assessing the Feasibility of Romidepsin Combined with Brentuximab Vedotin for Patients Requiring Systemic Therapy for Cutaneous T-Cell Lymphoma

Anti-PD-1 Antibody (Sintilimab) Plus Histone Deacetylase Inhibitor (Chidamide) for the Treatment of Refractory or Relapsed Extranodal Natural Killer/T Cell Lymphoma, Nasal Type (r/r-ENKTL): Preliminary Results from a Prospective, Multicenter, Single-Arm, Phase Ib/II Trial (SCENT)

Background: ENKTL is a highly aggressive NHL related to Epstein-Barr virus, with a higher incidence in Asia. Patients with r/r-ENKTL have a poor prognosis after failing asparaginase based regimen, and there is lack of effective treatment. Anti-PD-1 antibody represented a favorable treatment for rr-ENKTL. ORIENT-4 trial demonstrated Sintilimab was effective and well tolerated in r/r-ENKTL. The efficacy of Chidamide, an oral HDACi was reported on rr-ENKTL(CHIPEL trial, 2017 ASH). Here we present preliminary results of Sintilimab plus Chidamide for r/r-ENKTL. Methods: This trial enrolled eligible patients with histologically confirmed r/r-ENKTL failing from asparaginase-based regimen; ECOG performance status ≤ 2; adequate organ function and bone marrow function; and at least one measurable or evaluable lesion. This study consisited of a Phase Ib (dose escalation) portion followed by a Phase II expansion portion. In the Phase Ib, a standard "3+3" design was utilized to identify the MTD, DLT and recommended Phase II dosage (RP2D) of Chidamide plus Sintilimab. In the phase II portion, patients received 6 cycles of Sintilimab (200 mg) plus Chidamide (RP2D) every 3 weeks. Patients with complete response (CR) or partial response (PR) received up to 1 year. The primary endpoint was objective response rate (ORR) assessed by investigators per RECIL 2017 criteria. Key secondary endpoints included TTR, DOR,PFS,OS and safety. Adverse events (AEs) were defined according to CTCAE 5.0. Pretreatment formalin-fixed, paraffin-embedded (FFPE) tumor samples were obtained. Samples were tested using Dako PD-L1 22C3. PD-L1 protein expression was determined using tumor proportion score (TPS) and combined positive score (CPS). CPS ≥1 was considered positive. All patients' blood samples were collected for ctDNA assessment before treatment in each of cycles. ctDNA samples were analyzed by capture-based NGS targeting 475 lymphoma- and cancer- relevant genes. This trial was registered at ClinicalTrials.gov (NCT 03820596) Results: From March 2019 to May 2020, 41 patients were screened and 37 eligible patients were enrolled from 5 institutions. Median age 48 years (range, 20-72), 27 (73.0%) male, 26 (70.3%) patients with Stage IV of disease at screening, 20 (54.1%) patients with PINK-E score ≥ 3 points, 16 (43.2%) patients received ≥ 2 lines of prior systemic therapy. In Phase Ib , no MTD or DLT events were observed, RP2D of chidamide was 30 mg twice a week. Of 36 response evaluable patients, 21 (58.3%) achieved response including 16 (44.4%) patients with CR and 5 (13.9%) with PR(Figure 1). The median time to initial response was 6.0 weeks (5.0-12.4w). The median DOR time was 9.2+ months (1.3 -14.5+m) (Figure 2). The median follow-up time was 7.3 (0.9-16.1) months. Estimated 1-year OS rate was 79.1%, 1-year PFS rate was 66.0%. 19 (51.3%) patients remained on treatment,18 (48.7%) patients had discontinued from study treatment (16 for PD, 1 for AEs, 1 for personal reasons). The OS and PFS of patients with CR/PR is significantly superior to patients with SD/PD. Estimated 1-year OS rate for CR/PR and SD/PD was 95.0% and 51.9% (P&amp;lt;0.001), 1-year PFS rate was 95.0% and 31.2%, respectively (P&amp;lt;0.001). Among 27 patients with available FFPE tissue specimens, PD-L1 expression in more than 50% and 10% of tumor cells were observed in 12 (44.4%) and 8 patients (29.6%). The median value of CPS was 40.0, patients with PD-L1 CPS≥30 exhibited benefit more from treatment. Dynamics ctDNA assay is in progress, data in detail will be reported at the ASH conference. 21 (56.8%) patients reported treatment-related AEs (TRAEs). The most frequently observed (≥10%) TRAEs were neutropenia (51.4%), thrombocytopenia (45.9%), transaminase increased (29.7%), nausea (24.3%). The most frequent Grade (G) ≥3 TRAEs were neutropenia (16.2%) and thrombocytopenia (10.8%). Immune-related AEs were reported in 16 (43.2%) patients including a G4 exfoliative dermatitis, and the most common irAEs were G1 hypothyroidism and rash. No death was related to the study. Conclusion: Sintilimab plus Chidamide showed manageable safety profile and yielded effective antitumor activity, durable response in patients with r/r-ENKTL for the first time. It is a promising therapeutic option for this population, especially for those with CPS≥30. Epigenetic strategies synergize with anti-PD-1 antibody maybe enhanced antitumor responses to r/r-ENKTL, further investigation is warranted. Disclosures No relevant conflicts of interest to declare.

A Phase 2 Study of Odronextamab (REGN1979), a CD20 x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

A Phase 2 Study of Odronextamab (REGN1979), a CD20 x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Efficacy and Safety of Baricitinib in Refractory Chronic Graft-Versus-Host Disease (cGVHD): Preliminary Analysis Results of a Phase 1/2 Study

Background : Chronic Graft-versus-Host Disease (cGVHD) is a multi-organ disorder characterized by immune dysregulation, impaired organ function, and decreased survival. Refractory cGVHD remains an unmet need with limited effective treatment options. Janus kinase (JAK) inhibition targeting JAK-STAT is promising in cGVHD due to this multifaceted pathway's key role in immune cell development, function, and inflammation. Baricitinib is a JAK1/2 inhibitor FDA-approved at 2 mg daily for treatment of rheumatoid arthritis, and which has shown therapeutic promise in preclinical models of GVHD. Herein, we report the preliminary analysis results of a phase 1/2 study exploring the efficacy and safety of the JAK 1/2 inhibitor baricitinib in therapy-refractory cGVHD. Methods : Patients (pts) with therapy-refractory moderate-severe cGVHD per NIH criteria were enrolled on an NCI sponsored treatment protocol (NCT02759731). This is a phase 1/2 single center, single arm study of baricitinib starting at an oral dose of 2 mg daily, given for 28-day cycles, with intra-patient dose escalation to 4 mg daily after 3 months (mos) for a total of 12 cycles. Adverse events (AEs) were monitored and graded per CTCAEv4.3. Clinical responses were measured every 3 mos per the 2014 NIH cGVHD Response Criteria. The primary efficacy endpoint was ORR (CR+PR) at 6 mos; if PR or SD, pts were treated for up to 12 mos and monitored for 12 mos post-completion. Subjects self-report questionnaires included the Lee symptom bother scale (LSS). Peripheral blood samples were collected for pharmacokinetic and correlative studies at several time points throughout study. Results: Twenty pts with refractory cGVHD were enrolled. Median patient age was 54 years (24-68), 55% female, 90% Caucasian. Median time from cGVHD diagnosis to study enrollment was 36.8 mos, with median baseline KPS of 80%. cGVHD NIH global score was severe in all pts (due to sclerotic skin in all except one oral), involving a median of 4 (2-6) organs, and treated with a median of 4 (2-7) lines of prior systemic therapy including ibrutinib in 3. At study enrollment, all but 3 (85%) were on concurrent systemic immunosuppression, including steroids for 12 (60%) at a median dose of 10 mg (2.5-30) prednisone daily. ORR at 6-months was 63% (95% CI 47-87%), with durable responses seen in 7 of 8 evaluable pts at 12-mos. ORR at any time was 90% (85-100%), with median time to ORR of 1.4 mos (1.4-6.3). Organ-specific responses were seen in all involved organs except for lungs (11 organ-specific CRs at 6-mos). Clinically significant improvements in LSS (≥ 6-point reduction) were seen in 7 of 14 (50%) evaluable pts at 6-mos. Median steroid dose-reduction of 4 mg prednisone daily was achieved in 6 (50%) of those on steroids at enrollment. With a median follow up of 24.2 mos, median failure-free survival (FFS) was 20.6 mos (19-NR). 1- and 2-year FFS was 74% (57-97%) and 37% (18-78%), respectively. Of the 8 evaluable pts who completed study, 3 progressed at a median of 7.3 mos (6.9-11.9) after drug discontinuation. No DLT was observed with the 2 mg dose of baricitinib; 16/20 (80%) pts reached dose-escalation to 4 mg at 3 mos. Three pts required dose-reductions: two due to neutropenia, and one due to refractory myalgias. Common AEs, possibly treatment-related, included upper respiratory infection (URI) (13), neutropenia (6), hypophosphatemia (12), and hypertriglyceridemia (5). Asymptomatic, transient reactivation of CMV occurred in 6, EBV in 7, BK viruria in 5 - none of which required treatment. HPV-related eyelid papilloma developed in 2, with no visual changes. One patient with EBV viremia/lymphadenopathy at enrollment was diagnosed with biopsy-proven EBV-PTLD &amp;lt;1 cycle into study. 11 SAEs were reported, of which 5 were possibly drug-related, including hospitalizations for joint infection (n=1), cellulitis (n=2), and URI (n=2). Eleven pts (55%) required dose-interruptions due to AEs, and 9 pts (45%) discontinued treatment at a median 5.6 mos (0.8-10.7) post-initiation due to PD (n=3), EBV-PTLD (n=1), decreased DLCO (n=1), viral URI (n=1), pneumonia (n=1), and other (n=2). There were no deaths on study. Conclusion: The JAK 1/2 inhibitor baricitinib appears well-tolerated and effective for pts with severe cGVHD who progressed through multiple lines of prior therapy. Responses were achieved rapidly and seen across all involved organs, except lungs. Full study results for a total of 31 pts are expected in early 2022. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Baricitinib is currently FDA-approved in the U.S. for treatment of rheumatoid arthritis at a dose of 2 mg by mouth once daily.

Outcomes of Treatment with the Chimeric Antigen Receptor (CAR) T Cell Therapy Lisocabtagene Maraleucel (liso-cel) in the Nonuniversity Setting: Initial Results from the Outreach Study

Outcomes of Treatment with the Chimeric Antigen Receptor (CAR) T Cell Therapy Lisocabtagene Maraleucel (liso-cel) in the Nonuniversity Setting: Initial Results from the Outreach Study

Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients with Steroid-Refractory/Steroid-Dependent Chronic Graft-Vs-Host Disease (cGVHD): Primary Findings from the Phase 3, Randomized REACH3 Study

Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients with Steroid-Refractory/Steroid-Dependent Chronic Graft-Vs-Host Disease (cGVHD): Primary Findings from the Phase 3, Randomized REACH3 Study

Addition of Brentuximab Vedotin to Gemcitabine in Relapsed or Refractory T-Cell Lymphoma: Results of a Lysa Multicenter, Phase II Study. “the TOTAL Trial”

Addition of Brentuximab Vedotin to Gemcitabine in Relapsed or Refractory T-Cell Lymphoma: Results of a Lysa Multicenter, Phase II Study. “the TOTAL Trial”

Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Marginal Zone Lymphoma (CITADEL-204)

Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Marginal Zone Lymphoma (CITADEL-204)

Is Molecular Characterization Useful for Targeted Therapy Orientation in Patients with Relapsed or Refractory DLBCL Included in Early Phase Clinical Trials?

Is Molecular Characterization Useful for Targeted Therapy Orientation in Patients with Relapsed or Refractory DLBCL Included in Early Phase Clinical Trials?

Combined Immunotherapy and Hypofractionated Radiotherapy for Metastatic Cancers

The effects of treatment with immunotherapy (IO) and hypofractionated radiotherapy (HFRT) are poorly understood. HFRT could enhance the efficacy of IO; however randomized data regarding clinical significance and safety are lacking. Here we reviewed a series of patients who underwent both IO and HFRT in the setting of metastatic disease to assess for characteristics of treatments and outcomes. After obtaining institutional review board approval, records from a single institution were reviewed to identify patients who received immunotherapy and HFRT. Patient information including demographics, tumor characteristics, treatment types, and outcomes were retrospectively extracted. Local failure was assessed as progression on post-treatment imaging or recurrence of symptomatic disease. Abscopal effect was defined as radiographic or clinical response of non-radiated lesions following HFRT. Concurrent treatment was defined as any overlap in dates of immunotherapy and HFRT. A total 36 patients treated for 91 metastatic lesions with HFRT over a median 2 courses per patient (course number ranged 1-12) from 07/2014 – 12/2019 were reviewed with 9.6 months of median follow up. The most common primary tumor site was liver/gallbladder (50%) followed by colorectal/small bowel (19%) and the most common radiation targets were bone (51%) and liver (22%). Radiation was given as 8-60 Gy in 1-5 fractions. HFRT treatment rationale was for oligometastatic disease (7%), oligoprogression (46%), palliative intent (41%), or IO enhancement (7%). Patients received a median 2 (range 0-5) lines of systemic therapy prior to HFRT. Sequencing of therapies was variable with 45% receiving IO before HFRT, 28% concurrent, and 27% HFRT before IO. Overall, local failure occurred in 9 (10%) irradiated lesions among 6 (17%) patients, distant control was achieved in 14% of patients, and abscopal effects were observed in 2 patients (6%). Most local failure occurred in irradiated bone (8 of 9 cases) and received 8 Gy in 1 fraction (4 of 9 cases). Both patients with observed abscopal effect were treated with IO preceding HFRT, with single agent IO, and with RT to one site. This single institution experience reviews a modern cohort of patients in the immunotherapy era. The combination of IO and HFRT was most commonly used in patients previously failing several prior lines of systemic therapy and often with oligoprogressive disease or palliative intent. Further study may identify predictors for improved response such as treatment timing, the role of dose and fractionation, and tumor characteristic which will inform design of prospective trials.

Myeloma Of The Head: Is Palliative Radiation Worth It?

Multiple myeloma (MM) of the head can present with central nervous system (CNS) involvement (brain metastases (BM) and/or leptomeningeal disease (LMD)), cranial neuropathies (CN) from base of skull (BOS) lesions, or pain. These groups may be referred for radiotherapy (RT), but prognosis and best RT management are unknown. We hypothesized CNS MM has worse clinical response and survival than compressive CN or pain. We screened RT courses delivered at our institution from 2008-2019 to find those associated with ICD-9/10 codes for plasma cell dyscrasias (203 or C90). We identified 49 delivered to the head for MM. Treatment groups were defined as 1) RT for LMD or BM, 2) RT for CN from BOS lesions not in group 1, and 3) RT for pain not in groups 1 or 2. We recorded clinicopathologic features for each patient as well as prior and concurrent therapies. Clinical responses (symptomatic and/or radiographic) were recorded categorically as progressive disease versus no, partial, or complete response. Logistic and multivariate regressions were run to identify factors predictive of clinical response and survival, respectively. Patient and treatment characteristics are shown in Table 1. 40/46 courses were evaluable for clinical response. Survival for group 1 trended worse, but clinical response and survival were no different between groups (p = 0.19 and 0.16, respectively). 16/18 patients treated for CN had at least partial response. Increased RT dose was the only significant predictor of clinical response on logistic regression (p = 0.008) and survival on linear regression (p = 0.042). Non-significant predictors were treatment group, age, number of prior lines of systemic therapy, history of prior stem cell transplant, presence of high-risk mutations, positive lumbar puncture, concurrent therapy (systemic or intrathecal), and prior progression to plasma cell leukemia. Survival and clinical response trended worse for MM of the CNS (LMD and BM), but good response rates for BOS lesions causing CN warrant RT consideration. Dose was the only significant factor associated with improved clinical response and survival. This retrospective study may be limited by small numbers and potential selection bias. Future collaborations will help elucidate the role of RT for these patients.Abstract 3768; TableGroupRT coursesMedian age (range)Median prior lines therapy (range)High-risk genetics* (positive/patients tested)Median dose (Gray) (range)Median survival (days) (range)Clinical Response (number of courses)ProgressionNo responsePartial responseComplete response11060 (41-69)7.5 (0-11)7/820.5 (4-30)79 (10-151)124021861 (45-82)4.5 (1-16)2/921 (9-40)160 (6-1640)0213331862 (43-74)6.5 (2-14)6/1422.5 (6-30)102 (8-1169)1374*high-risk mutations include t(4;14), t(14;16), t(14;20), del17p, and gain1q Open table in a new tab