bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of racial disparities accounting for treatment received in chronic lymphocytic leukemia: A real-world cohort analysis.
Authors: Kittai Adam , Huang Ying , Bhat Seema Ali , Clark Abi , Grever Michael R. , Roberts Melyssa , Rogers Kerry Anne , Teschemaker Anna , Munoz-Sagastibelza Maria , Woyach Jennifer Ann , Barrientos Jacqueline Claudia
Published: June 2023

7533

Background: Recent population-based studies have shown that Black patients (pts) with CLL have worse overall survival (OS) than White pts with CLL. These studies could not account for the use of modern therapies, CLL prognostic variables, or comorbidity and thus the root cause of this disparity remains unclear. Here, we use the Flatiron Health Database (FHD) to study this disparity, while accounting for disease-specific variables and treatment (tx) received. Methods: Retrospective analysis of pts with CLL in the FHD treated between 2002 to 2022 was performed. Pt characteristics such as age at diagnosis (dx), year (yr) of dx, months (mos) from dx to first tx, race, sex, IGHV status, ECOG performance status (PS), and use of small molecule inhibitors at any time (including BTK inhibitors, venetoclax, PI3K inhibitors, and lenalidomide) were collected and analyzed. OS was measured from tx start. Multivariable cox regression (MVA) was used to determine adjusted odds of survival. Results: 13646 pts with CLL were identified. Mean age at dx was 65.3 yrs, and mean time from dx to tx was 32.3 mos. 81.2%, 8.4%, and 10.4% of pts were White, Black, or other race, respectively, and 63.2% of pts were male. 61.4% of pts were IGHV unmutated, and 89.1% of pts had a ECOG PS 0/1. 58.7% of pts were treated with a small molecule inhibitor at any point during their tx. After a median follow-up of 5.3 yrs, the median OS was 10.5 yrs (95% CI: 10.2-10.8). Black pts were younger at dx (63.1 vs 65.4), had shorter time to first tx (23.6 mo vs 34 mo), were more likely to be IGHV unmutated than White pts (83% vs 60.1%), and had more small molecule inhibitor use (69% vs 58.5%). These differences were all statistically significant (p <0.01). 90.8% and 89.1% of Black and White pts had an ECOG PS of 0/1, respectively. Median OS for Black pts was 10 yrs (95% CI: 9.1-11.1) vs 10.5 yrs (95% CI: 10.2-10.8) for White pts. On MVA, Black pts had higher risk of death than White pts of the same age despite increased use of small molecule inhibitor (Table). However, the interaction between age and race was also significant, indicating a decreasing disparity between Black and White race as pts aged. Time to first tx, IGHV unmutated status, and ECOG PS were also independently associated with worse OS. Conclusions: Black race especially at younger age was independently associated with worse OS despite the use of small molecule inhibitors, IGHV status, and ECOG PS. [Table: see text]
Outcomes among adult recipients of CD19 CAR T-cell therapy for Burkitt lymphoma.
Authors: Samples Laura S. , Sadrzadeh Hossein , Frigault Matthew J. , Jacobson Caron Alyce , Hamadani Mehdi , Gurumurthi Ashwath , Strati Paolo , Shouval Roni , Riedell Peter A. , Dahiya Saurabh , Yared Jean , Jain Michael D. , Locke Frederick L. , Leslie Lori Ann , Epperla Narendranath , Ghosh Monalisa , Skarbnik Alan , Hill Brian T , Kamdar Manali K. , Shadman Mazyar
Published: June 2023

7571

Background: Burkitt lymphoma (BL) is a rare, but highly aggressive B-cell lymphoma associated with especially poor outcomes in patients with relapsed/refractory disease. Multiple CD19 chimeric antigen receptor (CAR) T-cell products have been FDA approved to treat relapsed/refractory B-cell non-Hodgkin lymphoma in the second-line setting, however little is known about CAR T-cell responses in patients with BL. This multicenter study aims to assess real-world outcomes among patients with BL treated with CAR T-cell therapy across the United States. Methods: This multicenter, retrospective chart review was conducted by abstracting data from the medical charts of patients with BL who received CAR T-cell therapy. Demographic characteristics were assessed along with pre-CAR treatments, bridging therapies, infusion-related complications, CAR-T responses, and the use of post-CAR systemic therapy and/or hematopoietic stem cell transplant. Results: A total of 13 patients with relapsed/refractory BL received CAR T-cell therapy after a median of 3 prior therapies (range 1-6). Most patients received axi-cel (n = 8), although tisa-cel (n = 3) and liso-cel (n = 2) were also represented. The median age of these patients was 38 (range 24-68). A total of 6 (46.2%) had evidence of central nervous system involvement at diagnosis and 5 (38.5%) had a prior history of autologous stem cell transplant. The overall response rate 1 month after infusion was 69.2% with a complete response rate of 53.8%. All patients experienced grade 1-2 cytokine release syndrome (CRS). No one experienced grade ≥3 CRS, but 2 patients developed grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS). Twenty-eight-day mortality was 23%, including one patient who died from grade 4 ICANS. Regarding long term data, only 4 (30.8%) patients sustained a complete response for more than 6 months. Median progression-free survival was 4.2 months (95% CI 28.2-257.6), and the 1-year overall survival rate was 61.5% (95% CI 0.56-0.67). Two (15.4%) patients received consolidative allogeneic stem cell transplants after CAR T-cell therapy, but both ultimately developed progressive disease. Conclusions: Relapsed/refractory BL is a rare and aggressive disease that remains challenging to treat despite the advent of CAR T-cell therapy. Further investigation is needed to determine the most effective management of these patients. We expect to include additional patients in this analysis over the coming months.
A phase 3, open-label, randomized study to evaluate the efficacy and safety of single-agent belantamab mafodotin (belamaf) compared to pomalidomide plus low-dose dexamethasone (Pd) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): DREAMM-3.
Authors: Weisel Katja , Hungria Vania TM , Radinoff Atanas , Delimpasi Sosana , Mikala Gabor , Masszi Tamas , Li Jian , Capra Marcelo , Matsumoto Morio , Sule Neal , Li Mary , McKeown Astrid , He Wei , Bright Shelley , Currie Brooke , Boyle Julia , Opalinska Joanna , Dimopoulos Meletios A.
Published: June 2023

8007

Background: Belamaf, an antibody-drug conjugate targeting B-cell maturation antigen, induces cell death by direct cell kill and immune-mediated mechanisms. The DREAMM-2 trial (NCT03525678) showed rapid, deep and durable responses to belamaf monotherapy in pts with RRMM. The Phase 3, open-label, randomized, multicenter DREAMM-3 trial (NCT04162210) evaluated belamaf monotherapy vs Pd in adult pts with RRMM at second relapse (third line) or later. Methods: Pts were randomized (2:1) to belamaf 2.5 mg/kg Q3W or Pd (pom 4 mg PO daily on days 1–21 of 28 day cycle; dex, 40mg PO [20mg if >75 years]) Q1W. The primary endpoint was progression free survival (PFS). Results: 325 pts were enrolled (belamaf n=218, Pd n=107). Median (range) age was 68 (38–90) years; 57% were male. Median (range) duration of exposure for belamaf was 4.1 (0.4, 22.9) months (mo) and 5.3 (0.4, 24.0) for Pd. Median (range) duration of follow-up was 11.5 (0.6, 24.2) mo for belamaf and 10.8 (0.0, 26.4) mo for Pd. Median PFS was longer for belamaf (11.2 [6.4, 14.5] mo) vs. Pd (7.0 [4.6, 10.6] mo). There was no statistically significant difference in PFS between the 2 treatment groups, (HR 1.03 [95% CI: 0.72, 1.47]), based on the stratified Cox model (p=0.558). Belamaf induced deeper responses vs Pd (Table). Median duration of response (DoR) was more durable for belamaf than for Pd (Table). At 12 mo, the probability (95% CI) of maintaining response was 0.768 (0.641, 0.854) for belamaf and 0.484 (0.258, 0.679) for Pd. Median PFS2 was 18.7 mo (95% CI 14.5, NR) for belamaf and 12.7 mo (9.3, 21.1) for Pd. PFS2 rate at 6 mo was 73% for belamaf and 76% for Pd. Overall survival (OS) data were immature (37.5% overall maturity) at this analysis; median OS was 21.2 mo (95% CI 18.7, NR) for belamaf and 21.1 mo (15.1, NR) for Pd (HR 1.14 [95% CI 0.77, 1.68]; p=0.746). Adverse events (AEs) were reported in 97% and 93% of patients (Table). The safety profile was consistent with previous reports for belamaf and Pd. Conclusions: Belamaf monotherapy did not demonstrate PFS superiority when compared to a doublet (Pd). However, median PFS was longer for belamaf monotherapy and belamaf induced deeper, more durable responses than Pd. No new safety signals were observed. Subgroup analyses and PRO outcomes will be reported. Belamaf continues to be investigated in combination with established and novel agents.[Table: see text]
Updated OS of patients with AL amyloidosis after CAEL-101.
Authors: Hughes Michael Sang , Pan Samuel M , Chakraborty Rajshekhar , Raikhelkar Jayant , Maurer Mathew , Mapara Markus Y. , Eisenberger Andrew , Lentzsch Suzanne , Bhutani Divaya
Published: June 2023

8026

Background: Morbidity and mortality remain high in immunoglobulin light chain (AL) amyloidosis due to organ involvement despite hematologic remission. Few anti-amyloid fibril therapies for AL amyloidosis exist. We previously published the results of the phase 1a/1b study of CAEL-101 in AL amyloidosis showing significant improvement in organ response rates.1 We report long-term outcomes. Methods: Patients enrolled in NCT02245867 with relapsed/refractory AL amyloidosis received in phase 1a, a one-time dose-finding CAEL-101 infusion and in phase 1b, 4 weekly CAEL-101 infusions with preplanned dose escalation. Patients were evaluated for organ response for 12 weeks after last infusion. We extracted clinical, laboratory, and pathology data regarding clinical course beyond 12 weeks after last treatment. We performed a review of all AL amyloidosis patients at our center not treated with CAEL-101 1/01/2012-12/30/19 as clinical comparisons. Results: 22 patients were enrolled in CAEL-101. 5 patients were treated in both phase 1a and phase 1b. With median follow-up of 81.3 months (IQR 60.4-87.7), long term follow-up data are available for 19/22 patients. 5 patients died during long term follow-up: 3 from progressive AL amyloidosis; 1 from organ transplantation complication; and 1 from venous thromboembolism sequelae. Among patients with organ data available, 10/17 had hematologic progression and received next line therapy. 5/17 patients had organ progression. All patients with organ PD had previous/concomitant hematologic PD. Median OS was not reached; median organ PFS was 93.3 months (38.9-NR). No delayed adverse events occurred. Comparison with historical control groups revealed trends toward improved OS: HR 0.42 (0.09-1.81 p=0.23) in all comers AL amyloid controls, and HR 0.20 (0.03-1.16 p=0.07) in cardiac controls. Kaplan-Meier analysis and Cox regression were performed. Conclusions: Patients with relapsed/refractory AL amyloidosis who received a low cumulative amount of the novel anti-amyloid CAEL-101 in a phase 1a/1b study had lengthy overall and progression-free survival compared to historical controls. Patterns of organ progression after initial response may reflect intrinsic differences in organ vulnerability. The CAEL101-301 and CAEL101-302 phase 3 clinical trials are underway to confirm these findings. Reference: 1. Edwards CV, Rao N, Bhutani D, et al: Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. Blood 138:2632-2641, 2021. [Table: see text]
Long-term outcomes with isatuximab-carfilzomib-dexamethasone (Isa-Kd) in relapsed multiple myeloma patients with 1q21+ status: Updated results from the phase 3 IKEMA study.
Authors: Facon Thierry , Moreau Philippe , Spicka Ivan , Suzuki Kenshi , Yong Kwee , Mikhael Joseph , Fukao Taro , Bisht Kamlesh , Armstrong Nicole , Macé Sandrine , Risse Marie-Laure , Martin Thomas G.
Published: June 2023

8029

Background: Gain or amplification of 1q21 (1q21+, ≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma (MM), has a negative impact on prognosis due to its potential involvement in resistance to MM therapy and disease progression. In the prespecified, long-term analysis of the Phase 3 IKEMA trial in relapsed MM patients (pts), treatment with Isa-Kd showed continued, significant improvement in progression-free survival (PFS) vs Kd (HR 0.58; 95.4% CI 0.42–0.79), with meaningful increase in depth of response (complete response or better [≥CR] 44.1% vs 28.5%; minimal residual disease negativity [MRD-] 33.5% vs 15.4%, MRD- ≥CR 26.3% vs 12.2%), and a manageable safety profile. In this subgroup analysis of IKEMA, we evaluated efficacy of Isa-Kd in pts with 1q21+ status (with or without high-risk chromosomal abnormalities [HRCA]) and related subgroups – isolated 1q21+ (≥3 copies without HRCA), gain(1q21), amp(1q21) – at long-term follow-up (44.2 months). Methods: Pts with 1–3 prior lines of therapy were randomized to Isa-Kd (n=179) or Kd (n=123). Assessment was prespecified (at 30% cut-off by FISH) for 1q21+ status as ≥3 copies, gain(1q21) as 3 copies, and amp(1q21) as ≥4 copies. Results: In the Isa-Kd and Kd arms, 41.9% and 42.3% of pts had 1q21+ status, 26.3% and 25.2% isolated 1q21+, 24.0% and 30.1% gain(1q21), 17.9% and 12.2% amp(1q21) respectively. Greater PFS benefit was achieved with Isa-Kd vs Kd in pts with 1q21+ status (HR 0.58, 95% CI 0.37–0.92) and in pts with isolated 1q21+, gain(1q21), or amp(1q21) (Table). Responses deepened by adding Isa to Kd, with increased rates of very good partial response or better (≥VGPR), ≥CR, MRD-, and MRD- ≥CR (Table). Conclusions: 1q21 abnormalities affect PFS in MM pts. Our results at long-term follow-up of pts with 1q21+ status (with or without HRCA) in the IKEMA study continue to show greater PFS benefit and deeper responses with Isa-Kd than Kd, consistent with the overall population and earlier 1q21+ subgroup interim analyses. Thus, they support Isa-Kd as an effective treatment option also for difficult-to-treat, 1q21+ pts with relapsed MM. Clinical trial information: NCT03275285.[Table: see text]
Patient-derived MicroOrganoSpheres (MOS) and precision clinical decision-making for patients with multiple myeloma.
Authors: Xi Rui , Wang Xiaobei , Baro Nicholas , Raman Renuka , Steele Shaun , Helman Elena , Ding Shengli , Kang Yubin , Shen Xiling
Published: June 2023

8047

Background: There are many multiple myeloma (MM) treatments and nearly all patients undergo continual cycles of treatment, response, and resistance. Selecting an effective therapeutic strategy is of critical importance; but there is currently a lack of patient-derived MM models that can enable functional precision medicine to help real-time clinical decision-making to guide individual patient treatment. Methods: We show a method to rapidly establish MM patient-derived MicroOrganoSheres (MOS), which are microscale, droplet-sized patient avatars that sustain the native tumor niche, including both stromal and immune compartments. We generated first-of-its-kind data showing that MM MOS predicted patient treatment outcomes and have the potential to guide clinical treatment decisions. We further developed high-throughput drug screen to demonstrate MM MOS response to FDA-approved single and combination therapies and developed MOS assays to predict patient responses to immunotherapies including bispecific and phagocytosis-inducing antibodies. Results: MM MOS established from patient bone marrow (BM) biopsies preserved CD138/CD38 tumor cells, stromal (e.g., osteoblast) cells, and all major immune cell populations (T, NK, B, macrophage, dendritic, and myeloid-derived suppressor cells) for 11 days in culture. We performed single and combo drug testing on MOS derived from 7 MM patients within 10 days of biopsy collection. Patients went on receiving treatments and their responses were assessed using International Myeloma Working Group response criteria. The MOS assay predicted responses of both treatment-naïve and refractory patient to standard-of-care regimens, including combinations of proteasome inhibitors (bortezomib, carfilzomib), immunomodulatory agents (lenalidomide) and DCEP. Moreover, the BM biopsy-derived MOS enabled high-throughput drug testing of single agents and combinations in 9-dose titrations, providing clinicians the ability to evaluate alternative treatment options. Furthermore, because MOS retain the immune compartments of the original tumor niche, we were able to evaluate patients’ response to bispecific T cell engagers and developed a phagocytosis assay to measure anti-tumor phagocytosis activity, which showed efficacy in both single-agent and combo settings. Multi-modal profiling and an AI image analysis pipeline provided robust measurements that confirmed the unique phenotypic profile of each patient sample, highlighting the critical unmet need to guide each patient to the optimal treatment. Conclusions: Based on this groundbreaking feasibility study, a subsequent clinical trial of 40 patients is current under IRB review to further validate the clinical power of MM MOS to predict patient outcome and to demonstrate utility as a viable functional precision medicine approach to inform treatment decisions in the clinic.
Outcomes of patients with primary refractory multiple myeloma in the era of triplet and quadruplet induction therapy.
Authors: Charalampous Charalampos , Goel Utkarsh , Kapoor Prashant , Binder Moritz , Buadi Francis , Cook Joselle , Dingli David , Dispenzieri Angela , Gertz Morie A. , Gonsalves Wilson I. , Hayman Suzanne R. , Hobbs Miriam A. , Hwa Yi Lisa , Kourelis Taxiarchis , Lacy Martha , Leung Nelson , Lin Yi , Warsame Rahma M. , Rajkumar S. Vincent , Kumar Shaji
Published: June 2023

8051

Background: Patients with multiple myeloma (MM) that do not respond to initial therapy have worse outcomes compared to primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not been studied. Methods: From 2007-2019, we reviewed MM patients treated with triplet/quadruplet therapy in our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. Primary refractory disease was defined as either progressive disease or stable disease at 4-6 cycles. The Kaplan-Meier estimates were used for survival probabilities. PFS and OS were calculated from MM diagnosis to progression, escalation/change of treatment, or death, respectively. For the primary refractory group, the second PFS and second OS were measured from the start of second-line therapy. The Cox regression model was used for multivariable analysis with the following variables (age, ISS, induction therapy, FISH, and bone marrow plasma cells at diagnosis). Results: We identified 1127 patients, of which 1086 were evaluated for hematologic response after 4-6 cycles. Of these, 93.3% (1013) had evidence of response, while 6.7% (73) had primary refractory disease. With a median OS of 50.7 months, patients with primary refractory disease had an increased risk for shorter survival in univariable and multivariable analysis (HR: 3.6, 95% CI = 2.61 – 4.96, HR = 3.89, 95% CI = 2.68 – 5.65, respectively). In subgroup analysis of primary refractory patients, the median second PFS and second OS from the first relapse were 11.9 months (95% CI: 8.7 – 17.3 months) and 43.4 (95% CI: 31.4– 75.9 months), respectively. Patients that received 2nd line ASCT had increased second PFS (20.9 vs. 8.1 months, respectively, p < 0.01) and second OS (74.7 vs. 31.3 months, respectively, p = 0.02) compared to patients that did not. Patients that took daratumumab as the second line did not have any significant survival differences compared to those who did not, p = NS. Conclusions: We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population. [Table: see text]
Curability of multiple myeloma (MM) based on relative survival rate (RSR) in patients (pts) treated on earlier total therapy (TT) protocols.
Authors: Al Hadidi Samer , Ababneh Obada Ehab , Schinke Carolina D. , Thanendrarajan Sharmilan , Bailey Clyde , Zangari Maurizio , Tricot Guido , Shaughnessy John D. , Zhan Fenghuang , Sawyer Jeffrey , van Rhee Frits , Barlogie Bart
Published: June 2023

8059

Background: Long term overall survival (OS) follow-up data in pts with MM treated on clinical trials is limited. TT approach uses all MM-active drugs upfront to target drug-resistant subclones during initial treatment to prevent later relapse. We report the longest follow up of MM trials (TT1 (NCT00580372), TT2 (NCT00083551), TT3a (NCT00081939) and TT3b (NCT00572169)) reported to date with RSRs to assess for curability. Methods: Pts treated on TT1, TT2, TT3a and TT3b were followed at the University of Arkansas for Medical Sciences after completion of therapy including multi-agent chemotherapy, high dose melphalan followed by tandem autologous stem cell transplantation (ASCT) and fixed duration maintenance therapy with introduction of thalidomide (thal) (TT2+thal vs TT2-thal), bortezomib (TT3a) and lenalidomide (TT3b). Expected survival rate was defined as probability of a population surviving from yr to yr. RSR was defined as ratio between observed survival of trials to expected survival in population adjusting for age and sex based on enrollment year. Data cut-off was October 10, 2022. Results: 1379 pts were enrolled (TT1:231, TT2:668, TT3a:303, TT3b:177) with median follow up duration of 16.6 years (yrs) (TT1:25 yrs, TT2:18.4 yrs, TT3a:16.2 yrs, TT3b:14.2 yrs). 10-yr PFS increased from 8.8% (TT1) to 15.5% (TT2-thal) to 25.1% (TT2+thal) to 32.9% (TT3a) to 42.4% (TT3b). Median OS improved over time (TT1:5.8 yrs, TT2:10.4 yrs, TT3a:11.9 yrs, TT3b:10.1 yrs). 15-yrs OS improved from 24.2% in TT1, 33% in TT2, 40% in TT3a and 37% in TT3b. 20-yr OS is 24.4% for pts treated on TT2 protocol. Outcomes were better for standard risk disease defined by low-risk gene expression profiling (GEP) with 20-yrs OS of 30% in TT2 and 15-yrs OS of 45% in TT3a. RSRs approach 1 at 10-15 yrs for TT1, but this occurs earlier, at 5-10 yrs, for TT2+Thal, TT3a and TT3b [Table]. No difference in RSR between TT3a and TT3b was noted. Relative excess risk (RER) showed an estimated 23%, 44% and 54% lower excess mortality when comparing TT2 (+ thal), TT2 (-thal) and TT3a with TT1, respectively. Conclusions: In the longest follow up duration of any MM clinical trial, a subset of MM pts are cured as evidenced by RSRs approaching 1. Approximately one third of pts treated on TT2 protocol and one-half pts treated on TT3a are alive at 20 year and 15 yrs from initial diagnosis, respectively. Incorporation of immunomodulatory drugs and proteasome inhibitors along with tandem ASCT resulted in cumulative improvement of OS as evidenced by lower RER of mortality. Clinical trial information: NCT00580372 , NCT00083551 , NCT00081939 , NCT00572169 . [Table: see text]
T cell exhaustion markers in multiple myeloma patients before and after physical activity intervention.
Authors: Joseph Janine , Hillengass Michaela , Tario Joseph , Attwood Kristopher , Groman Adrienne , Cannioto Rikki A. , Moysich Kirsten B. , Abrams Scott I , Hillengass Jens , Wallace Paul K
Published: June 2023

8060

Background: There is substantial evidence that the immune system is dysfunctional in multiple myeloma (MM). Adaptive immune cells, such as CD4+ and CD8+ T cells, are ineffective at controlling MM progression, suggesting immunosuppression. Therefore, efforts to overcome immunosuppression are likely key to more effective tumor control. Recent evidence from pre-clinical models suggests that exercise represents a non-pharmaceutical means to reduce immune exhaustion, but few studies have examined the relationship between an exercise intervention and biomarkers of immune exhaustion in cancer patients, especially in MM – the objective of this study. Methods: In this feasibility trial, 24 MM patients participated in a six-month physical activity intervention. The strength training arm (n=12) performed twice weekly supervised resistance trainings. The walking arm (n=12) engaged in an unsupervised, home-based wearable activity tracker intervention. Subjects provided peripheral blood samples before the start and at the conclusion of the intervention. Comprehensive flow cytometry was utilized to assess the frequency of mononuclear cells of interest, including CD4+ and CD8+ T cells and subpopulations expressing the markers of exhaustion PD-1 and/or TIGIT, which are the two exhaustion markers with the highest expression in this study sample. Ratios of exhausted cells (expressing any, one, or both of those markers) to non-exhausted cells (expressing no exhaustion markers) were calculated. Changes in the median values of these ratios were compared using Wilcoxon signed-rank tests. Results: Results from the immune panels are shown for the combined sample (n=24). All ratios of exhausted to non-exhausted cells were lower at the end of the six-month intervention, compared to baseline. The ratio of CD4+ TIGIT+ to non-exhausted CD4+ cells was significantly reduced, from 0.71 to 0.57 (p=0.04). The ratio of CD8+ PD-1+ to non-exhausted CD8+ cells was borderline significantly reduced, from 1.81 to 1.48 (p=0.06). Conclusions: This pilot study suggests that physical activity induces changes in MM patients’ immune systems, potentially rendering a less exhausted T cell state. Larger studies are warranted to examine how exercise alters activation vs exhaustion phenotypes within specific T cell subsets (naïve, central memory, effector memory, regulatory) and to elucidate the effects of strength-based vs aerobic exercise on T cell function. [Table: see text]
Clinical and financial implications of ADUARA trial on a real-world population.
Authors: Muthusamy Bharathi , Zabor Emily Craig , Pennell Nathan A.
Published: June 2023

8526

Background: In the ADAURA trial, adjuvant (adj) osimertinib improved disease free survival (DFS) in resected, EGFR-mutant ( EGFRm) Stage IB-IIIA NSCLC compared to placebo. Based on these results, the FDA approved osimertinib in the adj setting. In this study, we have evaluated the hypothetical clinical and financial effects of adj osimertinib on the early-stage, EGFRm NSCLC patients at Cleveland Clinic who were treated prior to the FDA approval. Methods: Starting in 2010, Cleveland Clinic has been performing targeted molecular testing in all resected NSCLCs. With this information, we created a database of patients from 01/2010 to 01/2021 with resected, non-squamous NSCLC. The standard of care (SOC) arm of this study consisted of patients with stage IB-IIIA, EGFRm disease from our internal database. Data for the adj osimertinib arm were obtained through a microsimulation study by first generating the per-stage DFS distribution in the SOC arm, and then applying the per-stage hazard ratios from ADAURA to obtain the parameters of the exponential DFS distribution with osimertinib treatment. Outcomes and costs, such as treatment and imaging, were directly calculated for the SOC arm based on the amount of time each patient spent in a recurrence-free or recurrent state, and whether there was CNS involvement at recurrence. Costs and outcomes were averaged across 1000 simulated datasets for the osimertinib arm. Based on ADAURA we assumed that 78.4%, 16.2%, and 5.4% of DFS events were CNS- recurrence, CNS+ recurrence, or death. Results: 1,487 patients were included in the database. 724 of these patients had stage IB-IIIA disease and EGFR testing. 82 patients were EGFRm+ (exon 19 deletion or the L858R mutation), and their survival outcomes were used in the SOC arm. At 5 years, 32 (39%) of the patients were alive and disease free. With the addition of adj osimertinib, an estimated average of 61 (71.4%) of patients would have been disease free and alive. This corresponds to an average improvement in 5-year DFS of 35.4%. The cost of testing all 724 patients would have been $2,865.80 per patient eligible for osimertinib with single-gene EGFR testing or $5,279.11 per eligible patient with targeted NGS testing. The total treatment and healthcare costs with adj osimertinib in the 82 patients would have been $49,057,952.75 or $598,267.72 per patient. With SOC (surveillance +/- adj chemotherapy + osimertinib only upon recurrence), total and per patients costs were $12,297,374.11 and $149,967.98 respectively. This corresponds to an average increase in total costs of $448,299.74 per person with the use of adj osimertinib. Conclusions: Over a decade at Cleveland Clinic, about 5.5% (82/1,487) patients with early stage NSCLC would have been affected by the adj osimertinib approval. In our simulation, we estimated adj osimertinib would have improved 5-year DFS by 35.4% (29 more patients) but with a significant financial cost of about $450,000 per eligible patient.
Phase I/II combination study of tifcemalimab with toripalimab in patients with refractory extensive stage small cell lung cancer (ES-SCLC).
Authors: Cheng Ying , Wang Jie , Yu Yan , Wang Qiming , Yang Runxiang , Lv Dongqing , Xia Bing , Yi Tienan , Li Chong , Wang Xicheng , Zhang Wei , Han Liang , Liu Xiaoqing , Shen Minjie , Xu Jing , Xue Peng , Wang Weihua
Published: June 2023

8579

Background: The B- and T-lymphocyte attenuator (BTLA) is a novel inhibitory co-signaling receptor expressed on B cell, T cells and NK cells. Co-blockade of the BTLA and PD-1 pathways improved antigen specific anti-tumor T cell response. Tifcemalimab (JS004 or TAB004) is a humanized IgG4 monoclonal antibody with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand HVEM. In previous phase I studies, tifcemalimab has shown preliminary anti-tumor activities as monotherapy or in combination with toripalimab (anti-PD-1) with a manageable safety profile in patients with advanced malignancies. Methods: Eligible ES-SCLC patients refractory to prior therapies were enrolled in this I/II study (NCT05000684). Patients received 200mg tifcemalimab and 240mg toripalimab intravenously once every three weeks until disease progression, intolerable toxicity or 2 years of treatment. Study objectives included safety, anti-tumor activity and correlative biomarkers. Results: As of Jan 31, 2023, a total of 43 ES-SCLC patients refractory to prior therapy were enrolled. The median age was 60.0 (range 38-75) years. The median prior line of therapy was 1 and 14 (32.6%) patients received prior anti-PD-1/L1 treatment. By the cut-off date, the median follow-up duration was 12.1 weeks. Thirty-two (74.4%) patients experienced treatment-emergent adverse events (TEAEs); 12 (27.9%) patients experienced grade ≥ 3 TEAEs. The most common TEAEs were hyponatraemia (16.3%), alanine aminotransferase increased (14%), aspartate aminotransferase increased (14%), and blood creatine phosphokinase increased (14%). Three (7.0%) patients experienced treatment-related adverse events (TRAEs) led to interruption of study drugs and no TRAEs led to discontinuation of study drugs were reported. Fifteen (34.9%) patients experienced immune related AE (irAEs), and 2 (4.7%) patients experienced grade ≥ 3 irAEs. Among 38 efficacy evaluable patients, the ORR was 26.3% and the DCR was 57.9%. The ORR was 8.3% in immunotherapy treated patients and 40.0% in immunotherapy naïve patients. By the cut-off date, 70.0% of the responses were ongoing and the median duration of response was not reached. Tumor expression of HVEM and PD-L1 was evaluated to explore the correlation with clinical response. Conclusions: Tifcemalimab in combination with toripalimab were well tolerated in patients with refractory ES- SCLC. Further clinical evaluation of this combination treatment in SCLC is warranted. Clinical trial information: NCT05000684 .
IFCT-2105 lurbiclin real-world effectiveness and treatment sequences in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) who received lurbinectedin as part of the French Early Access Program (EAP-ATU).
Authors: Girard Nicolas , Guisier Florian , Swalduz Aurélie , Van Hulst Sylvie , Pichon Eric , Lavaud Pernelle , Greillier Laurent , Tiotiu Angelica , Madroszyk Anne , Bylicki Olivier , Canellas Anthony , Belmont Laure , Zysman Maeva , Hauss Pierre-Alexandre , Godbert Benoit , Audigier-Valette Clarisse , Lebreton Cléa , Morin Franck , Westeel Virginie
Published: June 2023

8584

Background: Novel options are needed for pts with ES-SCLC after the failure of first-line chemotherapy. Lurbinectedin demonstrated efficacy in a landmark phase II study [Trigo et al. Lancet Oncol. 2020 May;21(5):645], and was granted EAP-ATU in France in June 2020. Methods: Multicenter, retrospective cohort of consecutive pts with histologically or cytologically confirmed ES-SCLC, who received at least one dose of treatment with lurbinectedin as part of the French EAP-ATU from June 2020 until March 2021, and gave consent for the data collection, were enrolled in 47 sites. Primary and secondary endpoints were description of clinical characteristics, and exposure to treatment, response, PFS, OS, safety. Results: 312 pts – 64% male, median age 65 years, 72% PS0-1, 47% with brain metastasis, 58% with previous immunotherapy – were enrolled. Lurbinectedin was administered as second-line in 44% of pts; 58% were chemotherapy-refractory. Pts received a median number of 3 cycles of lurbinectedin. Concurrent radiotherapy on metastases was delivered to 38% of pts. Lurbinectedin was discontinued because of progression/death/toxicity/other reasons in 83%/8%/5%/4% of pts. Grade3/4 events were observed in 9%/5% of pts. Response rate was 22% [95%CI 17-27%], disease control rate was 38% [95%CI 32-44%]. After a median follow-up of 20.8 months, median PFS and OS were 1.9 [95%CI 1.8-2] and 4.7 [95%CI 4-5.4] months; 6-month PFS and OS were 7% [4-10%] and 42% [95%CI 37-48%]. PS≤2 and chemotherapy-free interval≥90days were associated with significantly longer OS (HR = 0.71 [95%CI 0.53-0.95] and HR = 0.58 [95% CI 0.44-076] respectively). Main sites of progression were the lung (39% of pts), the brain (39% of pts), the liver (30% of pts), and the mediastinum (30% of pts). Subsequent treatment was administered to 154 pts after discontinuation of lurbinectedin, mostly consisting of topotecan (26% of pts); response/disease control rates, and median PFS of first subsequent treatment were 11% [95%CI 6-17%], 35% [95%CI 27-44%], and 1.9 [95%CI 1.7-2.3] months. Conclusions: Lurbinectedin provides an additional option from second-line for ES-SCLC, with efficacy outcomes comparable to that of historical treatments.
Assessing inpatient outcomes for patients with small cell lung cancer presenting with superior vena cava thrombosis.
Authors: Vakil Jay , Turk Ekrem , Olafimihan Ayobami Gbenga , Deenadayalan Vaishali , Litvin Rafaella , Obeidat Khaldun , Ibrahim Muhammad Bilal , Batra Kunnal
Published: June 2023

8589

Background: Superior Vena Cava Syndrome (SVCS) is a condition characterized by obstruction of the SVC that can commonly be caused by thrombus formation in the SVC. Small cell lung cancer (SCLC) frequently results in obstruction of the SVC. When severe enough, SVCS can present as a life-threatening oncological emergency. In this study we aim to explore baseline characteristics of SVC thrombosis (SVCT) in patients with SCLC, the prevalence of US hospitalizations, and disparities with regards to race and socioeconomic status. Methods: National Inpatient Sample was utilized to obtain pertinent data. Total hospitalizations with coexistent comorbidities of SCLC were extracted from the 2016 to 2019 database. Adult patients with a secondary diagnosis of SVC thrombosis were determined by using ICD-10 codes. We studied the racial and socioeconomic differences as well as length of stay (LOS), total hospital charges (THC), and all-cause mortality outcomes in cancer patients with and without SVC thrombosis. Statistical analysis was performed on STATA, with logistic regression analyses and chi-square tests. Results: A total of 480,750 patients were hospitalized for SCLC. 720 of these patients had SVC thrombosis (0.15% of SCLC patients). The mean age of those with thrombi was significantly lower compared to those without thrombi (64 vs. 69, p < 0.001). The SCLC with SVCT cohort had statistically higher proportion of black patients than the other cohort. Charlson index was significantly higher in SCLC with SVCT cohort (5.8 vs. 5, p < 0.001). Average income between the two cohort groups were similar. Medicaid and private insurance utilization were more common in SCLC with SVCT admissions compared to without SVCT. Patients presenting with SVC thrombosis had an increased hospital LOS (10 vs. 6 days, p < 0.001) and cost compared to other cohorts ($117,320 vs. $80,806, p < 0.005). All-cause mortality in patients with SCLC was 7.7% and the presence of SVC thrombosis significantly increased the odds of inpatient mortality (18.0%). Non-White races were associated with higher odds of mortality in SCLC admissions. In addition, patients with SVC thrombus also had greater odds of having a concomitant pulmonary embolism during hospitalization. Conclusions: In this study we found that race, insurance type, and comorbidities impacted the likelihood of developing thrombosis in the superior vena cava in patients with SCLC. Though the incidence is rare, SVC thrombosis indicates a poor prognostic factor for patients with SCLC. Further studies to evaluate these disparities in race and socioeconomic factors are warranted. The development of thrombosis and subsequent SVC syndrome is a potentially life-threatening condition; addressing potential reversible risk factors could improve mortality in a large subgroup of hospitalizations related to SCLC.
Role of consolidative thoracic and prophylactic cranial radiation in extensive stage small cell lung cancer in chemo-immunotherapy era.
Authors: Khatri Jai Kumar , Voland Rick , Flickinger John Charles , Tirona Maria Tria , Pacioles Toni , Dotson Jennifer , Jamil Muhammad Omer , Anwar Khurram , Yadala Vivek , Wright Thomas , DeCamp Malcolm , Shweihat Yousef , Zander Zani S , Cooper Mark Hayden , Varlotto John M.
Published: June 2023

8595

Background: The role of consolidative thoracic and prophylactic brain radiation in extensive stage small cell lung cancer patients is controversial. We investigated the factors associated with the use of any radiation therapy (RT) and whether Radiation has a benefit to overall survival (OS) in the total patient group and whether this benefit is the same if Chemotherapy (CT) only is used, or chemo-immunotherapy (CT-IO) is used. Methods: The NCDB database was queried from years 2017-2019. Patients receiving systemic therapy- STX (CT or CT-IO) had to have at least 6 months of follow-up and have no brain metastases at diagnosis. All RT patients had to receive upfront systemic therapy, were treated 2 to 6 months from diagnosis, and if treated to the brain received 25Gy in 10 fractions only. Multi-variate analyses (MVA) were used to determine factors associated with OS and selection for any radiation. Propensity matching for factors affecting OS were used to generate Kaplan-Meier OS curves. Log-rank tests were used to determine differences in Kaplan Meier survival curves for the effects of RT on OS. Results: The total number of patients receiving RT or systemic therapy alone as well as their median follow-ups(months(mn) were (981, 33.02mn) and (8909, 30.59mn). The median time to the start of STX and RT were 22days and 135 days respectively. MVA noted that RT had a greater effect on OS (Thoracic, Brain, Both – HRs = 0.78, 0.75, and 0.68) than other interventions including IO (HR 0.87) and palliative care without RT (HR 1.07). Selection for radiation depended significantly upon factors affecting OS(HR) including liver metastases (0.59), females (1.21), age/10yr(0.78) and Charlson co-morbidity index of > 3(0.66), but did not depend upon insurance status, race, or county income/high school graduation rates. Propensity score matched OS curves noted the same effects of RT on OS whether CT or CT-IO was given. The lowest HRs were noted when both thoracic and brain RT were given (see table). Conclusions: The patient with extensive stage small cell lung cancer who reach candidacy and receive RT may have a significant improvement in OS compared to the patients treated only with CT or CT-IO. Combined thoracic and prophylactic brain RT seems to be better than either one alone. The impact of radiation whether given to one or two sites may be more beneficial than immunotherapy added to chemotherapy. [Table: see text]
Safety and preliminary efficacy of YK-029A, a novel EGFR TKI, in patients with advanced NSCLC harboring ex20ins, T790M or rare mutations.
Authors: Duan Jianchun , Zhao Jun , Zhang Li , Liu Baogang , Ren Xiubao , Li Mingjun , Shen Bo , Miao Liyun , Dai Xiumei , Pan Yueyin , Li Yupin , Yao Yu , Yang Kunyu , Wu Lin , Zhou Chengzhi , Yu Qitao , Xie Yanyan , Zeng Shan , Wang Jie ,   YK-029A-ASCO Authors' Group
Published: June 2023

9014

Background: This study aimed to evaluate the safety and preliminary efficacy of YK-029A, a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in treated or untreated patients with advanced NSCLC. Methods: This dose-escalation and dose-expansion phase 1 trial recruited previously untreated or treated patients with EGFR ex20ins mutant locally advanced or metastatic NSCLC and previously treated patients with EGFR T790M or rare mutations. In dose-escalation phase, patients with EGFR T790M mutation were enrolled. YK-029A was given at doses of 50, 100, 150, 200 to 250 mg/day (3+3 design). In dose-expansion phase, patients with EGFR T790M, EGFR ex20ins, or rare mutations were enrolled. The primary objective was safety. Dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) were explored. In the treatment-naïve cohort of EGFR ex20ins mutant NSCLC, patients were administered oral YK-029A 200 mg once daily in a 28-day cycle, and efficacy was assessed by the independent review committee. The study was registered (chinadrugtrials.org.cn,CTR20180350). Results: A total of 108 were included in the safety analysis set. DLT did not occur in dose-escalation phase. MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade and grade≥3 occurred in 106 (98.1%) and 41 (38.0%) patients, respectively. Treatment-related adverse events (TRAEs) of any grade and grade≥3 occurred in 102 (94.4%) and 30 (27.8%) patients, respectively. One patient had liver abscess related to YK-029A and died. Three patients terminated the treatment because of TEAEs. The most common TRAEs were diarrhea (46.3%), anemia (38.0%), and rash (32.4%). For the treatment-naïve EGFR ex20ins mutant cohort, 26 patients were included in the efficacy analysis set. Most patients were adenocarcinoma (96.4%) and at stage IV (85.7%). At the cut-off date on October 30, 2022, 19 patients (73.1%) had partial remission, five patients (19.2%) had stable disease, and two patients (7.7%) developed disease progression. The confirmed objective response rate achieved 73.1% (95% confidence interval [CI], 52.21% to 88.43%). The median progression-free survival was 9.3 months (95% CI, 5.85 to not evaluated). Conclusions: YK-029A was well tolerated and showed preliminary efficacy in treatment-naïve EGFR ex20ins mutant patients with locally advanced or metastatic NSCLC. [Table: see text]
Impact of EML4-ALK fusion variant and co-occurring TP53 mutation on treatment duration of first-line next-generation ALK TKIs in ALK fusion+ NSCLC.
Authors: Parikh Kaushal , Dimou Anastasios , Leventakos Konstantinos , Wan Yin , Lin Huamao Mark , Vincent Sylvie , Elliott Jennifer , Bonta Ioana R
Published: June 2023

9029

Background: Molecular biomarkers such as EML4-ALK fusion variant 3 (V3) and TP53 mutation are associated with poor prognosis in patients (pts) with anaplastic lymphoma kinase fusion positive ( ALK+) non–small cell lung cancer (NSCLC). We evaluated the effect of EML4-ALK fusion variants and TP53 mutation status on time to treatment discontinuation (TTD) of first-line (1L) treatment with a next-generation ALK tyrosine kinase inhibitor (TKI) in pts with ALK+ NSCLC in the real-world setting. Methods: Pts with advanced/metastatic NSCLC who were ALK+ in circulating tumor DNA by Guardant360 (G360) liquid biopsy test from Jan 1, 2018, to Dec 31, 2021, and received 1L monotherapy with a next-generation ALK TKI (alectinib, brigatinib, ceritinib, lorlatinib) were identified in the Guardant INFORM clinical-genomics database. Median TTD of 1L ALK TKI treatment was determined by Kaplan-Meier (KM) methods. The impact of EML4-ALK fusion variant and TP53 mutation status on TTD was evaluated. Results: Database search identified 495 pts with advanced/metastatic NSCLC who had ALK fusion by G360; of these, 214 pts received 1L treatment with a next-generation ALK TKI; 164 had G360 testing before treatment (alectinib, n=147; brigatinib, n=7; ceritinib, n=2; lorlatinib, n=8). Among these 164 pts, median age was 58.6 y, 53% were female, and 29% had baseline brain metastases. Median follow-up from start of 1L treatment was 14.8 mo. Median TTD was 19.6 mo (95% CI: 13.6–not reached [NR]). TP53 mutations were detected in 66 pts (40%). Median (95% CI) TTD in pts with TP53 mutation vs WT was 17.1 (9.5–28.5) vs 21.9 mo (14.3–NR; log-rank P=0.1712). Of 130 pts with EML4-ALK fusion variant type detected, 63 (48%) had V1, 54 (42%) V3, 8 (6%) V2, 4 (3%) V5, and 1 (1%) V8. In pts with EML4-ALK fusion V1 vs V3, median (95% CI) TTD was 19.0 (13.6–NR) vs 21.8 mo (8.7–NR; HR: 0.73; log-rank P=0.3039), with the KM plot showing numerically longer TTD in pts with V1 vs V3 during the first 18 mo and lines crossing at the tail end. Of 117 pts with both an EML4-ALK fusion variant (V1/V3) and TP53 data, 21 (18%) had both V3 and a TP53 mutation. Pts with co-occurring EML4-ALK V3 and TP53 mutation had the shortest TTD (median TTD 8.7 [3.9–NR; HR: 2.59; P=0.0219]; Table). Conclusions: Among pts with NSCLC and ALK fusion, co-occurrence of EML4-ALK V3 and TP53 mutation is common and associated with poor prognosis and high risk of early discontinuation of 1L treatment with a next-generation ALK TKI, most likely due to disease progression. Additional novel or combination therapies are warranted for this subpopulation. [Table: see text]