tbuckley/cabot-search huggingface dataset:
Investigation of the role of personalized molecular residual disease in the assessment of high-risk non-small cell lung cancer (NSCLC) post-operation.
Authors: Yu-Heng Zhou, Yaobin Lin, Bing-Yu Rao, Shoucheng Feng, Jiaman Teng, Shaochen Cheng, Jiasheng Zhong, Hao Long
Journal: Journal of Clinical Oncology (2024)

8027 Background: Radical surgical resection is preferred treatment for early-stage Non-Small Cell Lung Cancer (NSCLC) patients. Despite this, recurrence and metastasis significantly impact patient survival. High-risk factors like Tumor Thrombus (TT) and Spread Through Air Spaces (STAS) are known to exacerbnate the recurrence and metastasis rates, yet there is lacking research exploring the association between these riskes and treatment outcomes. The study aims to evaluate the utility of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) in assessing and monitoring high-risk NSCLC post-operatively. Methods: NSCLC patients underwent curative surgery (R0) were recruited in this study and their tissue samples were collected after surgical resection. Whole exome sequencing (WES) was performed to identify somatic mutation information across individual, from which bespke molecular residual disease (MRD) detection panel was designed and used in later detection. Plasma samples were collected 3-4 weeks post-surgery and analyzed for MRD status through using next-generation sequencing (NGS) at 100,000x sequencing depths. Results: The study enrolled 124 NSCLC patients with a median age of 60 years (ranged 29-86)., The cohort comprised 63 male (77.3%) and 61 females (22.7%). Pathologically, 92 patients were classified in stage I, 5 as stage II, 17 as stage III, and 10 as stage IV. A total of 10,260 somatic mutationwere identified across 6,315 genes, including 639 insertions/deletions (InDels), 9613 single nucleotide variants (SNVs), and 8 gene fusions. The most prevalent mutations were EGFR (58.87%), followed by TTN (45.97%), TP53 (40.32%), CEP192 (20.97%), XIRP2 (19.35%), ZFHX4 (19.35%), and TOPAZ1 (16.94%). The MRD positivity was observed in 29.0% (36/124) of patients, with a higher incidence in males (34.9%, 22/63) than females (22.9%, 14/61). By stage, MRD positivity was 16.3% (16/92) in stage I, 40.0% (2/5) in stage II, 47.0% (8/17) in stage III, and 100% (10/10) in stage IV patients. Among patients with risk factors, 31.6% (12/38) with STAS, , 60.0% (6/10) with TT, and 53.8% (7/13) with pleural invasion were MRD positive, which indicating a higher postoperative MRD positivity in high-risk groups. Conclusions: NSCLC patients with high-risk factors, such as STAS and TT, , exhibit a high rate postoperative MRD positivity, even after R0 resection. Current research reports indicate that the MRD post-operation is an indicator of recurrence, metastasis, and poor prognosis. The findings imply that NSCLC patients harboring these high-risk factors are more susceptible to recurrence and metastasis, possibly necessitating postoperative adjuvant therapy for effective management.
Cost-effectiveness in perioperative therapy in the era of immune checkpoint inhibitors.
Authors: Masahiro Fujioka, Toshihiko Aranishi, Takehito Shukuya, Yukina Shirai, Kazuhisa Takahashi
Journal: Journal of Clinical Oncology (2024)

8021 Background: The use of immune checkpoint inhibitors (ICIs) in lung cancer treatment, particularly in perioperative therapy, has significantly expanded. In Japan, atezolizumab was approved in 2022 for adjuvant therapy and nivolumab in 2023 for neoadjuvant therapy. Despite the long-term prognosis improvements associated with ICIs, their high costs have escalated healthcare expenses. This study evaluates the cost-effectiveness of perioperative therapies incorporating ICIs in Japan. Methods: A network meta-analysis (NMA) was conducted to derive hazard ratios (HRs) for disease-free survival (DFS) and overall survival (OS) from pivotal phase 3 clinical trials. Additionally, a partitioned survival model was developed to calculate quality-adjusted life years (QALYs) and life years (LYs). Cost data included drug and administration costs based on standard regimens. Results: ICIs with available DFS and OS data included atezolizumab, nivolumab, and pembrolizumab for adjuvant, neoadjuvant, and sandwich therapy, respectively. HRs (DFS/OS) compared to no perioperative therapy were as follows: adjuvant chemotherapy (0.81/0.86), neoadjuvant chemotherapy (0.87/0.80), adjuvant ICI (0.66/0.86), neoadjuvant ICI (0.55/0.49), and sandwich therapy (0.51/0.58). Cost/QALY/LY for each treatment were: no perioperative therapy (¥831,379/2.55/3.57), adjuvant chemotherapy (¥969,600/2.67/3.73), neoadjuvant chemotherapy (¥903,046/2.71/3.82), adjuvant ICI (¥9,209,863/2.70/3.74), neoadjuvant ICI (¥2,760,383/3.02/4.22), and sandwich therapy (¥8,235,047/2.95/4.10). Incremental cost-effectiveness ratios (ICERs) per QALY/LY were ¥425,189/¥295,036 for neoadjuvant chemotherapy and ¥6,152,576/¥4,592,090 for neoadjuvant ICI ($1 = \145). ICERs were not calculated for adjuvant chemotherapy, adjuvant ICI, and sandwich therapy due to extended dominance. Conclusions: In Japan, the general ICER threshold is ¥5,000,000, and ¥7,500,000 for treatments requiring special consideration, such as cancer therapies. The ICER for neoadjuvant chemotherapy was below the general threshold, and neoadjuvant ICIs below the special consideration threshold, making them cost-effective options for NSCLC patients in Japan. Other therapies were dominated, primarily due to 1) adjuvant chemotherapy being marginally more expensive and less effective than neoadjuvant chemotherapy, and 2) the high costs of long-term post operative ICI treatment for adjuvant ICI, and sandwich therapy.
Real-world outcomes of lisocabtagene maraleucel (liso-cel) in patients (pt) with Richter transformation (RT) from the Center for International Blood and Marrow Transplant Research (CIBMTR).
Authors: Allison Marie Winter, Sushma Bharadwaj, Alex Francisco Herrera, Chaitanya Iragavarapu, Sayeef Mirza, Maria Lia Palomba, Sagar S. Patel, Mecide Meric Gharibo, David Bernasconi, Tracy Krimmel, Fei Fei Liu, Debasmita Roy, Marcelo C. Pasquini
Journal: Journal of Clinical Oncology (2024)

7010 Background: Pts with RT have poor prognosis and no standard treatment options with median OS of 3–12 mo (Eyre TA. Hematology Am Soc Hematol Educ Program 2023), indicating an unmet need. We report the largest cohort of real-world pts with RT treated with commercial liso-cel, an autologous, CD19-directed, 4-1BB CAR T cell product. Methods: This analysis included US pts with RT from the CIBMTR who received commercial liso-cel between 02/2021 and 02/2023. Primary outcomes included ORR, CR rate, duration of response (DOR), PFS, OS, and safety (including cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] based on Lee 2018 criteria, and prolonged cytopenia defined as grade [gr] 4 thrombocytopenia and/or neutropenia persistent at 30 d after infusion). Results: At data cutoff (08/04/2023), 30 pts with RT were included. Demographics and baseline characteristics at liso-cel infusion are shown in the Table; additional data regarding the pts’ indolent disease and treatment history will be provided in the presentation. Median time from leukapheresis to liso-cel infusion was 35 d (range, 28–63). At median follow-up of 12.3 mo, ORR was 76% among evaluable pts (n = 29) with 66% in CR. Median time to first response was 1.1 mo (range, 0–3.1). Median DOR was not reached (NR); 12-mo DOR rate was 77% (95% CI, 49.5–91). Median PFS (n = 29) and median OS (n = 30) were NR; estimated 12-mo PFS was 54% (95% CI, 33–72) and 12-mo OS was 67% (95% CI, 44–83). Overall, 70% of pts had CRS (gr 3, 0; gr 4, 3%; gr 5, 3% [this pt also had hemophagocytic lymphohistiocytosis]); most common CRS treatments were corticosteroids and tocilizumab (23%) and tocilizumab (20%). ICANS was seen in 47% of pts (gr 3, 17%; gr 4, 10%; gr 5, 0) and most commonly treated with corticosteroids (23%), antiepileptics and corticosteroids (7%), and antiepileptics (7%). Prolonged cytopenia occurred in 17% of pts. One pt had a second primary malignancy (gastrointestinal). Eight (27%) pts died, including 7 because of progression. Conclusions: Pts with RT have poor prognosis with a high unmet need. Here, we show that liso-cel provided meaningful clinical benefit with low incidences of gr ≥ 3 CRS and ICANS observed. The high CR rate is promising in this difficult-to-treat population, and longer follow-up in a larger cohort is needed. [Table: see text]
Lisocabtagene maraleucel (liso-cel) vs standard of care (SOC) with salvage chemotherapy (CT) followed by autologous stem cell transplantation (ASCT) as second-line (2L) treatment in patients (pt) with R/R large B-cell lymphoma (LBCL): 3-year follow-up (FU) from the randomized, phase 3 TRANSFORM study.
Authors: Manali Kirtikumar Kamdar, Scott R. Solomon, Jon Arnason, Patrick B. Johnston, Bertram Glaß, Veronika Bachanova, Sami Ibrahimi, Stephan Mielke, Pim Mutsaers, Francisco J. Hernandez-Ilizaliturri, Koji Izutsu, Franck Morschhauser, Matthew Alexander Lunning, Victor A. Chow, Josu Santamaria, Silvia Colicino, Ken Ogasawara, Lara Stepan, Jeremy S. Abramson
Journal: Journal of Clinical Oncology (2024)

7013 Background: Liso-cel is an autologous, CD19-directed, 4-1BB CAR T cell product. In prespecified interim and primary analyses of TRANSFORM (NCT03575351), liso-cel showed significant improvements in efficacy vs SOC in pts with R/R LBCL. Here we report results after ~3-y FU. Methods: TRANSFORM is a randomized phase 3 study comparing liso-cel vs SOC (CT [R-DHAP, R-ICE, or R-GDP] then high-dose CT [HDCT] + ASCT) in adults aged ≤ 75 y with LBCL primary refractory to or relapsed ≤ 12 mo after first-line therapy and eligible for ASCT. Liso-cel arm pts underwent lymphodepletion followed by liso-cel (100 × 10 6 CAR + T cells). Bridging therapy was allowed. SOC arm pts received 3 cycles of CT; responding pts proceeded to HDCT + ASCT. Crossover to receive liso-cel was allowed for SOC arm pts if criteria were met. The primary endpoint was event-free survival (EFS) per independent review committee (IRC). Key secondary endpoints included CR rate and PFS per IRC, and OS. Endpoints were not statistically retested and are reported descriptively. Results: In total, 184 pts were randomized (92 per arm); baseline characteristics were reported (Abramson et al. Blood 2023). Median (range) FU was 33.9 mo (0.9–53.0). Median EFS, PFS, and duration of response (DOR) were longer for liso-cel vs SOC, similar to the primary analysis (Table). A total of 61 (66%) SOC arm pts crossed over to receive liso-cel. Median OS was not reached (NR) in either arm; 36-mo OS rates were numerically higher for liso-cel. Of 76 total deaths (liso-cel, n = 34; SOC, n = 42 [crossover pts, n = 33]), 10 occurred since the primary analysis (liso-cel, n = 6; SOC, n = 4 [all crossover pts]); most were due to disease progression or complications (n = 6). Safety results were consistent with the primary analysis. Cellular kinetics and B-cell aplasia will be presented. Conclusions: After median FU of 33.9 mo, liso-cel as 2L treatment in pts with primary refractory or early relapsed LBCL resulted in deepening of response and continued improvement in efficacy endpoints over SOC, confirming the ongoing benefit of liso-cel. Clinical trial information: NCT03575351 . [Table: see text]
Lisocabtagene maraleucel (liso-cel) in patients (pt) with R/R mantle cell lymphoma (MCL): Subgroup analyses by number of prior systemic lines of therapy (LOT) and by response to prior Bruton tyrosine kinase inhibitor (BTKi) from the TRANSCEND NHL 001 MCL cohort (TRANSCEND-MCL).
Authors: Maria Lia Palomba, Tanya Siddiqi, Leo I. Gordon, Manali Kirtikumar Kamdar, Matthew Alexander Lunning, Alexandre V. Hirayama, Jeremy S. Abramson, Jon Arnason, Nilanjan Ghosh, Amitkumar Mehta, Charalambos Andreadis, Scott R. Solomon, Ana Kostic, Ashvin Singh, Ricardo Espinola, Rashmi Bhatnagar, Anthony Raviele, Michael Wang
Journal: Journal of Clinical Oncology (2024)

7016 Background: In the TRANSCEND-MCL (NCT02631044) primary analysis, the CD19-directed, CAR T cell product liso-cel demonstrated a high, durable CR rate (CRR) with manageable safety in pts with heavily pretreated R/R MCL. Here, we report outcomes by number of prior LOTs and by response to prior BTKi. Methods: Pts had PET-positive R/R MCL after ≥ 2 prior systemic LOTs, including BTKi, alkylating, and CD20-targeted agents. Pts received liso-cel after lymphodepleting chemotherapy. Bridging therapy was allowed. Primary endpoints were treatment-emergent AEs (TEAE) and ORR by independent review committee (IRC) per Lugano 2014 criteria; secondary endpoints included CRR, duration of response (DOR), PFS, and OS. Results: 88 pts received liso-cel. Median follow-up was 16.1 mo (range, 0.4–60.5). For all pts, CRR was 72%; median DOR, PFS, and OS were 15.7, 15.3, and 18.2 mo, respectively (Table). ORR, CRR, and median DOR, PFS, and OS were similar to all pts for most subgroups, but numerically lower in pts with ≥ 5 prior LOTs and pts refractory to prior BTKi. Grade (gr) ≥ 3 TEAEs ranged from 67–96% across subgroups, similar to all pts (86%); most common gr ≥ 3 TEAE was neutropenia (33–58%). Most cytokine release syndrome (CRS) and neurological events (NE) were gr 1–2 (Table) with no gr 5 CRS/NE. Gr ≥ 3 infection (11–19%) and prolonged cytopenia (32–50%) in subgroups were similar to all pts (15% and 40%). Cellular kinetics will be presented. Conclusions: In TRANSCEND-MCL, all subgroups benefited from liso-cel and responses were generally comparable to the overall population, with numerically shorter duration in pts with ≥ 5 prior LOTs and disease refractory to prior BTKi, supporting study of liso-cel in earlier LOTs. Clinical trial information: NCT02631044 . [Table: see text]
A phase II, open-label, combination therapy of durvalumab and ceralasertib in relapsed and refractory small cell lung cancer (SUKSES-N4).
Authors: Se-Hoon Lee, Jiyeon Kim, Sehhoon Park, Peter G. Mortimer, Heejung (Rosa) Kim, Simon Smith, Emma Dean, Yu Jung Kim, Hyun Ae Jung, Jong-Mu Sun, Woong-Yang Park, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park
Journal: Journal of Clinical Oncology (2024)

8104 Background: In extensive stage small-cell lung cancer (SCLC), the standard first-line treatment is an immune checkpoint inhibitor (ICI) combined with chemotherapy. However, in the relapsed or refractory setting, the benefits of ICI-based combinations are modest, regardless of prior ICI exposure. Ceralasertib, a selective ATR inhibitor, not only enhances DNA damage, inducing apoptosis, but also affects immune and inflammatory pathways. This study assesses the safety and efficacy of combining durvalumab with ceralasertib in SCLC patients. Methods: This open-label, phase II, multi-cohort umbrella trial recruited relapsed and refractory SCLC patients independent of biomarker status. Initially, patients received 1500mg of durvalumab on day 1, followed by 240mg of ceralasertib twice daily from day 15 to 28 of a 28-day cycle (Dose A). An amendment aligned the dosing regimen to other studies to 240mg of ceralasertib twice daily from day 1 to 7, with 1500mg of durvalumab administered on day 8 (Dose B). The primary endpoint was the objective response rate (ORR), with a target enrollment of 40 evaluable patients. Results: Between June 2022 and May 2023, forty-two patients were recruited (Dose A: 27; Dose B: 15). The median age was 67 (range: 43-83), with a predominance of males (n = 36) and smokers (n = 40). ECOG PS scores were 0 (n = 1) or 1 (n = 41), and nearly half (n = 20, 47.6%) had prior ICI exposure. The ORR per RECIST was 9.5%, with a disease control rate of 26.2%, including 4 partial responses (PR) and 7 cases of stable disease (SD). Median progression-free survival (PFS) was 1.64 months (95% CI: 1.61-1.97), and overall survival was 7.16 months (95% CI: 6.07-13.9). The duration of responses was notable, showing PFS of 4.8, 17.0, and 18.3 months in ICI-naïve PR patients and 14.1 months in ICI-exposed patient currently still ongoing on treatment. A sustained clinical benefit of up to 10.7 months was observed in an ICI-naïve patient with SD. Hematologic adverse events (AEs) included thrombocytopenia as grade 4 (n = 9) and grade 3 (n = 3), anemia as grade 3 (n = 3), and neutropenia as grade 4 (n = 3) and grade 3 (n = 1). Other AEs were mostly grades 1 or 2 and manageable. Exploratory biomarker analysis is in progress and will be presented. Conclusions: Ceralasertib and durvalumab combination therapy have demonstrated durable responses in select patients with manageable hematologic toxicity. Biomarker research is ongoing to identify patients most likely to benefit from this treatment strategy. Clinical trial information: NCT04361825 .
A phase II study of tislelizumab (TIS) and chemotherapy as neoadjuvant therapy for potentially resectable stage IIIA/IIIB non-small cell lung cancer (NSCLC).
Authors: Ting Wang, Lu Li, Lin Huang, Jie Wei Liu, Da Xing Zhu, Jing Si Dong, Han Yu Deng, Xi Zheng, Long Tian, Li Li Jiang, Wei Ya Wang, Ping Zhou, Ming Gang Su, Dan Pu, Xu Yu Cai, Ming Yang Feng, Xue Jin Ou, Yongsheng Wang, Qing Hua Zhou
Journal: Journal of Clinical Oncology (2024)

8024 Background: Neoadjuvant immunotherapy and chemotherapy provide more surgical opportunities and survival benefits to potentially resectable locally advanced NSCLC remains unclear. Herein, we initiated a phase II study to evaluate the feasibility of neoadjuvant immunotherapy and chemotherapy in stage IIIA/IIIB NSCLC. We report the the updated analysis of the study. Methods: Patients (pts) with stage IIIA/IIIB EGFR/ALK/ROS wild-type NSCLC received 2 cycles of neoadjuvantchemoimmunotherapy (PD-1 inhibitor TIS, nab-paclitaxel, and cisplatin/carboplatin) and were reassessed for surgery.Thereafter, pts underwent surgery within 6 weeks and continued 2 cycles of TIS plus chemotherapy, followed by up to 15 cycles of TIS monotherapy. The primary endpoint was R0 resection rate, and secondary endpoints included major pathologic response (MPR), pathologic complete response (pCR), 1/2-year EFS rate, and overall survival, etc. Results: From Jan 2021 to Sep 2023, 33 pts were enrolled; 19 (58% ) pts with IIIA and 14 (42%) pts with IIIB disease, As of 14 Sep 2023, 27 pts completed neoadjuvant and 25 pts underwent resection. and 6 pts were on neoadjuvant. 2 pts downstaging had obvious downstaging after neoadjuvant treatment and were unwilling to surgery. 24 of 25 pts (96%) underwent successful R0 resection (Table). Of 25 pts who underwent resection,8 (32%) pts achieved pCR, 15 (60%) pts achieved pathologic response rate.Of the 7 pts who achieved MPR, 5 had only about 1% viable tumor cells in the resection specimen. The overall response rate (ORR) and disease control rate (DCR) were 88% (22/25) and 100 % (25/25), respectively. The clinical downstaging occurred in 22 of 25 pts (88%).The pathological downstaging occurred in 23 of 25 pts (92%).And The 1-year EFS rate 82.3% (95%CI 58.3-93.2), 2-year EFS rate 76.4% (95%CI 51.1-89.8). Conclusions: Neoadjuvant TIS plus chemotherapy increased surgical opportunities and survival benefits in potentially resectable locally advanced stage IIIA/IIIB NSCLC. [Table: see text]
Outcomes in high-risk subgroups after fixed-duration ibrutinib + venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Up to 5.5 years of follow-up in the phase 2 CAPTIVATE study.
Authors: William G. Wierda, Ryan Jacobs, Paul M. Barr, John N. Allan, Tanya Siddiqi, Alessandra Tedeschi, Thomas J. Kipps, Susan Mary O'Brien, Xavier C. Badoux, Andrea Visentin, Masa Lasica, Dennis Carney, Anna Elinder Camburn, Javier De La Serna Torroba, Edith Szafer-Glusman, Cathy Zhou, Anita Szoke, James P. Dean, Paolo Ghia, Constantine S. Tam
Journal: Journal of Clinical Oncology (2024)

7009 Background: The phase 2 CAPTIVATE study evaluated first-line ibrutinib (Ibr) + venetoclax (Ven) for CLL/SLL in 2 cohorts: minimal residual disease (MRD)-guided randomized discontinuation (MRD cohort) and Fixed Duration (FD cohort). Ibr±Ven retreatment was allowed in patients (pts) who had progressive disease (PD). Here, we report outcomes for pts with high-risk genomic features from the FD cohort and retreatment outcomes in pts from the FD cohort and MRD cohort placebo arm. Methods: Pts aged ≤70 y with previously untreated CLL/SLL without restriction on genomic risk factors received 3 cycles of Ibr, then 12 cycles of Ibr+Ven (Ibr, 420 mg/d orally; Ven, 5-wk ramp up to 400 mg/d orally). On-study retreatment included single-agent Ibr (FD cohort or MRD cohort placebo arm); pts with PD &gt;2 y after end of treatment (EOT) could be retreated with FD Ibr+Ven (FD cohort). Results: In the FD cohort (n=159) with a median follow-up of 61.2 mo (range, 0.8–66.3), 5-y PFS and OS rates (95% CI) were 67% (59–74) and 96% (91–98), respectively. 5-y PFS rates were higher in pts with undetectable MRD at 3 mo after EOT in peripheral blood (83%) or bone marrow (84%) vs those without (48% and 50%, respectively). 5-y PFS rates (95% CI) in pts with genomic risk factors were: del(17p)/mutated TP53 41% (21–59), complex karyotype 57% (37–72), del(11q) 64% (30–85), and unmutated IGHV 68% (50–80) (Table). In total, 18 second malignancies occurred in 13 pts (10 events in 8 pts during FD Ibr+Ven, 6 events in 4 pts after EOT and before retreatment, and 2 events in 2 pts during retreatment). Of 202 pts who completed Ibr+Ven (FD cohort, n=159; MRD cohort placebo arm, n=43), 63 have had PD to date; PD occurred &gt;2 y after EOT in 43/63 pts (68%). 32/63 (51%) pts initiated retreatment with Ibr (n=25) or Ibr+Ven (n=7). With a median time on Ibr retreatment of 21.9 mo (range, 0.03–50.4), ORR was 86% in 22 evaluable pts (best response: 1 CR; 1 nodular PR; 17 PR; 2 SD; 1 PD [Richter transformation]). With a median time on Ibr+Ven retreatment of 13.8 mo (range, 3.7–15.1), ORR was 71% in 7 evaluable pts (best response: 1 CR; 4 PR; 1 PR with lymphocytosis; 1 SD). Conclusions: With up to 5.5 y of follow-up, FD Ibr+Ven continues to provide clinically meaningful PFS in pts with high-risk genomic features, as well as in the overall population. Ibr-based retreatment provides promising responses in pts needing subsequent therapy after the all-oral FD regimen of Ibr+Ven. Clinical trial information: NCT02910583 . [Table: see text]