tbuckley/cabot-search huggingface dataset:
Real-world treatment patterns and outcomes in patients with myelofibrosis treated with pacritinib in the United States.
Authors: Michael Marrone, Robert Geller, Abiola Oladapo, Purvi Suthar, Anupama Vasudevan, Michael Vredenburg, Jia Zeng, Raajit Rampal, John Mascarenhas
Journal: Journal of Clinical Oncology (2024)

6579 Background: Pacritinib (PAC), a JAK1 sparing JAK2/IRAK1/ACVR1 inhibitor, has shown clinically significant activity in spleen volume and symptom reduction in patients (pts) with thrombocytopenic myelofibrosis (MF). Thrombocytopenic MF is challenging to manage and pts with platelets (PLT) &lt;50 x10 9 /L have limited median overall survival (OS) of 15 months (mo) (Masarova 2018). Since approval as the only agent for thrombocytopenic MF, real-world evidence of PAC use is limited. This study aims to assess treatment patterns, hematological outcomes, and survival in pts with MF treated with PAC in the US. Methods: For this retrospective study, Integra-PrecisionQ de-identified database was used to locate pts with MF (ICD-10: 75.81, D47.4) treated with PAC from 6/1/2022 to 8/31/2023. Treatment-related outcomes include PLT and hemoglobin (Hb) levels from PAC initiation (index) and 30-day intervals post-index. OS was assessed from index through the end of the study period. Data are presented as medians and interquartile ranges (IQR). Results: 142 pts with MF were treated with PAC, the majority being male (60%) or White (66%), with a median age at MF diagnosis of 72 years and median of 13.4 mo from diagnosis to index. In pts receiving ≥2 nd line (2L) PAC (65.5%), the median time from the end of prior MF therapy to PAC initiation was 1 day. Median follow up from index was 6 mo and median exposure to PAC during the observation period was 5.3 mo. In pts with PLT and Hb levels at index and follow up, 28.5% (34/119) had severe thrombocytopenia (PLT&lt;50 x10 9 /L) at index and 29% (35/119) had severe anemia (Hb &lt;8.0 g/dL). Median PLT count was 81 x10 9 /L (47.5,179) at index (n=119) and 96 x10 9 /L (68.5,125) at post-index day 360 (n=15). Median Hb level was 8.8 g/dL (7.9,10.3) at index (n=119) and 10.4g/dL (9.2,11.6) at post-index day 360 (n=15). Increases in PLT and Hb were observed across index PLT and Hb groups over follow up (Table 1). 1-year OS probability was 69.4% (95% CI=56.8-79.0) overall, 77.3% (95% CI=61.5-87.3) in pts treated with 1L PAC, and 75.2% (95% CI=46.3-90.0) for pts treated with 1L PAC with PLT &lt;50 x10 9 /L. Conclusions: In addition to spleen and symptom benefits, real-world outcomes demonstrate stability or improvement in thrombocytopenia and anemia in MF pts treated with PAC, with OS in the 1L setting comparing favorably with other JAK inhibitor historical controls. [Table: see text]
Long-term survival adjusted for treatment crossover in patients (pts) with myelofibrosis (MF) treated with momelotinib (MMB) vs danazol (DAN) in the MOMENTUM trial.
Authors: Vikas Gupta, Aaron Thomas Gerds, Alessandro Vannucchi, Jean-Jacques Kiladjian, Claire Harrison, Alisa Urbano, Jireh Huang, Catherine Elizabeth Ellis, Ruben A. Mesa
Journal: Journal of Clinical Oncology (2024)

6571 Background: Anemia and transfusion dependence affect nearly all pts with MF and are associated with poor prognosis.The phase 3 MOMENTUM trial (NCT04173494) evaluatedMMB—a JAK1, JAK2, and ACVR1 inhibitor—vs DAN (2:1 randomization) in JAK inhibitor (JAKi)–experienced pts with MF and anemia who had symptoms and splenomegaly. While MMB showed spleen, symptom, and anemia benefits vs DAN at wk 24, comparative estimates of long-term overall and leukemia-free survival (OS and LFS) are confounded and may underestimate the MMB effect, as all pts in the DAN arm who entered the open-label phase of the trial crossed over to receive MMB at wk 24. We used a rank-preserving structural failure time (RPSFT) model to estimate the OS and LFS that might have been observed without crossover. Methods: This exploratory analysis evaluated survival over the entire MOMENTUM trial period; most pts entered an extended access study (NCT03441113) after wk 48. The RPSFT model assumes that treatment slows the speed of disease progression and death proportionally regardless of time of crossover. Analyses were conducted with and without recensoring, and CIs were constructed to appropriately account for additional model fitting uncertainty. Results: As of December 29, 2022, 38 (29%) and 20 (31%) deaths had occurred in the MMB and DAN arms, respectively. Risk of death was reduced with MMB vs DAN by 11% (HR, 0.89) with no crossover adjustment, and by 22% (HR, 0.78) and 13% (HR, 0.87) using the RPSFT model with and without recensoring, respectively. Similarly, 40 (31%) and 22 (34%) LFS events had occurred at data cutoff in the MMB and DAN arms, respectively. Risk of an LFS event was reduced with MMB vs DAN by 20% (HR, 0.80) with no crossover adjustment, and by 36% (HR, 0.64) and 23% (HR, 0.77) using the RPSFT model with and without recensoring, respectively (Table). Conclusions: Consistent with the original unadjusted survival analysis, RPSFT models adjusting for the effects of treatment crossover showed prolonged OS and LFS in pts initially randomized to MMB vs those initially randomized to DAN; HRs in favor of MMB were lower after crossover adjustment. While these RPSFT analyses maintain the significance level of the original unadjusted analysis ( P&gt;.05), these results support the trend of long-term survival benefits with MMB vs DAN in JAKi–experienced pts with MF and anemia. Clinical trial information: NCT04173494 . Clinical trial information: NCT03441113 .[Table: see text]
Association between hemoglobin (Hb) improvement and patient-reported outcomes (PROs) in patients (pts) with myelofibrosis (MF) and anemia: Post hoc pooled analysis of momelotinib (MMB) phase 3 trials.
Authors: Jeanne M. Palmer, Flora Mazerolle, Tom Liu, Manal M'Hari, Antoine Regnault, Shiyuan Zhang, Anna Cardellino, Zhaohui Wang, Bryan Strouse, Jasmine Sahni, Thomas William LeBlanc
Journal: Journal of Clinical Oncology (2024)

6574 Background: Pts with MF experience debilitating symptoms that negatively impact health-related quality of life (HRQOL), a burden compounded in those with anemia. Prior analysis of the phase 3 SIMPLIFY-1 (S1) and SIMPLIFY-2 (S2) trials found that achieving transfusion independence at wk 24 was associated with improved PROs, but the association of anemia severity by Hb level with PROs was inconclusive (Mesa, ASCO 2023, Poster 7066). This new post hoc analysis explored the impact of Hb improvement on PROs in pts with MF and anemia. Methods: The pooled treatment-agnostic analysis set included pts with anemia (baseline [BL] Hb &lt;10 g/dL) from 3 phase 3 trials: S1 (JAK inhibitor [JAKi] naive; MMB vs ruxolitinib), S2 (JAKi experienced; MMB vs best available therapy), and MOMENTUM (JAKi experienced; MMB vs danazol). The EQ-5D-5L was administered, and health state index (UK value set) and visual analog scale (VAS) scores derived, in all 3 trials. Patient Global Impression of Change (PGIC) was administered in S1/S2. Hb improvement was defined as an increase of ≥1, ≥1.5, or ≥2 g/dL from BL at wk 24. Multivariate (MV) analyses included change in EQ-5D-5L scores from BL as the dependent variable, with wk 24 Hb improvement and key BL characteristics as independent variables. Results: Mean age of the anemic subpopulation (N=480) was 68.8 y; 62% were male, 81% were White, and 64% had primary MF.436 pts were evaluable for Hb improvement at wk 24; 298 and 297 were evaluable for EQ-5D-5L index and VAS scores, respectively. Mean improvements from BL in index and VAS scores were greater in pts who achieved Hb improvement at any threshold than in those who did not (Table). 241 pts were evaluable for Hb improvement at wk 24 in S1/S2; 215 were evaluable for PGIC. Hb improvement was associated with a higher percentage of pts with any symptom improvement and lower percentage with symptom worsening based on PGIC (Table). In MV analyses, Hb improvement at any threshold was significantly associated with positive change in EQ-5D-5L VAS scores at wk 24 (mean change estimates of 5.5 to 7.3); similar trends were observed in MV analyses for EQ-5D-5L index scores. Conclusions: In these trial populations, Hb improvement at wk 24 was associated with improved HRQOL and symptoms in pts with MF and anemia. These results highlight the value of treatments with anemia-related benefits in improving the pt experience in MF. Clinical trial information: NCT04173494 ; NCT02101268 ; NCT01969838 . [Table: see text]
Long term follow-up results of phase II clinical trial evaluating ruxolitinib (RUX) and azacitidine (AZA) combination therapy in patients (pts) with myelofibrosis (MF).
Authors: Sankalp Arora, Jayastu Senapati, Lucia Masarova, Naveen Pemmaraju, Prithviraj Bose, Guillermo Montalban Bravo, Dyana T Saenz, Habiba Halim, Lingsha Zhou, Abhishek Maiti, Gautam Borthakur, Tapan M. Kadia, Elias Jabbour, Guillermo Garcia-Manero, Hagop M. Kantarjian, Naval Guastad Daver
Journal: Journal of Clinical Oncology (2024)

6572 Background: Monotherapy with JAK inhibitors improve spleen and symptom burden in MF, but their disease modifying effect is less clear. We conducted a phase 2 clinical trial evaluating the combination of RUX with hypomethylating agent AZA in MF. The interim analyses (Masarova et al.Blood, 2018) showed objective responses in 72% pts. We report the long-term follow-up of the full cohort of pts treated on this trial. Methods: The trial was conducted at MD Anderson Cancer Center, Houston including adult pts (≥ 18 years) with MF intermediate (Int) 1-2 or high-risk disease by Dynamic International Prognostic Scoring System (DIPSS). Responses were assessed per the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. Results: From 3/2013-10/2021, 61 pts with a median age of 66 yrs (46-87) were treated (Table). Median Hb was 10.1 g/dl (6.8-16.2), and bone marrow blasts (BM) 2% (0-14%); 14 (23%) had BM blasts ≥ 5%. JAK 2 was mutated in 35 (57%); 38 pts (62%) had Int-2 or high risk DIPSS disease. IWG-MRT responses occurred in 44 pts (72%): clinical improvement (CI) in 37 (61%), including IWG-MRT CI spleen reduction &gt;50% in 28/46 pts (61%) with baseline length ≥5 cm below left costal margin, and 31/51 pts (61%) with baseline TSS&gt;12 having a &gt;50% improvement in total symptom score (TSS 50). Partial response was seen in 4 pts and cytogenetic complete remission in 3 pts. With a median follow up of 93 mos, median overall survival (OS) was 46 mos (95% CI: 25-66), median event free survival was 33 mos (95% CI: 24-43) and median duration of any objective response was 43 mos (95% CI: 24-62). Transformation to AML occurred in 14 pts (23%) with median time to transformation of 19 mos (1-46). 20 pts (33%) received a stem cell transplant (SCT), 11 (55%) with Int-2/high risk DIPPS disease. Pts in the Int-2/high risk DIPPS group who got SCT had a trend towards improved median OS vs. those who did not (38 vs 27 mos, p=0.2). Grade ≥ 3 adverse events (AE) regardless of treatment attribution occurred in 30 pts (49%), most common were pneumonia (10,16%), anemia (7,12%), and sepsis (5, 8%). 3 pts had grade 5 AEs, and 4 pts were taken off study due to toxicity. Conclusions: Long term follow up data from this phase 2 clinical trial shows good efficacy of the AZA-RUX combination in MF, with durable responses and promising survival outcomes. Clinical trial information: NCT01787487 . [Table: see text]
Association of elevated pulmonary artery systolic pressure with hematologic progression in myeloproliferative neoplasms.
Authors: Orly Leiva, Steven Soo, Chi-Joan How, Nathaniel Smilowitz, Binita Shah, Harmony Reynolds, Gabriela Hobbs, Samuel Bernard
Journal: Journal of Clinical Oncology (2024)

6575 Background: Pulmonary hypertension (PH) is associated with myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Prior studies have suggested that patients with MPN and cardiovascular disease (CVD) with PH are at increased risk of progression of MPN to secondary MF or acute leukemia. Further characterization of risk of hematologic progression among all-comers with MPN is lacking. Methods: In this single-center, retrospective cohort study, patients with MPN and ≥ 1 transthoracic echocardiogram (TTE) after diagnosis were identified. PH was defined as an estimated pulmonary artery systolic pressure (PASP) ≥ 40 mmHg on first TTE after MPN diagnosis. Primary outcome was hematologic end-point, composite of progression of MPN to secondary MF, acute leukemia, death related to MPN, or bone marrow transplantation (BMT). Secondary endpoint was major adverse cardiovascular events (MACE), composite of arterial thrombosis, venous thromboembolism, heart failure (HF) and CV death. Multivariable Fine-Gray competing-risk regression (with non-hematologic death and non-CV death as competing-risks for hematologic endpoint and MACE, respectively) were used to estimate risk of outcomes. Results: Of 272 patients with MPN identified, 69 (25.4%) had PH on first TTE. Patients with PH were older at MPN diagnosis, had more MF (27.5% vs 11.8%, p = 0.004), and prior HF (18.8% vs 6.4%, p = 0.004). Patients with PH had higher rates of secondary mutations (24.6% vs 13.3%, p = 0.024), particularly in ASXL1 (8.7% vs 2.5%, p = 0.034) and RUNX1(4.3% vs 0, p = 0.016). After a median follow-up of 46.2 months (IQR 29.3, 69.1), hematologic endpoint (30.4% vs 8.4%, p &lt; 0.001 and MACE (53.6% vs 23.6%, p &lt; 0.001) were higher in PH group. Rates of secondary MF (13.0% vs 4.9%, p = 0.030), acute leukemia (13.0% vs 0.5%, p &lt; 0.001), and death related to MPN (8.7% vs 1.5%, p = 0.01) but not BMT (2.9% vs 3.4%, p = 1.00) were higher in PH. After adjusting for age, sex, MPN type, mutation, and time from MPN to first TTE, PH was associated with higher risk of hematologic endpoint (aSHR 3.70, 95% CI 1.55 – 8.82). After adjusting for the same variables as well as LVEF, left atrial size, prior CVD, PH was associated with increased risk of MACE (aSHR 2.38, 95% CI 1.42 – 3.97). Conclusions: Among patients with MPN, PH on TTE was associated with increased risk of hematologic progression and MACE. Prospective studies are needed to confirm our findings. Further investigation into the underlying mechanisms of PH in MPN should be conducted. [Table: see text]
Cost analysis of targeted and immunotherapies in operable esophageal and non-small cell lung cancers.
Authors: Yahya Alwatari, Mohamed Shanshal, Nate C Johnson, Viengneesee Thao, Bijan J. Borah, Robert Shen
Journal: Journal of Clinical Oncology (2024)

8051 Background: The National Comprehensive Cancer Network (NCCN) currently recommends the use of Atezolizumab, Nivolumab, Osimertinib, and Pembrolizumab in the perioperative management of non-small cell lung cancers (NSCLC) and esophageal cancers (EC). As the therapeutic landscape evolves, we aim to evaluate the cost implications of these guidelines for eligible patients in the United States. Methods: The Medicare Part B payment allowance limits of each medication were ascertained except Osimertinib for which an approximate wholesale acquisition cost (WAC) was reported due to privately administered Medicare Part D coverage. Using national data and published literature, we estimated the annual incidence of patients with newly diagnosed EC and NSCLC who would be eligible for surgery combined with neoadjuvant and/or adjuvant immune and targeted therapy. We applied the estimated cost of the medication based on dosing and duration of treatment, which spanned 1 year for all but adjuvant Osimertinib, which spanned 3 years. Using these data, the cost per patient and the total cost for an incident cohort were estimated. Results: We estimated that 8,602 patients with newly diagnosed EC would be eligible for adjuvant Nivolumab; the cost to treat one patient was $248,529, and the cost to treat one incident cohort was approximately $2 billion (Table). We estimated that 50,409 patients with NSCLC will meet the criteria for neoadjuvant Nivolumab with a total cost of three cycles of $32,894 per patient and $1.7 billion per cohort. Among NSCLC patients who may undergo resection and qualify for adjuvant therapy (Stage IB – IIA with high-risk features or IIB-IIIA), 85,063 patients are anticipated to be EGFR-negative and treated with adjuvant Atezolizumab or Pembrolizumab. Treatment costs range from $178,584 – $197,320 per patient with up to $16 billion cost per cohort. The cost to treat one patient with adjuvant Osimertinib was $556,720, and the cost to treat one incident cohort was close to $10 billion. In total, the cost to treat an incident cohort of eligible operable thoracic malignancies could exceed $30 billion. Conclusions: Neoadjuvant and adjuvant immune and targeted therapy in operable thoracic patients is associated with a significant cost burden. Prospective large-scale studies are needed to assess cost-effectiveness, particularly given the paucity of superior overall survival data with these agents. [Table: see text]
Analysis of outcomes in resected early-stage non-small cell lung cancer (NSCLC) with rare targetable driver mutations.
Authors: Nadia Ghazali, Jamie Feng, Katrina Hueniken, Thomas K. Waddell, Kazuhiro Yasufuku, Andrew Pierre, Laura Donahoe, Elliot Wakeam, Marcelo Cypel, Jonathan Yeung, Shaf Keshavjee, Marc De Perrot, Natasha B. Leighl, Geoffrey Liu, Penelope Ann Bradbury, Adrian G. Sacher, Lawson Eng, Tracy Stockley, Ming Sound Tsao, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2024)

8052 Background: As postoperative adjuvant NSCLC treatment has evolved with EGFR and ALK targeted therapies, consideration may be given to treating other NSCLC with targetable mutations. Thus, having baseline outcomes for early-stage NSCLC with these targetable mutations is crucial, given their rarity. This study reports on recurrence-free survival (RFS) and overall survival (OS) in patients with resected NSCLC with treatable rare driver mutations. Methods: A retrospective single centre study identified stage I-III NSCLC patients with rare targetable mutations who underwent curative surgery. Tissue based next-generation sequencing identified mutations in KRAS G12C, EGFR Exon20, ERBB2, ALK, ROS1, BRAFV600E, MET exon14 skipping, RET. Baseline characteristics, adjuvant chemotherapy, mutation subtype, and TP53 co-mutation were correlated with RFS and OS using Cox regression. The KRAS G12C cohort was used as the reference for survival comparisons. Results: Among 201 patients (mean age: 66.4, 63% female) 61% had stage I, 19% stage II, 20% stage III. Predominant histology was adenocarcinoma (95%) and lobectomy (77%) was the most common surgery. Adjuvant chemotherapy was given to 37% (median 4 cycles). Mutations identified included: KRAS G12C (87, 43%), EGFR Exon 20 (27, 13%), ERBB2 (23, 11%), MET (20, 10%), ALK (14, 7%), ROS1 (13, 6%), BRAF (10, 5%) and RET (5, 2%). For all patients, 5-year survival probabilities were 75% stage I, 56% stage II (Hazard ratio [HR]: 2.17, p=0.038), 55% for stage III (HR: 2.38, p=0.015). Stage was also a significant predictor of RFS: stage II (HR: 1.90, p=0.04), stage III (HR: 2.26, p=0.006) vs stage I. TP53 co-mutation was associated with poorer OS (stage-adjusted HR (aHR): 2.50, p=0.004) and RFS (aHR: 1.70, p=0.037). All patients with rare mutations had shorter RFS compared to those with KRAS G12C mutation (Table). The difference for ERBB2 was significant (aHR 2.26, p=0.014), with only 37% of patients relapse free at 5 years. In contrast, except for ERBB2, other mutations were associated with better OS, with fusion mutations having the greatest difference (aHR 0.24, p=0.021). ERBB2 mutation had the highest cumulative incidence of brain metastasis, 29% at 5 years. Conclusions: Despite consistently poorer RFS, our study shows that, with the exception of ERBB2, OS of all other rare mutations was superior to KRAS G12C mutated NSCLC. TP53 co-mutation was demonstrated to be prognostic of poorer outcome. These dichotomous results may be explained by the use of targeted treatments at relapse, and suggest a potential role of targeted agents in the adjuvant setting. [Table: see text]
Prediction of recurrence in stage I EGFR mutation-positive NSCLC: Combination of CT appearance and selected co-occurring gene alterations by machine learning.
Authors: Akiko Tateishi, Hidehito Horinouchi, Ken Takasawa, Nobuji Kouno, Takaaki Mizuno, Yu Okubo, Yukihiro Yoshida, Shun-ichi Watanabe, Mototaka Miyake, Masahiko Kusumoto, Koji Inaba, Hiroshi Igaki, Yasushi Yatabe, Masami Mukai, Katsuya Tanaka, Naoki Mihara, Kouya Shiraishi, Takashi Kohno, Yuichiro Ohe, Ryuji Hamamoto
Journal: Journal of Clinical Oncology (2024)

8053 Background: Predicting the risk of postoperative recurrence is becoming increasingly important in patients (pts) with resectable EGFR mutation positive ( EGFRm) non-small cell lung cancer (NSCLC) after the ADAURA trial. The presence of non-solid ground-grass opacity (GGO) component on computed tomography (CT) images is known to affect the prognosis of stage I lung cancer. Only a few reports investigating the relationship between gene alterations and CT images in stage I EGFRm NSCLC. Methods: We have developed a machine learning-based model to predict recurrence within five years in TNM stage I (UICC 8th) EGFRm NSCLC pts who underwent surgery between 1985 and 2019 using whole exome sequencing in the PRISM project. We evaluated the pts’ characteristics, recurrence-free survival (RFS), the CT appearance (pure GGO and part solid [GGO]), without GGO [pure solid]), and consolidation tumor ratio (CTraio). Then, we analyzed the correlation between the image findings and gene alterations predicting a high risk of recurrence. Results: Among 1351 pts, stage I, EGFRm were 308 (22.8%). The median RFS for stage I EGFR-m pts was 123.2 months (m). In the prediction model, TP53 and RBM10 genes were among the gene alterations that had a high impact on the high-risk recurrence within five years. Among the 302 stage I, EGFRm pts for whom CT images were available, 166 (55.6%) pts had GGO, and 137 (45.4%) pts had pure solid appearance. The median CTratio was 0.87. The median RFS was not reached (NR) for GGO, 86.5m for pure solid (hazard ratio [HR] 2.42 [1.58-3.73], p&lt;0.0001). There was a negative correlation indicating that the larger the CTratio, the shorter the RFS (p&lt;0.0047). The proportion of TP53 mutation (TP53m) was lower in GGO and higher in pure solid (p&lt;0.0001, Table). The median RFS was NR for GGO plus TP53m-negative pts, was 119.7m for GGO plus TP53m-positive pts, 84.8m for pure solid plus TP53m-negative pts, and 98.8m for pure solid plus TP53m-positive pts, respectively. Among pts with 0≦CTratio&lt;0.5 46 (15.2%), with 0.5≦CTratio&lt;1 119 (39.4%), and with CTratio=1 137 (45.4%), the proportion of TP53m increased as the CTratio increased. Conclusions: We found a linear relationship between CTratio and proportion of co-occurring TP53m with EGFRm. Combination of CT appearance (GGO or pure solid) and co-occurring TP53m can predict recurrence in stage I, EGFRm NSCLC. [Table: see text]