tbuckley/cabot-search huggingface dataset:
Tazemetostat in combination with topotecan and pembrolizumab in patients with recurrent small cell lung cancer.
Authors: Parth Anil Desai, Nobuyuki Takahashi, Delphine Lissa, Samantha Nichols, Linda Sciuto, Melissa Lauren Abel, Brett Schroeder, Christopher Schultz, Seth M. Steinberg, Danielle Pinkiert, Rasa J Vilimas, Anish Thomas
Journal: Journal of Clinical Oncology (2024)

TPS8130 Background: Small-cell lung cancer (SCLC) is the most fatal type of lung cancer characterized by exquisite chemo-sensitivity at diagnosis and chemoresistance at relapse. Despite a highly mutated genome, patients with SCLC derive little benefit from immunotherapy. EZH2 (enhancer of zeste homolog 2) is a master epigenetic regulator of SCLC neuroendocrine cell fate and plasticity. EZH2 inhibition 1) promotes upregulation of Schlafen 11 (SLFN11) which irreversibly blocks replication in response to DNA damaging agents and 2) enhances intrinsic immune signaling, leading to constitutive MHC I recovery, sensitizing resistant SCLC models to DNA damaging chemotherapy and immunotherapy. Tazemetostat is a selective oral EZH2 inhibitor. Methods: This is an investigator-initiated, NCI Cancer Therapy Evaluation Program (CTEP) sponsored, phase I dose escalation and dose expansion study which will evaluate safety and tolerability of combination of tazemetostat with topotecan, a selective TOP1 inhibitor, and programmed cell death protein 1 (PD-1) inhibitor antibody pembrolizumab. Adult patients with relapsed/recurrent SCLC after at least platinum doublet (limited stage-SCLC) or chemo-immunotherapy (extensive stage-SCLC) and ECOG performance 0-1 are eligible. The regimen design involves a 7-day “run-in” of oral tazemetostat BID followed by 21-day cycles of tazemetostat (1-21 days), intravenous (IV) topotecan (day 1-5) and IV pembrolizumab (Day 1). The dose escalation cohort aims to determine safety and optimal doses of tazemetostat and topotecan (with standard dose of pembrolizumab) using a 3+3 design by assessing for dose limiting toxicities. The dose expansion cohort aims to assess safety, tolerability and preliminary efficacy of the combination in 15 additional patients with relapsed SCLC. The study involves collection of mandatory biopsies at pre-treatment and post-treatment (cycle 1) to gain insights into mechanism of action and resistance of the combination using single cell and spatial transcriptomic approaches. For more questions regarding enrollment and eligibility please contact Rasa.vilimas@nih.gov or anish.thomas@nih.gov . Clinical trial information: NCT05353439 .
Clinical and genomic characteristics of multiple primary lung cancers with germline mutations.
Authors: Yingshun Yang, Mingwei Li, Xiaoxue Ma, Shuai Wang, Guotian Pei, Jiayue Qin, Jun Liu, Yuqing Huang
Journal: Journal of Clinical Oncology (2024)

e20054 Background: The number of multiple primary lung cancer (MPLC) patients has rapidly increased in recent years. However, germline mutations and information regarding the etiology of MPLC is very rare. In this study, we sought to determine the prevalence and clinical significance of germline pathogenic/likely pathogenic (P/LP) variants in patients with MPLC. Methods: A total of 111 MPLC patients undergoing radical surgery were enrolled in this study and 625 patients with single-focus lung cancer (SFLC) were analyzed as a control. Tumor and blood lymphocyte DNA from patients were sequenced using next-generation sequencing (NGS) platform interrogating up to 808 cancer-associated genes. Interpretation of sequence variations was classified according to the American College of Medical Genetics and Genomics guidelines. Results: A total of 15 germline P/LP mutations in 12.6% (14/111) of MPLC patients were observed, including one patient with 2 germline alterations; of these, 9 patients (64.3%) had germline mutations in DNA-damage repair (DDR) pathway genes in which the most commonly genes were WRN (14.3%, 2/14) and BRCA1/2 (14.3%, 2/14), followed by RAD50 and MSH3. Similarly, 68 germline mutations were identified in 67 (10.7%)SFLCs, and 54 (79.4%) mutation genes were DDR genes including RAD50 (10.4%, 7/67) showed the highest frequency. The somatic mutations of EGFR (59.5% vs. 48.5%) were enriched in P/LP alterations carriers, while TP53 (12.4% vs. 4.8%) was more common in MPLC patients without P/LP alterations. Besides, lower BRAF and MET mutation frequency were observed in SPLC with germline alterations (p &lt; 0.05), compared to those who did not. MPLC were more likely to be patients with family history of cancers (32.4% vs. 25.0%, p = 0.099) than SFLC, while the proportion of patients with family history of cancers found no significant difference between P/LP and non-P/LP groups. MPLC patients with germline P/LP variances were diagnosed at younger age ( &lt; 40 years old) compared to non-carriers. For MPLC, the ratio of males is not associated with P/LP variations. However, significantly higher proportion of germline P/LP mutations was detected in males in SFLC (61.2% vs. 48.4%, p = 0.048). Patients with a history of smoking were significantly less enriched in MPLC (p = 0.030) compared to SPLC but were independent of whether harbored germline mutations. Conclusions: Taken together, ur results show that in the first large Chinese cohort of MPLC, 12.6% of patients carry germline variants. In addition, a more detailed analysis of the spectrum of germline mutations and clinical characteristics of MPLC may provide clues for the oncology treatment strategy and cancer prevention for MPLC.
A phase II trial of monalizumab in combination with durvalumab (MEDI4736) plus platinum-based chemotherapy for first-line treatment of extensive stage small cell lung cancer (MOZART): Hoosier Cancer Research Network LUN21-530 study.
Authors: Hirva Mamdani, Seongho Kim, Ryan D. Gentzler, Misty Dawn Shields, Muhammad Furqan, Kristen Pizana, Qura Abid, Shadia Ibrahim Jalal
Journal: Journal of Clinical Oncology (2024)

TPS8129 Background: Chemoimmunotherapy consisting of platinum, etoposide, and PD-L1 inhibitor remains the standard of care first-line treatment for extensive stage small cell lung cancer (SCLC) yielding median overall survival (OS) of slightly over a year. NKG2A/CD94 is an immune checkpoint that is selectively expressed on natural killer (NK) cells and CD8+ T cells in the tumor microenvironment. When engaging with its ligand, HLA-E, NKG2A transduces inhibitory signals that suppress immune-mediated cytotoxicity. Thus, NKG2A blockade enhances anti-tumor immunity by promoting both, NK and CD8+ T cell, effector functions. Monalizumab, a monoclonal antibody targeting NKG2A, enhances NK cell activity against tumor cells and rescues CD8+ T cell function in combination with PD-(L)1 axis blockade. Pre-clinical data have demonstrated that the absence of NK cells substantially enhances metastatic dissemination of SCLC tumor cells in vivo. NK cell function is modulated in response to cytotoxic chemotherapy, especially platinum. Post-chemotherapy NK cells display an induced expression of NKG2A compared with pre-chemotherapy patients and is associated with a reduced NK cell mediated anti-tumor activity. Hyperactivation of NK cell activity ameliorates SCLC metastases, an effect that is enhanced when combined with anti PD-(L)1 therapy. Altogether, these data suggest that addition of monalizumab to standard of care first-line treatment may be associated with improved efficacy in patients with SCLC. Methods: Patients with extensive-stage SCLC with ECOG performance status of 0-2 and adequate organ function are eligible for enrollment on this single-arm phase II study with an initial safety lead-in cohort. Patients may have received one prior cycle of platinum doublet with or without durvalumab and may have treated or untreated asymptomatic brain metastasis. Patients will receive platinum (cis or carbo), etoposide, durvalumab, and monalizumab every 3 weeks for 4 cycles followed by durvalumab and monalizumab every 4 weeks until disease progression or unacceptable toxicity. Primary endpoints include 1-year progression-free survival, safety, and tolerability. Secondary endpoints include objective response rate, 1-year overall survival, and intracranial progression-free survival. Exploratory objectives include analyzing association of treatment efficacy with minimal residual disease status, blood- and tissue-based genomic and transcriptomic signatures, tumor infiltrating immune cells, and peripheral blood NK cell and CD8+ T cell activity. Five of the planned 30 patients have been enrolled to date. Clinical trial information: NCT05903092 .
Neoadjuvant toripalimab plus chemotherapy for resectable stage II-IIIB non-squamous non-small cell lung cancer with EGFR mutations: A multi-center, multi-cohort, exploratory study.
Authors: Sida Cheng, Zihan Wei, Hecheng Li, Mingru Li, Yongde Liao, Song Xu, Xiaolong Yan, Desong Yang, Dongsheng Yue, Wenzhao Zhong, Lixin Zhou, Geyun Chang, Xiang Yan, Fan Yang
Journal: Journal of Clinical Oncology (2024)

TPS8120 Background: Neoadjuvant immunotherapy has been widely applied in the treatment of resectable stage II-IIIB NSCLC patients without driver gene mutation. However, as for the EGFR-positive patients, the therapeutic effect of neoadjuvant treatment, either TKI or chemotherapy, is far from satisfied and the outcome of neoadjuvant immunotherapy plus chemotherapy in these patients remains an unanswered but crucial question. Herein, we conducted a phase 2 prospective trial (NCT05962021). Methods: This is a multicenter, multi-cohort prospective phase 2 study in the treatment-naïve patients with resectable stage II-IIIB (N2) (AJCC 8 th edition) non-squamous NSCLC harboring EGFR mutations (19DEL or L858R). Enrolled patients will be divided into two cohorts according to EGFR status and receive neoadjuvant toripalimab (240mg, q3w) plus platinum-based doublet chemotherapy (pemetrexed 500mg/m 2 plus carboplatin AUC 5, q3w) for 3 cycles. Surgery will be performed after completion of neoadjuvant therapy based on the multidisciplinary discussion, while local radiotherapy will be considered if the patient cannot undergo surgery due to disease progression. Key inclusion criteria: non-squamous NSCLC, resectable stage II-IIIB (N2), EGFR mutations (19DEL or L858R), age≥18 years, ECOG PS 0-1 and adequate cardiopulmonary function. Exclusion criteria: prior systemic anticancer treatment, contraindication to immunotherapy, active autoimmune disease. Adequate pre-treatment tissue samples are required for RT-PCR or next-generation sequencing to determine the EGFR mutation status and PD-L1 expression immunohistochemical detection. The primary study endpoint is complete pathological response (pCR) rate, per blinded independent pathologist review. Simon's optimal two-stage design will be used to test the null hypothesis of pCR rate ≤5% and alternative hypothesis of pCR rate ≥15%, and 5 or more pCRs among 56 patients per arm are needed for the primary endpoint to be met. Secondary endpoints include major pathological response (MPR) rate, pCR/MPR rate in different EGFR mutation subgroups (19DEL or L858R) and different PD-L1 expression subgroups (TPS &lt; 1% and ≥ 1%), event-free survival and safety and tolerability. Peripheral blood, stool and tissue samples will be obtained longitudinally at baseline, during perioperation and at follow-ups for exploratory analysis. Clinical trial information: NCT05962021 .
JCOG2002: A randomized phase III study of thoracic radiotherapy for extensive stage small cell lung cancer.
Authors: Kaname Nosaki, Yoshitaka Zenke, Shogo Nomura, Tomonari Sasaki, Seiji Niho, Kiyotaka Yoh, Hiroshige Yoshioka, Yukio Hosomi, Isamu Okamoto, Hiroyasu Kaneda, Hiroaki Akamatsu, Hiroaki Okamoto, Keita Sasaki, Yuta Sekino, Hidehito Horinouchi, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2024)

TPS8132 Background: Consolidative thoracic radiotherapy (cTRT) has shown a marginal improvement in overall survival (OS) and progression-free survival (PFS) for extensive-stage small-cell cancer (ES-SCLC). Consequently, ASTRO and NCCN guidelines conditionally recommend the use of cTRT. Despite the recent establishment of anti-PD-L1 antibody (aPD-L1) combined with platinum-doublet chemotherapy as the standard first-line treatment for ES-SCLC, the impact of cTRT in the era of immunotherapy remains uncertain. Methods: The JCOG2002 study, a randomized, multicenter phase 3 trial, initiated in October 2021 to assess the superiority of additional cTRT in terms of OS for ES-SCLC following induction aPD-L1 plus platinum doublet chemotherapy. Eligibility patients must meet criteria for the first registration including ES-SCLC, no prior radiation or chemotherapy history, age 20 or older, ECOG performance status 0 or 1, and adequate organ function. Induction treatment involves atezolizumab + carboplatin + etoposide or durvalumab + cisplatin / carboplatin + etoposide. Responding patients proceed to the second registration, randomization (1:1 between 30 Gy in 10 fractions of cTRT plus aPD-L1 maintenance therapy and maintenance therapy only). The cTRT targets metastatic lymph nodes in stations #1-7 and ipsilateral stations #10-12 identified at diagnosis. The adjustment factors include response to induction treatment (CR/PR versus SD), presence of brain metastasis (yes versus no), participating institutions, and aPD-L1 type (atezolizumab versus durvalumab). The primary endpoint is OS, with secondary endpoints being PFS and safety. The study aims to enroll 240 randomized patients, with 330 in the first registration, providing 80 % power at a one-sided 5 % significance level to detect a hazard ratio of 0.69 with 3-year accrual period and 1-year follow-up. As of February 6, 2024, 239 patients initiated induction treatment, and 121 have been randomized. This trial is registered at Japan Registry of Clinical Trials as jRCTs031210393 (https://jrct.niph.go.jp/detail/jRCTs031210393). Clinical trial information: jRCTs031210393 .
A phase II exploratory trial of adebrelimab in combination with chemotherapy and concurrent radiotherapy as a first-line treatment for oligo-metastatic extensive-stage small-cell lung cancer.
Authors: Zhong-Yi Dong, Wei Wei, Yingchen Ruan, Xue Bai, Qisheng Li
Journal: Journal of Clinical Oncology (2024)

TPS8131 Background: Oligometastasis of extensive-stage small-cell lung cancer (ES-SCLC) is an intermediate state between local and extensive metastasis, characterized by reduced metastatic potential and a limited number of metastatic sites, which makes local treatment of each lesion possible. Multiple clinical studies have shown that adding local therapy to standard systemic therapy can improve the prognosis of patients with oligometastatic disease. The PD-L1 inhibitor adebrelimab combined with chemotherapy has become one of the standard regimens for first-line treatment of ES-SCLC. Based on these, we hypothesize that in patients with oligometastatic ES-SCLC at risk of early progression, the early addition of chest radiotherapy and stereotactic radiotherapy (SBRT) for metastatic lesions to first-line treatment with adebrelimab combined with chemotherapy may be expected to achieve local control, thereby improving survival benefits. Methods: This is a prospective, single-arm, multicenter, phase II exploratory trial. Patients will be eligible if they are 18 to 75 years of age; have histopathologically or cytologically confirmed ES-SCLC with the number of metastatic lesions of ≤ 5 and organ metastasis of ≤ 3 (i.e. oligometastases); have an ECOG PS of 0-1; and have no previous systemic treatment. The treatment period in this trial is subdivided into induction therapy, concurrent chemoradiotherapy, and consolidation and maintenance therapy. In the induction setting, patients will receive two 3-week cycles of adebrelimab (20 mg/kg on day 1), carboplatin (AUC of 5 mg/mL per min on day 1)/cisplatin (75 mg/m 2 on day 1), and etoposide (100 mg/m 2 on days 1-3). Patients who achieve partial response or stable disease after induction therapy will then receive concurrent chemoradiotherapy, of which chemotherapy regimen is the same as the induction setting. Radical IMRT radiotherapy (2.5-3 Gy/f, total dose 45-55 Gy) will be performed for the primary tumor in the chest and lymph node region, and SBRT radiotherapy will be given to metastatic lesions. Prophylactic cranial irradiation is optional. After the end of chemoradiotherapy, patients will receive 1-2 cycles of consolidation treatment with the same regimen as induction treatment, followed by adebrelimab monotherapy (20 mg/kg on day 1, q3w) as maintenance treatment until disease progression, intolerance toxicity, or up to 2 years of adebrelimab. The total cycle number of chemotherapy is 4-6. The primary endpoint is progression-free survival (PFS), and secondary endpoints are objective response rate, duration of response, overall survival (OS), 6-month and 1-year PFS rates, 1-year and 2-year OS rates, and safety. The trial is under recruitment, and a total of 62 patients are planned to be enrolled. Clinical trial information: NCT06177925 .
<i>PTPN11</i>variants in chronic myelomonocytic leukemia: Phenotypic and prognostic correlates.
Authors: Anuya Ajit Natu, Clifford Michael Csizmar, Mark Gurney, Terra L. Lasho, Christy Finke, Christopher Dean, Abhishek A Mangaonkar, Aref Al-Kali, Naseema Gangat, Hassan B. Alkhateeb, Ayalew Tefferi, Mrinal Patnaik
Journal: Journal of Clinical Oncology (2024)

6513 Background: PTPN11 (Ch12q24) is a proto-oncogene that codes for SHP2, a regulatory protein tyrosine phosphatase that impacts RAS/MAPK signaling. Germline variants have been described in juvenile myelomonocytic leukemia, while somatic variants have been associated with inferior survival in acute myeloid leukemia. PTPN11 variants are infrequent in chronic myelomonocytic leukemia (CMML), and their impact on disease phenotype and survival remains unclear. Methods: After IRB approval, 396 molecularly annotated CMML patients at Mayo Clinic were screened for somatic PTPN11 variants within 12 months of diagnosis while still in chronic phase disease. Overall (OS), acute myeloid leukemia (AML)-free survival (LFS), and predictors of survival were estimated using standard statistical measures. Results: 396 patients (median age 71 years; males 67%) with CMML were considered; pathogenic PTPN11 variants were seen in 12 (3%) with a median VAF of 20.5% (range: 4-50): A72T (n = 2), F285S (n = 2), and A72S (n = 2). Variants were most likely to be seen in the N-terminal SH2 domain (n = 7), followed by the PTP domain (n = 6), and the C-terminal SH2 domain (n = 1). PTPN11 variants clustered with CMML-2 (p = 0.02), higher absolute neutrophil count (p = 0.04), peripheral blood (p = 0.06) and bone marrow (p = 0.02) blast %, older age (p &lt;0.01), and were less likely to have SRSF2 comutations (p = 0.02). After a median follow-up of 18 months (range 0-193), 253 (64%) deaths and 68 (17%) AML transformations were recorded. PTPN11 variants negatively and independently impacted both OS (median 13 vs. 31 months; p &lt;0.01) and LFS (AML events: 42% (5/12) vs. 16% (63/384); p &lt;0.01). In age-adjusted multivariate analysis restricted to genetic risk factors, survival was negatively affected by abnormal karyotype and mutations involving PTPN11, DNMT3A, and SETBP1, and positively by TET2 mutations. All but SETBP1 retained significance in the presence of additional independent risk factors, namely male sex (p &lt;0.01) and leukocyte count (p &lt;0.01); HR in the latter analysis was 4.3 for PTPN11, 2.8 for DNMT3A, and 1.6 for abnormal karyotype. A similar analysis for LFS identified, as risk factors, PTPN11 (p = 0.01), DNMT3A (p &lt;0.01), and ASXL1 (p = 0.03) mutations, as well as bone marrow blast % (p &lt;0.01), absolute monocyte count ≥10 (p = 0.02), and immature circulating myeloid cells (p &lt;0.01). Conclusions: The current study identifies PTPN11 and DNMT3A mutations as independent risk factors for both OS and LFS in CMML. In regard to additional genetic risk factors, OS was positively affected by TET2 mutations and negatively by abnormal karyotype, while LFS was negatively affected by ASXL1 mutations.
A real-world picture of patients with a new diagnosis of acute myeloid leukemia in Italy.
Authors: Immacolata Esposito, Giulia Ronconi, Letizia Dondi, Silvia Calabria, Carlo Piccinni, Leonardo Dondi, Irene Dell'anno, Alice Addesi, Nello Martini
Journal: Journal of Clinical Oncology (2024)

6520 Background: Acute myeloid leukemia (AML) is a blood malignancy with poor prognosis. Antineoplastic strategies are still mostly restricted to fit patients. This analysis of administrative healthcare data identified and described newly AML diagnosed patients, their antineoplastic treatment and survival from the perspective of the Italian National Health Service (SSN). Methods: From the Fondazione ReS (Ricerca e Salute) database (~5 million inhabitants/year), among adults with primary/secondary in-hospital diagnosis of AML in 2018 (index date) and analysable look-back period until 2013, patients newly AML diagnosed were selected. They were characterized by age, sex and comorbidities (cardiometabolic, thyroid and cerebrovascular disorders, chronic kidney and liver disease, and inflammatory bowel diseases). During 1 year following index date, antineoplastic treatment and allogeneic stem cell transplantation (alloSCT) were assessed. Among patients undergoing antineoplastic therapy, those fit and unfit for intensive chemotherapy (ICHT) were categorized according to proxies based on the setting of chemotherapy administration (i.e., overnight hospitalization=fit, while daily hospitalization or local outpatient ambulatory=unfit). The 2-year overall survival (OS) of treated patients was assessed through a Kaplan Meyer analysis. Results: In 2018, 228 newly AML diagnosed patients (incidence: 5.7x100,000 adult inhabitants) were identified. Males were 56.6%. Mean age was 69±16 years, and 61% patients had ≥2 comorbidities. During 1 year following index date, 75% of newly AML diagnosed patients received antineoplastic treatment (males were 57%, mean age was 66±15 years, and 49% had ≥2 comorbidities). Of them, 19% underwent alloSCT (mean age was 50±14 years). On average, remaining untreated patients (57/228; 25%) were older (77±14 years) and affected by more comorbidities (79% with ≥2 comorbidities) than treated patients. At 2 years following index date, 97% of treated patients survived (vs 65% of untreated patients; p&lt;0.01). Among treated patients, 51% (mean age was 64±15 years) were considered fit for ICHT, and 24% were considered unfit for ICHT (mean age was 71±15 years). At 2 years following index date, 38% of patients fit for ICHT survived (vs 29% of patients unfit for ICHT; p&lt;0.01). Conclusions: This real-word analysis suggests that patients receiving antineoplastic treatments, regardless of a following alloSCT, were younger and affected by less comorbidities than untreated patients. Also, older patients are likely to be excluded from the ICHT option, as recommended by most of guidelines. However, these findings suggest that being treated with chemotherapy and/or alloSCT can increase survival probabilities.