Small-cell lung cancer (SCLC) is an aggressive disease with distinct biological and clinical features. The clinical course of SCLC is generally characterised by initial sensitivity to DNA-damaging therapies, followed by early relapse and broad cross resistance to second line agents. Whilst there has been an enormous expansion of effective targeted and immune-based therapeutic options for non-small cell lung cancer (NSCLC) in the last decade, little improvement has been achieved in SCLC treatment and survival due, at least in part, to underappreciated inter- and intra-tumoral heterogeneity. Here we review the current treatment paradigm of SCLC including recent advances made in utilizing immunotherapy and the challenges of identifying a predictive biomarker for immunotherapy response. We examine emerging new targeted therapies, combination immunotherapy and future directions of SCLC treatment research.

https://www.mdpi.com/1422-0067/24/9/8129/pdf?version=1682932626

Small-Cell Lung Cancer—An Update on Targeted and Immunotherapies

Therapy for multiple myeloma (MM), a hematologic neoplasm of plasma cells, has undergone remarkable changes over the past 25 years. Small molecules (molecular weight of less than one kDa), together with newer immunotherapies that include monoclonal antibodies, antibody-drug conjugates, and most recently, chimeric antigen receptor (CAR) T-cells, have combined to double the disease’s five-year survival rate to over 50% during the past few decades. Despite these advances, the disease is still considered incurable, and its treatment continues to pose substantial challenges, since therapeutic refractoriness and patient relapse are exceedingly common. This review focuses on the current pipeline, along with the contemporary roles and future prospects for small molecules in MM therapy. While small molecules offer prospective benefits in terms of oral bioavailability, cellular penetration, simplicity of preparation, and improved cost–benefit considerations, they also pose problems of toxicity due to off-target effects. Highlighted in the discussion are recent developments in the applications of alkylating agents, immunomodulators, proteasome inhibitors, apoptosis inducers, kinesin spindle protein inhibitors, blockers of nuclear transport, and drugs that affect various kinases involved in intracellular signaling pathways. Molecular and cellular targets are described for each class of agents in relation to their roles as drivers of MM.

/pdf/recent-advances-in-the-applications-of-small-molecules-in-30nph0ke.pdf

Recent Advances in the Applications of Small Molecules in the Treatment of Multiple Myeloma

3102 Background: Senaparib (or IMP4297) is a PARP inhibitor with a novel chemical structure. Preliminary data demonstrate senaparib has significant anti-tumor activity with good tolerability in some patients with advanced solid tumors. DNA damage caused by temozolomide, a non-classic oral alkylating agent, can sensitize tumors to the effects of PARP inhibitors. In a xenograft model, synergistic antitumor effect was observed with the combination of senaparib and temozolomide, supporting this trial (NCT04434482). Methods: This is a phase Ⅰb/Ⅱ dose-escalation and dose-expansion study. Patients with advanced solid tumors were enrolled for dose escalation to evaluate the safety, tolerability using a modified “3+3” design. Low dose temozolomide (20 to 30 mg, once daily, days 1 to 21) in combination with continuous senaparib (40 to 80 mg, once daily, days 1 to 28) of each 28-day cycle was evaluated. Dose expansion will establish anti-tumor activity and safety of the combination in patients with extensive stage small cell lung cancer (ES-SCLC). Results: A total of 14 patients were enrolled for dose escalation as follows: Cohort 1 (1 patient; senaparib 40 mg plus temozolomide 20 mg), Cohort 2 (3 patients; senaparib 60 mg plus temozolomide 20 mg), Cohort 3 (7 patients; senaparib 80 mg plus temozolomide 20 mg), Cohort 4 (3 patients; senaparib 80 mg plus temozolomide 30 mg). One DLT (Grade 4 thrombocytopenia) was observed in Cohorts 3 and 4. The MTD and RP2D were determined as: senaparib 80 mg plus temozolomide 20 mg. Anaemia, neutropenia and thrombocytopenia were the only Grade ≥3 TEAEs occurring in > 1 patient. All AEs were manageable, and no treatment related deaths were reported. The ORR was observed in 3 of 12 (25.0%) evaluable patients, including 2 confirmed PR and 1 unconfirmed PR. The DCR was 83.3% (10 of 12 evaluable patients). Two patients remain on treatment for more than 1 year. Conclusions: Preliminary results suggest that low dose temozolomide (D1-21 of a 28-day cycle) in combination with continuous senaparib is generally well tolerated with encouraging anti-tumor activity. Recruitment for dose expansion for ES-ECLC patients has commenced (Sep 2021). Clinical trial information: NCT04434482.

A study of senaparib in combination with temozolomide for the treatment of patients with advanced solid tumors and extensive-stage small cell lung cancer.

Background: Background: The proteasome inhibitor is an effective treatment strategy for multiple myeloma (MM). TQB3602 is a novel oral proteasome inhibitor derived from multiple rounds of optimization based on ixazomib. It has an addition of an acridine ring to the structure of ixazomib, which maintains high activity and selectivity, resulting in better metabolic stability. In preclinical models of MM, TQB3602 displayed potent kinase inhibiting activity for 20S proteasome enzyme with IC50 15.3 nM. It also inhibited cell proliferation in the MM.1S cell line with IC50 10.1 nM. In the MM.1S MM CB-17 CDX model, TQB3602 also showed antitumor efficacy. TQB3602 represents a promising clinical candidate for treating MM. Aims: Aims: This study presents the first-in-human trial designed to evaluate the safety, tolerance, pharmacokinetics, dose-limiting toxicity and maximum tolerated dose of TQB3602 in relapsed/refractory MM (RRMM). Methods: Methods: This study is a multicenter, open-label, 3+3 dose-escalation phase I trial (NCT04275583). Adult patients with RRMM who had received at least two kinds of therapy, including bortezomib,

https://doi.org/10.1097/01.hs9.0000846680.89917.3a

P953: phase i study of tqb3602 capsule, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma

Introduction: Although novel therapies have significantly improved the prognosis of multiple myeloma (MM) patients, there are still a subgroup of MM patients experienced early relapse or disease progression. To early identify the patients with compromised prognosis in our center, the study aimed to establish a predictive model for ultra-high risk (UHR) in MM. Methods: A study from a tertiary hospital in western China analyzed the patients with newly diagnosed MM (NDMM) receiving bortezomib and/or lenalidomide-included regimens from January 2015 to June 2021. The last follow-up date was December 31, 2022. The patients were randomly divided (2:1) into training and validation cohorts, and the patients with progression-free survival (PFS) less than 12 months were defined as UHR. Univariate and multivariate Cox regression analyses were performed for clinical feature selection. Independent baseline factors were incorporated and scored to develop the predictive model. The UHR group was then defined beyond the optimal cut-off value of total scores. Results: A total of 314 MM patients were enrolled and 102 (32.5%) patients underwent autologous hemopoietic stem cell transplantation (ASCT). The median time of follow-up was 36.6 months. Disease progression and death occurred in 178 (56.7%) and 69 (22.0%) patients. The median PFS (mPFS) was 36.5 months, and the median overall survival (mOS) was not reached. The mPFS of patients stratified into R-ISS III, R2-ISS III, R2-ISS IV, IMWG high-risk and mSMART double/triple hit was 23.8, 25.6, 10.0, 17.2 and 10.5 months, respectively. Among 54 patients at UHR, less than half of them could be identified by the aboved stratification systems. In the training cohort, elevated LDH, hypercalcemia, 1q21 gain/amplification (1q+) and the presence of extramedullary disease (EMD) showed significant association with UHR in NDMM. Referring to the results, the UHR predictive model was developed as 5 points for elevated LDH, 6 points for hypercalcemia, 7 points for 1q+ and 10 points for EMD. Patients with total scores of more than 12 points can be predicated as UHR. This model identified UHR and non-UHR groups with significantly different mPFS (9.8 v.s. 37.5 months, HR = 3.24, 95% CI:2.09-5.03, P < 0.001) and 5-year OS (63.3% vs. 83.8%, HR = 2.92, 95% CI: 1.47-5.81, P = 0.002). The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.77, and in the validation cohort, the UHR model kept good discrimination (AUC: 0.79) at the latest follow-up. Conclusions: In this study, elevated LDH, hypercalcemia, 1q+ and EMD were selected and scored to develop the UHR model for NDMM patients. At present, the extension of follow-up time and expansion of sample size in the validation cohort are still ongoing. External validity is also designed to verify the generalizability of the model. The research was funded by: Natural Science Foundation of Sichuan Province, China, Grant/Award Number: 2022NSFSC1299 Keywords: Risk Models, Multiple Myeloma No conflicts of interests pertinent to the abstract. 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/hon.3165_625

A predictive model for ultra‐high risk in patients with newly diagnosed multiple myeloma: a single‐center study in china

Activity and safety of preclinical and a phase 1 study of purinostat mesylate, a uniquely potent and selective hdac i/iib inhibitor in relapsed or refractory lymphoma

Introduction: Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. Standard CHOP (Cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy is still the most widely used regimen for front-line management. To explore new targeted drugs in PTCL, we conducted a phase 2, multi-center, non-randomized clinical trial, comparing the efficacy and safety of targeted agents combined with CHOP (CHOPX) with CHOP in newly diagnosed patients with PTCL. Methods: The primary outcome was complete response rate (CRR) at the end of treatment (EOT). Patients with newly diagnosed PTCL had enough tumor tissue for next generation sequencing (NGS) and were assigned to CHOPX and CHOP group based on investigators’ discretion. Patients in CHOPX group received intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (up to a maximum of 2 mg) on day 1, and oral prednisone 60 mg/m2 (up to a maximum of 100 mg) on day 1–5 every 21 days at the first cycle. X (i.e., targeted agent) was added from the second to sixth cycles as following, intravenous decitabine 10 mg/m2 on day -5 to -1 if with TP53 mutation. Subcutaneous azacytidine 100 mg on day −7 to −1 if with TET2/KMT2D mutation. Oral chidamide 20 mg on day1, 4, 8, 11 if with CREBBP/EP300 mutation. Oral lenalidomide 25 mg on day 1–10 if without above mutations. Patients in control group received standard CHOP regimen for 6 cycles. Analysis of efficacy and safety was of the intent-to-treat population. The study was registered with ClinicalTrials.gov, number NCT04480099. Results: Between 20 June 2020 and 22 September 2022, 108 patients were assessed for eligibility in the study. Ten patients met exclusion criteria and 2 patients withdrew informed consent before treatment. Forty-eight patients in the CHOPX group and 48 patients in the CHOP group were included into intent-to-treatment population. Baseline patient characteristics like age, gender, Ann Arbor stage, performance status, prognostic risk group was comparable between CHOPX and CHOP groups. The most common pathological subtypes were angioimmunoblastic T-cell lymphoma (67% vs. 60%), PTCL-not otherwise specified (17% vs. 21%), anaplastic T-cell lymphoma (6% vs. 8%) in the CHOPX and CHOP groups. As of 1 February 2023, 91 patients completed response evaluation at EOT. CRR in the CHOPX group was higher than the CHOP group (58% [25/43] vs. 33% [16/48]). The most common grade 3–4 hematological adverse events in CHOPX group were neutropenia (61%) and febrile neutropenia (27%). Conclusions: Preliminary analysis showed targeted agents combined with CHOP was effective and safe compared with standard CHOP in PTCL. Therapeutic strategy specifically towards molecular features may change current PTCL management in front-line setting. Keywords: combination therapies, molecular targeted therapies No conflicts of interests pertinent to the abstract. 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/hon.3163_42

Targeted agents combined with chop compared with chop as the first‐line therapy for peripheral t‐cell lymphoma: preliminary results from a phase 2 guidance‐03 trial

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