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Background: Sotorasib 960 mg once daily is approved to treat KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Sotorasib exhibits non-dose proportional pharmacokinetics and clinical responses at lower doses; therefore, we evaluated the efficacy and safety of sotorasib 960 mg and 240 mg., Methods: In this phase 2, randomized, open-label study, adults with KRAS G12C-mutated advanced NSCLC received sotorasib 960 mg or 240 mg once daily. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics. The study was not powered for formal statistical hypothesis testing., Results: In the 960 mg group (n = 104), ORR was 32.7 % and DCR was 86.5 %. In the 240 mg group (n = 105), ORR was 24.8 % and DCR was 81.9 %. Median PFS was 5.4 months (960 mg) and 5.6 months (240 mg). At a median follow-up of 17.5 months, median OS was 13.0 months (960 mg) and 11.7 months (240 mg). AUC 0-24 h and C max were 1.3-fold numerically higher with the 960 mg dose. Treatment-emergent adverse events (TEAEs, ≥10 %) for 960 mg and 240 mg doses, respectively, were diarrhea (39.4 %; 31.7 %), nausea (23.1 %; 19.2 %), increased alanine aminotransaminase (14.4 %; 17.3 %), and increased aspartate aminotransferase (13.5 %; 13.5 %)., Conclusions: Patients treated with sotorasib 960 mg once daily had numerically higher ORR and DCR, and longer DOR and OS, than patients treated with 240 mg in this descriptive analysis. TEAEs were manageable with label-directed dose modifications., Clinical Trial Registration: NCT03600883., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. J. Hochmair: Financial Interests, Personal, Other, Consulting or Advisory role: Takeda, Roche, Lilly, AstraZeneca/Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Lilly, MSD Oncology, Novartis, Roche, Amgen. K. Vermaelen: Financial Interests, Personal, Research Grant: Bristol Myers Squibb (BMS); Financial Interests, Personal, Other, Honoraria: BMS; Financial Interests, Personal, Other, Support for Attending Meetings: AstraZeneca, BMS, Merck; Financial Interests, Personal, Other, Patents Planned/Issued/Pending: Ghent University; Financial Interests, Personal, Other, Data Safety Monitoring Board or Advisory Board: Amgen, AstraZeneca, BMS, Merck. G. Mountzios: Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca, BMS GmbH & Co. KG, Boehringer Ingelheim, MSD, Novartis, Roche, Takeda; Financial Interests, Personal, Other, Consulting or Advisory Board: Amgen, AstraZeneca/Greece, BMS GmbH & Co. KG, MSD, Novartis, Roche, Takeda; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, MSD; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: AstraZeneca, BMS GmbH & Co. KG, Ipsen, MSD, Novartis, Roche. E. Carcereny: No conflicts to disclose. C. Dooms: No conflicts to disclose. S.-H. Lee: Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca/MedImmune, Lilly, Merck, Roche; Financial Interests, Personal, Other, Consulting or Advisory Role: AstraZeneca, BMS/Ono, IMBdx, Janssen, Lilly, Merck, Pfizer, Roche, Takeda; Financial Interests, Personal, Research Grant: AstraZeneca, Lunit, Merck; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Novartis. E. Morocz: No conflicts to disclose. T. Kato: Financial Interests, Personal, Advisory Board, Speaker, Consultancy: AstraZeneca, Eli Lilly, Merck Biopharma, MSD; Financial Interests, Personal, Advisory Board, Speaker: Pfizer, Amgen, Janssen; Financial Interests, Personal, Other, Consultancy: Daiichi Sankyo, Takeda, Taiho; Financial Interests, Personal, Other, Consultancy, Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Ono, Novartis, BMS, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: BeiGene, GSK; Financial Interests, Personal, Advisory Board, Steering Committee: Roche; Financial Interests, Personal, Full or Part-Time Employment, Family Member: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Chugai, MSD, Pfizer, Eli Lilly, AbbVie, Regeneron, Novartis, Amgen, Merck Biopharma, Haihe Biopharma, Blueprint Medicines, Turning Point, BeiGene, Gilead, GSK, Janssen, Bayer, Takeda, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Local PI: AstraZeneca. T.-E. Ciuleanu: Financial Interests, Personal, Other, Consulting or Advisory Role: Astellas Pharma, Janssen, BMS, Merck Serono, Amgen, Roche, Pfizer, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Merck Sharp & Dohme (MSD), Sanofi, Novartis, Servier, A&D Pharma; Financial Interests, Personal, Other, Travel Support: Pfizer, Sanofi, Boehringer Ingelheim, Merck, Servier, Ipsen, Amgen, A&D Pharma, AstraZeneca, Genentech, BMS, MSD Oncology, Eli Lilly, Janssen, Novartis, Astellas Pharma. G. K. Dy: Financial Interests, Personal, Other, Consulting or Advisory Role: AstraZeneca, Mirati Therapeutics, Lilly, Amgen, Regeneron, Eli Lilly; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Mirati Therapeutics, Lilly, Sanofi, BioAtla, Regeneron, Iovance Biotherapeutics, Revolution Medicines. B. Parente: No conflicts to disclose. K. J. O’Byrne: Financial Interests, Personal, Stocks/Shares: Carpe Vitae Pharmaceuticals, DGC Diagnostics, Replica Pharmaceuticals; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Ipsen, Janssen-Cilag, Merck Group, MSD, Novartis, Pfizer, Roche, Seagen, Takeda, TriStar, Yuhan; Financial Interests, Personal, Other, Consulting or advisory Role: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Ipsen, Janssen-Cilag, MSD, Novartis, Pfizer, Roche/Genentech, Sanofi, Seagen, Yuhan; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: three active patents. Q. S. Chu: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AnHeart Therapeutics, Astellas, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Jazz Pharmaceutical, Johnson and Johnson, Merck, Novartis, Pfizer, Roche, Takeda. G. De Castro Jr.: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Pfizer, MSD, BMS, Novartis, Roche, Amgen, Janssen, Merck Serono, Daiichi Sankyo, Sanofi, Lilly; Financial Interests, Personal, Other, Consulting or Advisory Role: Boehringer Ingelheim, Pfizer, Bayer, Roche, MSD, BMS, AstraZeneca, Yuhan, Merck Serono, Janssen, Libbs, Sanofi, Novartis, Daiichi Sankyo, Lilly; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Bayer, Novartis, Roche, Merck Serono, BMS, MSD, Boehringer Ingelheim, Pfizer, Janssen, Amgen, Lilly, Daiichi Sankyo; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: MSD, Novartis, Pfizer, Roche, AstraZeneca, Boehringer Ingelheim, Bayer, BMS, Merck Serono, Daiichi Sankyo. N. Girard: Financial Interests, Personal, Research Grant: AstraZeneca, Amgen, Boehringer Ingelheim, Eli Lilly, Hoffmann-La Roche, Janssen, Merck, MSD, Novartis, Pfizer, Sivan, Trizell; Financial Interests, Personal, Other, Consulting or Advisory Role: BMS, AstraZeneca, AbbVie, Amgen, Boehringer Ingelheim, Eli Lilly, Hoffmann-La Roche, Janssen, Merck, MSD, Mirati, Novartis, Pfizer, Roche, Sanofi, Sivan; Financial Interests, Personal, Expert Testimony: AstraZeneca; Financial Interests, Personal, Invited Speaker, Participation in Data Safety Monitoring Board: Roche; Financial Interests, Personal, Other, Leadership Role: International Thymic Malignancy Interest Group; Financial Interests, Personal, Full or Part-Time Employment, Employment of a Family Member: AstraZeneca. W. Snyder, Q. Tran, W. Kormany, B. Houk, B. Mehta: Financial Interests, Personal, Full or Part-Time Employment: Amgen Inc.; Financial Interests, Personal, Stocks/Shares: Amgen Inc. A. Curioni-Fontecedro: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Boehringer Ingelheim, MSD, Novartis, Amgen, Roche, Takeda, Janssen; Non-Financial Interests, Personal, Leadership Role: Swiss Academy for Clinical Cancer Research (SAKK); Non-Financial Interests, Personal, Principal Investigator of Clinical Trials: Roche; Non-Financial Interests, Personal, Principal Investigator, Clinical Trials: Takeda, MSD, BMS., (Copyright © 2024. Published by Elsevier Ltd.)

This open-label, multicenter, single-arm, phase 2 study assessed the safety and efficacy of blinatumomab consolidation therapy in adult patients with newly diagnosed, high-risk diffuse large B-cell lymphoma (DLBCL; International Prognostic Index 3-5 and/or double-/triple-hit or double MYC/BCL-2 expressors) who achieved complete response (CR), partial response (PR), or stable disease (SD) following run-in with 6 cycles of R-chemotherapy (NCT03023878). Of the 47 patients enrolled, 28 received blinatumomab. Five patients (17.9%) experienced grade 4 treatment-emergent adverse events of interest (neutropenia, n  = 4; infection, n  = 1). Two deaths reported at the end of the study were unrelated to treatment with blinatumomab (disease progression, n  = 1; infection, n  = 1). 3/4 patients with PR and 4/4 patients with SD after R-chemotherapy achieved CR following blinatumomab. Consolidation with blinatumomab in patients with newly diagnosed, high-risk DLBCL who did not progress under R-chemotherapy was better tolerated than in previous studies where blinatumomab was used for treatment of patients with lymphoma.

Introduction: The safety and efficacy of blinatumomab, a CD19/CD3 bispecific T-cell engager (BiTE®) molecule, was evaluated in an expansion cohort of the phase 1b/2 study (NCT02412306) in Japanese adult (n = 14) and pediatric (n = 17) patients with relapsed/refractory Philadelphia-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL)., Materials and Methods: Globally recommended blinatumomab doses were administered to adult (9-28 μg/day) and pediatric (5-15 μg/m2/day) patients. Primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and treatment-related AEs., Results: All adult and pediatric patients experienced ≥1 TEAE. Grade ≥3 TEAEs were observed in 11 (79%) adult and 15 (88%) pediatric patients. Blinatumomab was discontinued in 1 (6%) pediatric patient due to treatment-related grade 4 cytokine release syndrome. Fatal AEs such as disease progression and multiple-organ dysfunction syndrome, which were not treatment-related, were reported in 2 (12%) pediatric patients. Eleven (79%) adults achieved complete remission (CR)/CR with partial hematological recovery (CRh) within the first two blinatumomab cycles. Nine of 10 adult patients with CR/CRh and evaluable minimal residual disease (MRD) achieved MRD response. CR/CRh was achieved by 5 (29%) pediatric patients, of which two had MRD response., Conclusion: In conclusion, blinatumomab was safe and efficacious in Japanese patients with relapsed/refractory BCP ALL., (© 2022 S. Karger AG, Basel.)

Blinatumomab is the first-and-only Food and Drug Administration (FDA)-approved cluster of differentiation (CD) 19-directed CD3 bispecific T-cell engager (BiTE ® ) immunotherapy. It is currently FDA approved for the treatment of adults and children with Philadelphia chromosome-positive (Ph+) and Philadelphia chromosome-negative (Ph-) relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL) and B-cell precursor ALL with minimal residual disease. Similarly, initial marketing authorization for blinatumomab in the European Union was granted for the treatment of adults with Ph- R/R B-cell precursor ALL. The benefits of treating R/R B-cell precursor ALL patients with blinatumomab include increased overall survival, more favorable hematologic remission and molecular response rates, and a lower incidence rate of selected adverse events when compared with standard-of-care chemotherapy. The key risks associated with blinatumomab treatment include cytokine release syndrome, neurotoxicity, and medication errors. Here, we review the benefits and risks of blinatumomab treatment and describe how these risks can be mitigated.

In the phase 3 TOWER study, blinatumomab demonstrated an overall survival benefit over standard-of-care chemotherapy (SOC) in adults with relapsed or refractory (r/r) Philadelphia chromosome-negative (Ph - ) B-precursor acute lymphoblastic leukemia (ALL). Nearly all patients in both treatment arms experienced an adverse event (AE), and the incidence rate of serious AEs was higher for blinatumomab. However, as treatment exposure differed between the 2 arms, we conducted an exploratory safety analysis comparing exposure-adjusted event rates (EAERs) of blinatumomab vs SOC. Analyses were conducted for all patients who received therapy (safety population). Patients received a median (range) of 2 cycles (1-9) of blinatumomab (N = 267) vs 1 cycle (1-4) of SOC (N = 109). Grade ≥3 AE rates were generally higher in cycle 1 of blinatumomab than in cycle 2 (76% vs 37%). After adjusting for time on treatment, EAERs of grade ≥3 were significantly lower for blinatumomab vs SOC overall (10.73 vs 45.27 events per patient-year; P < .001) and for events of clinical interest, including infections (1.63 vs 6.49 events per patient-year; P < .001), cytopenias (3.64 vs 20.07 events per patient-year; P < .001), and neurologic events (0.38 vs 0.95 events per patient-year; P = .008). The EAER of grade ≥3 cytokine-release syndrome was higher for blinatumomab than for SOC (0.16 vs 0 events per patient-year; P = .038). These data further support the role of blinatumomab as an efficacious and well-tolerated treatment option for patients with r/r Ph - ALL. This trial was registered at www.clinicaltrials.gov as #NCT02013167., (© 2018 by The American Society of Hematology.)