Targeted Oncology最新文献

Background

Neoadjuvant immunotherapy with programmed death-ligand 1 blockade for colon cancer, especially for mismatch repair-deficient (dMMR)/high microsatellite instability (MSI-H) colon cancer, has gained considerable attention recently.

Objective

This study aimed to assess the safety and efficacy of neoadjuvant subcutaneous envafolimab in patients with dMMR/MSI-H locally advanced colon cancer.

Methods

Patients with dMMR/MSI-H locally advanced colon cancer treated with envafolimab at Sun Yat-sen University Cancer Center and Yunnan Cancer Hospital from October 2021 to July 2023 were retrospectively reviewed and analyzed. The primary endpoint was the pathological complete response (CR) rate, and secondary endpoints were treatment-related adverse events and complete clinical response rate.

Results

Overall, 15 patients were analyzed. After neoadjuvant immunotherapy with envafolimab, six patients achieved a CR, with five partial responses, and four stable disease. Three patients achieving a complete clinical response chose to accept a “watch and wait” strategy, and surgery was performed in 12 patients. Postoperative pathology results revealed seven patients achieved pathological CRs, and five patients achieved tumor regression grade 2, with 66.7% of the total CR rate. The most common treatment-related adverse events were pruritus and rash (40%), with no severe cases. No recurrences occurred over a 7.9-month follow-up.

Conclusions

Envafolimab yielded promising surgical outcomes and safety in dMMR/MSI-H locally advanced colon cancer, representing a promising treatment modality for this population.

Background

In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors.

Objective

This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting.

Patients and methods

The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea).

Results

Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13–0.90; p < 0.01] and immunotoxicity G < 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24–0.99; p = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43–0.95; p = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38–0.85; p = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65–0.95; p < 0.01), arterial hypertension G < 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52–0.87; p < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64–0.98; p = 0.03) as independent prognostic factors for progression-free survival.

Conclusions

As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab.

Background

MEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer.

Objective

This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies.

Patients and methods

Adults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity.

Results

As of 26 March 2020, 67 patients were treated (AML: n = 27; MM: n = 18; DLBCL: n = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUC_inf geometric CV%: 62.3–134.2, and 74.8–126.1, respectively). SG3199 (PBD dimer) plasma concentrations were below the limit of quantification for all patients after Study Day 8. Anti-drug antibody (ADA) prevalence was 7.7%, ADA incidence was 1.9%, and persistent-positive ADA was 5.8%.

Conclusions

Thrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD.

The study was registered with ClinicalTrials.gov (NCT03106428).

Background

The clinical and genetic characteristics, as well as treatment outcomes, of diffuse large B-cell lymphoma (DLBCL) patients with different MYD88 and CD79B mutation status merit further investigation.

Objective

This study aims to investigate the distinctions in clinical manifestations, genetic characteristics, and treatment outcomes among MYD88-CD79B^co-mut, MYD88/CD79B^single-mut, and MYD88-CD79B^co-wt DLBCL patients.

Patients and Methods

Clinical and genetic characteristics, along with treatment outcomes among 2696 DLBCL patients bearing MYD88-CD79B^co-mut, MYD88/CD79B^single-mut, and MYD88-CD79B^co-wt treated with R-CHOP/R-CHOP-like regimens from the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and six external cohorts were analyzed. Potential molecular mechanisms were investigated through Gene Set Enrichment Analysis and xCell methodology.

Results

In the MCD subtype, patients with MYD88-CD79B^co-mut showed comparable progression-free survival (PFS) and overall survival (OS) compared to MYD88/CD79B^single-mut or MYD88-CD79B^co-wt. However, in the non-MCD subtype, patients with MYD88-CD79B^co-mut exhibited significantly inferior OS than MYD88/CD79B^single-mut or MYD88-CD79B^co-wt, while there was no significant OS difference between MYD88/CD79B^single-mut and MYD88-CD79B^co-wt (median OS: 68.8 [95% CI 22–NA] vs NA [95% CI 112–NA] vs 177.7 [95% CI 159–NA] months; MYD88-CD79B^co-mut vs MYD88/CD79B^single-mut: p = 0.02; MYD88-CD79B^co-mut vs MYD88-CD79B^co-wt: p = 0.03; MYD88/CD79B^single-mut vs MYD88-CD79B^co-wt: p = 0.33). Regarding patients with MYD88-CD79B^co-mut, there was no significant difference in PFS and OS between the MCD and non-MCD subtypes. Within the MYD88-CD79B^co-mut group, patients with PIM1^mut had better PFS than PIM1^wt (median PFS: 8.34 [95% CI 5.56–NA] vs 43.8 [95% CI 26.4–NA] months; p = 0.02). Possible mechanisms contributing to the superior PFS of PIM1^mut patients may include activated lymphocyte-mediated immunity and interferon response, a higher proportion of natural killer T cells and plasmacytoid dendritic cells, as well as suppressed angiogenesis and epithelial-mesenchymal t

Background

Ruxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically.

Objective

This study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP).

Methods

In this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1–21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed.

Results

Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3–12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range 0.5–36.2 months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8–36.2 months). Twenty (69%) patients who showed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7–15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3–25.9 months).