Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study

Simonelli, Matteo; Garralda, E.; Eskens, Ferry A.L.M.; Gil-Martín, Marta; Yen, Chia Jui; Obermannová, Radka; Chao, Yee; Melichar, B; Moreno, V.; Yu, Ming‐Lung; Bongiovanni, Alberto; Calvo, Emiliano; Rottey, Sylvie; Machiels, J.-P.; González-Martín, Antonio; Paz‐Ares, Luis; Chang, Christie; Mason, W. P.; Lin, Chin‐Hsien; Reardon, David A.; Vieito, M.; Santoro, Armando; Meng, Robin; Abbadessa, Giovanni; Menas, Fatima; Lee, H.; Liu, Q.; Combeau, Cécile; Ternès, Nils; Ziti-Ljajic, Samira; Massard, Christophe

doi:10.1016/j.esmoop.2022.100562

Cited by 17 publications

(13 citation statements)

References 14 publications

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“…24 In this study, where renal function was even worse due to majority of patients being on dialysis, isatuximab PK exposure was comparable with those from other studies. 25–27 Overall, these results complement the previous analyses mentioned above, showing no effect of renal impairment on isatuximab PK exposure. These results were expected as isatuximab is a monoclonal antibody, and thus a large molecule, and is eliminated by catabolism.…”

Section: Discussionsupporting

confidence: 89%

Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant

Vincenti,

Bestard,

Brar

et al. 2023

JASN

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Background Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. Methods This was an open-label single-arm Phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, Cohorts A and B, which enrolled cPRA ≥99.90% and 80.00%–<99.90%, respectively. Results 23 patients (12 Cohort A, 11 Cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38+ plasmablasts, plasma cells, and NK cells; and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, based on a pre-defined composite desensitization end-point, was 83.3% and 81.8% in Cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall cPRA values were minimally impacted, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cut-off (median follow-up 68 weeks), 6 patients received transplant offers, of which 4 were accepted. Conclusions In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity.

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Section: Discussionsupporting

confidence: 89%

Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant

Vincenti,

Bestard,

Brar

et al. 2023

JASN

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“…All 20 studies reported the incidences of any grade and grade three or more trAEs (Table 1). Nine studies were anti-PD1 monotherapy, [3][4][5][14][15][16][17][18][19] eight studies were anti-PDL1 monotherapy, 6,7,[20][21][22][23][24][25] seven studies were ICIs combination therapy, [6][7][8]14,20,26,27 five studies were median duration of treatment ≤3months, eight studies were >3 months, nine studies were RCT, and 11 studies were non-RCT. Seventeen studies reported the incidence of treatment-related deaths, among which eight studies were anti-PD1 monotherapy, eight studies were anti-PDL1 monotherapy, and six studies were ICIs combination therapy.…”

Section: Study Characteristics and Quality Assessmentmentioning

confidence: 99%

Toxicity profiles of immune checkpoint inhibitors for recurrent or metastatic head and neck squamous cell carcinoma: A systematic review and meta‐analysis

Dang,

Li,

Liu

et al. 2024

Cancer Medicine

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BackgroundImmune checkpoint inhibitors (ICIs) are widely used in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC); however, the toxicity profiles are inconclusive.MethodsClinical trials evaluating ICIs for R/M HNSCC were searched from online databases. The characteristics of the studies and the results of incidences of any grade treatment‐related adverse events (trAEs), grade three or more trAEs, treatment‐related deaths, trAEs leading to discontinuation of treatment, and specific trAEs were extracted.ResultsTwenty studies with 3756 patients were included. The pooled incidences of any grade trAEs, grade three or more trAEs, treatment‐related deaths, trAEs leading to discontinuation of treatment for overall population were 62.07% (95% CI, 59.07%–65.02%), 13.82% (95% CI, 11.23%–16.62%), 0.39% (95% CI, 0.15%–0.71%), 3.99% (95% CI, 2.36%–5.95%), respectively. Programmed cell death protein 1 (PD‐1) inhibitors monotherapy and ICIs combination therapy had significantly higher incidences of any grade trAEs (odds ratio [OR], 1.25, 95% CI, 1.05–1.49 and 1.36, 95% CI, 1.15–1.60, respectively), grade three or more trAEs (OR, 1.41, 95% CI, 1.08–1.84 and 1.79, 95% CI, 1.39–2.30, respectively), trAEs leading to discontinuation of treatment (OR, 3.98, 95% CI, 2.06–7.70 and 10.14, 95% CI, 5.49–18.70, respectively) compared with programmed death‐ligand 1 (PD‐L1) inhibitors monotherapy. ICIs combination therapy had a significantly higher incidence of grade three or more trAEs compared with PD‐1 inhibitors monotherapy (OR, 1.27, 95% CI, 1.03–1.55); however, the incidences of any grade trAEs and trAEs leading to discontinuation of treatment were not significant different.ConclusionsOur study suggests that the incidences of grade three or more trAEs, treatment‐related deaths, and trAEs leading to discontinuation of treatment are low in R/M HNSCC patients treated with ICIs. PD‐L1 inhibitors monotherapy may be safer compared with PD‐1 inhibitors monotherapy and ICIs combination therapy.

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“…The multicenter phase trial study conducted by Simonelli et al found that the combination of isatuximab plus atezolizumab, an anti-CD3 monoclonal antibody, and an anti-PD-L1 monoclonal antibody, respectively, has a well-tolerated and manageable safety profile in treating advanced solid tumors. When combined with isatuximab, the efficacy of atezolizumab was found to be increased [118]. A STRIDE (Single Tremelimumab Regular Interval Durvalumab) study conducted by Ghassan et al found that the combination of tremelimumab plus durvalumab in 393 patients with unresectable HCC had a significant survival rate of 30.7% compared to durvalumab (24.7%, n = 389) and sorafenib (20.2%, n = 389) alone [119].…”

Section: Combination Immunotherapymentioning

confidence: 99%

Therapeutic options in hepatocellular carcinoma: a comprehensive review

et al. 2023

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Hepatocellular carcinoma (HCC) is a chronic liver disease that is highly fatal if not detected and treated early. The incidence and death rate of HCC have been increasing in recent decades despite the measures taken for preventive screening and effective diagnostic and treatment strategies. The pathophysiology of HCC is multifactorial and highly complex owing to its molecular and immune heterogeneity, and thus the gap in knowledge still precludes making choices between viable therapeutic options and also the development of effective regimens. The treatment of HCC demands multidisciplinary approaches and primarily depends on tumor stage, hepatic functional reserve, and response to treatment by patients. Although curative treatments are limited but critical in the early stages of cancer, there are numerous palliative treatments available for patients with intermediate and advanced-stage HCC. In recent times, the use of combination therapy has succeeded over the use of monotherapy in the treatment of HCC by achieving effective tumor suppression, increasing survival rate, decreasing toxicity, and also aiding in overcoming drug resistance. This work focuses on reviewing the current and emerging treatment strategies for HCC.

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Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study

Cited by 17 publications

References 14 publications

Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant

Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant

Toxicity profiles of immune checkpoint inhibitors for recurrent or metastatic head and neck squamous cell carcinoma: A systematic review and meta‐analysis

Therapeutic options in hepatocellular carcinoma: a comprehensive review

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