Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS)

Morschhauser, Franck; Flinn, Ian W.; Advani, Ranjana H.; Sehn, Laurie H.; Diefenbach, Catherine; Kolibaba, Kathryn S.; Press, Oliver W.; Salles, Gilles; Tilly, Hervé; Chen, Andy I.; Assouline, Sarit; Cheson, Bruce D.; Dreyling, Martin; Hagenbeek, Anton; Zinzani, Pier Luigi; Jones, Surai; Cheng, Ji; Lü, Dan; Penuel, Elicia; Hirata, Jamie; Wenger, Michael; Chu, Yu Waye; Sharman, Jeff P.

doi:10.1016/s2352-3026(19)30026-2

Cited by 189 publications

(170 citation statements)

References 23 publications

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“…PK analyses were conducted on data from five clinical trials in which pola was administered either as a single agent or in combination with other therapies in patients with B-NHL. The included studies were: JO29138 (JAPI-CCTI-142580; Japanese phase 1 study of pola monotherapy) [19]; DCS4968g (NCT01290549; global phase 1 study of pola alone or in combination with rituximab) [8]; GO27834 (NCT01691898; phase 1b/2 study of pola with rituximab or obinutuzumab) [20][21][22]; GO29044 (NCT01992653; phase 1b/2 study of pola with R-CHP or G-CHP [obinutuzumab, cyclophosphamide, doxorubicin, and prednisone]) [23]; and GO29365 (NCT02257567; phase 1b/2 study of pola-BR or pola with bendamustine plus obinutuzumab) [9] (Supplementary Table 1 in Online Resource 1). In these studies, pola was administered as a single agent or in combination at various dose levels by IV infusion over 30 − 90 min; full details of the methods used in these trials were previously reported [8,9,[19][20][21][22][23] and study dosing is provided in Supplementary Table 1 in Online Resource 1.…”

Section: Data Sources and Study Populationsmentioning

confidence: 99%

Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma

Shi¹,

Tong²,

Ku³

et al. 2020

Cancer Chemother Pharmacol

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Purpose The CD79b-targeted antibody–drug conjugate polatuzumab vedotin (pola), alone and with chemoimmunotherapy, has clinical efficacy and a tolerable safety profile in B-cell non-Hodgkin lymphoma (B-NHL). We assessed (a) whether exposure from global studies of pola is comparable to Asian patients, and (b) if the recommended pola dose is appropriate in Asian patients based on exposure. Methods The pharmacokinetics (PK) of pola in Asian and global populations was characterized for three analytes (antibody-conjugated monomethyl auristatin E (MMAE) [acMMAE], total antibody, and unconjugated MMAE) in five phase 1b/2 single-agent and combination studies in B-NHL patients (JO29138 [JAPICCTI‐142580], DCS4968g [NCT01290549], GO27834 [NCT01691898], GO29044 [NCT01992653], and GO29365 [NCT02257567]). PK data were compared between Japanese phase 1 JO29138 (JAPICCTI‐142580) and global phase 1 DCS4968g (NCT01290549) studies and between Asian and non-Asian patients in the randomized relapsed/refractory B-NHL cohorts of the phase 1b/2 study GO29365 (NCT02257567). A population PK (popPK) model was used to assess the effects of Asian race and region on acMMAE and unconjugated MMAE exposure. Results PK non-compartmental analysis (NCA) parameters for the key analyte acMMAE in the Japanese JO29138 (JAPICCTI‐142580) and global phase 1 DCS4968g (NCT01290549) studies were similar. In GO29365 (NCT02257567), the phase 1b/2 combination study, mean exposure to the analytes was generally lower in Asian patients (by ~ 9.9 to 17.5%), but not to a clinically meaningful extent. Overall, the popPK model further suggested comparable PK in Asian patients with B-NHL (race or region) versus non-Asian patients. Conclusion Race has no clinically meaningful effect on pola PK. These results (and observations from efficacy/safety exposure–response analyses) support no pola dose adjustments are warranted for Asian patients with DLBCL.

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Section: Data Sources and Study Populationsmentioning

confidence: 99%

Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma

Shi¹,

Tong²,

Ku³

et al. 2020

Cancer Chemother Pharmacol

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“…Incorporation of 1.8 mg/kg of polatuzumab vedotin did not alter the safety profile described previously with R/G-CHOP in patients with DLBCL. While the AE profile in the current study varied by treatment arm, with a slightly larger incidence of grade 3-4 neutropenia and thrombocytopenia within the G-CHP arm compared to the R-CHP arm [18], exposures of acMMAE and unconjugated MMAE in both arms were similar at the 1.8-mg/kg dose level of pola. It has been shown that acMMAE is the key analyte driving both the safety and efficacy of pola [45,49], although unconjugated MMAE is also associated with safety.…”

Section: Discussionmentioning

confidence: 63%

“…After internalization, the linker is cleaved, resulting in the intracellular release of MMAE, which binds to tubulin to inhibit polymerization triggering tumor cell death [11]. Pola has demonstrated promising activity with combination agents in several clinical trials in patients with B-NHL and continues to be investigated in a phase III clinical trial [13][14][15][16][17][18]. Combining pola with rituximab or obinutuzumab plus cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) has a manageable safety profile and promising preliminary clinical activity in newly diagnosed DLBCL [19], supporting the initiation of a phase III trial comparing pola + R-CHP to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma

Shemesh¹,

Agarwal²,

Tong³

et al. 2020

Cancer Chemother Pharmacol

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Purpose The phase Ib/II open-label study (NCT01992653) evaluated the antibody-drug conjugate polatuzumab vedotin (pola) plus rituximab/obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) as first-line therapy for B-cell non-Hodgkin lymphoma (B-NHL). We report the pharmacokinetics (PK) and drug-drug interaction (DDI) for pola. Methods Six or eight cycles of pola 1.0-1.8 mg/kg were administered intravenously every 3 weeks (q3w) with R/G-CHP. Exposures of pola [including antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE] and R/G-CHP were assessed by non-compartmental analysis and/or descriptive statistics with cross-cycle comparisons to cycle 1 and/or after multiple cycles. Pola was evaluated as a potential victim and perpetrator of a PK drug-drug interaction with R/G-CHP. Population PK (popPK) analysis assessed the impact of prior treatment status (naïve vs. relapsed/refractory) on pola PK. Results Pola PK was similar between treatment arms and independent of line of therapy. Pola PK was dose proportional from 1.0 to 1.8 mg/kg with R/G-CHP. Geometric mean volume of distribution and clearance of acMMAE ranged from 57.3 to 95.6 mL/kg and 12.7 to 18.2 mL/kg/day, respectively. acMMAE exhibited multi-exponential decay (elimination half-life ~ 1 week). Unconjugated MMAE exhibited formation rate-limited kinetics.

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“…Grade ≥3 AEs occurred in 77% of DLBCL patients and 50% of FL patients, mainly as neutropenia, anemia, and diarrhea. 107 Furthermore, the findings of a phase 2 study (NCT02257567) pointed out that adding polatuzumab vedotin to bendamustine and rituximab (BR) treatment improved survival in patients with relapsed or refractory DLBCL. 108 The combination of polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP) vs R-CHOP in DLBCL is currently being investigated in a phase 3 study (POLARIX, NCT03274492).…”

Section: Cd52mentioning

confidence: 99%

Advances in targeted therapy for malignant lymphoma

Wang

Qin

Huo

et al. 2020

Sig Transduct Target Ther

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The incidence of lymphoma has gradually increased over previous decades, and it ranks among the ten most prevalent cancers worldwide. With the development of targeted therapeutic strategies, though a subset of lymphoma patients has become curable, the treatment of refractory and relapsed diseases remains challenging. Many efforts have been made to explore new targets and to develop corresponding therapies. In addition to novel antibodies targeting surface antigens and small molecular inhibitors targeting oncogenic signaling pathways and tumor suppressors, immune checkpoint inhibitors and chimeric antigen receptor T-cells have been rapidly developed to target the tumor microenvironment. Although these targeted agents have shown great success in treating lymphoma patients, adverse events should be noted. The selection of the most suitable candidates, optimal dosage, and effective combinations warrant further investigation. In this review, we systematically outlined the advances in targeted therapy for malignant lymphoma, providing a clinical rationale for mechanism-based lymphoma treatment in the era of precision medicine.Signal Transduction and Targeted Therapy (2020) 5:15; https://doi.

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Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS)

Cited by 189 publications

References 23 publications

Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma

Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma

Advances in targeted therapy for malignant lymphoma

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