Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study

Jackisch, Christian; Kim, S.-B.; Семиглазов, Владимир; Melichar, Bohuslav; Pivot, Xavier; Hillenbach, Carina; Stroyakovskiy, Daniil; Lum, Bert L.; Elliott, Robert S.; Weber, Heinz; Ismael, Gustavo

doi:10.1093/annonc/mdu524

Cited by 97 publications

(90 citation statements)

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“…Continuing in the development program, there were no cases of severe hypersensitivity reactions, such as anaphylaxis in the pivotal phase 3 HannaH trial comparing SC versus intravenous (IV) trastuzumab formulations. At 12 months median follow-up, only 11% of patients reported injection-site pain, which was predominantly Grade 1 [12], which was further confirmed with the 20-month median follow-up [13]. The Phase 3 SABRINA trial that assessed SC versus IV rituximab with rHuPH20 in combination with chemotherapy also showed that both formulations had similar tolerability; the proportion of patients with Grade 3 or worse AEs or SAEs did not differ between groups [11].…”

Section: Clinical Experience With Rhuph20mentioning

confidence: 53%

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The Activity of Hyaluronan and Hyaluronidase PH20 in Inflammation-A Role by Reagent Contaminants?

Huang¹

2015

J Clin Cell Immunol

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Section: Clinical Experience With Rhuph20mentioning

confidence: 53%

“…In recent years, the development of rHuPH20 has facilitated subcutaneous administration of monoclonal antibodies such as trastuzumab and rituximab [11][12][13]. In addition, high levels of HA in tumors is associated with treatment resistance to monoclonal antibodies and poor clinical outcomes.…”

Section: Lettermentioning

confidence: 99%

The Activity of Hyaluronan and Hyaluronidase PH20 in Inflammation-A Role by Reagent Contaminants?

Huang¹

2015

J Clin Cell Immunol

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“…Moreover, the neoadjuvant setting allows the use of pCR, which is a better efficacy assessment criterion and is related to survival outcome. [16][17][18] ORR for metastatic lesions is not related to survival outcomes, and has not been used for the basis of any drug registration in breast cancer. 19 Considering these points, the neoadjuvant setting is considered to be an important area for development in HER2-positive breast cancer.…”

Section: Mainmentioning

confidence: 99%

Can we establish a hierarchy among trastuzumab biosimilar candidates?

Pivot¹,

Petit²

2018

Br J Cancer

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The European patent for intravenous trastuzumab lapsed in 2017, and this stimulated research into a number of trastuzumab biosimilars. Quality assessment of their development and clinical results might enable establishment of a clinical hierarchy of these agents. This editorial will underline the key points for consideration when determining such an evaluation.British Journal of Cancer (2018) 119:263-265; https://doi.org/10.1038/s41416-018-0171-1 MAINThe extraordinary clinical achievements of trastuzumab have made history in the systemic management of breast cancer. Unfortunately, it is not uniformly available for routine use owing to its prohibitively high cost. With financial contingencies following the economic crisis together with rapidly increasing healthcare costs, even the richest countries are exploring ways to reduce their healthcare expenditures. In 2017, the patent for intravenous trastuzumab (Herceptin) expired across Europe, which stimulated the development of numerous trastuzumab biosimilar agents (Table 1). [1][2][3][4][5] In this issue of the British Journal of Cancer, Lammers et al. report evidence establishing another step towards the registration of PF-05280014, a trastuzumab biosimilar candidate developed by Pfizer. 1,[6][7][8] This significant trial has provided clinical efficacy results of this candidate in patients with early breast cancer, and insight into its pharmacokinetic (PK) non-inferiority.The development of a biosimilar drug requires the collation of extensive pre-clinical comparability studies to demonstrate similar structural, physicochemical, and functional biological characteristics with the referent medical product. 9,10 . PK comparability in animal models is required prior to the first in-human study, and this is usually aimed at demonstrating PK equivalence between the biosimilar candidate and the referent. These steps have already been successfully achieved for PF-05280014.6,7 Treatment with trastuzumab can result in the production of anti-trastuzumab antibodies; therefore, initial phase I trials for PK assessment include healthy male subjects, because they are less likely to require treatment with trastuzumab for breast cancer in the future. Notably, several previous studies have validated the absence of observable discrepancies in PK profiles for trastuzumab between healthy volunteers and patients. 2,4,11,12 Iterative drug administration causes an accumulation of plasma drug levels, thus resulting in an increase of the average AUC (0-t) . For trastuzumab exposure, large variability in the AUC (0-t) is observed up to cycle 5, beyond which the values become stable and homogeneous over time. 13,14 Therefore, a large randomised study aimed at comparing the activities should also perform a PK assessment in patients receiving iterative administration.A randomised clinical study represents the ultimate step in the path towards drug registration, with the intention of providing evidence for similar efficacy between the biosimilar candidate and the reference medical product in a...

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“…17 Trastuzumab has tolerable immunogenicity that does not affect its serum concentration and the pathologic complete response of patients. 18,19 It would be useful to explore whether RabMAbs can be directly humanized by comparison with human sequences, in a similar way to humanization of mouse antibodies. In one study, humanized anti-VEGF RabMAbs have been made by substituting non-critical residues with human residues within both the frameworks and CDR regions.…”

Section: Introductionmentioning

confidence: 99%

Humanization of rabbit monoclonal antibodies via grafting combined Kabat/IMGT/Paratome complementarity-determining regions: Rationale and examples

Zhang

2017

mAbs

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Rabbit monoclonal antibodies (RabMAbs) can recognize diverse epitopes, including those poorly immunogenic in mice and humans. However, there have been only a few reports on RabMAb humanization, an important antibody engineering step usually done before clinical applications are investigated. To pursue a general method for humanization of RabMAbs, we analyzed the complex structures of 5 RabMAbs with their antigens currently available in the Protein Data Bank, and identified antigen-contacting residues on the rabbit Fv within the 6 Angstrom distance to its antigen. We also analyzed the supporting residues for antigen-contacting residues on the same heavy or light chain. We identified "HV4" and "LV4" in rabbit Fvs, non-complementarity-determining region (CDR) loops that are structurally close to the antigen and located in framework 3 of the heavy chain and light chain, respectively. Based on our structural and sequence analysis, we designed a humanization strategy by grafting the combined Kabat/IMGT/Paratome CDRs, which cover most antigen-contacting residues, into a human germline framework sequence. Using this strategy, we humanized 4 RabMAbs that recognize poorly immunogenic epitopes in the cancer target mesothelin. Three of the 4 humanized rabbit Fvs have similar or improved functional binding affinity for mesothelin-expressing cells. Interestingly, 4 immunotoxins composed of the humanized scFvs fused to a clinically used fragment of Pseudomonas exotoxin (PE38) showed stronger cytotoxicity against tumor cells than the immunotoxins derived from their original rabbit scFvs. Our data suggest that grafting the combined Kabat/IMGT/Paratome CDRs to a stable human germline framework can be a general approach to humanize RabMAbs.

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Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study

Abstract: NCT00950300.

Cited by 97 publications

References 5 publications

The Activity of Hyaluronan and Hyaluronidase PH20 in Inflammation-A Role by Reagent Contaminants?

The Activity of Hyaluronan and Hyaluronidase PH20 in Inflammation-A Role by Reagent Contaminants?

Can we establish a hierarchy among trastuzumab biosimilar candidates?

Humanization of rabbit monoclonal antibodies via grafting combined Kabat/IMGT/Paratome complementarity-determining regions: Rationale and examples

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