Skip to main content

Advertisement

SpringerLink
Log in

Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads

  • REVIEW
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background Antibody drug conjugates (ADCs) utilize a monoclonal antibody to deliver a cytotoxic payload specifically to tumor cells, limiting exposure to healthy tissues. Major clinical toxicities of ADCs include hematologic, hepatic, neurologic, and ophthalmic events, which are often dose-limiting. These events may be off-target effects caused by premature release of payload in circulation. A meta-analysis was performed to summarize key clinical safety data for ADCs by payload, and data permitting, establish a dose-response model for toxicity incidence as a function of payload, dose/regimen, and cancer type. Methods A literature search was performed to identify and extract data from clinical ADC studies. Toxicity incidence and severity were collected by treatment arm for anemia, neutropenia, thrombocytopenia, leukopenia, hepatic toxicity, peripheral neuropathy, and ocular toxicity. Exploratory plots, descriptive summaries, and logistic regression modelling were used to explore Grade ≥ 3 (G3/4) toxicities and assess the impact of covariates, including cancer type and dose/regimen. Results The dataset contained 70 publications; quantitative analysis included 43 studies with G3/4 toxicity information reported for the endpoints above. G3/4 anemia, neutropenia and peripheral neuropathy were consistently reported for MMAE ADCs, thrombocytopenia and hepatic toxicity for DM1, and ocular toxicity for MMAF. Safety profiles of MMAE, DM1, and DM4 ADCs differed between solid and hematologic cancers. Conclusions Published ADC clinical data is limited by non-uniform reporting for toxicity and lack of dosing information, limiting the ability to develop quantitative models relating toxicity to exposure. However, the current analysis suggests that key G3/4 toxicities of ADCs in the clinic are likely off-target and related to payload.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Beck A, Goetsch L, Dumontet C, Corvaia N (2017) Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov 16(5):315–337. https://doi.org/10.1038/nrd.2016.268

    Article  CAS  PubMed  Google Scholar 

  2. Bouchard H, Viskov C, Garcia-Echeverria C (2014) Antibody-drug conjugates-a new wave of cancer drugs. Bioorg Med Chem Lett 24(23):5357–5363. https://doi.org/10.1016/j.bmcl.2014.10.021

    Article  CAS  PubMed  Google Scholar 

  3. Chari RV, Miller ML, Widdison WC (2014) Antibody-drug conjugates: an emerging concept in cancer therapy. Angew Chem Int Ed Engl 53(15):3796–3827. https://doi.org/10.1002/anie.201307628

    Article  CAS  PubMed  Google Scholar 

  4. Agresti AC, Brent A (1998) Approximate is better than "exact" for interval estimation of binomial proportions. Am Stat 52(2):119–126

    Google Scholar 

Download references

Funding

This study was funded by Pfizer, Inc.

Author information

Authors and Affiliations

  1. Clinical Pharmacology, Oncology, Global Product Development, Pfizer Inc., 10555 Science Center Drive, San Diego, CA, 92121, USA

    Joanna C. Masters

  2. Global Pharmacometrics, Global Product Development, Pfizer Inc., 10555 Science Center Drive, San Diego, CA, 92121, USA

    Dana J. Nickens & Michael Amantea

  3. Clinical Pharmacology, Early Oncology Development & Clinical Research, Worldwide Research and Development, Pfizer Inc., 10777 Science Center Drive, San Diego, CA, 92121, USA

    Dawei Xuan

  4. Inspyr Therapeutics, Inc., 31200 Via Colinas, Suite 200, Westlake Village, CA, 91362, USA

    Ronald L. Shazer

Authors
  1. Joanna C. Masters
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dana J. Nickens
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dawei Xuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ronald L. Shazer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Amantea
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joanna C. Masters.

Ethics declarations

Conflict of interest

Joanna C. Masters, Dana Nickens, Dawei Xuan, and Michael Amantea are employees of Pfizer and hold Pfizer stock. Ronald L. Shazer is an employee of Inspyr Therapeutics, Inc. and was a former employee of Pfizer, Inc. at the time of this analysis and holds Pfizer stock.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplement of References Used in the Analysis

Supplement of References Used in the Analysis

Bracketed [] numbers match ID number in forest plots

[1] Advani R, Lebovic D, Brunvand M, Chen AI, Goy A, Chang JE, Maeda LS, Ho W, Kahn R, Lu D, Su Z, Chu Y, Cheson BD (2012) A phase I study of DCDT2980S, an antibody-drug conjugate (ADC) targeting CD22, in relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL). Blood 120: 59

[2] Bartlett N, Forero-Torres A, Rosenblatt J, Fanale M, Horning SJ, Thompson S, Sievers EL, Kennedy DA (2009) Complete remissions with weekly dosing of SGN-35, a novel antibody-drug conjugate (ADC) targeting CD30, in a phase I dose-escalation study in patients with relapsed or refractory Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL). J Clin Oncol 27:1–5

[3] Bartlett N, Brice P, Chen RW, Fanale MA, Gopal AK, Matous J, Rosenblatt JD, Grove LE, Forero-Torres A (2012) Retreatment with brentuximab vedotin in CD30 positive hematologic malignancies: a phase II study. J Clin Oncol 30:8027

[4] Bartlett NL, Sharman JP, Oki Y, Advani RH, Bello CM, Winter JN, Yang Y, Kennedy DA, Jacobsen ED (2013). A phase 2 study of brentuximab vedotin in patients with relapsed or refractory CD30-positive non-Hodgkin lymphomas: interim results in patients with DLBCL and other B-cell lymphomas. Blood 122:848

[5] Beeram M, Krop IE, Burris HA, Girish SR, Yu W, Lu MW, Holden SN, Modi S (2012) A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer. Cancer 118:5733–5740

[6] Bendell JMK, Qin A, Johnson D, Schindler J, Papadopoulos K, Tolcher AW (2010) A phase I study of IMGN388, an antibody drug conjugate targeting alpha(v) integrin, in patients with solid tumors. Euro J Cancer 8:152

[7] Boni V, Rixe O, Rasco D, Gomez-Roca C, Calvo E, Morris JC, Tolcher AW, Assadourian S, Guillemin H, Delord JP (2013) A phase I first-in-human (FIH) study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors. Mol Cancer Ther 12 (supplement):A73

[8] Burris H, Burris H, Saleh M, Bendell J, Bendell J, Hart L, Hart L, Rose A, Dong Z, Siegel P, Crane M, Donovan D, Crowley E, Simantov R, Vahdat L (2009) A phase (Ph) I/II study of CR011-VcMMAE, an antibody-drug conjugate, in patients (pts) with locally advanced or metastatic breast cancer (MBC). Cancer Res 69:6069

[9] Burris HA III, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, Tan-Chiu E, Krop IE, Michaelson RA, Girish S, Amler L, Zheng M, Chu YW, Klencke B, O Shaughnessy JA (2001) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 29:398–405

[10] Burris HA, Gordon MS, Gerber DE, Spigel DR, Mendelson DS, Schiller JH, Wang Y, Choi Y, Kahn RS, Wood K, Maslyar DJ, Infante JR (2014) A phase I study of DNIB0600A, an antibody-drug conjugate (ADC) targeting NaPi2b, in patients (pts) with non-small cell lung cancer (NSCLC) or platinum-resistant ovarian cancer (OC). J Clin Oncol 32:2504

[11] Coiffier B, Thieblemont C, Guibert SD, Dupuis J, Ribra V, Bouabdallah R, Morschhauser F, Cartron G, Gouill SL, Casasnovas O, Holte H, Hatteville L, Zilocchi C, Oprea C, Tilly H (2013) Phase II study of anti-CD19 antibody drug conjugate (SAR3419) in combination with rituximab: clinical activity and safety in patients with relapsed/refractory diffuse large B-cell lymphoma. Blood 122:4395

[12] Duvic M, Tetzlaff M, Gangar P, Clos AL, Talpur R (2013) Phase II trial of brentuximab vedotin (SGN-35) for CD30+ cutaneous T-cell lymphomas and lymphoproliferative disorders. J Investig Dermatol 133:S180

[13] Fanale MA, Forero-Torres A, Rosenblatt JD, Advani RH, Franklin AR, Kennedy DA, Han TH, Sievers EL, Bartlett NL (2012) A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies. Clin Cancer Res 18:248–255

[14] Galsky MD, Eisenberger M, Moore-Cooper S, Kelly WK, Slovin SF, DeLaCruz A, Lee Y, Webb IJ, Scher HI (2008) Phase I trial of the prostate-specific membrane antigen-directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer. J Clin Oncol 26:2147–2154

[15] Gan HK, Fichtel L, Lassman AB, Merrell R, Bent MJVD, Kumthekar P, Scott AM, Pedersen M, Gomez E, Fischer J, Ames W, Xiong H, Dudley MW, Munasinghe W, Roberts-Rapp L, Ansell P, Holen KD, Reardon DA (2014) A phase 1 study evaluating ABT-414 in combination with temozolomide (TMZ) for subjects with recurrent or unresectable glioblastoma (GBM). J Clin Oncol 32:2021

[16] Gibb A, Jones C, Bloor A, Kulkarni S, Illidge T, Linton K, Radford J (2013) Brentuximab vedotin in refractory CD30+ lymphomas: a bridge to allogeneic transplantation in approximately one quarter of patients treated on a Named Patient Programme at a single UK center. Haematologica 98:611–614

[17] Hatake K, Ogura M, Tobinai K, Ishizawa K, Uike N, Uchida T, Suzuki T, Aoki T, Watanabe T, Maruyama D, Takubo T, Kagehara H, Matsushima T (2013) Phase 1/2 study of brentuximab vedotin in Japanese patients (pts) with relapsed/refractory (RR) Hodgkin’s lymphoma (HL) or systemic anaplastic large cell lymphoma (SALCL). Hematol Oncol 31:268

[18] Helft PR, Schilsky RL, Hoke FJ, Williams D, Kindler HL, Sprague E, DeWitte M, Martino HK, Erickson J, Pandite L, Russo M, Lambert JM, Howard M, Ratain MJ (2004) A phase I study of cantuzumab mertansine administered as a single intravenous infusion once weekly in patients with advanced solid tumors. Clin Cancer Res 10:4363–4368

[19] Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA (2013) Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 31:1157–1163

[20] Hwu P, Sznol M, Pavlick A, Kluger H, Kim KB, Boasberg P, Sanders D, Simantov R, Crowley E, Hamid O (2009) A phase I/II study of CR011-vcMMAE, an antibody-drug conjugate (ADC) targeting glycoprotein NMB (GPNMB) in patients (pts) with advanced melanoma. J Clin Oncol 27:9032

[21] Krop IE, Mita M, Burris HA, Birkner M, Girish S, Tibbitts J, Holden SN, Lutzker SG, Modi S (2009) A phase I study of weekly dosing of trastuzumab DM1 (T-DM1) in patients with advanced HER2+ breast cancer. Cancer Res 69:3136

[22] Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W, Girish S, Tibbitts J, Yi JH, Sliwkowski MX, Jacobson F, Lutzker SG, Burris HA (2010) Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 28:2698–2704

[23] Krop IE, LoRusso P, Miller KD, Modi S, Yardley D, Rodriguez G, Guardino E, Lu M, Zheng M, Girish S, Amler L, Winer EP, Rugo HS (2012) A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol 30:3234–3241

[24] Miller K, Gianni L, Andre F, Dieras V, Mahtani RL, Harbeck N, Huang JE, Shih T, Choi Y, Burris HA III (2010) A phase Ib/II trial of trastuzumab-DM1 (T-DM1) with pertuzumab (P) for women with HER2-positive, locally advanced or metastatic breast cancer (BC) who were previously treated with trastuzumab (T). J Clin Oncol 28:1012

[25] Morris MJ, Bruce JY, Reyno LM, Anand B, Hartford A, Maxwell KJ, Lackey J, Eisenberger MA (2012) Phase I trial of ASG-5ME in metastatic castration-resistant prostate cancer (CRPC). J Clin Oncol 30:4568

[26] Palanca-Wessels MC, Flinn IW, Sehn LH, Patel M, Sangha R, Czuczman MS, Salles GA, Morschhauser F, Advani R, Press OW, Ho W, Kahn R, Lu D, Su Z, Chu YW, Assouline SE (2012) A phase I study of the anti-CD79b antibody-drug conjugate (ADC) DCDS4501A targeting CD79b in relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL). Blood 120:56

[27] Petrylak DP, Kantoff PW, Mega AE, Vogelzang NJ, Stephenson J, Fleming MT, Stambler N, Petrini M, Huang K, Israel RJ (2013) Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): a phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane. J Clin Oncol 31:5018

[28] Petrylak DP, Smith DC, Appleman LJ, Fleming MT, Hussain A, Dreicer R, Sartor AO, Shore ND, Vogelzang NJ, Youssoufian H, Olson WC, Stambler N, Huang K, Israel RJ (2014) A phase II trial of prostate-specific membrane antigen antibody drug conjugate (PSMA ADC) in taxane-refractory metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 32:5023

[29] Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, Matous J, Ramchandren R, Fanale M, Connors JM, Yang Y, Sievers EL, Kennedy DA, Shustov A (2012) Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 30:2190–2196

[30] Ribrag V, Dupuis J, Tilly H, Morschhauser F, Laine F, Houot R, Haioun C, Copie C, Varga A, Lambert J, Hatteville L, Ziti-Ljajic S, Caron A, Payrard S, Coiffier B (2014) A dose-escalation study of SAR3419, an anti-CD19 antibody maytansinoid conjugate, administered by intravenous infusion once weekly in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res 20:213–220

[31] Rodon J, Garrison M, Hammond LA, de Bono J, Smith L, Forero L, Hao D, Takimoto C, Lambert JM, Pandite L, Howard M, Xie H, Tolcher AW (2008) Cantuzumab mertansine in a three-times a week schedule: a phase I and pharmacokinetic study. Cancer Chemother Pharmacol 62:911–919

[32] Rupp U, Schoendorf-Holland E, Eichbaum M, Schuetz F, Lauschner I, Schmidt P, Staab A, Hanft G, Huober J, Sinn HP, Sohn C, Schneeweiss A (2007) Safety and pharmacokinetics of bivatuzumab mertansine in patients with CD44v6-positive metastatic breast cancer: final results of a phase I study. Anticancer Drugs 18:477–485

[33] Stathis A, Maddocks KJ, Flinn I, Mejia A, Palomba ML, Zildjian S, Murphy M, Deckert J, Ruiz-Soto R, Freedman A (2014) Preliminary findings from a phase I, multicenter, open-label study of the anti-CD37 antibody-drug conjugate (ADC), IMGN529, in adult patients with relapsed or refractory non-Hodgkin lymphoma (NHL). J Clin Oncol 32:8526

[34] Takahashi S, Kashiwaba M, Takao S, Ito Y, Doihara H, Rai Y, Matsubara M, Kanatani K, Masuda N (2013) A phase 2 study of trastuzumab emtansine in Japanese patients with HER2 positive metastatic breast cancer. Ann Oncol 24 (supplement 9):ix20 [35] Tannir NM, Forero-Torres A, Ramchandren R, Pal SK, Ansell SM, Infante JR, de Vos S, Hamlin PA, Kim SK, Whiting NC, Gartner EM, Zhao B, Thompson JA (2014) Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma. Invest New Drugs 32:1246–1257

[36] Tolcher AW, Ochoa L, Hammond LA, Patnaik A, Edwards T, Takimoto C, Smith L, de Bono J, Schwartz G, Mays T, Jonak ZL, Johnson R, DeWitte M, Martino H, Audette C, Maes K, Chari RV, Lambert JM, Rowinsky EK (2003) Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study. J Clin Oncol 21:211–222

[37] Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Dieras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783–1791

[38] Vogel CL, Burris HA, Limentani S, Borson R, O’Shaughnessy J, Vukelja S, Agresta S, Klencke B, Birkner M, Rugo H (2009) A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (MBC): Final results. J Clin Oncol 27:1017

[39] Yasenchak CA, Chen R, Sharman JP, Boccia RV, Holkova B, Rosen PJ, Friedberg JW, O’Meara MM, Forero-Torres A (2013) A phase 2 study of single-agent brentuximab vedotin for front-line therapy of Hodgkin’s lymphoma in patients age 60 years and above: interim results. Blood 122:4389

[40] Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, Forero-Torres A (2010) Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363:1812–1821

[41] Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, Bartlett NL, Cheson BD, de Vos S, Forero-Torres A, Moskowitz CH, Connors JM, Engert A, Larsen EK, Kennedy DA, Sievers EL, Chen R (2012) Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 30:2183–2189

[42] Younes A, Kim S, Romaguera J, Copeland A, Farial Sde C, Kwak LW, Fayad L, Hagemeister F, Fanale M, Neelapu S, Lambert JM, Morariu-Zamfir R, Payrard S, Gordon LI (2012) Phase I multidose-escalation study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered by intravenous infusion every 3 weeks to patients with relapsed/refractory B-cell lymphoma. J Clin Oncol 30:2776–2782

[43] Zambrano CC, Almhanna K, Messersmith WA, Ahnert JR, Ryan DP, Faris JE, Jung J, Fasanmade A, Wyant T, Kalebic T(2014) MLN0264, an investigational antiguanylyl cyclase C (GCC) antibody-drug conjugate (ADC), in patients (pts) with advanced gastrointestinal (GI) malignancies: phase I study. J Clin Oncol 32:3546

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Masters, J.C., Nickens, D.J., Xuan, D. et al. Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads. Invest New Drugs 36, 121–135 (2018). https://doi.org/10.1007/s10637-017-0520-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-017-0520-6

Keywords

Search

Navigation