Author Manuscript Published OnlineFirst on April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 1 Antibody Drug Conjugates: Future Directions in Clinical and Translational Strategies to 2 Improve the Therapeutic Index 3 4 Authors: Steven Coats1, Marna Williams1, Benjamin Kebble1, Rakesh Dixit1, Leo Tseng1, Nai- 5 Shun Yao1, David A. Tice1, and Jean-Charles Soria1,2 6 7 Affiliations: 1AstraZeneca, Gaithersburg, MD, USA. 2University Paris-Sud, Orsay, France. 8 9 Running title: Advances in Antibody Drug Conjugate Clinical Development 10 11 Corresponding Author: Steven Coats 12 Research and Development Oncology 13 AstraZeneca 14 1 MedImmune Way 15 Gaithersburg, MD 20878 16 Email: [email protected] 17 18 DISCLOSURE OF POTENTIAL CONFLICT OF INTEREST 19 All authors are employees of AstraZeneca and hold stock/stock options in AstraZeneca. Dr. 20 Soria also holds stock/stock options in Gritstone. Over the last 5 years, Dr. Soria has received 21 consultancy fees from AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission 22 Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, 23 Symphogen, and Takeda. 24 25 26 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2 27 ABSTRACT 28 Since the first approval of gemtuzumab ozogamicin (Mylotarg; CD33 targeted), 2 additional 29 antibody drug conjugates (ADCs)—brentuximab vedotin (Adcetris; CD30 targeted) and 30 inotuzumab ozogamicin (Besponsa; CD22 targeted)—have been approved for hematologic 31 cancers and 1 ADC, trastuzumab emtansine (Kadcyla; HER2 targeted), has been approved to 32 treat breast cancer. Despite a clear clinical benefit being demonstrated for all 4 approved ADCs, 33 the toxicity profiles are comparable to those of standard-of-care chemotherapeutics, with dose- 34 limiting toxicities associated with the mechanism of activity of the cytotoxic warhead. However, 35 the enthusiasm to develop ADCs has not been dampened; approximately 80 ADCs are in 36 clinical development in nearly 600 clinical trials, and 2 to 3 novel ADCs are likely to be approved 37 within the next few years. While the promise of a more targeted chemotherapy with less toxicity 38 has not yet been realized with ADCs, improvements in technology combined with a wealth of 39 clinical data are helping to shape the future development of ADCs. In this review we discuss the 40 clinical and translational strategies associated with improving the therapeutic index for ADCs. 41 42 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 3 43 Introduction 44 Antibody drug conjugates (ADCs) were initially designed to leverage the exquisite specificity of 45 antibodies to deliver targeted potent chemotherapeutic agents with the intention of improving 46 the therapeutic index (the ratio between the toxic dose and the dose at which the drug becomes 47 effective; Figure 1) (1, 2). Unfortunately, the greatest challenge to date for developing ADCs is 48 a therapeutic index far narrower than expected (3-5). Of approximately 55 traditional ADCs for 49 which clinical development has been halted, we estimate that at least 23 have been 50 discontinued due to a poor therapeutic index; however, this is likely a conservative estimate 51 based on the availability of clinical data. A narrow therapeutic window limits the dose that can 52 be achieved, often resulting in toxic effects occurring before an ADC reaches its maximally 53 efficacious dose. Furthermore, these toxicities limit the number of dosing cycles that patients 54 can tolerate and often result in skipped doses, dose reductions, or study discontinuations (6, 7). 55 56 In this review we discuss clinical and translational strategies to improve the therapeutic index of 57 ADCs that are based on the latest clinical efficacy and safety data with next-generation 58 antibodies and warheads currently in development. While technology plays a crucial role in 59 expanding the therapeutic index of ADCs, we refer readers to several excellent reviews that 60 cover novel advancements in antibody, linker, and warhead technologies in significant depth (2, 61 3, 8, 9) 62 Overview of ADCs in Clinical Development 63 Four ADCs have been approved over the last 20 years (Figure 2A)(2). The first ADC approved 64 for clinical use was gemtuzumab ozogamicin (Mylotarg; CD33 targeted) for relapsed acute 65 myeloid leukemia in 2000 (10). In 2010, gemtuzumab ozogamicin was withdrawn from the US 66 market when a confirmatory trial showed that it was associated with a greater rate of fatal 67 toxicities vs standard-of-care chemotherapy (5.8% vs 0.8%) (10, 11). In 2017, gemtuzumab 68 ozogamicin was reapproved for relapsed/refractory acute myeloid leukemia after a phase 3 trial 69 with a fractionated dosing schedule lowered the peak serum concentration and improved the 70 safety profile, with a complete response rate of 26% (12). These clinical data demonstrate the 71 importance of understanding the relationship between the exposure, safety, and efficacy of 72 ADCs in clinical development. 73 Other ADCs that have been approved are brentuximab vedotin (Adcetris; CD30 targeted) (13) 74 and inotuzumab ozogamicin (Besponsa; CD22 targeted) (14), which were approved for Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 4 75 hematologic malignancies, and trastuzumab emtansine (Kadcyla; HER2 targeted), which was 76 approved for breast cancer (15). Across phase 2 and 3 studies, response rates were 77 significantly higher in patients treated with ADCs than in those treated with standard intensive 78 chemotherapy (14, 16-18). 79 Clear clinical benefits have been demonstrated with all 4 approved ADCs; however, each has 80 reported toxicity profiles that are specific to its cytotoxic warhead and, therefore, they cannot be 81 differentiated from standard-of-care chemotherapies (13-15) in terms of safety. Regardless of 82 the obstacles, there is intense interest in developing ADCs—approximately 80 ADC candidates 83 are reportedly in clinical development, with nearly 600 clinical trials ongoing—and it is likely that 84 several new ADCs will be approved over the next few years (Figure 2A) (19) led by the recent 85 Biologics License Application filing for polatuzumab vedotin (CD79b targeted) in 86 relapsed/refractory DLBCL. Although ADCs have not yet delivered on the promise of a more- 87 targeted chemotherapy with an improved toxicity profile, new strategies may prove crucial to 88 improving the therapeutic index of ADCs (4, 20, 21). These strategies include the use of 89 warheads with lower potencies and alternative mechanisms of activity as described below. 90 Two examples of ADCs in clinical development that use warheads that inhibit topoisomerase I 91 activity include trastuzumab deruxtecan targeting HER2 in breast and gastric cancers and 92 sacituzumab govitecan targeting Trop2 in breast and lung cancers (22, 23). A Biologics License 93 Application has been filed for sacituzumab govitecan for metastatic triple-negative breast 94 cancer, and trastuzumab deruxtecan is currently in multiple late-stage pivotal clinical trials. The 95 clinical data for trastuzumab deruxtecan from an ongoing phase 1 study in HER2-high 96 metastatic breast cancer (post trastuzumab emtansine) showed an ORR of 55% with median 97 progression-free survival not reached (Table 1). Updated recent data have shown a median 98 duration of response of 20.7 months, which compares favorably with trastuzumab emtansine, 99 which, in a pivotal study in HER2-high metastatic breast cancer, showed an ORR of 43.6%, a 100 median progression-free survival of 9.6 months, and a median duration of response of 12.6 101 months (22). In a phase 1 trial in third-line triple-negative breast cancer, sacituzumab govitecan 102 demonstrated an ORR of 31% and a median progression-free survival of 5.5 months (Table 1). 103 In this trial, sacituzumab govitecan was dosed at 10 mg/kg on days 1 and 8 every 21 days and 104 showed improved tolerability compared with other ADCs targeting Trop2 such as PF-06664178, 105 which had a maximum tolerated dose of 2.4 mg/kg, showed limited efficacy, and was terminated 106 due to high toxicity (23). 107 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 5 108 The results from this phase 1 trial with sacituzumab govitecan provide an example of the 109 importance of matching the right drug to the right target for the right patient. Even when 110 comparing ADCs that use the same antibody against the same target in a similar patient 111 population, trastuzumab emtansine and trastuzumab deruxtecan have demonstrated clinical 112 activity, whereas a trastuzumab tesirine conjugate (ADCT-502) was recently discontinued due 113 to a narrow therapeutic index (24). HER2 is known to be expressed in several normal tissues 114 such as in the lung and the gastrointestinal tract (25). This creates 2 potential problems for an 115 ADC. First, the normal expression of the antigen creates a sink for the ADC that must be 116 overcome to maximize exposure to the tumor (26, 27).