HER destiny too

Some (most) famous people who have made huge contributions to science and society may not have anticipated their lasting fame; then again, if early on they visualized their success to the point of reckoned certainty, then they may, surely, have been bound for greatness. Central to this premise is the appreciable activity and perceived ascendancy of trastuzumab deruxtecan (T-DXd) in the treatment hierarchy of human epidermal growth factor receptor 2-positive (HER2⁺) breast cancer. In the course of appraising the recently published paper by André et al. (1), this commentary attempts to address the meaning of destiny in the context of the DESTINY-Breast02 (hereafter referred to as DESTINY 02) clinical trial.

Destiny is a relatively simple term with multiple synonyms, all referring to a futuristic happening (usually of great import). Yet another conviction relates to providence in that the occurrence has been predetermined and beyond any form of control. From the mindset of the latter, trials involving human subjects should not be conducted with the outcomes being left to fate alone. With this in mind, the impressive results of DESTINY 02 favoring T-DXd raise the provocative question whether the striking differences in the key survival endpoints were destined to happen. At the crux of this supposition is the perceived dominion of this particular antibody-drug conjugate (ADC). As it happens, sequential deductions of outcomes from several HER2 clinical trials appear to substantiate the preclinical promise and preliminary activity observed in phase 1 clinical trials (2,3).

Even though cross-study analyses should be performed with caution, a number of telltale signs are provided to support of the proffered rhetorical question. First, the two treatment arms (in DESTINY 02), T-DXd and physician’s choice of capecitabine (C) plus either trastuzumab or lapatinib. Another aspect of the design were the participants, nearly all of who had been treated previously with ado-trastuzumab emtansine (T-DM1). Looking back at two primary endpoints of the EMELIA study (4), median progression-free survival (mPFS) was 9.6 months in the T-DM1 arm and 6.4 months with C plus lapatinib [hazard ratio (HR), 0.65; 95% confidence interval (CI): 0.55–0.77; P<0.001] (Table 1); median overall survival (mOS) was also significantly longer with T-DM1 (30.9 vs. 25.1 months). Similar developments with respect to the same two endpoints (Table 1) were observed in the TH3RESA clinical trial comparing T-DM1 and physician’s choice of treatment; improved mPFS (5,6). Prior data such as these concede the apparent inferiority of both regimens of physician’s choice in DESTINY 02. In addition, since the closure of DESTINY 01 coincided with the opening of DESTINY 02, it is conceivable that some of the positive outcomes (with T-DXd) from the earlier trial were already beginning to materialize in a population of subjects whose prior therapies included trastuzumab and T-DM1; and in who, more than 50% previously received pertuzumab or other anti-HER2 therapies. Second, the configuration of T-DXd. Similar to T-DM1, tumor selectivity of T-DXd is conferred by binding of the antibody to an epitope located in the extracellular domain of HER2. Allowing that the antibody mechanisms of action will be identical (more on this later), elements related to the conjugation process manifest fundamental differences with apparent consequential effects. For instance, the tetrapeptide-based linker utilized in the antibody-DXd conjugate enhances plasma stability and undergoes cathepsin-mediated cleavage, liberating a cytotoxin with enhanced membrane permeability (7). The latter property is believed (though not uniformly accepted) to facilitate transcellular diffusion of DXd leading to a “bystander effect”, a lethal digression encompassing cells in close proximity to HER2⁺ tumor cells (8). Equally fascinating was the laboratory finding that the killing effect included tumor cells which did not express the oncogenic receptor. In contrast, conjugation in T-DM1 is achieved via a non-cleavable thioether [maleimidomethyl cyclohexane-1-carboxylate (MCC)] bond. Lysosome-bound uncoupling of the antibody results in release of lysine-MCC-DM1⁺, a less permeable complex that has to be actively transported across lysosomal membranes in order to interact with tubulin (9). Furthermore, the less permeable linker-drug complex limits diffusion and (possible) induction of neighboring tumor cell kill (10). Third, the comparative activities of T-DXd and T-DM1. As a surrogate indicator of anti-tumor efficacy, mPFS was 9.6 months with T-DM1 (EMELIA) and 17.8 months (DESTINY 02); and 16.4 months (DESTINY 01) (11). Considering the generally accepted belief that prior lines of therapy affect clinical efficacy outcomes, (median) numerations for this variable were ≤1 and 2–3 in EMELIA and DESTINY 02, respectively; but perhaps even more notable was the mPFS in DESTINY 01 in subjects having a median of six prior cancer regimens. And aside from the purported bystander effect, a potentially valid explanation for the shorter mPFS in EMELIA relates to inclusion of patients who progressed on prior taxane therapy suggesting alterations in tubulin dynamics manifested as partial cross-resistance to the maytansinoid derivative (DM1). The substantially shorter mPFS (6.8 months with T-DM1 vs. 28.8 months with T-DXd) in DESTINY 03 adds further credence to this supposition (12,13). Fourth, trastuzumab’s contribution to the overall antitumor effect. Even though developed to inhibit formation of HER2 homodimers thereby hindering activation of downstream signaling pathways, the bulk of the antibody’s therapeutic activity occurs via Fc-dependent recruitment of innate cellular and protein components (14,15). The importance of immune mechanisms such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) should, therefore, not be underestimated. Accordingly, and even if speculative, the extent of exposure to trastuzumab could be meaningful. Based on the dosages of the ADCs (5.4 mg/kg, T-DXd vs. 3.6 mg/kg, T-DM1) used in the clinical trials, the uncertainty relates to whether the 50% higher dose of the former translates to more favorable immunomodulatory effects of the antibody.

Although initially considered a third-line option in the metastatic disease setting, the results of DESTINY 02 (and 03) support recommendations for use after progression on trastuzumab/pertuzumab plus a taxane. While the notable activity observed in all of the DESTINY-Breast clinical trials merits its place in therapy, two subject matters emerge. One, pertains to the perceived superiority of the microtubule as a breast cancer target. It is widely accepted that the taxanes are one of the two most active classes of drugs in this disease. Moreover, four other classes of agents, including the maytansine derivative, that disrupt microtubule activity have also been approved. Conversely, early reports involving targeted inhibition of topoisomerase I for patients with taxane-refractory breast cancer did little to argue otherwise (16,17). However, the emergence of T-DXd revives the initial resolve of topoisomerase I as a viable therapeutic mark. Still, and again heeding the caution of inter-study comparisons, the mPFS of 17.8 months (and 28.8 months) in DESTINY 02 (and 03), respectively, rivals (and even exceeds) the 18.7 months achieved with front-line pertuzumab/trastuzumab/docetaxel (CLEOPATRA) (18). And though not inevitable, contemplating human trials to further define front-line therapy may soon be a matter of course. In view of this, a clinical trial comparing T-DXd plus pertuzumab against trastuzumab, taxane, and pertuzumab as initial therapy in the metastatic disease setting would address this clinically relevant question (NCI Clinical Trials.gov identifier: NCT04784715). At the same time, the study may not be able to determine target superiority conclusively. Nonetheless, and because of DESTINY, the efficacy endpoints should favor the T-DXd-based regimen, an end result that cannot be attributed to topoisomerase I inhibition alone without considering the contributions of tumor-specific drug delivery and collateral tumor cell kill. Regardless whether the outcomes are comparable, the results could still be beneficial from a safety perspective. On the whole, while drug-related adverse events (any grade) occurred in nearly all (98%) subjects treated with T-DXd, the incidence of grade ≥3 neutropenia (8% vs. 2%), nausea/emesis (4–7% vs. 1–3%), and anemia (8% vs. 3%) were higher with T-DXd compared to physician’s choice of treatment (in DESTINY 02). Arguably, the major concern associated with T-DXd relates to pulmonary toxic events. Forty-two [vs. 1 in the physician’s choice (PC) arm] subjects developed interstitial lung disease/pneumonitis; two of which were fatal. Of note, the latter figure was lower despite having approximately 70% more subjects than DESTINY 01, an outcome which could be attributed to closer monitoring and earlier intervention of any suspected lung disease. Lastly, while the frequency of drug discontinuations was higher with T-DXd, drug-related dose reductions and treatment interruptions occurred more often among those in the PC arm. If the T-DXd-containing regimen is found to be advantageous, then the second matter relates to whether microtubule catastrophe following progression on initial targeted inhibition of topoisomerase I will be as bold in the reverse order. Intuitively, it should as the mechanisms of action are distinct. Even so, one common mechanism of resistance to topoisomerase inhibitors is upregulation of MDR1 (the multi-drug resistance) gene resulting in overexpression of the drug efflux pump protein, P-glycoprotein. And cross-resistance to both topoisomerase and microtubule inhibitors has been observed (19,20).

Though unrelated to the direct evaluation of T-DXd, one other aspect of the study that requires reflection concerns the unbalanced allocation format. In DESTINY 02, twice as many patients were randomized to the new intervention relative to the comparator arm. This assignment schema may be appropriate when the treatments being tested are costly. Likewise, unequal allocation is defensible especially when acquisition of additional safety information could be of consequence. In this scenario, the larger number of subjects in the arm of interest confers a gain in statistical power for assessing particular adverse effects. In addition, though more assumption than science, is the assertion that asymmetrical designation expedites recruitment or minimizes withdrawal and could (albeit not absolutely) benefit a greater percentage of the enrolled subjects. While the use of disproportionate assignment can be justified in some instances, a number of arguments can be made to the contrary. Foremost, if the treatment arms were of clinical parity, then there would be no reason to believe that the new intervention would be better than the comparator regimen. Again, this may not have been the case as initially posed. Furthermore, pre-established lack of treatment equipoise would inevitably result in dissimilar clinical benefit. Next, ethical concerns may be present. For example, while the claim regarding accelerated enrollment and reduced egress may in fact be true, willingness to participate because the odds are greater (i.e., probability) of receiving what is perceived by the investigators as being better must be balanced against the equally important implication that one-third of the subjects will knowingly be designated to the inferior treatment arm. Is it also possible that some clinicians were reluctant to have their patients participate because of the chance of randomization to the latter arm? Endmost, uneven allocation requires a larger sample size to achieve comparable statistical power. Specifically, 12% more subjects will be required with a 2:1 randomization compared to assignment on a 1:1 basis (21).

Notwithstanding the foregoing comments, T-DXd is highly active, and a significant addition and therapeutic option for HER2 (high and low)-expressing breast cancers. Even if the spirit in which this commentary initially embraced the concept of divine will, a more tangible, secular aspect of DESTINY 02 which ultimately inspired the outcomes of this study appears to be related to the ADC itself. While subtle, a few innovative features could account for its perceived superiority. Although sharing the same basic framework as T-DM1, the second-generation ADC features a cytotoxic munition parcel that is 10 times more potent than the active form of the topoisomerase I inhibitor irinotecan (8). Considering the magnitude of potency, it is intriguing to speculate that the activity of the exatecan derivative may parallel anthracycline-mediated inhibition of topoisomerase II as both enzymes have essential roles in DNA replication. And ever mindful of the safety profile, the potential for intolerable systemic toxicity appears to be attenuated by the selective, lysosomal-confined, cleavage of the plasma-stable linker. Different also, the drug-antibody ratio (DAR) of approximately 8 is more than double the DAR of T-DM1 enabling delivery of more DXd (per binding event) to tumor cells (7).

More than a decade ago, an editorial appeared in the New England Journal of Medicine related to the promise of ADCs in breast cancer (22). In that paper, T-DM1 was lauded for the improvement in mPFS and mOS, differences of 3.2 and 5.8 months, respectively, as second-line therapy over the comparator regimen. In DESTINY 02, the mPFS was nearly double (and mOS was >8 months longer than) those figures with T-DXd (in the third-/fourth-line settings). If the results were meaningful then (i.e., 2012), certainly the outcomes from the current paper must be even more noteworthy, and confirmatory of DESTINY 01. Lastly, regardless of the meaning of destiny alluded to in this opinion piece, ultimately it is the patients who, potentially, are poised to benefit. And that is their destiny too.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1431/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1431/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work including ensuring that questions related to the accuracy or integrity of any part of the work have been appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. André F, Hee Park Y, Kim SB, et al. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet 2023;401:1773-85. [Crossref] [PubMed]
2. Doi T, Shitara K, Naito Y, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol 2017;18:1512-22. [Crossref] [PubMed]
3. Tamura K, Tsurutani J, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol 2019;20:816-26. [Crossref] [PubMed]
4. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783-91. [Crossref] [PubMed]
5. Krop IE, Kim SB, González-Martín A, et al. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol 2014;15:689-99. [Crossref] [PubMed]
6. Krop IE, Kim SB, Martin AG, et al. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol 2017;18:743-54. [Crossref] [PubMed]
7. Nakada T, Sugihara K, Jikoh T, et al. The Latest Research and Development into the Antibody-Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy. Chem Pharm Bull (Tokyo) 2019;67:173-85. [Crossref] [PubMed]
8. Ogitani Y, Hagihara K, Oitate M, et al. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci 2016;107:1039-46. [Crossref] [PubMed]
9. Erickson HK, Park PU, Widdison WC, et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res 2006;66:4426-33. [Crossref] [PubMed]
10. Saeki H, Oki E, Kashiwada T, et al. Re-evaluation of HER2 status in patients with HER2-positive advanced or recurrent gastric cancer refractory to trastuzumab (KSCC1604). Eur J Cancer 2018;105:41-9. [Crossref] [PubMed]
11. Modi S, Saura C, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med 2020;382:610-21. [Crossref] [PubMed]
12. Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 2023;401:105-17. [Crossref] [PubMed]
13. Cortés J, Kim SB, Chung WP, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med 2022;386:1143-54. [Crossref] [PubMed]
14. Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 2007;357:39-51. [Crossref] [PubMed]
15. Gennari R, Menard S, Fagnoni F, et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res 2004;10:5650-5. [Crossref] [PubMed]
16. Perez EA, Hillman DW, Mailliard JA, et al. Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol 2004;22:2849-55. [Crossref] [PubMed]
17. Taguchi T, Tominaga T, Ogawa M, et al. A late phase II study of CPT-11 (irinotecan) in advanced breast cancer. CPT-11 Study Group on Breast Cancer. Gan To Kagaku Ryoho 1994;21:1017-24. [PubMed]
18. Swain SM, Kim SB, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2013;14:461-71. [Crossref] [PubMed]
19. Niero EL, Rocha-Sales B, Lauand C, et al. The multiple facets of drug resistance: one history, different approaches. J Exp Clin Cancer Res 2014;33:37. [Crossref] [PubMed]
20. Wu Q, Yang Z, Nie Y, et al. Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett 2014;347:159-66. [Crossref] [PubMed]
21. Meinert CL. ClinicalTrials: Design, Conduct and Analysis. 2nd Ed. New York: Oxford University Press; 1986.
22. Teicher BA, Doroshow JH. The promise of antibody-drug conjugates. N Engl J Med 2012;367:1847-8. [Crossref] [PubMed]