Central nervous system (CNS) tumors remain a challenge in oncology, as both primary brain tumors and brain metastases are characterized by dismal survival prognosis and high symptomatic burden. In fact, brain tumors are responsible for the highest number of potential life years lost as they also affect younger individuals1. While drug development proceeds at fast pace in many tumor entities, the number drug of approvals in brain tumors falls far below that of other malignancies.
For instance, the standard treatment of glioblastoma - the most frequent malignant primary brain tumor in adults - has not considerably changed since 2005 and still relies on a combination of radiotherapy with “classical” cytotoxic chemotherapy2. Numerous efforts including targeted therapy and immunotherapy approaches have not shown a benefit in unselected patient populations. The situation is somewhat more promising in brain metastases, where intracranial responses have been observed for targeted agents3,4 and immunotherapy5–7; still, data derived from dedicated trials are rare.
Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the activity of cytotoxic agents. By binding exclusively to cancer cells, their cytotoxic payload is released in (or in proximity to) malignant cells, reducing systemic side effects and allowing higher effective doses within the tumor. Representing a long-awaited addition to the toolbox of oncologists, these “Trojan horses” provided meaningful survival benefits in cancers with otherwise abysmal prognosis. For instance, the next-generation ADC trastuzumab deruxtecan (T-DXd) prolongs survival even in a subset of triple-negative breast cancers (considered as the deadliest of breast malignancies) – and not surprisingly, the presentation of these results at the Annual Meeting of the Americal Society of Clinical Oncology (ASCO) in 2022 was welcomed by frenetic applause and standing ovations8.
But what about brain tumors? As ADCs have entered the treatment of solid tumors in breast cancer, breast cancer brain metastases have been among the first where ADCs have been systematically evaluated. The first ADC approved for a certain breast cancer subgroup (those with human epidermal growth factor 2 (HER2) amplifications) was trastuzumab emtansine (T-DM1); however, data on intracranial efficacy mainly stem from retrospective studies9,10 and post-hoc analyses11,12. However, with T-DXd, also dedicated trials have been performed – and here, co-authors of our review had leading roles in relevant trials. For instance, the TUXEDO-1 trial13 (performed at our department with Rupert Bartsch as PI) and DEBBRAH (with contribution by co-author Javier Cortes)14 showed promising intracranial efficacy in up to >70% of included patients. In stark contrast, the situation is totally different in glioblastoma, where INTELLANCE-115 and -216 (with co-authors Andrew B. Lassman and Martin van den Bent in leading positions) failed to show a meaningful benefit for depatuxizumab mafodotin (Depatux-M).
These results leave us with the (so far) still elusive enigma why brain metastases seem to behave completely differently compared to primary brain tumors. In our review, we outline both tumor- and ADC-related factors that need to be considered in ADC development. For instance, the blood-brain/blood-tumor barrier (BBB/BTB) in brain tumors is characterized by a broad spectrum between (nearly) intact and disrupted according to tumor entity and progression, also significantly impacting drug delivery17. Moreover, heterogeneity in antigen expression directly affects binding (and thereby internalization and payload release) of ADCs. Considering these factors, optimal ADC design enhances the so-called “bystander” effect, where the payload exerts antiproliferative activity also on nearby cells with lower antigen expression or “behind” the BBB/BTB. Moreover, multiple efforts are being made for approaches to surpass the BBB/BTB harnessing pharmacological, physical and chemical principles; clinical validation and transfer of these strategies to ADCs remain to be awaited.
In the end, optimal trial design remains a cornerstone in bringing pharmacological innovations to patients. Alarmingly, many large phase 3 trials exclude patients with brain metastases (particularly those performed under industry sponsorship18). Reasons are manifold and include logistical challenges (such as obtaining informed consent in patients with tumor-associated cognitive impairment), but also a priori worse outcomes and higher risk for toxicities. Therefore, initiatives for dedicated clinical trials are urgently needed – especially in patients with active, untreated brain metastases, but also primary brain tumors, considering brain tumor-specific response assessment criteria, such as those defined by the Response Assessment in Neuro-Oncology (RANO) group19,20. In addition, preclinical and early-phase clinical studies are of prime importance to shed light on intracranial bioavailability. So-called “window-of-opportunity” trials where the drug of interest is administered prior to surgery can provide valuable data to assess intracranial drug accumulation.
So, what’s next? Based on promising data in breast cancer brain metastases, we strongly believe that the best is yet to come – development of refined compounds, innovative trial designs and inclusion of relevant patient cohorts may pave the way for ADCs in neuro-oncology, as we and our patients strive for therapeutic advances in the field.
- Rouse, C., Gittleman, H., Ostrom, Q. T., Kruchko, C. & Barnholtz-Sloan, J. S. Years of potential life lost for brain and CNS tumors relative to other cancers in adults in the United States, 2010. Neuro Oncol 18, 70–77 (2016). https://doi.org/10.1093/neuonc/nov249
- Stupp, R. et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med 352, 987–996 (2005). https://doi.org/10.1056/NEJMoa043330
- Lin, N. U. et al. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol 38, 2610–2619 (2020). https://doi.org/10.1200/JCO.20.00775
- Park, S. et al. A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy. Ann Oncol 31, 1397–1404 (2020). https://doi.org/10.1016/j.annonc.2020.06.017
- Margolin, K. et al. Ipilimumab in patients with melanoma and brain metastases: An open-label, phase 2 trial. Lancet Oncol 13, 459–465 (2012). https://doi.org/10.1016/S1470-2045(12)70090-6
- Long, G. V. et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol 19, 672–681 (2018). https://doi.org/10.1016/S1470-2045(18)30139-6
- Goldberg, S. B. et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 17, 976–983 (2016). https://doi.org/10.1016/S1470-2045(16)30053-5
- Modi, S. et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med 387, 9–20 (2022). https://doi.org/10.1056/NEJMoa2203690
- Bartsch, R. et al. Activity of T-DM1 in Her2-positive breast cancer brain metastases. Clin Exp Metastasis 32, 729–737 (2015). https://doi.org/10.1007/s10585-015-9740-3
- Jacot, W. et al. Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases. Breast Cancer Res Treat 157, 307–318 (2016). https://doi.org/10.1007/s10549-016-3828-6
- Krop, I. E. et al. Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA. Ann Oncol 26, 113–119 (2015). https://doi.org/10.1093/annonc/mdu486
- Montemurro, F. et al. Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial☆. Ann Oncol 31, 1350–1358 (2020). https://doi.org/10.1016/j.annonc.2020.06.020
- Bartsch, R. et al. Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial. Nat Med 28, 1840–1847 (2022). https://doi.org/10.1038/s41591-022-01935-8
- Pérez-García, J. M. et al. Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial. Neuro Oncol 25, 157–166 (2022). https://doi.org/10.1093/neuonc/noac144
- Lassman, A. B. et al. Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: a phase III randomized clinical trial. Neuro-Oncology 25, 339–350 (2022). https://doi.org/10.1093/neuonc/noac173
- Van Den Bent, M. et al. INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFR amplified glioblastoma. Neuro Oncol 22, 684–693 (2020). https://doi.org/10.1093/neuonc/noz222
- Steeg, P. S. The blood–tumour barrier in cancer biology and therapy. Nat Rev Clin Oncol 18, 696–714 (2021). https://doi.org/10.1038/s41571-021-00529-6
- Patel, R. R. et al. Exclusion of patients with brain metastases from cancer clinical trials. Neuro Oncol 22, 577–579 (2020). https://doi.org/10.1093/neuonc/noz246
- Lin, N. U. et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol 16, e270–e278 (2015). https://doi.org/10.1016/S1470-2045(15)70057-4
- Wen, P. Y. et al. Response Assessment in Neuro-Oncology Clinical Trials. J Clin Oncol 35, 2439–2449 (2017). https://doi.org/10.1200/JCO.2017.72.7511
Please sign in or register for FREE
If you are a registered user on Nature Portfolio Cancer Community, please sign in