Advances in personalized medicine and nanotechnology
James Fleck: Anticancerweb 07(07), 2020
According to WHO, breast cancer is the main malignant disease in women, reaching a global incidence of almost 2.1 million (ASR = 46.3). Her2-positive breast cancer is found in approximately 20% of patients and reveals metastatic disease in roughly 30% of cases, affecting 120,000 women a year worldwide. Although Her2-positive metastatic breast cancer is an incurable disease, long-term survival has been achieved with well-designed sequential treatments. Disruption of Her2-mediated signaling pathway was achieved with two monoclonal antibodies with complementary mechanism of action. First, trastuzumab was developed, binding to the extracellular domain of the Her-2 receptor, promoting cytotoxicity and additional independent blockade of cell proliferation. Subsequently, pertuzumab was identified, binding to a distinct epitope (subdomain II) of the extracellular domain of Her-2 receptor. This action prevented receptor dimerization, leading to impaired tumor cell function. The potential benefit obtained from the combined use of the two MoAb was assessed by a phase III prospective randomized trial called CLEOPATRA. The end-results were presented in the 2019 ASCO Annual Meeting in Chicago after a median follow-up of 99 months. The median OS difference, favoring the double blockade (pertuzumab + trastuzumab + docetaxel) was 16.3 months, when compared to the control arm (placebo + trastuzumab + docetaxel). The median duration of progression-free survival (PFS) and overall survival (OS) were 18.7 months and 56.5 months, respectively. The landmark analysis after 8 years of follow up in the ITT population showed an unprecedent 37% OS in Her-2 positive metastatic breast cancer patients, leading to the concept of disease chronification.
Despite the encouraging results of the CLEOPATRA trial, most patients (63%) with Her2-positive metastatic breast cancer will progress after double blockade. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) made up of trastuzumab, stable linked to a highly potent chemotherapy (DM1). Similar to the pharmacodynamics of vinca alkaloids, the binding of DM1 to tubulin prevents the assembly of microtubules, but, being 100 times more potent, it will express dose-limiting toxicity. The clinical use of DM1 was only possible due to the development of nanotechnology. A non-reducible thioether linker (MCC), referred as the proprietary drug linker keeps trastuzumab attached to the proprietary payload (DM1) in the T-DM1 ADC. As a consequence, T-DM1 expresses a very effective pharmacokinetics, since T-DM1 ADC could be selectively decomposed inside tumor cells, while remaining stable in the systemic circulation, preventing extensive, nonspecific and undesirable release of chemotherapy. Breast cancer cells expressing Her2 gene amplification have up to 1 - 2 million receptors per cell, favoring specific binding of T-DM1. The Her2-T-DM1 complex is then endocytosed and fused with a lysosome, where it undergoes proteolytic degradation, finally releasing the active chemotherapy DM1 (proprietary payload). Two phase III prospective randomized trial, sequentially published in Lancet Oncology, revealed the clinical benefit of using T-DM1 in Her2-positive metastatic breast cancer patients who had progressed on two or more Her2-directed regimens. In the TH3RESA trial, T-DM1 was compared to clinician’s choice therapy and in EMILIA trial, it was compared with lapatinib + chemotherapy. There was an improvement in the overall survival favoring T-DM1 in both studies. The median OS observed in T-DM1 arm was 22.7 and 31 months in the TH3RESA trial and EMILIA trial, respectively. The routine clinical use of T-DM1 further expanded the concept of Her2- positive metastatic breast cancer as a chronic disease.
The median duration of the response to T-DM1 varies according to previous treatments, ranging from 6 to 10 months. In February 2020, the New England Journal of Medicine published two additional treatment options for Her2-positive metastatic breast cancer who has progressed after trastuzumab emtansine. In the HER2CLIMB trial, Her2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and T-DM1 were randomly assigned to receive tucatinib (experimental arm) or placebo (control arm). In both arms, patients also received trastuzumab and capecitabine. Tucatinib is an oral tyrosine kinase inhibitor (TKI) highly selective for Her2 kinase domain. When tucatinib was combined to trastuzumab + capecitabine in the experimental arm of HER2CLIMB trial, the observed 2-year OS was 44.9%, significantly higher than the 26.6% observed in the control arm (P=0.005). A PFS benefit was observed even in patients with CNS metastases. The 1-year PFS was 24.9% in the tucatinib-combination arm versus zero in the placebo-combination arm (P<0.001). Another promise drug is trastuzumab deruxtecan. Here, nanotechnology was used to combine an anti-Her2 antibody (trastuzumab) to a cytotoxic topoisomerase I inhibitor (proprietary payload), using a cleavable tetrapeptide-based linker (proprietary drug linker). In the DESTINY open label, single group, multicenter, phase 2 study, 184 Her2-positive metastatic breast cancer patients who had undergone a median of six previous treatments, including T-DM1, received the recommended dose (5.4 mg per kilogram of body weight) of trastuzumab deruxtecan. The response rate was 60.9% and 6% of the patients had a complete response. The PFS was 16.4 months, suggesting that, even at a very advanced stage and refractory to multiple drugs, there is still hope for Her2-positive metastatic breast cancer patients. Unfortunately, in the DESTINY study, the drug was associated with interstitial lung disease (ILD) in 13.6% of patients, in addition to other grade 3 adverse events. Further studies are needed to define who are the patients at greatest risk for ILD and what would be the best strategy to mitigate this limiting toxic effect.
WHO = World Health Organization, ASR = Age-standardized rate, ASCO = American Society of Clinical Oncology, ITT = Intention-to-treat
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7. Photo by Ravi Patel on Unsplash