Discussion
breast cancer, cancer, TNBC, EGFR-expressing malignancies, glioblastoma
GLIOBLASTOMA, CANCER, DISEASE, BREAST CANCER
Incorporating technological advances, in particular the use of targeted delivery of potent cytotoxic chemotherapy, is under exploration in the treatment of metastatic TNBC. Especially for antibody drug conjugates, outcome benefits for this patient group have been reported: Sacituzumab govitecan, an antibody–drug conjugate coupling a topoisomerase I inhibitor with a humanized antitrophoblast cell-surface antigen 2 (Trop 2) mAbhRS7 IgG1κ, led to improved PFS and OS in patients with previously treated TNBC when compared to the investigator’s choice of treatmentWe have developed anti-EGFR immunoliposomes for the targeted delivery of doxorubicin to EGFR-overexpressing cells. Directed immunoliposomes loaded with a cytotoxic agent follow the same principle as antibody–drug conjugates offering a targeted delivery of a potent drug; however, due to the liposomal encapsulation they alter the tissue distribution and pharmacokinetics of the drug, increasing its therapeutic index, thus providing a unique feature, which could help evolve the landscape of targeted treatments in cancer patients. In addition, the payload carried by an anti-EGFR-ILs nanocarrier is considerably larger than the number of drug molecules used in antibody–drug conjugates. This could potentially further increase the therapeutic efficacy of the compound. In the present trial, we have investigated an anti-EGFR-ILs-dox in a cohort of patients with advanced TNBC. Liposomal encapsulation of doxorubicin and targeted delivery of the compound to EGFR overexpressing breast cancer cells was hypothesized to improve efficacy while at the same time causing less safety signals in comparison to free and untargeted application. This is a novel approach, which, to our knowledge, has not yet been assessed in this entity. While the safety profile of the new compound was acceptable and did not differ from previous results with liposomal doxorubicin, the efficacy of anti-EGFR-ILs-dox in the assessed TNBC population was lower than expected. Thus, this trial did not reach its primary endpoint.Whether the observed limited efficacy of anti-EGFR-ILs-dox in TNBC is due to the compound itself or to the biology of the disease, remains unclear. In metastatic HER2 + BC a greater efficacy of antibody–drug conjugates depending on the cytotoxic agent was observed, suggesting the importance of the drug delivered by directed therapiesTaken together, there are no signals of efficacy to motivate further development pf anti-EGFR-ILs-dox for treatement of TNBC.The question arises whether anti-EGFR-ILs-dox would offer more opportunities in other EGFR-expressing malignancies, where targeting EGFR has already shown anticancer effects. This was assessed by our group in glioblastoma (GBM)Anti-EGFR-ILs-dox, however, uses immunoliposomes and, thus has a more extensive payload carrying capacity than other drug conjugates. Indeed, we have recently demonstrated that anti-EGFR-ILs-dox can be safely used to deliver cytotoxic molecules to GBM tissue in patients with relapsed GBM (n = 9) harboring an EGFR gene amplification