Exceptional response to lurbinectedin and irinotecan in BRCA-mutated platinum-resistant ovarian cancer patient: a case report

Abstract

Lurbinectedin is responsible for DNA recognition and binding, producing double-strand DNA (dsDNA) breaks thus resulting in apoptosis. Sensitivity to lurbinectedin is linked to the nucleotide excision repair (NER) system. Furthermore, irinotecan, a topoisomerase I inhibitor, provokes dsDNA breaks that could be reinforced abrogating the NER system using lurbinectedin. BRCA-mutated patients, already treated with platinum-derived drugs, who suffered DNA damage, cannot repair the breaks due to lurbinectedin interaction, whereas irinotecan provokes a dsDNA break that promotes synthetic lethality. This article describes an exceptional response to lurbinectedin alone followed by the association with irinotecan in a BRCA-mutated platinum-resistant ovarian cancer patient. A 44-year-old BRCA1-mutated ovarian cancer patient was treated in sixth line with lurbinectedin and irinotecan with a time to further progression (TTFP) equal to 8 months. In our case, the association with irinotecan overcame the resistance to lurbinectedin alone. In conclusion, lurbinectedin and irinotecan demonstrated a promising response in platinum-resistant patients. However, further studies should be conducted to validate our findings and future trials will be important to further define the clinical utility of lurbinectedin.

Trabectedin and Lurbinectedin Modulate the Interplay between Cells in the Tumour Microenvironment—Progresses in Their Use in Combined Cancer Therapy

“…LUR has been evaluated in combination with ICIs (anti-PD-L1 and anti-CTLA-4 [ 152 ]) and in combination with irinotecan [ 153 , 154 ], ATR [ 122 , 155 ] alone or combined with ATM [ 156 ] and PARP [ 157 ] inhibitors, anti-VEGF [ 158 ] combined with cisplatin [ 83 , 159 , 160 ], paclitaxel [ 158 ], gemcitabine [ 161 ], capecitabine [ 162 ], doxorubicin [ 41 , 163 , 164 ], and immunomodulatory biomolecules such as antibody-drug complexes commonly referred to as ADCs (4C9-DM1 that targets c-Kit [ 165 ]).…”

“…LUR has been combined with several agents as it is shown in Table 2 where, again, it is indicated in which pathologies/cellular or murine models the combinations are applied. LUR has been combined with irinotecan in ovarian cell clear carcinoma cell lines showing synergistic effects [ 154 ] and in a case report showing BRCA-mutated platinum-resistant ovarian cancer patients had exceptional clinical responses [ 153 ]. LUR + olaparib (PARP inhibitor), in a phase I clinical trial for advanced solid tumours, is feasible and exhibited a disease control rate of 72.6% [ 157 ].…”

“…Redirects T-lymphocyte cytotoxicity to AXL-expressing cells Osteosarcoma [150] TRB + L19-mTNF Pro-inflammatory cytokine Fibrosarcoma [133] Physical agents TRB + radiotherapy Lung cancer, colon cancer [138] Advanced soft tissue sarcoma [139] Localized resectable myxoid liposarcoma [140,141] Retroperitoneal leiomyosarcoma [151] TRB + hyperthermia Osteosarcoma, liposarcoma, synovial sarcoma [137] LUR has been evaluated in combination with ICIs (anti-PD-L1 and anti-CTLA-4 [152]) and in combination with irinotecan [153,154], ATR [122,155] alone or combined with ATM [156] and PARP [157] inhibitors, anti-VEGF [158] combined with cisplatin [83,159,160], paclitaxel [158], gemcitabine [161], capecitabine [162], doxorubicin [41,163,164], and immunomodulatory biomolecules such as antibody-drug complexes commonly referred to as ADCs (4C9-DM1 that targets c-Kit [165]).…”

“…Ovarian clear cell carcinoma [154] BRCA-mutated platinum-resistant ovarian cancer patient [153] LUR + olaparib PARP inhibitor Advanced solid tumours [157] LUR + berzosertib ATR inhibitor Small-cell lung cancer [155] Biological agents…”

DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities

“…Indeed, trabectedin together with PLD is indicated for the treatment of patients with relapsed platinum-sensitive OC [241]. Based on these preclinical studies, several clinical trials have recently explored the effectivity of trabectedin and lurbinectedin in monotherapy and in combination with PLD or other drugs [172][173][174][175][176][177][178][179][180][181][182][189][190][191][192][193] (Table 5).…”