maytansine and Cerebral-Hemorrhage

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that does not cross an intact blood-brain barrier. In the EMILIA trial of T-DM1 vs capecitabine/lapatinib for HER2 positive advanced breast cancer, all patients had baseline brain imaging, and 9/450 (2%) of patients with negative baseline imaging developed new brain disease during T-DM1. We assessed the frequency of brain progression in clinical practice, without routine baseline imaging. We undertook a retrospective study of all patients treated with T-DM1 at the Royal Marsden Hospital from 2011 to 2016. Data collected included baseline characteristics, previous treatment for advanced breast cancer, sites of metastatic disease, duration of T-DM1, sites of progression, and treatment of CNS progression. Fifty-five patients were identified who had received a median of two prior lines of treatment (range 0-5). All were HER2 positive; 45 patients had IHC 3+ tumors and 10 were ISH positive. Patients received a median of 12 cycles of T-DM1 (range 1-34), and six remain on treatment at the time of analysis. Before commencing T-DM1, 16/55 (29%) had known brain metastases (treated with whole brain [9] stereotactic radiotherapy [6] or both [1]). Brain was the first site of progression in 56% (9/16) patients, with a median time to brain progression of 9.9 months (95% CI 3.9-12.2). In patients without known baseline brain metastases, 17.9% (7/39) developed new symptomatic brain disease during T-DM1, after a median of 7.5 months (95%CI 3.8-9.6). Brain progression was isolated, with control of extra-cranial disease in 4/7 patients. Only one patient was suitable for stereotactic radiotherapy. Median time to extra-cranial progression in all patients was 11.5 months (95% CI 9.1-17.7), and median OS in all patients was 17.8 months (95% CI 14.2-22). In patients not screened for brain metastases at baseline, the brain was the first site of progression in a significant proportion. Baseline brain imaging may have a role in standard practice for patients commencing T-DM1 therapy.

Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Brain Neoplasms; Breast Neoplasms; Cerebral Hemorrhage; Female; Humans; Maytansine; Middle Aged; Receptor, ErbB-2; Retrospective Studies; Trastuzumab; Treatment Outcome

The toxicity of maytansine given by sc administration was studied in 5-week-old mald F344 rats. The LD50 (14-day) was 0.48 mg/kg. A dose response to drug administration was indicated by body weight changes and diarrhea. A single, acutely toxic dose of maytansine was shown to possess marked activity against dividing cells which was regarded as an important factor in the pathogenesis of acute lesions in tissues with a normal high rate of cell division. Histologically, mitotic figues were observed in many tissues from 6 to 24 hours after drug administration. Subsequently, necrotizing lesions led to atrophic changes in gastrointestinal tract mucosa, thymus, spleen, bone marrow, and testis. Maytansine also induced hemorrhagic lesions in parenchymatous organs and brain and perivascular monomuclear infiltration in the meninges, and chromatolysis and vacuolation of dorsal root ganglion cells, accompanied by clinical signs of ataxia. Ulcerative skin lesions were observed at the sc site of drug administration.

Topics: Acute Disease; Animals; Atrophy; Body Weight; Bone Marrow; Cerebral Hemorrhage; Diarrhea; Dose-Response Relationship, Drug; Gastric Mucosa; Injections, Subcutaneous; Intestinal Mucosa; Male; Maytansine; Necrosis; Oxazines; Rats; Rats, Inbred F344; Spleen; Testis; Thymus Gland