The safety and maximum tolerated dose ( MTD ) of Sunitinib malate( Sutent ) in combination with Bevacizumab ( Avastin ) has been assessed in patients with metastatic renal cell carcinoma ( mRCC ) in a phase I study, exploring 3 cohorts using a fixed dose of Avastin at 10 mg/kg/IV every 2 weeks and escalating doses of Sunitinib that included 25 mg, 37.5 mg, and 50 mg orally daily given in a 4 week on / 2 week off schedule.
To date, a total of 25 patients have been treated in this study with 12 assigned to the highest Sunitinib dose level. Five out of the 12 patients in this cohort exhibited laboratory findings consistent with microangiopathic hemolytic anemia ( MAHA ). No patient assigned to the lower Sunitinib dose cohorts was diagnosed with MAHA.
Microangiopathic hemolytic anemia is a subgroup of hemolytic anemia caused by thrombotic lesions in the microvessels and other mechanical causes, and is associated with thrombocytopenia and red blood cell fragmentation. This is diagnosed by schistocytes on microscopy of the blood film, together with other laboratory abnormalities such as LDH increase and reductions in serum haptoglobin.
Two of the 5 cases were considered severe with presence of additional adverse events such as thrombocytopenia, anaemia, reticulocytosis, reductions in serum haptoglobin, modest increases in serum creatinine levels, and severe hypertension, reversible posterior leukoencephalopathy syndrome ( RPLS ), and proteinuria. The findings in these two cases were reversible within three weeks upon discontinuation of both drugs without additional intervention.
The information above led to the closure of a Genentech-sponsored Phase II trial of Sunitinib at 50 mg with or without Bevacizumab, with a similar dosing schedule in first line mRCC. In this study a preliminary review identified two additional cases of MAHA similar to those described above.
Another dose-escalation Phase I, NCI-sponsored study of Sunitinib in combination with Bevacizumab in multiple tumor types has not reported evidence of MAHA to date.
Similarly, to date, no events of MAHA have been reported in two other Genentech-sponsored studies of this combination added to chemotherapy in non-small cell lung cancer ( NSCLC ) and breast cancer. However, these two Genentech studies, which had different dosing regimes from those of the studies discussed above ( full dose Bevacizumab and escalating doses of sunitinib up to 37.5mg ) were also closed due to poor tolerability, primarily due to myelosuppression, fatigue and gastrointestinal complications ( e.g, diarrhea, anorexia, dehydration, stomatitis ).
Bevacizumab is not approved for use in combination with Sunitinib malate for any disease state.
Avastin is approved in combination with: fluoropyrimidine-based chemotherapy for treatment of patients with metastatic carcinoma of the colon or rectum; Paclitaxel for first-line treatment of patients with metastatic breast cancer; Platinum-based chemotherapy for first-line treatment of patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology; Interferon alfa-2a for first line treatment of patients with advanced and/or metastatic renal cell cancer.
Source: Medicines and Healthcare product Regulatory Agency MHRA, 2008