Axitinib: great results for the new cancer drug
A phase II trial on axitinib, a new experimental drug for treating patients with cytokine-refractory, metastatic kidney cancer who have a poor response to more traditional drugs has shown promising results according to a new study published in the The Lancet Oncology.
Professor Olivier Rixe of the University of Paris, France, and colleagues assessed the activity and safety of axitinib in a group of patients with metastatic renal-cell cancer who had failed to respond to cytokine-based treatments.
The researchers enrolled 52 patients between October 2003 and April 2004. Each patient had at least one measurable lesion that could be targeted and was given an oral dose of axitinib starting at 5 mg twice a day.
Rixe and colleagues assessed the percentage of patients who responded either completely or partially using the Response Evaluation Criteria In Solid Tumors (RECIST) method, as well as how long they took to respond, the time to progression, overall survival, safety and other measures.
In an intention to treat analysis, the study produced the following results:
- Of the 52 patients, 2 responded completely and 21 partially.
- This equated to an objective response rate of 44.2 per cent.
- The median response rate was 23.0 months (range 4.2 to 29.8 months).
- But 12 of 23 initial responders progressed with response durations of 4.2 to 26.5 months.
- Also, 22 patients showed stable disease for more than 8 weeks, with 13 of them for 24 weeks or more.
- 4 patients had early disease progression, 3 had missing response data.
- Median time to progression was 15.7 months (range 0.03 to 31.5 months).
- Median overall survival was 29·9 months (range 2·4 to 35·8 months).
- Adverse events linked to treatment included diarrhoea, hypertension, fatigue, nausea, and hoarseness.
- High blood pressure was found in 30 patients.
- Of these, all but 8 responded to blood pressure treatment. 7 of the 8 had a history of high blood pressure at enrollment.
The researchers concluded that:
“Axitinib shows clinical activity in patients with cytokine-refractory metastatic renal-cell cancer. Although 28 patients had grade 3 or grade 4 treatment-related adverse events, these adverse events were generally manageable and controlled by dose modification or supportive care, or both. Further studies are needed to confirm these findings.”
Kidney cancer is the sixth leading cause of cancer deaths in the US, and thought to be responsible for nearly 13,000 deaths a year. Kidney cancer is actually a range of cancers, each with a different histology or tissue characteristics. Each type of kidney cancer also develops differently and needs different kinds of treatment.
The most common type of kidney cancer is clear-cell renal cancer, found in 75 per cent of kidney cancer patients.
There are few treatment options for kidney cancer and most patients die. Even with chemotherapy, hormone or biological therapy with the latest targeted drugs, the survival rate is rarely more than 10 per cent.
Axitinib is a selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. By selectively targeting a single growth factor receptor pathway, treatments with this drug could provide a way to adjust dosage and combine with other drugs aimed at specific parts of the pathway. This would potentially minimise toxicity as well as optimise therapeutic outcomes suggested the researchers.
Rixie said that although a randomized controlled trial was now needed:
“The objective response and time to progression in our study suggest that axitinib might be a promising drug in the treatment of patients with metastatic renal-cell cancer.”
In an accompanying article in the same issue of the journal, Dr W Marston Linehan of the US National Cancer Institute, said that these findings “suggest that a drug such as axitinib has promise as a second-line treatment in cytokine-refractory metastatic renal-cell carcinoma, and might have potential as first-line treatment or in combination with other agents targeting the Von Hippel-Lindau pathway (or both).”
“Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study.”
Olivier Rixe, Ronald M Bukowski, M Dror Michaelson, George Wilding, Gary R Hudes, Oliver Bolte, Robert J Motzer, Paul Bycott, Katherine F Liau, James Freddo, Peter C Trask, Sinil Kim and Brian I Rini.
Abstract:
Background
Axitinib (AG-013736) is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We aimed to assess the activity and safety of axitinib in patients with metastatic renal-cell cancer who had failed on previous cytokine-based treatment.
Methods
Between Oct 3, 2003, and April 7, 2004, 52 patients were enrolled. All patients who had at least one measurable target lesion received axitinib orally (starting dose 5 mg twice daily). The primary endpoint was objective response (ie, percentage of patients with confirmed complete response or partial response by use of Response Evaluation Criteria In Solid Tumors [RECIST] criteria. Secondary endpoints were duration of response, time to progression, overall survival, safety, pharmacokinetics, and patient-reported health-related quality of life. This trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00076011.
Findings
In an intention-to-treat analysis, two complete and 21 partial responses were noted, for an objective response rate of 44·2% (95% CI 30·5–58·7). Median response duration was 23·0 months (20·9–not estimable; range 4·2–29·8). However, 12 of 23 initial responders progressed with response duration ranging from 4·2 months to 26·5 months. Additionally, 22 patients showed stable disease for longer than 8 weeks, including 13 patients with stable disease for 24 weeks or longer. Four patients had early disease progression. Three patients had missing response data. Median time to progression was 15·7 months (8·4–23·4, range 0·03–31·5) and median overall survival was 29·9 months (20·3–not estimable; range 2·4–35·8). Treatment-related adverse events included diarrhoea, hypertension, fatigue, nausea, and hoarseness. Treatment-related hypertension occurred in 30 patients and resolved with antihypertensive treatment in all but eight patients, of whom seven patients had a history of hypertension at baseline.
Interpretation
Axitinib shows clinical activity in patients with cytokine-refractory metastatic renal-cell cancer. Although 28 patients had grade 3 or grade 4 treatment-related adverse events, these adverse events were generally manageable and controlled by dose modification or supportive care, or both. Further studies are needed to confirm these findings.