Afinitor – Anti-Cancer Therapy

Afinitor (everolimus), formerly known as RAD001, is a macrolide antibiotic derived from rapamycin that is being investigated by Novartis as a potential treatment for various solid tumours, including advanced kidney cancer. Afinitor is also used as a cure for pancreatic neuroendocrine tumours (NET), gastric cancer and breast cancer.

Rapamycin is an interesting drug because of its diverse clinical applications. Indeed, marketed under the brand name Certican, Novartis' everolimus is already an approved medication for the prevention of organ rejection in patients undergoing heart and kidney transplantation.

Besides potent immunosuppressant effects, everolimus also inhibits mTOR protein. It is this property that is being exploited in the development of Afinitor (everolimus) as a potential anti-cancer medication.

Phase III clinical trials on Afinitor were aborted by the data monitoring committee as interim results proved 67% progression-free survival in patients who received the drug, compared to placebo and thus the trials met the principal endpoint.

The European Commission (EC) and the US Food and Drug Administration (FDA) granted regulatory approvals for the use of Afinitor in treating renal cell cancer (RCC) in August and March 2009 respectively. The EC's decision is applicable in 27 EU states. Afinitor is under regulatory review in Switzerland, Japan and other countries.

Targeting mTOR

Mammalian target of rapamycin, or mTOR, is a protein kinase that regulates cell growth, cell proliferation, cell motility and cell survival, as well as protein synthesis.

Studies suggest that the mTOR growth pathway may be hyperactive in some cancers, making it a potentially attractive cancer therapy target.

Novartis' Afinitor (everolimus) is a serine-threonine kinase inhibitor of mTO that continuously inhibits the mTOR protein and so acts to prevent tumour cell division and blood vessel cell growth.

Prior to Afinitor's approval, Wyeth's mTOR inhibitor temsirolimus (ToriselÒ) was the only marketed cancer therapy that specifically inhibits mTOR. ToriselÒ was approved for the treatment of advanced RCC in 2007.

Afinitor shows efficacy in RCC

The efficacy and safety of Afinitor (everolimus) was demonstrated in the Phase III RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) trial, which enrolled more than 400 patients with advanced RCC whose cancer had progressed despite prior treatment with a range of first-line therapies. This included treatment with two of the newest drugs for RCC, sorafenib and sunitinib.

Interim results from RECORD-1, a multicentre randomised, double-blind, placebo-controlled trial, showed that treatment with Afinitor more than doubled the time to tumour progression after failure of first-line therapy. An independent data monitoring committee stopped the RECORD-1 trial in early 2008 as Afinitor was the first drug to show significant benefits after the failure of approved therapies Sutent and Nexavar.

Median progression-free survival (primary endpoint) was four months for patients in the Afinitor arm compared with 1.9 months in the placebo arm (p<0.0001), a 70% reduction in the risk of cancer progression. The study findings were presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois, US on 31 May 2008. The updated RECORD-1 data was presented on 16 September 2008 at the 33rd European Society for Medical Oncology Congress in Stockholm, Sweden.

No significant differences were observed with respect to secondary efficacy endpoints, which included overall survival and objective response rate. A central review of the patients evaluable for best percentage change in target lesions showed evidence of tumour shrinkage in 50% of Afinitor-treated patients during the double-blind phase, compared with 8% of placebo recipients.

Afinitor appeared generally well tolerated by patients in this study, with 6% prematurely discontinuing because of adverse effects.

Potential in other cancers

In addition to RCC, Afinitor is also being investigated for its potential to treat other cancers. Studies are ongoing to see whether it can bring therapeutic benefit to patients with pancreatic endocrine tumours, the results for which are expected towards the end of 2008.

Other cancers for which Afinitor is being explored include carcinomas of the breast, stomach and lung. The drug's potential in NET, lymphoma solo or tandem therapy for tuberous sclerosis and other cancers is also being explored.

Clinical trials

Afinitor underwent clinical trials in three phases, which included trials to test the drug's efficacy in different cancer types.

A multicentre Phase I clinical trial of daily and weekly everolimus in combination with weekly paclitaxel and trastuzumab was carried out in patients with HER2 over-expressing metastatic breast cancer with prior resistance to trastuzumab.

A randomised, double-blind, Phase II placebo-controlled trial was conducted after enrolling 270 postmenopausal women as a part of Afinitor's breast cancer clinical trials. The clinical response rate with Afinitor (68%) when combined with letrozole was higher than that of letrozole (59%). Ultrasound results proved in favour of Afinitor.

As a part of Afinitor's clinical trials in evaluating the drug's efficacy in gastric cancer patients, a Phase II trial was conducted. The trial was a multi-centre study of 54 patients conducted in Japan. Tumour growth was halted in 55% of advanced gastric cancer patients. Severe adverse events included anaemia, hyponatraemia, raised liver function, fatigue, stomatitis, anorexia, hyperglycaemia, hypophosphataemia, ileus and lymphopenia.

Phase I and Phase II results were presented at the 44th annual meeting of the ASCO in Chicago, Illinois, US in 2008. The Phase II trial results released on 13 January 2009 revealed efficacy in patients with advanced gastric cancer. Phase II study findings also revealed tumour shrinkage when the drug was given in combination with letrozole (Femara) to post-menopausal women diagnosed with estrogen receptor-positive (ER+) breast cancer. Femara is a fertility drug.

Results from two Phase I-II trials showed efficacy when Afinitor was combined with trastuzumab (Herceptin) and other chemotherapy agents. This combination overcame resistance to trastuzumab and achieved complete responses in a few patients and partial responses in majority of patients.

Marketing commentary

RCC, which develops in the renal tubules, is the most common cancer of the kidney. It accounts for about 2–3% of all new cancers. Surgery to remove the tumour is standard treatment and can be effective if the tumour is confined to the kidney.

However, if the tumour recurs following surgery prognosis is often poor. Generally resistant to radiotherapy and chemotherapy, RCC has proved one of the more difficult cancers to treat once the disease has spread.

Some important advances have been seen in the treatment of RCC with the arrival of targeted therapies such as the multi-kinase inhibitors sorafenib and sunitinib. Although not curative, they can significantly prolong progression free survival in advanced RCC. As results from the RECORD-1 trial demonstrate, treatment with Afinitor may further extend progression-free survival in patients with metastatic RCC after failure with these newer drugs.