Hemoglobin Modifier Enhances RT in Advanced NSCLC

ORLANDO—Patients with locally advanced, un1resectable, non-small-cell lung cancer (NSCLC) who received the radiation enhancer RSR13 (efaproxiral) along with thoracic radiation therapy (RT) had a median survival of more than 20 months, according to a phase II study presented at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 1236).

Mechanism of Action

Malignant tumors often have a poorly regulated blood supply caused by disorganized growth of new blood vessels into the tumor. This leads to the formation of hypoxic regions in the tumor. Hypoxic tumors are substantially more resistant to radiation therapy than oxygenated tumors.

After picking up oxygen in the lungs and circulating to various tissues in the body, each hemoglobin protein releases one of its four oxygen molecules on average and retains the other three in reserve. RSR13 binds to hemoglobin and changes the structure of the hemoglobin protein, resulting in increased unloading of oxygen from hemoglobin to the hypoxic tissues.

The fact that RSR13 does not have to enter the cancer cell to be effective is an important difference between RSR13 and other attempts to improve radiation therapy, according to Allos Therapeutics. The oxygen released diffuses across the cancer cell membrane to oxygenate the tumor. Radiation is applied to the now oxygenated tumor, enhancing its effects.

RSR13 is a synthetic small molecule that increases the release of oxygen from hemoglobin by reducing hemoglobin oxygen binding affinity. By increasing tumor oxygenation, RSR13 has the potential to enhance the efficacy of standard radiation therapy (see box). It is being developed by Allos Therapeutics, Inc., Westminster, Colorado.

The open-label, multicenter phase II study included 49 evaluable patients who received two courses of induction chemotherapy with paclitaxel (Taxol) 225 mg/m² and carboplatin (Paraplatin) to AUC 6 every 3 weeks for two cycles, followed by thoracic radiation therapy with concurrent daily infusion of RSR13 for 32 doses.

With a median follow-up of 22.9 months, median survival was 20.6 months, 1-year survival was 67%, and 2-year survival was estimated at 35%. Grade 3-4 toxicities included transient hypoxemia (16%) and radiation pneumonitis (12%), but no esophagitis, the researchers said.

"NSCLC can be aggressive and very difficult to treat," said Abdenour Nabid, MD, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, who presented the study at a poster session. "The combination of RSR13 and thoracic radiation therapy was very well tolerated by these patients."

Hak Choy, MD, clinical director, Center for Radiation Oncology, Vanderbilt-Ingram Cancer Center, Nashville, was the principal investigator for the study. "A median survival of 20.6 months continues to be very encouraging, considering that the results from the relevant comparison group for this study (the LAMP trial, ASCO abstract 1160, arm 1) showed 12.5 months for the identical treatment, minus RSR13," Dr. Choy commented.

Allos Therapeutics is preparing a protocol for a phase III clinical study of RSR13 in patients with stage III NSCLC. Currently, the company is conducting a pivotal phase III randomized study evaluating the safety and efficacy of RSR13 and whole brain radiation therapy in patients with brain metastases.