Nektar Therapeutics announced positive results from a phase II clinical study evaluating single-agent NKTR-102 in patients with metastatic breast cancer during the 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS). NKTR-102, a novel investigational topoisomerase I inhibitor-polymer conjugate, is Nektar's lead oncology candidate and is being evaluated in multiple cancer indications. The randomized Simon two-stage study presented at SABCS evaluated two 145 mg/m2 dose schedules of single-agent NKTR-102, every two weeks (q14d) and every three weeks (q21d), in 70 metastatic breast cancer patients who failed a prior taxane therapy. Eighty-seven per cent (61/70) of patients in the study received a prior anthracycline/taxane with or without capecitabine.

More than one million women worldwide are diagnosed with breast cancer every year and anywhere from 30% to 80% develop metastatic disease. A total of 66 of the 70 patients treated in the phase 2 study were assessable for the primary endpoint of Objective tumour Response Rate (ORR), including confirmed complete and partial responses per RECIST. As of October 26, 2010, confirmed ORR for all evaluable patients was 32% (10/31) for the q14d schedule and 26% (9/35) for the q21d schedule, including two confirmed Complete Responses (CRs) on the q14d schedule. An additional four patients had near CRs, with 100% disappearance of all target lesions. The combined ORR for all evaluable patients was 29% (19/66). Clinical benefit rate for the 66 evaluable patients was 41% (defined as CR+PR+SD greater than or equal to 6 mos).

“These are important new results for NKTR-102 in patients with metastatic breast cancer,” said Prof. Ahmad Awada, Head of the Medical Oncology Clinic at the Institute Jules Bordet in Brussels, Belgium. “The high confirmed objective response rate continues to show that NKTR-102 is one of the most active single agents in this disease. This is particularly evident given the number of patients with dramatic reduction in lung and liver metastases.”

The confirmed ORR was maintained in poor prognosis and heavily pre-treated subsets within the study, including patients previously treated with anthracycline/taxane/capecitabine: 33% (5/15); patients with metastatic triple-negative breast cancer: 39% (7/18); and patients with visceral disease: 29% (17/58). As of October 26, 2010, preliminary median Progression-Free Survival (PFS) for all patients was 20 weeks.

“We are in critical need of effective new therapeutic options whose mechanism of action is different from those already available for women with metastatic breast cancer,” continued Dr. Awada. “This is especially true for those patients whose disease has progressed despite treatment with anthracyclines and taxanes. NKTR-102 is emerging as an important investigational treatment in metastatic breast cancer and has the potential to be the first topoisomerase 1 inhibitor in this disease. NKTR-102 should enter phase III clinical studies as quickly as possible.”

Patients treated in the single-agent NKTR-102 study had a median of two lines of prior cytotoxic treatments for metastatic disease. Seventy-three per cent (51/70) of the patients received neoadjuvant and/or adjuvant therapy and 87% (61/70) had visceral disease.

“NKTR-102 is quickly emerging as a very important potential new drug in the fight against cancer,” said Lorianne Masuoka, MD, Senior Vice President and Chief Medical Officer. “The drug has consistently high response rates as a single-agent in multiple phase I and II clinical studies to-date, including our study in platinum-resistant ovarian cancer and now in metastatic breast cancer. This clinical benefit we've observed in tumour settings, where a highly active topoisomerase 1 inhibitor could be extremely useful, makes us very excited about the future of NKTR-102.”

Side effects were generally manageable with dose-limiting toxicity consisting primarily of Grade 3 diarrhoea (20-23%) typically occurring after three months of therapy for both schedules. Only one patient of 70 patients treated with NKTR-102 experienced Grade 2 alopecia and no patient experienced grade 3 or 4 neuropathy.  Both neuropathy and alopecia are significant adverse events commonly associated with standard breast cancer therapies.

More than one million women worldwide are diagnosed with breast cancer globally every year. The chance of developing invasive breast cancer at some time in a woman's life is a little less than one in eight (12%). Anywhere from 30% to 80% of women with breast cancer develop metastatic disease. Metastatic breast cancer refers to cancer that has spread from the breast to distant sites in the body.

Anthracyclines and Taxanes (AT) are the most active and widely used chemotherapeutic agents for breast cancer, but the increased use of these agents at an early stage of disease often renders tumours resistant to these drugs by the time the disease recurs, thereby reducing the number of treatment options for metastatic disease. Drugs used to treat patients who progress following AT treatment can be as high as 20-30%; however, resistance develops rapidly and new agents with different mechanisms of action, such as topoisomerase I inhibitors, are needed to allow novel ways to overcome the problem of drug resistance.(2)  There are currently no FDA-approved topoisomerase I inhibitors to treat breast cancer.

Nektar is developing NKTR-102, a topoisomerase I inhibitor-polymer conjugate with reduced peak concentrations and a continuous concentration profile. NKTR-102 was invented by Nektar using its advanced polymer conjugate technology platform, and is the first oncology product candidate to leverage Nektar's releasable polymer technology platform.

In addition to the fully-enrolled phase II studies in platinum-refractory/resistant ovarian cancer and metastatic breast cancer, NKTR-102 is also being tested in a separate phase II clinical trial in patients with second-line colorectal cancer and a phase I clinical trial evaluating NKTR-102 in combination with 5-FU therapy.  An expansion arm of the phase II study of single-agent NKTR-102 in platinum-refractory/resistant ovarian cancer in women who failed prior Doxil therapy is also currently enrolling.

Nektar Therapeutics is a biopharmaceutical company developing novel therapeutics based on its PEGylation and advanced polymer conjugation technology platforms. Nektar's technology and drug development expertise have enabled nine approved products in the US or Europe for leading biopharmaceutical company partners, including UCB's Cimzia for Crohn's disease and rheumatoid arthritis, Roche's Pegasys for hepatitis C and Amgen's Neulasta for neutropenia.

Nektar has created a robust pipeline of potentially high-value therapeutics to address unmet medical needs by leveraging and expanding its technology platforms to improve and enable molecules.  In addition to the releasable polymer technology, Nektar is the first company to create a permanent small molecule-polymer conjugate with enhanced oral bioavailability and restricted entry into the CNS.