NKTR 102 Will Move to a Phase III Trial in Pretreated Metastatic Breast Cancer

Edith A. Perez, MD

Final results of a phase II study of NKTR 102 suggest that this agent will find a role in the treatment of patients with heavily pretreated metastatic breast cancer whose disease is progressing. NKTR 102 achieved about a 30% objective response rate (ORR) in heavily pretreated patients with poor prognosis, including subsets of patients with triple-negative metastatic breast cancer (ORR 39%), patients with visceral metastasis (ORR 30%), and patients previously treated with anthracyclines, taxanes, and capecitabine. The drug NKTR 102 will be brought forward to a phase III study called Breast Cancer Outcomes with NKTR 102 (BEACON).

“We are very fortunate to have a new formulation of irinotecan,” said senior investigator Edith A. Perez, MD, deputy director of the Mayo Clinic Cancer Center, Gainesville, Florida. Perez presented the final results of the study at the Chemotherapy Foundation Symposium.

NKTR 102 is a topoisomerase inhibitor polymer conjugate, which is an improved formulation of irinotecan, showing superior tumor control in xenografts in breast cancer models. NKTR 102 does not penetrate the vasculature of normal tissues, but the prodrug does enter the leaky vasculature of tumors and releases active drug.

“Moreover, other pharmacokinetic properties make it appealing in the setting of breast cancer,” Perez explained. These include its extended halflife compared with irinotecan, as well as a lower peak initial concentration and higher trough level, which suggests improved consistency in exposure to active drug.

The phase II trial included 70 patients with metastatic breast cancer who received at least 2 prior regimens. Patients were randomized to a onceevery- 14-day schedule (q 14 days) versus a once-every-21-day schedule (q 21 days), with the primary endpoint of ORR. Patients who responded in stage I moved on to stage II.

Median age was about 54 years, about two-thirds were estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive, and about one-third were triple-negative (ER-, PR-, and HER2-negative). About 90% received prior anthracyclines, and 100% received prior taxanes.

“The median time from administration of last chemotherapy was 1.1 months, which suggests the highly refractory nature of these patients,” Perez said.

ORR by Response Evaluation Criteria in Solid Tumors (RECIST) was 29% (32% for q 14 schedule and 26% for q 21 schedule). Clinical benefit (ORR plus stable disease for at least 6 mo) was 46% overall, and 42% and 49%, for the q 14 and q 21 schedules, respectively.

“Looking at response rates by prior therapy, we saw an outstanding rate of ORR independent of treatment with the three classic agents for metastatic breast cancer: taxanes, anthracyclines, and capecitabine,” Perez said.

The rate of overall progression-free survival (PFS) was a median of 4.6 months: 3.5 months for q 14 days and 5.3 months for q 21 days. The rate of overall survival was a median of 10.3 months: 8.8 for q 14 days and 13.1 for q 21 days.

Drug-related adverse events of interest were grade 3 diarrhea (17% and 23% on the 2 schedules, respectively) and grade 3 neutropenia (6% and 9%, respectively). No patients developed febrile neutropenia on the q 14-day schedule, and 3% developed it on the q 21- day schedule. The rate of grade 2 alopecia was very low: 0 for the q 14-day schedule and 3% for the q 21-day schedule.

“Of note, we did not premedicate these patients to prevent diarrhea or neutropenia,” Perez said. “The pattern for grade 3 or higher diarrhea and neutropenia was for it to occur with continuing therapy, typically after 3 months.”

The q 21-day schedule will be moved forward to the phase III BEACON trial because it had slightly better tolerability, higher response rates, and more convenience for patients. BEACON, now in the planning stages in the US and other parts of the world, has a target enrollment of 840 patients with advanced refractory metastatic breast cancer pretreated with anthracyclines, taxanes, and capecitabine. Patients will be randomized to single-agent NKTR 102 q 21 days or physician’s choice for single-agent therapy, with the primary endpoint of overall survival. Perez will be a lead investigator.