Subcutaneous nemvaleukin dosing for advanced ovarian cancer

For heavily pretreated patients with advanced solid tumors, including ovarian cancer, the selected phase 2 dose of 3 mg every 7 days for subcutaneous nemvaleukin alfa (Alkermes) was generally well tolerated as monotherapy and in combination with pembrolizumab, according to study results presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held virtually from June 4-8.

Subcutaneous nemvaleukin resulted in increased natural killer(NK) cells and CD8+ T cells, with minimal expansion of regulatory T cells (Tregs).

Omid Hamid, MD

The pharmacodynamic effects also were comparable to or greater than those observed with intravenous (IV) nemvaleukin.

“I believe in combinatorial immunotherapeutic regimens in an attempt to increase efficacy and durability of response,” said principal investigator Omid Hamid, MD, director of clinical research and immunotherapy at The Angeles Clinic and Research Institute in Los Angeles, an affiliate of Cedars-Sinai Medical Center, who has experience administering high-dose interleukin-2 (IL-2) cytokines and has seen its benefits. “This allows an approach that provides the advantages of IL-2 cytokine, but without the toxicity,” he said.

The phase 1 trial of the ongoing phase 1/2 ARTISTRY-2 study was conducted at multiple centers in the United States, Canada, EU and Asia.

In ARTISTRY-2, various doses and schedules of subcutaneous nemvaleukin for 6 weeks as monotherapy were compared, ranging from 0.3 to 6 mg once every 7 days or 1 mg to 10 mg once every 21 days.

The 6-week lead-in period was followed by a combination with pembrolizumab 200 mg. Pembrolizumab was administered once every 21 days in all cohorts.

Safety, pharmacodynamic effects and preliminary clinical activity outcomes as of March 19, 2021 were presented.

Among the 57 patients (median age 61 years and 80.7% white) treated, the most frequent tumors types (in at least 5 patients each) were colorectal, pancreatic, ovarian, and lung.

The median number of prior therapies was four, ranging from 1 to 17.

Treatment-related adverse events occurring in over 25% of patients were pyrexia (50.9%), fatigue (45.6%), chills (42.1%), injection-site erythema (40.4%), nausea (38.6%), vomiting (33.3%), injection-site reaction (28.1%), anemia (26.3%) and lymphopenia (26.3%).

For the 7 patients who were on the 3 mg every 7 days regimen, there were no drug-related dose reductions, discontinuations or deaths, either during the monotherapy or combination periods.

However, 6 mg was considered the maximum tolerated dose for the once every 7 days regimen, because 2 of the 8 incurred dose-limiting toxicities.

For the 8 patients who were on a treatment plan of 6 mg every 21 days, there was also no drug-related dose reductions, discontinuations or deaths during monotherapy; however, combination period data are not mature.

The maximum tolerated dose for once every 21 days dosing was declared 10 mg, due to 1 of 9 patients experiencing dose-limiting toxicities and 3 patients having treatment-related adverse events leading to dose reductions.

Systemic exposure to nemvaleukin rose with an increasing dose.

Increases in NK cells and CD8+ T cells of roughly 16-fold and 3-fold, respectively, at 3 mg once every 7 days, and about 8-fold and 3-fold, respectively, at 6 mg once every 21 days, were observed, with minimal change in Tregs.

Of the 37 patients who had at least 2 on-treatment scans as of the data cut-off date, 46% attained stable disease on at least 2 consecutive scans.

Based on the totality of the safety, pharmacodynamic effects and antitumor activity data, 3 mg once every 7 days was selected as the regimen of choice for subcutaneous SC nemvaleukin.

Since the selection of the phase 2 dose, the study has expanded to assessing efficacy. In this stage, as of the data cutoff date, a 69-year-old female with high-grade serious ovarian cancer achieved a 47% reduction in tumor, which is consistent with a partial response and a 99% decrease in the cancer antigen 125 detected in her blood.

“Nemvaleukin has been granted orphan drug designation for mucosal melanoma by the FDA,” Hamid told Contemporary OB/GYN®. “IV and subcutaneous nemvaleukin are also being evaluated in mucosal and cutaneous melanoma, respectively, in the newly opened ARTISTRY-6 study.”

Hamid said an additional study of IV nemvaleukin in ovarian cancer is planned and that expansion cohorts of ARTISTRY-2 include gastric, non-small cell lung cancer (NSCLC), ovarian and head and neck.

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Disclosure

Hamid is a paid consultant and an investigator for Alkermes.

Reference

Hamid O. ARTISTRY-2, a phase 1/2 study sharing the recommended phase 2 dose (RP2D) for nemvaleukin administered subcutaneously. Data presented at: American Society of Clinical Oncology Annual Meeting; June 4-8, 2021. Virtual. Accessed June 8, 2021.