Potential IL2 Substitute Shrinks Solid Tumors

Engineered cytokines may retain the benefits of the original molecules while reducing their side effects. A study presented at the 2022 American Society of Clinical Oncology Annual Meeting, held June 3–7, in Chicago, IL, reveals that the engineered cytokine nemvaleukin alfa (Alkermes), a potential alternative to high-dose IL2, shrinks a variety of tumors alone and when paired with the PD-1 inhibitor pembrolizumab (Keytruda; Merck).

IL2 was the first approved immuno­therapy, receiving FDA approval in 1992 for metastatic renal cell carcinoma (RCC). The drug stimulates natural killer cells and CD8-positive T cells to attack tumors. However, the high doses required to produce benefits can trigger severe side effects, including capillary leak syndrome. IL2 can also be counterproductive because it boosts regulatory T-cell numbers, which may protect tumors from immune system attacks.

Nemvaleukin alfa, one of the first engineered IL2 alternatives, may avoid these downsides. It binds to a form of the IL2 receptor that occurs on resting natural killer cells and CD8-positive T cells but does not bind to the form carried by regulatory T cells. The phase I/II ARTISTRY-1 trial is testing the drug alone and with pembrolizumab in patients with a range of solid tumors.

For 46 patients with advanced melanoma who received nemvaleukin alfa monotherapy, the overall response rate (ORR) was 13% and the median duration of response (DOR) was 8.1 weeks, Ulka Vaishampayan, MD, of the University of Michigan Rogel Cancer Center in Ann Arbor, told conference attendees. Another 22 patients with advanced RCC received the drug as a monotherapy. The ORR in this group was 18.2%, and the median DOR was 15.6 weeks.

Vaishampayan also reported results for patients with a variety of solid tumor types, including melanoma, non–small cell lung cancer, and ovarian cancer, who were treated with nemvaleukin alfa and pembrolizumab. The patients had received a median of three previous therapies, and some had received PD-1 or PD-L1 checkpoint inhibitors. Among the 137 evaluable patients, the ORR was 16.1% and the median DOR was 23.2 weeks.

One subgroup stood out—the 14 patients with platinum-resistant ovarian cancer, none of whom had previously been treated with checkpoint inhibitors. “The impressive thing,” said Vaishampayan, “was that the median duration of response was noted to be 53.4 weeks.” The ORR of 28.6% was also higher than for the entire cohort. The FDA has granted the combination fast-track designation for this indication.

In the monotherapy group, the most common side effect was fever, which affected 64% of patients. Forty-three percent developed grade 3 or grade 4 neutropenia. The most common side effects for the combination group were chills (56%) and fever (50%). Eighteen percent of patients developed grade 3 or grade 4 neutropenia. No patients in either arm of the trial suffered from capillary leak syndrome, Vaishampayan noted.

Because nemvaleukin alfa appears safe and works in a range of tumors, it could “broaden the application of IL2-type therapy,” possibly to patients who are older or have comorbidities, said Vaishampayan.

Discussant Kim Margolin, MD, of Saint John's Cancer Institute in Santa Monica, CA, praised the trial researchers for designing a study to determine whether the drug can “divert the IL2 effect from toxicity and anti–effector cell activity to the support of therapeutic cells.” Two trials that may clarify the drug's usefulness—one testing it as a monotherapy and the other combining it with pembrolizumab—are underway in patients with melanoma or platinum-resistant ovarian cancer. –Mitch Leslie

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