Nemvaleukin Alone and in Combination with Pembrolizumab Produces Efficacy in Advanced RCC

The IL-2 variant immunotherapy nemvaleukin alfa (ALKS 4230; nemvaleukin) elicited responses and demonstrated safety as a single agent and in combination with pembrolizumab (Keytruda) in patients with advanced renal cell carcinoma (RCC), according to results from the phase 1/2 ARTISTRY-1 trial (NCT02799095) presented at the 2022 Genitourinary Cancers Symposium.¹

Among 23 evaluable patients, nemvaleukin monotherapy demonstrated an overall response rate of 17.4%, with all 4 patients achieving a partial response (PR). Notably, all 4 of those patients received prior treatment with a checkpoint inhibitor. Additionally, 43.5% of all patients had stable disease, and 39.1% had progressive disease.

In the 4 patients who achieved a PR, 3 had confirmed PRs, and their maximum decreases in target lesions were 48%, 38%, and 60%, respectively. The 1 patient with an unconfirmed PR saw a 31% maximum decrease in target lesions.

Among 10 patients who advanced to received nemvaleukin plus pembrolizumab, 2 achieved a PR, including 1 patient who had a PR from nemvaleukin alone. Additionally, 6 patients had stable disease.

“Nemvaleukin immunotherapy provided evidence of single-agent antitumor response in patients with advanced RCC,” lead study author Emiliano Calvo, MD, PhD, of START Madrid, said in the poster presentation. “Preliminary clinical data showed the potential to achieve responses in RCC with nemvaleukin plus pembrolizumab. Nemvaleukin was generally well-tolerated as monotherapy.”

Although checkpoint inhibitors can improve outcomes in patients with advanced RCC, more than 60% of patients do not respond to first-line checkpoint inhibitor monotherapy, and approximately 40% of patients do not respond to combination therapy.²

Nemvaleukin is designed to bind the intermediate-affinity IL-2 receptor to activate the CD8⁺ T and natural killer (NK) cells and limit the expansion of regulatory T cells.

The non-randomized, open-label, phase 1/2 ARTISTRY-1 trial evaluated the efficacy and safety of single-agent nemvaleukin and the combination of nemvaleukin plus pembrolizumab in patients with solid tumors.

Previous responses have been observed with nemvaleukin in patients with solid tumors when utilized as a single agent and in combination with pembrolizumab. Part B of the trial focused on a cohort of patients with advanced RCC.

To enroll in part B of ARTISTRY-1, patients were required to have advanced RCC and be refractory to or intolerant of established treatment options. Patients who did or did not receive prior treatment with a checkpoint inhibitor were allowed to enroll. Patients were also required to have an ECOG performance status of 0 or 1 with a life expectancy of at least 3 months, and adequate renal function, hepatic function, and hematologic reserve.

In part B, patients received 6 µg/kg of intravenous (IV) nemvaleukin for 5 days every 14 days in the first cycle, followed by 21 days in every additional cycle for up to 2 years, or until disease progression or unacceptable toxicity.

Patients who experienced disease progression after at least 2 cycles of nemvaleukin monotherapy or stable disease after at least 4 cycles were moved onto part C of the trial to receive a combination of IV nemvaleukin at 3 µg/kg once daily for the first 5 days, plus 200 mg of pembrolizumab on the first day of every 21-day cycle.

The results presented at the meeting included antitumor activity per RECIST v1.1 criteria, pharmacodynamics, and safety.

The median age of evaluable patients in part B was 69 years (range, 39-77) and 24 of the 27 patients were male. Moreover, the median number of prior lines of therapy was 2 (range, 1-8). Notably, 44% of patients were naïve to prior checkpoint inhibitor therapy and 56% received prior treatment with a checkpoint inhibitor.

The study found that nemvaleukin led to a robust expansion of CD8⁺ T and NK cells with minimal effect on T regulatory cells.

Regarding safety, all evaluable patients experienced at least 1 adverse effect (AE) of any grade and 40.7% experienced at least 1 serious AE. Additionally, 74% of patients (n = 20) encountered a grade 3 or 4 treatment-related AE. Notably, 1 patient discontinued nemvaleukin due to treatment-related AEs. No patients had any nemvaleukin-related AEs that led to death, although 1 patient experienced a non–treatment-related AE that led to death.

Common AEs of any grade included pyrexia (63%), chills (52%), nausea (30%), and anemia (30%). Notable grade 3 or higher treatment-related AEs included chills (4%) and anemia (7%).

The study authors noted that further clinical evaluation of nemvaleukin is ongoing. Nemvaleukin as a single agent and in combination with other drugs is being explored in additional tumor types, including in the phase 2 ARTISTRY-6 trial (NCT04830124), which is examining nemvaleukin monotherapy in advanced melanoma, and the phase 3 ARTISTRY-7 trial (NCT05092360), which is examining nemvaleukin monotherapy and nemvaleukin plus pembrolizumab in platinum-resistant ovarian cancer.

References

1. Calvo E, Boni V, Chaudhry A, et al. Nemvaleukin alfa in patients with advanced renal cell carcinoma: ARTISTRY-1. J Clin Oncol. 2022;40(suppl 6):330. doi:10.1200/JCO.2022.40.6_suppl.330
2. Ding L, Dong HY, Zhou TR, et al. PD-1/PD-L1 inhibitors-based treatment for advanced renal cell carcinoma: mechanisms affecting efficacy and combination therapies. Cancer Med. 2021;10(18):6384-6401. doi:10.1002/cam4.4190