ARTISTRY-7: phase III trial of nemvaleukin alfa plus pembrolizumab vs chemotherapy for platinum-resistant ovarian cancer

Ovarian cancer (OC) is a life-threatening disease and is the eighth most common cause of cancer mortality in women worldwide [1]. OC accounts for approximately 314,000 new cases and 207,000 deaths worldwide [1]. In the USA in 2022, an estimated 19,880 women were diagnosed with OC, and an estimated 12,810 women died from this disease [2]. Epithelial OC (EOC) is the most common type of OC, accounting for approximately 90% of cases [3]. Histologically, high-grade serous ovarian carcinoma accounts for more than three quarters of all EOC; other types of EOC include endometrioid, clear cell, low-grade serous and mucinous carcinoma [3].

Standard frontline treatment for EOC is platinum-based chemotherapy, alone or with an antiangiogenic agent such as bevacizumab. In the maintenance setting, bevacizumab and poly ADP-ribose polymerase (PARP) inhibitor therapy may be used alone or in combination [4,5]. The rate of initial response to platinum-based regimens is high (80% in patients with high-grade serous ovarian carcinoma) [3]. However, 80% of patients who respond have recurrent disease within 2 years of completing treatment [3]. For patients who have exhausted all of these available treatments, there is a high unmet need for new therapeutic options. The current standard of care for patients with recurrent platinum-refractory or platinum-resistant (platinum non-amenable) OC (PROC) is single-agent nonplatinum chemotherapy, which offers a low likelihood of durable response, with an objective response rate (ORR) ranging from 6 to 20% and progression-free survival (PFS) of approximately 3–4 months [3,5–7]. There is an unmet medical need for more effective therapies that improve response and overall survival (OS) in patients with PROC, and participation in clinical trials is highly recommended [5] as the development of new treatments offers the best hope to improve outcomes [8].

Checkpoint inhibitor therapy in PROC

Over the last decade, immunotherapy with checkpoint inhibitors (CPI) has dramatically changed the treatment landscape for many solid tumors [9]. Several phase II and III trials have investigated the use of CPIs as monotherapy or in combination with other agents in patients with PROC, with CPI-based combination regimens eliciting ORRs ranging from 16 to 43% (Table 1) [10–19]. In comparative trials, CPI monotherapy has not shown significant improvements over other agents [10,11]. Moreover, only one trial of a combination of two CPIs, the phase II open-label, randomized NRG-GY003 trial, has shown a significant improvement in outcome versus CPI monotherapy [18]. In this trial, nivolumab plus ipilimumab elicited a significantly higher ORR within 6 months of enrollment than nivolumab alone (31.4 vs 12.2%, respectively [odds ratio 3.28, 85% CI: 1.5 to infinity]; p = 0.034) [18]. However, there was an increase in toxicity with nivolumab plus ipilimumab compared with nivolumab alone [18].

Biomarkers, including high programmed death ligand 1 (PD-L1) expression, high tumor mutational burden and high microsatellite instability, are known to predict response to CPIs in some tumor types [20,21]. A relatively low incidence of PD-L1 expression (~8%) has been reported for OC [22] and, to date, trials of CPIs in patients with PROC have reported conflicting data regarding a correlation between PD-L1 expression and response, although these trials differed in study design, patient characteristics and the CPIs (anti–programmed cell death protein-1 [PD-1], anti-PD-L1 or anti-CTLA-4) and combinations investigated (Table 1). Thus, the potential predictive value of PD-L1 expression in patients with PROC is yet to be determined.

IL-2 & nemvaleukin

IL-2 has both immunosuppressive and immunostimulatory functions, mediated by its interaction with different IL-2 receptor (IL-2R) complexes (Figure 1) [23], and high-dose IL-2 was approved by the US FDA in the mid-1990s as an immunotherapeutic agent for the treatment of metastatic melanoma and renal cell carcinoma [24,25]. In the PROCLAIM study, best ORR following high-dose IL-2 was 23% for metastatic melanoma and 24% for advanced renal cell carcinoma [26]. In patients with advanced renal cell carcinoma, 1-, 2- and 3-year survival rates were 78, 61 and 52%, respectively. However, despite the proven antitumor activity of IL-2, its use has been limited, in part due to its associated toxicities, including the risk of capillary leak syndrome through preferential binding to the high-affinity IL-2R [27–29].

IL-2 preferentially activates the high-affinity IL-2R (consisting of subunits α, β and γ), leading to expansion of regulatory T cells, which may counteract its antitumor activity [31–34]. Thus, high concentrations of recombinant IL-2 are required to induce antitumor signaling through the intermediate-affinity IL-2R complex (consisting of subunits β and γ) on memory cluster of differentiation 8⁺ (cytotoxic CD8⁺) T cells and natural killer (NK) cells [23,35]. Reports of high-dose IL-2 use in PROC are limited. In a phase II study in 31 patients with platinum-resistant or -refractory OC, intraperitoneal IL-2 demonstrated antitumor activity (median OS 2.1 years, ORR 25% in 24 evaluable patients) [36].

Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel cytokine designed to capture and expand the therapeutic potential of IL-2 by harnessing the proven antitumor activity of high-dose IL-2, while mitigating certain associated hallmark toxicity issues [23]. Nemvaleukin is a stable fusion of circularly permuted IL-2 to the extracellular portion of the IL-2Rα chain and is sterically occluded from binding to and activating the high-affinity IL-2R [23,27]. Nemvaleukin is designed to be inherently active without requiring any metabolic or proteolytic conversion and does not degrade to native IL-2. Selective activation of the intermediate-affinity IL-2R leads to preferential expansion of memory CD8⁺ T cells and NK cells, with a minimal, non-dose-dependent effect on CD4⁺ regulatory T cells (Figure 1) [23,27,37]. Thus, the selectivity of nemvaleukin may provide enhanced tumor killing and improved safety and tolerability compared with high-dose IL-2 [23]. Additionally, immunostimulation with nemvaleukin has the potential to be combined strategically with other agents for the treatment of many types of cancer due to potential complementary and synergistic mechanistic effects that may enhance the effectiveness of cancer treatment [38–41]. Notably, anti-PD(L)-1 immunotherapies help reinvigorate exhausted effector T cells, thereby promoting T cell-mediated destruction of cancer cells and making them potential candidates for combination with nemvaleukin [42,43].

Clinical and preclinical studies have shown responses to nemvaleukin across a broad range of tumor types [44–47]. In the first-in-human ongoing phase I/II ARTISTRY-1 trial (NCT02799095), durable responses were observed with nemvaleukin monotherapy across a range of tumors, including melanoma and renal cell carcinoma, at interim analysis [46,47]. Furthermore, this interim data report showed that deep and durable responses were observed with the novel combination of nemvaleukin and pembrolizumab in heavily pretreated patients with OC (ORR 29% among 14 evaluable patients with PROC; five patients showed a response or had durable stable disease) [47,48]. These preliminary findings suggest that nemvaleukin plus pembrolizumab showed evidence of antitumor activity in heavily pretreated patients with PROC. The observed safety profile of nemvaleukin thus far has been manageable and consistent with its design and mechanism of action. The combination of nemvaleukin and pembrolizumab was generally well tolerated, with a safety profile in OC patients consistent with that of the overall population [47,48]. The most common grade 3/4 treatment-related adverse events in the overall population were anemia (10%), neutropenia (9%) and decreased neutrophil count (9%) [47]. This is an ongoing study, but to date there have been no reports of capillary leak syndrome with intravenous nemvaleukin.

The ARTISTRY-7 trial

Here we describe the rationale and design of the global phase III, open-label, randomized ARTISTRY-7 trial (GOG-3063; ENGOT-OV68; NCT05092360) evaluating the novel combination of nemvaleukin plus pembrolizumab in patients with PROC.

Background & rationale

The findings from ARTISTRY-1 on the activity and safety of nemvaleukin plus pembrolizumab in patients with PROC provided the rationale for the design and conduct of ARTISTRY-7. As nemvaleukin has a mechanism of action that differs from that of CPIs [49], it is hypothesized that nemvaleukin will act synergistically with pembrolizumab to improve efficacy outcomes compared with the individual components without significantly increasing toxicity. The primary objective of ARTISTRY-7 is to investigate the efficacy of nemvaleukin plus pembrolizumab compared with chemotherapy in patients with PROC. Pembrolizumab monotherapy has shown modest clinical activity in a subset of patients with advanced recurrent OC [15], but data on outcomes with pembrolizumab are limited in patients with PROC.

The decision to conduct a phase III trial was based on the fact that there is a significant unmet medical need for new treatments for PROC and clinical trials incorporating novel approaches are recommended for this patient population. Investigator-assessed PFS was chosen as the primary end point because PFS provides a more precise evaluation of the index treatment and a more rapid result than OS [50,51]. An open-label design was chosen to avoid the need to administer multiple placebo infusions due to the different dosage regimens in each treatment arm.

Methods

Study design

ARTISTRY-7 (GOG-3063, ENGOT-OV68; NCT05092360) is a global phase III, multicenter open-label, randomized trial of nemvaleukin in combination with pembrolizumab versus protocol-specific investigator's choice of chemotherapy in adult patients with platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer. The study is to be conducted at approximately 150 active or planned sites in 19 countries across Europe, North America and Asia-Pacific. Approximately 376 patients are planned to be randomized in a 3:1:1:3 ratio across four treatment arms: nemvaleukin plus pembrolizumab (n = 141), pembrolizumab monotherapy (n = 47), nemvaleukin monotherapy (n = 47) and investigator's choice of chemotherapy (n = 141; Figure 2). Both drugs are investigational in this setting so, consistent with published regulatory guidance documents, monotherapy arms were included to establish the component effect of each individual agent [52].

Eligibility criteria

Eligible patients (Table 2) are women (aged ≥18 years) with platinum-resistant/refractory epithelial OC (high-grade serous, any-grade endometrioid or clear cell), fallopian tube cancer or primary peritoneal cancer with evidence of progression on most recent line of therapy assessed radiographically or based on the cancer antigen-125 response per the Gynecologic Cancer InterGroup criteria, an Eastern Cooperative Oncology Group performance status of 0 or 1, an estimated life expectancy of ≥3 months and adequate hematologic reserve and hepatic and renal function. They must have received at least one prior line of platinum-based therapy and no more than five prior lines of systemic anticancer therapy in the platinum-resistant setting and at least one line of therapy that included bevacizumab; prior PARP inhibitors were required for patients with a BRCA mutation. As bevacizumab forms part of the treatment paradigm in front-line therapy and in advanced recurrent OC [53,54], the goal is to enroll patients who have exhausted these treatment options, including bevacizumab. Patients who received only one prior line of platinum-based therapy must have received at least four cycles of therapy, have had a complete or partial response, and then progressed ≥3 to ≤6 months after the last dose. Patients will be randomized according to the following stratification factors: PD-L1 status (immunohistochemistry combined positive score [CPS] ≥10 vs CPS <10; central laboratory assessment), histological subtype (high-grade serous vs non-high-grade serous) and investigator's choice of chemotherapy (paclitaxel vs other chemotherapies) at randomization to ensure key prognostic factors are equally distributed in the study arms.

Study treatments

Nemvaleukin 6 μg/kg/day will be administered by intravenous (iv.) infusion over 30 min on days 1 through 5 of 21-day cycles, and pembrolizumab 200 mg will be delivered iv. over 30 min on day 1 of 21-day cycles (Figure 2). The nemvaleukin dose of 6 μg/kg/day iv. was determined as the recommended phase II dose based on its pharmacodynamic effects on immune cell expansion, safety, preliminary exposure-response analysis and the activity of iv. nemvaleukin monotherapy in the phase I/II ARTISTRY-1 trial [45,47]. The 200-mg iv. dose of pembrolizumab was chosen based on collective data from its development program that demonstrated 200 mg IV every 21 days as an appropriate dose for adults across all indications, regardless of tumor type.

Protocol-specific investigator's choice for chemotherapy (considered standard of care) includes pegylated liposomal doxorubicin (PLD), paclitaxel, topotecan or gemcitabine (Figure 2). The choice of chemotherapy for each patient is to be selected by the investigator prior to randomization and each patient should be enrolled in the relevant chemotherapy arm. PLD 40 mg/m² iv. will be administered on day 1 of 28-day cycles at 1 mg/min in cycle 1 and then over 60 min in subsequent cycles. Paclitaxel 80 mg/m² iv. will be administered over 60 min on days 1, 8, 15, and 22 of 28-day cycles. Topotecan will be administered over 30 min at 4 mg/m² iv. on days 1, 8, and 15 of 28-day cycles or at 1.25 mg/m² iv. on days 1 through 5 of 21-day cycles. Gemcitabine 1000 mg/m² iv. will be given over 30 min on days 1 and 8 of 21-day cycles.

Study procedures

Tumor assessment will be performed every 6 weeks for the first year on study treatment and every 12 weeks thereafter. Tumor scans will be collected for blinded independent central review. Patients will be allowed to continue nemvaleukin (as monotherapy or combined with pembrolizumab) or chemotherapy until disease progression, unacceptable toxicity or any other protocol-specified criterion for withdrawal. Patients will receive pembrolizumab (alone or in combination with nemvaleukin) for a maximum of 35 cycles, while patients in the combination therapy arm will be permitted to continue nemvaleukin beyond 35 cycles. Patients will be followed for survival until study conclusion or up to 3 years from first dose of study treatment, whichever occurs first. Crossover between investigational study arms is not permitted on study.

Adverse events will be coded using the Medical Dictionary for Regulatory Activities and severity will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5. Adverse events and serious adverse events will be collected throughout the conduct of the study and during the safety follow-up period. The relationship of adverse events to study treatment will be assessed by the investigator.

Study objectives & end points

The primary objective of ARTISTRY-7 is to investigate the efficacy of nemvaleukin plus pembrolizumab compared with chemotherapy in patients with PROC. The primary end point is investigator-assessed PFS using Response Evaluation Criteria In Solid Tumors (RECIST v1.1) for the combination therapy arm compared with the chemotherapy arm [55]. Investigator assessment was used for the primary analysis of PFS.

Secondary end points for the nemvaleukin plus pembrolizumab arm compared with the chemotherapy arm include investigator-assessed ORR (proportion of patients with complete response or partial response; RECIST v1.1), disease control rate (proportion of patients with complete response or partial response or stable disease), duration of response (DOR), and time to response (TTR). Other secondary end points for these treatment arms are OS, cancer antigen-125 response as defined by the Gynecologic Cancer InterGroup (GCIG) and safety, including treatment-emergent adverse events and clinical laboratory parameters.

For the monotherapy arms, exploratory end points include investigator-assessed PFS, ORR, DOR, TTR (RECIST v1.1) and OS. Other exploratory end points for these treatment arms include measurement of health-related quality of life (using the Functional Assessment of Cancer Therapy – Ovarian [FACT-O] questionnaire and the EuroQol 5 Dimension 5-Level [EQ-5D-5L] questionnaire) and the pharmacokinetics and pharmacodynamic effects (including circulating CD8⁺ T cells, regulatory T cells and NK cells, and serum concentrations of interferon-γ, IL-6 and other soluble proteins) of nemvaleukin and/or pembrolizumab.

Statistical analysis

The intent-to-treat population, all randomized patients regardless of study drug received, will be used for efficacy analyses. The safety population, all randomized patients who receive at least one dose of nemvaleukin, pembrolizumab or investigator's choice chemotherapy, will be used for safety analyses.

A futility analysis is planned for each monotherapy arm, but no statistical comparison will be conducted against or between these arms. Additional interim analyses may be performed per protocol. An independent data monitoring committee will review and interpret the data at the interim analysis.

Conclusion

Standard single-agent nonplatinum chemotherapy provides only a modest benefit in a small proportion of patients with PROC. In clinical trials, investigational CPI monotherapy agents have shown limited antitumor activity for the treatment of PROC [10,11]. Consequently, there remains an unmet medical need for newer and more effective therapies for this important group of patients.

There is promising preliminary evidence from the ARTISTRY program that the novel cytokine nemvaleukin, either alone or in combination with pembrolizumab, improves outcomes in patients with PROC and with other advanced tumors [47]. The aim of the phase III ARTISTRY-7 trial is to confirm and expand on these findings in a large controlled clinical trial and provide more robust evidence of the benefits and risks of nemvaleukin plus pembrolizumab for the treatment of patients with PROC.

Nemvaleukin in combination with pembrolizumab has been granted FDA Fast Track designation for the treatment of PROC in the USA.

In addition to ARTISTRY-7, several other phase II and III trials of CPIs in patients with PROC are ongoing (Table 3). These trials are investigating CPI monotherapy or a CPI in combination with another CPI, an antibody-drug conjugate, chemotherapy and/or an antiangiogenic agent. In most of these trials, as in ARTISTRY-7, the primary objective is PFS. Patient populations across these trials vary in the number of prior lines of therapy in the platinum-resistant setting, from ≤5 for ARTISTRY-7 to ≤1 for the phase II PROMPT trial (NCT03430700). Results from these trials will provide further insights into the efficacy and safety of CPIs and CPI-based combinations for the treatment of PROC.