LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma

Renal cell carcinoma (RCC) is a heterogenous disease accounting for approximately 85% of all kidney tumors [1] and comprises several distinct histologies, with clear cell RCC (ccRCC) accounting for more than 70% of all cases [2]. Approximately a third of patients present with metastatic disease at diagnosis, and an estimated 20–50% of localized tumors will progress after resection [3]. In the past decade, significant improvements in the treatment of advanced ccRCC have been demonstrated through the use of antiangiogenic and immunotherapy agents [4,5]. Immune checkpoint inhibitors (ICI) targeted to programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1), administered in combination with cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitors or vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs)–targeted therapies have evolved as first-line treatment of advanced ccRCC [6,7]. These therapies have been shown to demonstrate clinically meaningful outcomes in phase III studies in advanced ccRCC [8–12], and the standard of care has shifted from a single-agent VEGF-TKI to ICI-based combinations [7,13,14]. Despite advances in treatment options with combination therapy, advanced ccRCC remains difficult to treat, and most patients will experience disease progression and require additional lines of therapy [13,15]. Furthermore, fewer than 20% of patients achieve a complete response (CR) with these ICI-based combination therapies [8–11]. New treatment strategies are currently under investigation for the treatment of RCC, including agents that target pegylated interleukin-2 and lymphocyte-activation gene-3 and dendritic cell vaccines [16]. Hypoxia-inducible factor 2α (HIF-2α) inhibitors, a new class of agents, have also become an option for RCC treatment [16]. Novel combinations including additional targeted agents may improve clinical outcomes in advanced ccRCC [17]. Recently, positive results were reported with the phase III trial of the triplet combination cabozantinib, nivolumab and ipilimumab compared with nivolumab and ipilimumab alone in patients with advanced renal cell carcinoma [18]. The median progression-free survival (PFS) was not reached (95% CI: 14.0 months–could not be estimated) in the experimental arm compared with 11.3 months (95% CI: 7.7–18.2) in the control arm [18].

LITESPARK-012 study

This phase III LITESPARK-012 study (NCT04736706) will evaluate the efficacy and safety of the HIF-2α inhibitor belzutifan plus pembrolizumab and lenvatinib or coformulated quavonlimab pembrolizumab and plus lenvatinib, versus pembrolizumab plus lenvatinib (control arm), as first-line treatment in patients with advanced ccRCC.

Background & rationale

The PD-1 pathway is a major immunomodulatory pathway often used by tumors to suppress physiologic antitumor activity [19]. Disruption of the PD-1/PD-L1 receptor/ligand interaction is an attractive therapeutic target to mediate and enhance antitumor responses [19–21]. Pembrolizumab is a highly selective humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab has demonstrated promising safety and efficacy as a monotherapy in advanced ccRCC [22], and combination therapies targeting additional pathways are of interest to further strengthen antitumor activity.

Positive phase III data have been reported for pembrolizumab in combination with vascular endothelial growth factor receptor (VEGFR)-targeted therapies in the first-line setting for RCC. CLEAR/KEYNOTE-581 is an ongoing phase III, randomized, open-label, multicenter, global study evaluating the efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab versus sunitinib alone as first-line treatment of patients with advanced RCC [8]. PFS was shown to be significantly longer with lenvatinib plus pembrolizumab than with sunitinib, with a median PFS of 23.3 months (95% CI: 20.8–27.7) versus 9.2 months (95% CI: 6.0–11.0; hazard ratio [HR]; 0.42 [95% CI: 0.34–0.52]) [23]. Lenvatinib plus pembrolizumab provided statistically significant and clinically meaningful improvement in overall survival (OS) compared with sunitinib, with an HR of 0.72 (95% CI: 0.55–0.93; p = 0.005) [23]. The objective response rate (ORR) was 71.0% with lenvatinib plus pembrolizumab treatment versus 36.1% with sunitinib treatment, with 17.2% of patients achieving a CR in the lenvatinib plus pembrolizumab group compared with 4.2% in the sunitinib group [23]. Grade 3 or higher adverse events (AE) that occurred in 10% or more of patients in any group included hypertension, diarrhea, elevated lipase level and hypertriglyceridemia. Pembrolizumab in combination with lenvatinib is approved by the US FDA, European Commission and Japan Pharmaceuticals and Medical Devices Agency for treatment of advanced ccRCC [24–26], which provides further rationale for investigation into combinations of additional targeted agents that may provide further clinical benefit in this setting.

Belzutifan (MK-6482) is an orally available, small molecule inhibitor of HIF-2α that selectively disrupts the heterodimerization of HIF-2α with HIF-1β [27,28]. Belzutifan was evaluated in a pivotal phase I dose-escalation/expansion single-arm study that included patients with previously treated advanced ccRCC (median number of prior therapies: 3) [29]. 55 patients with ccRCC were enrolled at 120 mg once daily (QD) [29]. A confirmed ORR of 25% and a median PFS of 14.5 months were reported [29]. The most common all-grade AEs were anemia (76%) and fatigue (71%), and the most common grade 3 or above AEs were anemia (27%) and hypoxia (16%) [29]. A decrease in erythropoietin concentration was observed at doses of belzutifan ≥120 mg QD, which is a known effect of inhibiting HIF-2α [29–31]. Toxicities such as anemia and hypoxia are expected [30,31] and can be managed with an erythropoiesis-stimulating agent and/or blood transfusion or with supplemental oxygen [29]. Belzutifan is approved by regulatory authorities in the USA, Canada, Brazil, United Arab Emirates, Australia and UK for adult patients with von Hippel-Lindau disease who require therapy for associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery [28,32]. In a phase II trial of von Hippel-Lindau disease–associated RCC, belzutifan demonstrated antitumor activity with an ORR of 64% and had a manageable safety profile, with grade 3 treatment-related AEs occurring in 18% of patients [33].

Belzutifan monotherapy is well suited for use in a combination therapy because of its manageable safety profile. In a phase I study, the HIF-2α inhibitor PT2385 (MK-3795) in combination with nivolumab was well tolerated and had promising antitumor activity in patients with pretreated advanced RCC [34]. The median PFS in those with therapeutic exposures of PT2385 was 10 months [34], comparing favorably with historical studies of nivolumab monotherapy in patients with pretreated advanced RCC (median PFS in CheckMate 025, 4.6 months) [35]. The most common grade 3 AEs were anemia (4%), fatigue (4%) and hypoxia (4%); two grade 4 AEs of elevated alanine aminotransferase and increased lipase/amylase were observed [34]. Belzutifan in combination with the TKI cabozantinib has been evaluated in advanced ccRCC in a phase II study [36]. Results with approximately 2 years of follow-up from the cohort of patients who had previously treated disease demonstrated a PFS rate of 56% at 12 months and an OS rate of 77% at 12 months [36]. A manageable safety profile was observed, with 65% of patients experiencing grade ≥3 treatment-related AEs [36]. These data suggest that combining the HIF-2α inhibitor with other VEGFR-TKIs such as lenvatinib might provide promising therapeutic options. Belzutifan as monotherapy and combination therapy for treatment of RCC is currently being investigated in multiple clinical trials (NCT04195750, NCT05239728, NCT04586231, NCT04846920).

Immune checkpoint protein CTLA-4 is a negative regulator of immune response, and inhibition results in substantial increases of T cell infiltrates within tumor tissues [37,38]. Inhibition of both CTLA-4 and PD-1 results in activation of the immune system, showing promising antitumor activity in multiple tumor types [38]. The immunotherapy combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab was shown to be effective in intermediate- and poor-risk treatment-naive advanced ccRCC in the randomized phase III CheckMate 214 study [11], which led to FDA approval of the combination therapy [39]. Quavonlimab is a novel CTLA-4 monoclonal antibody currently being explored as a coformulation or combination with pembrolizumab in several clinical trials [40,41]. Evaluation of quavonlimab in combination with pembrolizumab is ongoing in a phase I study of treatment for advanced solid tumors [41]. In the dose-confirmation phase, encouraging antitumor activity was observed at all dose levels in the non-small-cell lung cancer cohort receiving the combination as first-line treatment, while the safety profile was similar to that of other anti–CTLA-4/PD-1 combinations [41]. This combination was also evaluated in the cohort of patients with previously treated extensive-stage small-cell lung cancer, demonstrating a tolerable safety profile with 33% of patients experiencing grade 3 AEs and no grade 4/5 events [42]. The safety profile reported was similar to that of the non-small-cell lung cancer cohort [42]. In the small-cell lung cancer cohort, ORR was 18% (95% CI: 7–33); seven patients (18%) had partial responses (PR) and eight patients (20%) had stable disease [42].

Novel combinations of these ICIs and targeted therapies may have the potential to inhibit multiple oncogenic signaling pathways involved in initiation, progression and metastasis of ccRCC, resulting in increased disease control and more favorable patient outcomes.

Study design

LITESPARK-012 is a randomized, open-label, multicenter, parallel-group, active-controlled, phase III study of belzutifan plus pembrolizumab and lenvatinib or coformulated quavonlimab and pembrolizumab plus lenvatinib versus pembrolizumab plus lenvatinib as first-line treatment in participants with advanced ccRCC (Figure 1). Approximately 1653 adults will be randomly assigned 1:1:1 to 1 of the following three arms: Arm A (belzutifan 120 mg orally QD plus pembrolizumab 400 mg intravenously [iv.] every 6 weeks [Q6W] and lenvatinib 20 mg orally QD); Arm B (coformulated quavonlimab 25 mg and pembrolizumab 400 mg iv. Q6W plus lenvatinib 20 mg orally QD) and Arm C (pembrolizumab 400 mg IV Q6W plus lenvatinib 20 mg orally QD). The combination of pembrolizumab plus lenvatinib was previously investigated in RCC in the CLEAR/KEYNOTE-581 trial and is included as the control arm in LITESPARK-012, albeit with a modified dosing schedule for pembrolizumab [8]. The rationale to modify the dosing schedule of pembrolizumab from 200 mg every 3 weeks to 400 mg Q6W is based off modeling and simulation analyses that showed consistent pharmacokinetic (PK) profiles for the regimens and exposure-response relationships supporting similar efficacy and safety [43]. These data were further supported by results from cohort B of the KEYNOTE-555 study, which demonstrated that the observed clinical PK of pembrolizumab 400 mg iv. Q6W was consistent with the PK profile predicted from modeling and simulation [44]. Randomization will be stratified by International Metastatic RCC Database Consortium (IMDC) prognostic scores (0 vs 1–2 vs 3–6) [45–47], geographic region (North America vs Western Europe vs rest of world) and sarcomatoid features (yes vs no).

Treatment with pembrolizumab or coformulated quavonlimab and pembrolizumab may continue for a maximum of 18 doses (~2 years). If a participant remains progression free after 18 doses, Arm A may continue belzutifan and lenvatinib, and Arms B and C may continue lenvatinib monotherapy until disease progression, all at the discretion of the investigator. If any therapies must be discontinued because of intolerance or toxicity, treatment with remaining therapies will be continued until disease progression. Participants will be enrolled over a period of approximately 26 months.

Eligibility criteria

Adults aged ≥18 years with a histologically confirmed diagnosis of unresectable, locally advanced/metastatic RCC with a clear cell component with or without sarcomatoid features are eligible for enrollment (Table 1). Participants should not have received prior systemic therapy; however, those who have undergone neoadjuvant/adjuvant systemic therapy for ccRCC will be accepted if completed ≥12 months before randomization. Participants must have measurable disease per RECIST v1.1 as assessed by the local site investigator/radiology and a Karnofsky Performance Scale score of at least 70%. Key exclusion criteria include any known additional malignancy that is progressing or has required active treatment within the past 3 years, central nervous system metastases and/or carcinomatous meningitis, radiotherapy treatment within 2 weeks prior to first dose of study intervention, hypoxia defined as a pulse oximeter reading of <92% at rest or requirement of supplemental oxygen (intermittent or long-term), or clinically significant cardiac disease ≤12 months before first dose of study intervention.

Outcome measures/end points

The dual primary end points of this study are OS, defined as the time from randomization to death from any cause, and PFS, defined as the time from randomization to the first documented disease progression or death from any cause, whichever occurs first, per RECIST v1.1 criteria by blinded independent central review (BICR). End points will be evaluated in Arm A versus Arm C and Arm B versus Arm C.

Secondary end points include ORR, defined as the proportion of patients with a best overall response of CR or PR; duration of response (DOR), defined as the time from first documented evidence of CR or PR until either disease progression or death from any cause, whichever occurs first; and safety. ORR and DOR will be evaluated using RECIST v1.1 criteria determined by BICR. Safety and tolerability will be assessed by AEs and study discontinuation because of AEs. Secondary end points will be evaluated in Arm A and Arm B compared with Arm C.

Exploratory end points include health-related quality of life, which will be measured using the Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index–Disease Related Symptoms (FKSI-DRS) and EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and health utility, which will be measured using EuroQol 5-dimension, 5-level questionnaire (EQ-5D-5L) instruments. Biomarker analyses using blood and/or tumor samples to support analyses of cellular components, other circulating molecules and germline genetic analyses will also be performed. Exploratory end points also include PK analysis of belzutifan and quavonlimab.

Study procedures

Initial radiographic evaluation by computed tomography (CT) or magnetic resonance imaging of the chest, abdomen, and pelvis will be performed within 28 days prior to the date of randomization to determine study eligibility. CT is strongly preferred, but contrast-enhanced magnetic resonance imaging may be used for the abdomen and pelvis if iodinated CT is contraindicated. A bone scan is also required for all participants during the screening period. On-study imaging assessments will be performed at week 12 from the date of randomization, then Q6W for the first 78 weeks, and every 12 weeks thereafter. If the patient has a positive baseline bone scan at screening, the first on-study bone imaging will be performed at week 18 and will continue every 12 weeks through week 78, then every 24 weeks thereafter. Imaging will continue until disease progression verified by BICR, the start of new anticancer treatment, pregnancy, withdrawal of consent, or death, whichever occurs first. Brain imaging is only required as clinically indicated.

AEs will be monitored through the study and for 90 days following cessation of study treatment. AEs will be graded per the guidelines outlined in Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A posttreatment safety follow-up visit will occur 30 days after cessation of study treatment or before the participant begins a new anticancer therapy regimen, whichever is earlier. Additional posttreatment safety follow-up visits will occur 60 and 90 days after discontinuation of study treatment.

Patient-reported outcome (PRO) questionnaires will be administered on days 1 and 22 of every 42-day cycle, at the treatment discontinuation visit, and at the 30-day posttreatment safety follow-up visit. Electronic PRO assessments will continue for up to 2 years or until safety follow-up after end of treatment. PROs will be administered before drug administration and other study procedures and assessments including AE evaluation.

Blood samples will be collected for belzutifan PK analysis from participants randomly assigned to Arm A, and pembrolizumab and quavonlimab PK and antidrug antibodies will be analyzed from participants randomly assigned to Arm B. Archival or newly obtained tumor tissue and blood for genetic, RNA, serum, plasma biomarker and ctDNA analyses will be collected from all participants to identify novel biomarkers and support exploratory analyses of cellular components (e.g., protein, RNA, DNA, metabolites) and other circulating molecules.

Statistical analysis

Primary efficacy analyses will be performed in the intention-to-treat population, defined as all randomly assigned patients. The nonparametric Kaplan-Meier method will be used to estimate PFS and OS in each treatment arm, and the treatment differences between arms will be assessed using the stratified log-rank test. The HR will be estimated using a stratified Cox proportional hazard model with the Efron method of tie handling. The secondary end point of ORR will be analyzed using the stratified Miettinen and Nurminen method [48] with strata weighted by sample size.

Safety analyses will be performed in the all-patients-as-treated population, defined as all randomly assigned patients who received at least one dose of study treatment. Safety results will be analyzed using a tiered approach.

Interim analyses are planned. Results will be routinely reviewed by an external data monitoring committee that will make recommendations for study discontinuation or protocol modifications where appropriate.

Conclusion

We described the rationale and design of the open-label, multicenter, active-controlled, randomized phase III LITESPARK-012 study, which will compare the efficacy and safety of belzutifan plus pembrolizumab and lenvatinib, or coformulated quavonlimab and pembrolizumab plus lenvatinib versus pembrolizumab plus lenvatinib for the first-line treatment of advanced ccRCC. Given the high risk of disease progression in patients with advanced ccRCC, more effective treatment options are needed. Results from this study may support the potential advantage of these novel combinations over current treatment regimens.