Belzutifan,HIF-2α Inhibitor,and Clear Cell Renal Cell Carcinoma With Somatic Von-Hippel-Lindau Loss-of-Function Mutation

Abstract

The Von-Hippel-Lindau (VHL) gene, acting as a tumor suppressor, plays a crucial role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Approximately 90% of individuals with advanced ccRCC exhibit somatic mutations in the VHL gene. Belzutifan, orally administered small-molecule inhibitor of hypoxia-induced factor-2α, has demonstrated promising efficacy in solid tumors associated with germline loss-of-function mutations in VHL, including ccRCC. However, its impact on cases with somatic or sporadic VHL mutations remains unclear. Here, we present 2 cases where belzutifan monotherapy was employed in patients with advanced ccRCC and somatic loss-of-function mutations in VHL. Both patients exhibited a swift and sustained response, underscoring the potential role of belzutifan as a viable option in second or subsequent lines of therapy for individuals with somatic VHL mutations. Despite both patients experiencing a pulmonary crisis with respiratory compromise, their rapid response to belzutifan further emphasizes its potential utility in cases involving pulmonary or visceral crises. This report contributes valuable insights into the treatment landscape for advanced ccRCC with somatic VHL mutations.

Introduction

Renal cell carcinoma (RCC) stands as the third most prevalent cancer within the genitourinary tract in the United States. The latest estimates from the American Cancer Society project around 81 000 new cases and 15 000 deaths attributed to RCC in 2023. ¹ Clear cell RCC (ccRCC) emerges as the predominant histologic subtype, constituting roughly 80% of all cases. ² The Von-Hippel-Lindau (VHL) tumor suppressor gene plays a pivotal role in ccRCC’s pathogenesis. Approximately 90% of ccRCC instances exhibit a sporadic or somatic loss-of-function (LOF) mutation or deletion in the VHL gene. This genetic alteration results in the accumulation of hypoxia-induced factor (HIF), particularly HIF-2α, instigating the upregulation of numerous genes associated with invasion, angiogenesis, and metastasis. Ultimately, this cascade propels the oncogenic process of tumor development. ³

Combined immunotherapy with PD-1/PD-L1 inhibitors and tyrosine kinase inhibitors (TKIs) have transformed the landscape of treatment for advanced ccRCC. Pembrolizumab with axitinib, ⁴ pembrolizumab with levatinib ⁵ and nivolumab with carbozantinib^6,7 are all approved frontline therapy in patients with advanced ccRCC, and each of these regimens provides benefits for progression-free survival (PFS) and overall survival (OS). However, despite these promising results, most patients with advanced ccRCC eventually develop resistance and tumor progression on these frontline therapies. Moreover, a subset of patients may develop a robust immune response to immunotherapy, leading to immunotherapy-associated adverse events, which can ultimately require the discontinuation of immunotherapy.

The enhanced comprehension of HIF’s role in driving ccRCC oncogenesis has spurred the development of HIF-2α inhibitors. Belzutifan (MK-6482, formerly PT2977) represents a second-generation, orally administered, small-molecule HIF-2α inhibitor. This inhibitor selectively disrupts HIF-2α’s heterodimerization with HIF-1β and exhibits superior pharmacological properties compared with the first-generation compound MK-3795 (formerly PT2385) in individuals with germline VHL-associated advanced ccRCC.^8,9 In the phase I/II LITESPARK-001 dose-escalation/expansion study, belzutifan demonstrated efficacy as a second-line and subsequent therapy for advanced ccRCC patients, yielding an overall response rate (ORR) of 25%. The median duration of response was not reached during a median follow-up of 41.2 months. ¹⁰

Herein, we report a series of 2 patients with advanced ccRCC and somatic loss-of-function of VHL who received belzutifan monotherapy. The first case highlights the potential role of belzutifan monotherapy in patients with severe immune-related adverse events and progression on first-line therapy who present with widespread bony metastases and numerous bilateral lung metastasis with respiratory compromise. The second case highlights the potential role of belzutifan monotherapy in heavily pretreated patients who have progressed on immunotherapy, TKIs, vascular endothelial growth factor inhibitors, and multikinase inhibitors and who have pulmonary metastasis, malignant pleural effusion, and respiratory distress.

Case Presentation

Case 1

A 41-year-old man with no past medical history initially presented to the hospital with abdominal and back pain as well as cauda equina syndrome. Further work-up with biopsy identified right renal ccRCC that was metastatic to lung, mediastinal nodes, and bones, resulting in central canal stenosis at the thoracic and lumbar spine, leading to spinal cord compression at T9 and T10 and cauda equina pressure at L4. Based on International Metastatic RCC Database Consortium (IMDC) risk model and Memorial Sloan-Kettering Cancer Center (MSKCC/Motzer) scores, this patient’s disease was classified as high-risk metastatic ccRCC. He was treated with ipilimumab plus nivolumab but unfortunately developed a grade 4 immunotherapy-associated adverse reaction (autoimmune hepatitis, immunotherapy-induced myocarditis with EF <20% requiring a temporary balloon pump) in May 2022, which necessitated the interruption and subsequent discontinuation of immunotherapy. In late June 2022, the patient presented to the hospital again with acute respiratory distress that required high-flow oxygen. Subsequent computed tomography (CT) chest showed progression with numerous bilateral lung metastases (Figure 1).

Figure 1.

CT chest of case 1 obtained in June 2022 showing numerous bilateral pulmonary metastases.

Next-generation sequencing was performed on the patient’s bone biopsy and showed somatic mutations on VHL (p.N78K missense variant, LOF 21%) and PBRM1 (p.T1484fs frameshift LOF 22%). The patient had no germline mutation. He was then started on lenvatinib with no immediate response in 2 days, then subsequently switched to belzutifan 120 mg in mid-July 2022. Within a week of starting belzutifan, the patient had improved respiration and was able to wean off oxygen. He ultimately improved and was discharged home without oxygen 1 week after starting belzutifan. A repeat CT chest in August showed a remarkable response to belzutifan (Figure 2). The patient continued to take oral belzutifan 120 mg daily; in April 2023, levatinib 10 mg daily was added due to slight intratumoral progression of the renal mass and a new liver lesion. Patient is currently still taking both belzutifan 120 mg daily and levatinib 10 mg daily, tolerating the regimen well with no significant side effects. The patient’s disease has maintained this stable response up to the date of manuscript submission.

Figure 2.

Repeat CT chest of Case 1 obtained in August 2022 after approximately 1 month on belzutifan 120 mg daily, showing a remarkable disease response.

Case 2

A 65-year-old Hispanic woman was initially diagnosed with left ccRCC that was metastatic to lung and mediastinal nodes. She initially was classified as having favorable-risk metastatic ccRCC based on the IMDC risk model and MSKCC/Motzer score. She had cytoreductive left nephrectomy in 2017, then subsequently had disease progression on sunitinib, ipilimumab plus nivolumab, pembrolizumab plus axitinib, cabozantinib monotherapy, everolimus plus lenvatinib, pazopanib monotherapy, and tivozanib monotherapy. CT chest in April 2022 showed a large pleural-based lung metastases and malignant pleural effusion (Figure 3). She had very poor performance status with these pulmonary metastases, required 24-hour home oxygen, and used a wheelchair. In light of the patient’s poor performance status, a discussion of hospice and comfort care was initiated in April 2022 after she progressed on tivozanib. However, the patient and her family were still interested in life-prolonging therapy and expressed a desire to consider clinical trials. Subsequently, the patient underwent next-generation sequencing by Tempus on lung biopsy tissue that showed 4.7% VHL p.T133fs frameshift LOF mutation. She had no germline mutation. The patient was started on oral belzutifan 120 mg daily in April 2022. She showed rapid improvement in her breathing and performance status within days of starting belzutifan. One month after starting on belzutifan, the patient was ambulatory and even able to exert herself without supplemental oxygen use. The patient remains on belzutifan 120 mg daily, tolerating it well with minimal side effects. Her disease has maintained a strong response with no progression seen on a repeat CT chest 1.5 years later (Figure 4). This highlights the effectiveness of belzutifan in highly pretreated advanced ccRCC with VHL mutation, as well as its potential role in patients with pulmonary crisis.

Figure 3.

CT chest of case 2 in April 2022 showing large pleural-based lung metastases and malignant pleural effusion: (A) axial view and (B) coronal view.

Figure 4.

CT chest of case 2 obtained 1 year later showing a remarkable response with no progression: (A) axial view and (B) coronal view.

Discussion

Hypoxia-induced factors play a crucial role in orchestrating cellular responses to low oxygen levels. These transcription factors, including 3 major oxygen-labile HIF-α subunits (HIF-1α, HIF-2α, and HIF-3α) and a constitutive HIF-1β subunit, undergo stabilization in hypoxic conditions, initiating a series of cellular adaptations to alleviate the impact of oxygen deprivation. ¹¹ In normoxic environments, the HIF-α subunit undergoes hydroxylation and associates with the VHL tumor suppressor protein, facilitating its targeted ubiquitin-dependent proteasomal degradation. Conversely, in hypoxia, HIF-α subunits translocate to the nucleus, forming active HIF transcription complexes with HIF-1β. These complexes bind to hypoxia-responsive elements on HIF target genes, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor beta (PDGF-β), c-Met, transforming growth factor alpha (TGF-α), and cyclin D1, promoting angiogenesis, tumorigenesis, invasion, and growth. ¹² Moreover, cancer-related HIF activation has been implicated in augmenting metastatic potential and contributing to resistance against chemotherapy and radiotherapy. ¹³ Belzutifan, a second-generation oral small-molecule inhibitor, specifically targets the HIF-2α subunit by binding to it. In conditions of hypoxia or impaired VHL protein function, belzutifan disrupts the interaction between HIF-2α and HIF-1β, leading to diminished expression of HIF-2α target genes.^8,9

Von-Hippel-Lindau disease is an autosomal-dominant hereditary cancer syndrome. It is caused by a germline LOF in the VHL gene, located at 3p25. ¹⁴ HIF-2α is thus able to escape ubiquitylation and accumulate in cells, leaving it free to bind HIF-1β. Subsequently, the complex stimulates hypoxia-inducible gene transcription, promoting erythropoiesis, angiogenesis, and cellular proliferation, which can lead to cancer cell growth. ¹⁵ As a result, patients with VHL disease are at a high risk of developing tumors, including ccRCC, hemangioblastomas of the central nervous system (CNS) and retina, cystadenomas, pancreatic neuroendocrine tumors (pNETs), and paragangliomas such as pheochromocytomas. ¹⁴ Belzutifan was approved by the FDA in 2021 for the treatment of patients with VHL-associated ccRCC, hemangioblastomas of CNS and retina, cystadenomas, and pancreatic neuroendocrine tumors when surgery is not immediately required. ¹⁶

In addition to germline LOF in VHL, sporadic or somatic mutation is also common; approximately 90% of ccRCCs have somatic LOF of the VHL gene. The current first-line treatment in the metastatic setting of ccRCC consists of a TKI/VEGF inhibitor combined with immunotherapy. Due to its substantial involvement in clear cell renal cell carcinoma (ccRCC) carcinogenesis, HIF-2α has emerged as a promising therapeutic target. The HIF-2α inhibitor belzutifan underwent examination in a phase I trial (LITESPARK-001, NCT02974738) involving heavily pretreated advanced ccRCC patients. ¹⁰ Results revealed a 25% ORR with a median follow-up of 41.2 months, and the ccRCC cohort exhibited a median progression-free survival (PFS) of 14.5 months. ¹⁰ In a phase 2 study exploring belzutifan in germline VHL-associated RCC, the ORR reached 49%, with 49% of patients maintaining stable disease (SD), and only 3% experiencing disease progression. Impressively, 96% demonstrated PFS at the 24-month mark. ¹⁷ Another phase 2 trial combined belzutifan with cabozantinib for patients with advanced ccRCC previously treated with immunotherapy. With a median follow-up of 24.6 months, 30.8% achieved an objective response, including 2% with a complete response (CR) and 29% with a partial response (PR). In addition, 62% of patients had SD, and 3% had progressive disease. The median PFS and overall survival (OS) were 13.8 and 24.1 months, respectively. ¹⁸

The role of belzutifan in somatic or sporadic LOF in VHL remains to be elucidated. On December 14, 2023, approval was granted for belzutifan by FDA in the treatment of advanced ccRCC patients, regardless of VHL status, who have progressed after receiving frontline PD-1/PD-L1 inhibitor and a VEGF-TKI. This approval was based on the preliminary findings from the LITESPARK-005 (NCT04195750), an open-label, randomized trial encompassing 746 patients with unresectable locally advanced or metastatic ccRCC that had advanced post initial treatment with both a PD-1 or PD-L1 checkpoint inhibitor and a VEGF-TKI. Patients were randomly allocated to either the 120 mg belzutifan group or the 10 mg everolimus group in a 1:1 ratio. Belzutifan exhibited a statistically significant improvement in progression-free survival (PFS) compared with everolimus, with a hazard ratio of 0.75 (95% CI: 0.63, 0.90; 1-sided P = 0.0008). Kaplan-Meier curves depicted nonproportional hazards, revealing comparable median PFS estimates of 5.6 months (95% CI: 3.9, 7.0) in the belzutifan arm and 5.6 months (95% CI: 4.8, 5.8) in the everolimus group. While overall survival (OS) results were preliminary, with 59% of deaths reported, no apparent trend toward detriment was observed. ¹⁹ The potential efficacy of belzutifan particularly in patients with LOF in VHL remains an area for future investigation.

At present, there are ongoing clinical trials investigating the effects of the PD-L1 inhibitor pembrolizumab, the multitargeted TKI lenvatinib (NCT04626518, NCT05030506), or cabozatinib (NCT03634540, NCT04586231) combined with belzutifan as a second-line treatment for ccRCC irrespective of VHL status.

Our case series highlights the efficacy and potential role of belzutifan in advanced ccRCC in patients with somatic LOF mutations of the VHL gene. The effects were seen not only our patient receiving belzutifan as second-line therapy but in a heavily pretreated patient. In addition, the effect of belzutifan was rapid and durable in both of the patients in our case series, which highlights its potential role as a therapeutic option in patients undergoing pulmonary or visceral crisis.

Belzutifan is generally well-tolerated, presenting an acceptable adverse effect profile. In the phase 2 trial MK-6482-004, the most prevalent adverse events included anemia, fatigue, headache, and dizziness. Generally, these events were of grade 1 or 2 severity. Among the participants, 20 individuals (20%) encountered grades 3 to 5 adverse events, with 9 patients (15%) attributing grade 3 events to the treatment. Notably, no deaths resulting from treatment-related adverse events were documented in this study. ¹⁷ In our case series, both patients continue to exhibit good tolerance to belzutifan at a daily dose of 120 mg, with minimal side effects.

Conclusion

Our case series highlights the potential role of belzutifan in the treatment of advanced ccRCC with somatic/sporadic VHL mutation in addition to a germline LOF mutation. This emerging observation will open the door to more targeted therapy in patients with advanced ccRCC as well as improve the PFS and OS of this dreadful disease.