Q&A: Immunotherapy in Renal Cell Carcinoma (RCC)

As we look at the history of renal cell carcinoma (RCC), we recognize that the role and benefits of immunotherapy are evolving.

Medscape recently had the opportunity to talk to Karl J. D'Silva, MD, clinical assistant professor of medicine in the Department of Hematology and Oncology at Tufts University School of Medicine, and medical director of Lahey Hospitals and Medical Center (Burlington, Massachusetts), about these advancements. Here, D'Silva reviews the overall significance of immunotherapy in RCC, particularly as it pertains to guidelines, plus ASCO updates, high mortality rates, and genetic outcomes.

Thank you for taking time to talk about the impact that immunotherapy has on RCC. What are some of the symptoms present during diagnosis and staging of RCC?

Just to give you some background, RCC is a common type of adult kidney cancer. It accounts for approximately 85% of neoplasms arising from the kidney. Smoking, obesity, and hypertension are established risk factors for RCC development. There are several RCC types, the most common being clear cell RCC (ccRCC). Less common cell types include papillary, chromophobe, translocation, and Bellini duct (collecting duct) tumors. Symptoms associated with RCC may include hematuria, weight loss, flank pain, and malaise. The presence of these symptoms prompts RCC staging.

What are recent guidelines and recommendations for the treatment of at-risk groups?

Multiple guidelines recommend VEGFR/PD-1 [vascular endothelial growth factor receptor/programmed cell death–1] inhibitor–targeted combinations for first-line treatment of patients with ccRCC.

Guidelines recommend VEGFR/PD-1 inhibitor–targeted combinations for first-line treatment of advanced ccRCC, irrespective of risk groups. Different combinations of agents' regimens are recommended for poor- and intermediate-risk patient groups with ccRCC.

The guidelines also recommend monoclonal antibody therapy, with the combination of ipilimumab + nivolumab as a preferred treatment option for intermediate- and poor-risk patients with ccRCC. However, this is not a preferred option for favorable-risk patients. Data from the randomized phase 3 CheckMate 214 trial helped to inform this recommendation. The study's co-primary endpoints were objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) in intermediate- and poor-risk patients only. In intermediate-/poor-risk patients, combination therapy led to higher ORR and CR rates vs tyrosine kinase inhibitor (TKI) monotherapy.

The data presented at the 2024 ASCO Annual Meeting on activating transcription factors continue to show durability of response with the immunotherapy combination.

Immune checkpoint inhibitors have revolutionized the treatment landscape for RCC by offering a powerful new strategy to counteract cancer's evasion of the immune system. Immune checkpoint inhibitors target specific molecules on T cells and tumor cells, restoring the immune system's ability to recognize and destroy cancer cells. Immunotherapy combinations have become a cornerstone in managing advanced RCC, thus establishing a new standard of care.

With the mortality rate of genitourinary cancers steadily rising, what is the prevalence of brain metastases in RCC?

Brain metastases in patients with metastatic RCC generally signifies a poor prognosis. Surgical resection is an option for patients with a single metastasis and good extracranial disease control. Stereotactic radiosurgery is an option for patients with limited-volume brain metastases, whereas patients with more widespread disease require whole-brain radiotherapy.

TKIs have limited activity in brain metastases related to RCC.

Immuno-oncology therapies such as nivolumab and pembrolizumab have central nervous system activity in patients with brain metastases from RCC.

What are the risk models for direct treatment?

It is important to talk about the risk models to direct treatment.

There are two primary risk models to direct treatment: the Memorial Sloan Ketting Cancer Center (MSKCC) Prognostic Model and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Criteria.

Both are key in making improvements in care.

The MSKCC Prognostic Model focuses on prognostic factors as well as prognostic risk groups. There are five prognostics factors: interval from diagnosis to treatment of less than a year; a Karnofsky performance status of less than 80%; must have a serum LDH greater than 1.5 times the upper limit of normal (ULN); a corrected serum calcium greater than the ULN; and a serum hemoglobin less than the lower limit of normal (LLN). For the prognostic groups, the MSKCC Prognostic Model has a low-risk group with no prognostic factors, an intermediate-risk group with one or two prognostic factors, and a poor-risk group with anywhere from three to six prognostic factors.

There are six prognostic factors as part of the IMDC Criteria and three prognostic risk groups. The prognostic factors are that it must be less than a year from the time of diagnosis to systemic therapy, and must have a performance status of less than 80% (same as the Karnofsky performance status). Also, there must be hemoglobin less than the LLN (normal: 120 g/L or 12 g/dL) and a calcium level of greater than the ULN (normal: 8.5-10.2 mg/dL). In addition, the neutrophil levels must be greater than the ULN (normal: 200-7.0x10⁹/L) and the platelets are greater than the ULN (normal: 150,000-400,000). The prognostic groups are favorable risk with no prognostic factors, intermediate risk with one or two prognostic factors, and poor risk with three to six prognostic factors.

Are there any new developments related to genetics and genetic makeup?

Genetic alteration and immune dysregulation in RCC is particularly important. One of the important genomic alterations is the von Hippel-Lindau (VHL) gene mutation. As you know, kidney cancers are immunogenic and intergenic. Due to the disruption of immunogenicity and intergenicity, which results in the development of kidney cancer, they also have genetic markers, called the VHL gene mutation. The good news is that we now have a drug which targets this VHL gene mutation, the HIF-2 alpha inhibitor called belzutifan.

The VHL gene is a key factor, regarding genetics in RCC. Hereditary RCC and management of localized renal masses in patients with VHL disease is typically guided under the 3-cm rule. The idea is to intervene at a point of maximum benefit to the patient for the best chance of limiting the development of metastatic disease, but also to consider the recurrent and multiple dissection. Patients should undergo partial refractory therapy. Ablative therapy may be considered for patients with significant medical surgical risk.

Now, the VHL gene in metastatic RCC is being targeted by the approval of belzutifan (Welireg), which was recently approved, in December of 2023. The FDA approved a plan for patients with advanced RCC following treatment with PD-L1, PD-1, and TKIs. Based on the randomized phase 3 LITESPARK-005 trial (NCT04195750), belzutifan led to a statistically significant improvement in PFS vs everolimus (Afinitor) (HR, 0.75; 95% CI, 0.63-0.90; 1-sided P =.0008). Median PFS was 5.6 months (95% CI, 3.9-7.0) with belzutifan vs 5.6 months (95% CI, 4.8-5.8) with everolimus.

Treatment with belzutifan led to improved patient-reported quality-of-life outcomes vs treatment with everolimus in patients with previously treated advanced RCC, according to findings from the phase 3 LITESPARK-005 trial (NCT04195750), which were presented during the 2024 ASCO Genitourinary (GU) Cancers Symposium in San Francisco.

Belzutifan was also associated with a meaningful improvement in time to disease progression, as measured with the Functional Assessment of Cancer Therapy-Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS) and the EORTC QLG Core Questionnaire (EORTC QLQ-C30).

When looking at the overall immune landscape of RCC, are there any targeted therapies or groundbreaking developments?

Targeted therapies, which include small molecules and monoclonal antibodies, act on specific molecular targets, such as growth factors and angiogenesis receptors, involved in cancer growth and spread. This precision offers a complementary mechanism to immune checkpoint inhibitors, potentially reducing immunosuppression caused by tumors and amplifying the immune response. The integration of targeted therapies, which inhibit the VEGF receptor, has marked a significant advancement, outperforming previous treatments like interferon alpha with better efficacy and fewer side effects.

This synergistic potential has led to groundbreaking developments, with the FDA approving several combinations of immune checkpoint inhibitors and targeted therapies for heralding a new era in RCC management. These combinations have been endorsed in the guidelines as the preferred first-line treatment for advanced RCC, demonstrating superior outcomes in OS and PFS compared with traditional monotherapies.

Were there any ASCO GU 2024 updates on immunotherapy guidelines with a focus on OS?

They did talk about the adjuvant setting. Based on the KEYNOTE-564 study, according to the February 2024 summary from ASCO, adjuvant pembrolizumab improved OS for patients with high-risk kidney cancer. This study also found that adjuvant pembrolizumab improved OS for all patients. The summary shows the improved OS in high-risk patients. Adjuvant pembrolizumab improves the OS for patients with high- risk kidney cancer compared with placebo.

Can you talk more about the KEYNOTE-564 study in RCC, presented at the 2024 ASCO GU Cancers Symposium?

This was a randomized, multicenter, double-blind trial, designed to evaluate the efficacy of pembrolizumab as an adjuvant therapy in patients with ccRCC.

Patients had a median follow-up of approximately 57 months. At 48 months, the estimated OS rate was 91.2% for the pembrolizumab group vs 86.0% for the placebo group.

As we move into a new era of treatment for patients with RCC, we are hopeful that we'll continue to see improved outcomes.

Credits:
Lead Image: Deborah A Baumgarten, MD, MPH
Image 1: Karl D'Silva, MD

Medscape © 2024 WebMD, LLC

Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.

Cite this: Q&A: Immunotherapy in Renal Cell Carcinoma (RCC) - Medscape - Mar 08, 2024.