Paolo Tarantino, MD is an Advanced Research Fellow in the Breast Oncology Program at Dana-Farber Cancer Institute and Harvard Medical School.

Welcome to OncLive On Air®! I’m your host today, Jax DiEugenio.

OncLive On Air is a podcast from OncLive®, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, OncLive covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, we invited experts from across oncology specialties to discuss the abstracts and presentations they are most looking forward to seeing at the 2024 ESMO Congress.

Emre Yekedüz, MD, an associate professor of medical oncology at Ankara University in Turkey and a research fellow at Dana-Farber Cancer Institute in Boston, Massachusetts, shared insights on his latest work in genitourinary malignancies, particularly muscle-invasive bladder cancer. 

Thach-Giao Truong, MD, a hematologist and medical oncologist at the Cleveland Clinic in Ohio who specializes in skin cancers including basal cell carcinoma, melanoma, and Merkel cell carcinoma, highlighted her recent findings in targeted therapies for advanced skin cancers.

John H. Strickler, MD, an associate professor of medicine in the Division of Medical Oncology at Duke University in Durham, North Carolina, emphasized key updates in the treatment of gastroesophageal malignancies, where he sees significant progress on the horizon.

David Spigel, MD, chief scientific officer and medical oncologist at Sarah Cannon Research Institute in Nashville, Tennessee, discussed the expanding lung cancer clinical trial program he oversees, ensuring patients have access to cutting-edge therapies.

Finally, Paolo Tarantino, MD, a researcher at the European Institute of Oncology and clinical research fellow at Dana-Farber Cancer Institute, focused on advancements in breast cancer research, particularly in HER2-targeted therapies and antibody-drug conjugates.

That’s all we have for today! Thank you for listening to this episode of OncLive On Air. Check back on Mondays and Thursdays for exclusive interviews with leading experts in the oncology field.

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Experts from across oncology specialties discuss the abstracts and presentations they are most looking forward to seeing at the 2024 ESMO Congress.

Oncology Experts Preview Top Abstracts From the 2024 ESMO Congress 

Dr Yekedüz on a Case Study of Adjuvant Treatment Options in ccRCC

Emre Yekedüz, MD, research fellow, Dana-Farber Cancer Institute, 

discusses a case study shared via social media

that evaluated treatment options for a patient with clear cell renal cell carcinoma (ccRCC).

In a social media poll to members of the oncology community, which was posted to X (previously Twitter), Yekedüz highlighted a case study that prompted conversations about the applicability of different RCC management avenues.Notably, this was done to raise awareness for World Kidney Cancer Day, which took place on June 20, 2024. The poll read: “[A] 62-year-old man underwent radical nephrectomy for a 75-mm left renal mass diagnosed as ccRCC with sarcomatoid features. [The] tumor invaded perirenal sinus fat but did not [extend] beyond Gerota’s fascia, with clear surgical margins. Imaging revealed no distant metastases. What’s [the] next step?”

The patient in the case was diagnosed with pathological T3 and grade 4 ccRCC with sarcomatoid features, Yekedüz begins. The key question posed by the poll was about the next step for adjuvant treatment for this patient with ccRCC, he reports.

According to the poll results, 69% of responders selected adjuvant pembrolizumab (Keytruda) as the preferred treatment option, Yekedüz explains. This outcome is not unexpected given that the phase 3 KEYNOTE-564 trial (NCT03142334) was the first to demonstrate improved overall survival with pembrolizumab vs placebo in the adjuvant setting in patients with kidney cancer, he says. Prior to these findings, TKIs had not been successful agents for treating patients with early-stage kidney cancer in the adjuvant setting, making the KEYNOTE-564 trial a significant milestone, Yekedüz notes.

The National Comprehensive Cancer Network Guidelines suggest that pembrolizumab should be the first adjuvanttreatment consideration for patients with ccRCC based on KEYNOTE-564 data. However, it’s important to consider individual patient factors, such as preexisting autoimmune diseases, which may increase the risk of immune-related adverse effects during pembrolizumab treatment, he emphasizes. These conditions must be carefully evaluated before initiating therapy, highlighting the importance of personalized treatment approaches in clinical practice, Yekedüz concludes.

Videos

Emre Yekedüz, MD, discusses a case study shared via social media that evaluated treatment options for a patient with clear cell renal cell carcinoma.

Dr Yekedüz on the Importance of the KEYNOTE-564 Trial in Adjuvant ccRCC

Emre Yekedüz, MD, research fellow, Dana-Farber Cancer Institute, discusses results from a case study on a patient with clear cell renal cell carcinoma (ccRCC), highlighting adjuvant treatment options for this individual.

Yekedüz used social media to poll members of the oncology community about the management of RCC to raise awareness for World Kidney Cancer Day, which took place on June 20, 2024. 

 “62-year-old man underwent radical nephrectomy for a 75-mm left renal mass diagnosed as ccRCC with sarcomatoid features. Tumor invaded perirenal sinus fat but did not [extend] beyond Gerota’s fascia, with clear surgical margins. Imaging revealed no distant metastases. What’s [the] next step?”

Some poll responders opted for adjuvant sunitinib (Sutent) as the treatment choice for this patient, Yekedüz begins. This decision was likely influenced by clinical trial data demonstrating that adjuvant sunitinib can improve disease-free survival, according to Yekedüz. However, it is important to note that despite this benefit, sunitinib has not generated an overall survival (OS) advantage in this setting, he explains. Therefore, it’s crucial to consider pembrolizumab (Keytruda) as an adjuvant treatment option for RCC, he notes. The rationale for this consideration stems from the findings of the phase 3 KEYNOTE-564 trial (NCT03142334), which indicate that pembrolizumab should be a key option in the adjuvant setting for this patient population, Yekedüz emphasizes.

The importance of discussing how oncologists approach adjuvant therapy for ccRCC cannot be overstated, he shares. KEYNOTE-564 was a landmark trial, as it was the first to demonstrate an improvement in OS in the adjuvant setting for patients with ccRCC. This breakthrough makes it essential to evaluate patients according to their risk categories—specifically, those with intermediate/high-risk or high-risk disease, Yekedüz emphasizes. For patients falling into these categories, pembrolizumab should be strongly considered as a treatment option in the adjuvant setting, he says.

Understanding risk stratification is also critical, he expands. Patients with T2, T3, or grade 4 disease, or those with sarcomatoid features, can be classified as having intermediate/high-risk disease, and those with T4 and node-positive disease are considered to have high-risk disease. Additionally, in the metastatic setting, if there is no evidence of disease, adjuvant pembrolizumab should still be considered, Yekedüz explains. This approach aims to maximize the potential benefits of adjuvant therapy, thereby improving outcomes for patients with RCC, Yekedüz concludes.

Emre Yekedüz, MD, discusses a case study on a patient with clear cell renal cell carcinoma, highlighting adjuvant treatment options for this individual.

Dr Yekedüz on the Benefits of Biomarker-Driven Treatment in Kidney Cancer

Emre Yekedüz, MD, research fellow, Dana-Farber Cancer Institute, discusses key takeaways from the phase 3 IMmotion010 trial (NCT03024996), highlighting the importance of utilizing biomarker-driven treatment in patients with kidney cancer.

, several kidney cancer studies focused on biomarkers, but unfortunately, most of these studies did not yield positive results, Yekedüz begins. However, when considering the broader context of KIM-1 in kidney cancer research, one notable finding emerged: KIM-1 appears to be associated with response to atezolizumab (Tecentriq) treatment in high-risk patients with this disease, he explains. This observation stems from the the IMmotion010 study, he adds. This topic is significant because such biomarkers could play a crucial role in identifying patients who are more likely to benefit from immunotherapy or combination therapies, Yekedüz notes.

IMmotion010 revealed that patients with RCC who had high KIM-1 levels at baseline (n = 300) experienced a median disease-free survival (DFS) of 35.88 months vs a DFS of 57.23 months for those with low KIM-1 levels at baseline (n = 452; HR, 1.75; 95% CI, 1.40-2.17). Investigators identified a baseline KIM-1 level of 86 pg/mL as the optimal threshold for distinguishing between high and low KIM-1 subgroups.

Oncologists categorize patients based on their clinical risk, he continues, adding that without the use of biomarkers, some patients may be overtreated. By incorporating specific biomarkers into treatment decision-making, it is possible to more accurately select patients who are likely to derive the most benefit from immunotherapy and other combination therapies, both in the adjuvant and metastatic settings, Yekedüz emphasizes.

Overall, the outlook for kidney cancer treatment is promising, particularly with the anticipation of triplet therapies in the metastatic setting, Yekedüz expands. Additionally, new combination therapies, such as immunotherapy paired with HIF2 inhibitors in the adjuvant setting, are on the horizon, he states. This progress is exciting, and investigators eagerly await the upcoming results that will further enhance the ability to treat patients more effectively, Yekedüz concludes.

Emre Yekedüz, MD, discusses key takeaways from IMmotion010, highlighting the importance of biomarker-driven treatment in patients with kidney cancer.

In 2024, kidney cancer is projected to be one of the top 10 cancers in terms of incidence rate in the United States, with an estimated 81,610 new diagnoses.

 with an estimated 81,610 new diagnoses. Renal cell carcinoma (RCC) accounts for approximately 80% to 90% of all kidney cancer cases, with the predominant subtype being clear cell RCC (ccRCC).

Fortunately, we have been witnessing remarkable advancements in the treatment of patients with RCC with the advent of angiogenesis and immune checkpoint inhibitors.

 gene is a hallmark of ccRCC pathogenesis.

 Aberrations in the VHL protein (pVHL) increase the activity of hypoxia-inducible factor-2 (HIF-2), which plays a crucial role in carcinogenesis.

 Understanding the roles of pVHL and HIF-2α not only reveals how mammalian cells sense and respond to oxygen in normal cellular processes but also elucidates the underlying mechanisms involved in cancer development. For their research in this area, William G. Kaelin Jr., MD; Sir Peter J. Ratcliffe, MD, FRS, FMedSci; and Gregg L. Semenza, MD, PhD, were awarded the Nobel Prize in Physiology or Medicine in 2019.

 is part of the E3 ubiquitin ligase complex degrading HIFs under normal oxygen levels.

 HIF-2α, also known as endothelial PAS domain protein 1, is a transcription factor that plays a role in the cellular response to hypoxia.

 Under hypoxic conditions, HIF-2α binds to an aryl hydrocarbon receptor nuclear translocator, also known as HIF-1β, and becomes an active transcription complex, inducing the expression of proteins active in angiogenesis, proliferation, and migration.

 In ccRCC, accumulation of HIF-2α is due to the loss of the VHL protein, leading to a state of pseudohypoxia.

Belzutifan (Welireg) is a second-generation and more potent inhibitor of HIF-2α than the previously developed MK-3795.11 The agent binds to the inner pocket of HIF-2α and inhibits the formation of the HIF-2α and HIF-1β complex. Thus, it blocks abnormal protein expression caused by the abnormal accumulation of HIF-2α (Figure).

Figure: VHL–HIF-2α Pathway and Mechanism of Action of Belzutifan

As a result of this mechanism of action, in the first-in-human phase 1 LITESPARK-001 study (NCT02974738), anemia was among the most common grade 3 or higher adverse effects (AEs) due to decreased levels of erythropoietin, a down-stream HIF-2 inducible gene.

 Reduction in erythropoietin levels usually occurs early in the treatment course and is closely associated with the plasma level of belzutifan.

 Therefore, packed ed blood cell transfusions and/or erythropoiesis-stimulating agents can be used to manage significant anemia. Hypoxia is another potential AE.

 The precise cause of hypoxia is not fully understood; however, it is considered multifactorial, potentially involving impaired hypoxia sensing in various body parts responsible for ventilation.

 To manage hypoxia, close monitoring with a pulse oximeter and dose adjustments should be made when hypoxic conditions are detected (SpO2 < 88% at rest).

LITESPARK-001 marked the transition of HIF-2α inhibitors to the clinical setting. Investigators evaluated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and anticancer activity of belzutifan in 55 patients with refractory ccRCC.

 The most recent data update, published in January 2024, showed that, at a median follow-up of 41.2 months (range, 38.2-47.7), the objective response rate (ORR) was 25%.

Accounting for the underlying biology, the safety and efficacy of belzutifan were investigated in patients with von Hippel-Lindau disease,
a rare autosomal dominant disorder that results from a germline variant in VHL.

 The corresponding phase 2 LITESPARK-004 study (NCT03401788) demonstrated initial significant activity in patients with RCC with an ORR of 49% (95% CI, 36%-62%) and other non-RCC neoplasms associated with
von Hippel-Lindau disease (n = 61), such as retinal hemangioblastomas.

 The findings supported the FDA approval of belzutifan for this distinct patient population in August 2021.

Another phase 2 study, LITESPARK-003 (NCT03634540), assessed the effects of combining the HIF-2α–targeting approach with the multitargeted tyrosine kinase inhibitor cabozantinib (Cabometyx). Cohort 2 (n = 52), which consisted of patients in their second or third line of treatment after previous immunotherapy, achieved an ORR of 31% (95% CI, 19%-45%). Cohort 1 (n = 50), which included treatment-naive patients with RCC, experienced an ORR of 70%.

Focusing on the optimal dosage, the phase 2 LITESPARK-013 study (NCT04489771) compared the efficacy and safety profile of belzutifan at daily doses of 120 mg vs 200 mg. With similar efficacy in both arms, this trial supported using the conventional 120-mg daily dose. The incidence of treatment-related AEs was consistent with previous studies and was slightly higher in the 200-mg arm.

Table: Ongoing Clinical Trials of HIF-2 Inhibitors in RCC

The phase 3 LITESPARK-005 study (NCT04195750) was the last major step before belzutifan’s milestone FDA approval for patients with advanced RCC in December 2023.

 The trial included 746 pretreated patients with 1 to 3 prior lines of systemic therapy. Participants were randomly assigned 1:1 to receive the mTOR-inhibitor everolimus (Afinitor) or belzutifan. Treatment with belzutifan resulted in a 25% risk reduction for progression or death (HR, 0.75; 95% CI, 0.63-0.90; 

 < .001). Despite that, OS data did not reach statistical significance. The ORR was 21.9% (95% CI, 17.8%-26.5%) vs 3.5% (95% CI, 1.9%-5.9%) with belzutifan compared with everolimus, respectively. Notably, in this heavily pretreated population, time to deterioration of cancer symptoms also favored belzutifan.

Due to extensive research and clinical advancements, HIF-2α inhibition has emerged as a valid and promising therapeutic option for the treatment of patients with kidney cancer. Ongoing studies and accumulating evidence, especially in combination regimens and earlier lines of therapy, continue to bolster the potential of HIF-2α inhibitors (Table).

Articles

Kidney cancer is projected to be a top 10 cancer in the U.S. by 2024, with renal cell carcinoma (RCC) as the predominant type. Advances in treatment, particularly with angiogenesis and immune checkpoint inhibitors, have been significant. The VHL gene's role in RCC pathogenesis is crucial, with HIF-2α being a key target. Belzutifan, a HIF-2α inhibitor, has shown promise in clinical trials, leading to FDA approval for certain conditions. Ongoing research continues to explore its potential, especially in combination therapies and earlier treatment lines.

Emre Yekeduz, MD

Articles

Oncology Experts Preview Top Abstracts From the 2024 ESMO Congress

Dr Yekedüz on a Case Study of Adjuvant Treatment Options in ccRCC

Dr Yekedüz on the Importance of the KEYNOTE-564 Trial in Adjuvant ccRCC

Dr Yekedüz on the Benefits of Biomarker-Driven Treatment in Kidney Cancer

From Bench to Bedside: HIF-2α Inhibition in RCC