Dr Drakaki on Nivolumab/Ipilimumab in Advanced RCC With Sarcomatoid Differentiation

Alexandra Drakaki, MD, PhD, associate professor, Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, discusses the role of combination therapy with nivolumab (Opdivo) and ipilimumab (Yervoy) in the treatment of advanced renal cell carcinoma (RCC) with sarcomatoid differentiation.

Nivolumab plus ipilimumab has demonstrated efficacy in patients with advanced RCC, including those with sarcomatoid features. Drakaki notes that this aggressive histologic subtype is associated with poorer prognosis.

Updated data from the phase 3 CheckMate 214 trial (NCT02231749)

, which evaluated nivolumab plus ipilimumab vs sunitinib (Sutent) in the first-line setting, demonstrated that patients in the overall population treated with the combination therapy achieved a median overall survival (OS) of 52.7 months compared with 37.8 months for those given sunitinib.

In a post hoc analysis, at a median follow-up of 42 months for those with sarcomatoid RCC and intermediate- or poor-risk disease, the median OS was not reached (NR; 95% CI, 25.2-not estimable [NE]) in patients treated with the combination (n = 74) vs 14.2 months (95% CI, 9.3-22.9) for those given sunitinib (n = 65; HR, 0.45; 95% CI, 0.3-0.7; 

 = .0004). The median progression-free survival was 26.5 vs. 5.1 months, respectively (HR, 0.54; 95% CI, 0.33-0.86; 

 = .0093). The respective confirmed overall response rate was 60.8% with nivolumab plus ipilimumab compared with 23.1% with sunitinib, including respective complete response rates of 18.9% and 3.1%.

Drakaki explains that RCC with sarcomatoid differentiation is particularly challenging to treat due to its aggressive clinical nature and potential resistance to certain therapies. The combination of nivolumab and ipilimumab targets both the PD-1 and CTLA-4 pathways, which could enhance the immune response against these aggressive tumor cells.

Drakaki concludes that the efficacy of nivolumab and ipilimumab in RCC with sarcomatoid differentiation highlights the value of dual immunotherapy for this difficult-to-treat subset of patients. The improved survival and ORR observed in this subgroup during the CheckMate 214 trial reinforce the rationale of targeting PD-1 and CTLA-4 pathways in patients with sarcomatoid RCC, underscoring the need for future research to refine patient selection and optimize outcomes in this high-risk patient population.

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Alexandra Drakaki, MD, PhD, discusses nivolumab plus ipilimumab in the treatment of renal cell carcinoma with sarcomatoid differentiation.

Dr Drakaki on a Case Study in ALK+ Refractory Metastatic RCC

Alexandra Drakaki, MD, PhD, associate professor, hematology/oncology, urology, Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, discusses 

a patient with refractory metastatic renal cell carcinoma

The use of next-generation sequencing (NGS) to understand deregulated pathways in kidney cancer is critical, Drakaki begins. In this case study, published in 

, investigators focused on a patient with metastatic RCC who sought a second opinion after their disease did not respond to immune checkpoint inhibitors, targeted therapies, and combination treatments, she explains. Recognizing that recycling the same drug classes would likely be ineffective, investigators opted to biopsy the tumor to gain new insights, Drakaki states.

Unexpectedly, Drakaki explains that investigators discovered an 

 rearrangement in the tumor, which had been present since the initial diagnosis but was either missed or not specifically looked for at that time. Based on this finding, oncologists chose alectinib (Alecensa), an ALK inhibitor, as the treatment. Alectinib was selected due to its efficacy in lung cancer and its known ability to penetrate the blood-brain barrier and central nervous system, she continues. When the patient began treatment, he had significant liver metastases, she notes. Within just a few months, he demonstrated a remarkable response, with imaging showing substantial improvement in both lung and liver metastases, Drakaki expands. At the time of the study’s publication, this patient had been receiving alectinib for approximately 4 years, with continued clinical and radiographic responses, according to Drakaki.

This case highlights the importance of personalized medicine in oncology, she emphasizes. By identifying and targeting specific mutations, such as the 

 rearrangement in this patient, investigators can achieve better outcomes and potentially extend survival, she says. The positive outcomes of this case underscore the need to thoroughly search for targetable mutations as a pathway to improve the longevity and quality of life for patients with metastatic cancer, Drakaki concludes.

Alexandra Drakaki, MD, PhD, discusses a case study of a patient with refractory metastatic renal cell carcinoma harboring an ALK rearrangement.

Dr Drakaki on Paradigm-Shifting Trials in Non–Clear Cell RCC

Alexandra Drakaki, MD, PhD, associate professor, Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, discusses key trials that have shaped the treatment paradigm in non–clear cell renal cell carcinoma (RCC).

Several trials have provided a foundation for current treatment approaches in non–clear cell RCC, Drakaki begins. One pivotal study was the phase 2 KEYNOTE-427 trial (NCT02853344), which evaluated the efficacy of single-agent pembrolizumab (Keytruda) in patients with non–clear cell RCC. The trial grouped several tumor subtypes together, including papillary, chromophobe, and unclassified RCC, Drakaki reports. Complete responses were observed in some patients treated with pembrolizumab monotherapy, showing that immunotherapy could be effective even in the non–clear cell RCC setting. This study served as proof-of-concept for the broader incorporation of immunotherapy approaches in these diverse subtypes, she explains.

Another noteworthy aspect of the KEYNOTE-427 trial was the inclusion of treatment-free survival as an end point, Drakaki says. She adds that a proportion of patients who discontinued treatment for various reasons maintained durable responses. This highlighted the potential long-term benefit of immunotherapy even after cessation of therapy, Drakaki notes.

Building on the success of KEYNOTE-427, new data have emerged supporting the combination of pembrolizumab with lenvatinib (Lenvima), Drakaki continues. The phase 2 KEYNOTE-B61 trial (NCT04704219) evaluated this combination in advanced non–clear cell RCC, following promising results from the phase 3 CLEAR trial (NCT02811861), which focused on first-line treatment for patients with clear cell RCC, she reports. Given the efficacy observed in the clear cell setting, it was logical to explore this combination in non–clear cell RCC, Drakaki emphasizes.

, findings from KEYNOTE-B61 confirmed that most patients responded to pembrolizumab plus lenvatinib, though the median overall survival had not yet been reached at the time of publication in 

 that same year. These results offer hope for the use of this combination in non–clear cell RCC, Drakaki concludes.

Alexandra Drakaki, MD, PhD, discusses key trials that have shaped the treatment paradigm in non–clear cell renal cell carcinoma.

Dr Drakaki on the Evolution of Non–Clear Cell RCC Subtype Classifications

Alexandra Drakaki, MD, PhD, associate professor, Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, discusses how the classification of non–clear cell renal cell carcinoma (RCC) subtypes has evolved in recent years.

Historically, kidney cancer was thought to comprise 5 primary subtypes, Drakaki begins. Clear cell RCC, characterized by 

 mutations, was considered the most common subtype, she notes. Other subtypes included papillary type 1, papillary type 2, chromophobe, and oncocytoma, she details. However, the classification of non-clear cell RCC has expanded to include additional subtypes, such as collecting duct carcinoma, kidney medullary carcinoma, unclassified tumors, translocation-associated tumors, and kidney cancers with sarcomatoid features, Drakaki details.

A new classification system for kidney cancer was introduced in 2022, and reflected advancements in the understanding of this disease, she expands. With next-generation sequencing providing an accurate tool for tumor analysis, investigators can now identify more molecularly-defined subtypes within RCC, Drakaki states. These include tumors characterized by fumarate hydratase or succinate dehydrogenase deficiencies, which indicate unique metabolic vulnerabilities. Additionally, oncologists are seeing an increase in tumors with 

-deficient RCC is often associated with renal medullary carcinoma, a rare but aggressive form of kidney cancer, she explains.

This updated classification is crucial for guiding treatment decisions, as it allows for more precise diagnoses and potential targeting of therapies based on molecular characteristics, Drakaki continues. She adds that deeper understanding of kidney cancer continues will lead to further expansion of the classification system, which reinforces the importance of individualized treatment plans. Identification of specific RCC subtypes allows treatment approaches to be tailored to each patient's unique genetic and molecular profile, thereby enhancing long-term outcomes, Drakaki concludes.

Alexandra Drakaki, MD, PhD, discusses how the classification of subtypes of non–clear cell renal cell carcinoma has evolved in recent years.

Dr Drakaki on the Investigation of Zanzalintinib in Advanced Non–Clear Cell RCC

Alexandra Drakaki, MD, PhD, associate professor, Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, discusses the potential role of zanzalintinib (XL092) for patients with non–clear cell renal cell carcinoma (RCC).

Zanzalintinib is a novel TKI targeting the VEGFR, MET, and TAM kinases. Drakaki notes that zanzalintinib is currently being investigated as a first-line treatment option for patients with non-clear cell RCC in 

the phase 3 STELLAR-304 study (NCT05678673)

, where patients are being randomly assigned 2:1 to receive treatment with zanzalintinib plus nivolumab (Opdivo) or sunitinib (Sutent) alone.

The dual primary end points of the STELLAR-304 trial are progression-free survival (PFS) and objective response rate (ORR) per RECIST 1.1 criteria, assessed by blinded independent central review. Secondary end points include overall survival (OS) and safety. The trial currently recruiting patients across Europe, North and South America, and the Asia-Pacific region.

Drakaki explains that this trial marks the first large-scale, phase 3 randomized study to evaluate a novel TKI combined with immunotherapy in patients with advanced non–clear cell RCC. Unlike clear cell RCC, where an array of immuno-oncology–based combination regimens are the standard of care in the frontline setting, patients with advanced non–clear cell RCC lack similarly robust treatment options due to the distinct molecular and clinical characteristics of this subtype of RCC.

The multi-targeted approach of zanzalintinib aims to disrupt several critical pathways involved in tumor growth and metastasis, including angiogenesis through VEGFR inhibition, MET-driven tumor progression, and TAM kinases' role in the tumor microenvironment.

Drakaki underscores the potential of zanzalintinib to expand treatment options for patients with non–clear cell RCC by targeting the complex biology of non–clear cell subtypes. This phase 3 trial could establish a new standard for combining multi-targeted TKIs with immunotherapy, aiming to improve patient outcomes in this difficult-to-treat setting, she concludes.

Alexandra Drakaki, MD, PhD, discusses the potential role of zanzalintinib in advanced non–clear cell renal cell carcinoma.

Alexandra Drakaki, MD, oncologist/hematologist at the University of California, Los Angeles, discusses the design of the MORPHEUS-mUC trial in advanced/metastatic urothelial carcinoma.

With the use of immunotherapy, investigators are trying to enable preexisting immunity to create an effective response to cancer, says Drakaki. The phase Ib/II MORPHEUS-mUC trial will evaluate 6 immunotherapy combinations compared with a single immunotherapy control in patients with locally advanced/metastatic urothelial carcinoma who progressed during or after a platinum-containing regimen.

The PD-L1 inhibitor atezolizumab (Tecentriq) will be combined with agents that target different mechanisms via CD47, CD38, DPP-4, nectin-4, interleukin-6 receptor, and PARP, adds Drakaki.

Patients enrolled in the study will start in stage I of the trial, in which they will be randomized to either the control arm of atezolizumab monotherapy or 1 of the following experimental arms: atezolizumab plus either enfortumab vedotin-ejfv (Padcev), niraparib (Zejula), magrolimab (Hu5F9-G4), isatuximab-irfc (Sarclisa), linagliptin (Tradjenta), or tocilizumab (Actemra).

At the time of progression, if they have a good performance status, no safety concerns, and available tissue, they will undergo biopsy. Then, they will be moved into the stage II portion of the trial, says Drakaki. In stage II, patients will be randomized to receive either atezolizumab plus either enfortumab vedotin-ejfv or linagliptin, concludes Drakaki.

Alexandra Drakaki, MD, discusses the design of the MORPHEUS-mUC trial in advanced/metastatic urothelial carcinoma.

Alexandra Drakaki, MD

Articles

Dr Drakaki on Nivolumab/Ipilimumab in Advanced RCC With Sarcomatoid Differentiation

Dr Drakaki on a Case Study in ALK+ Refractory Metastatic RCC

Dr Drakaki on Paradigm-Shifting Trials in Non–Clear Cell RCC

Dr Drakaki on the Evolution of Non–Clear Cell RCC Subtype Classifications

Dr Drakaki on the Investigation of Zanzalintinib in Advanced Non–Clear Cell RCC

Dr. Drakaki on the Design of the MORPHEUS-mUC Trial in Urothelial Carcinoma