Rare Case Study of ALK+ Advanced RCC Highlights Drive for Personalized Medicine in Kidney Cancer

Rare and under-studied tumors remain an area of interest for ongoing clinical investigations in the renal cell carcinoma (RCC) therapeutic space, making next-generation sequencing (NGS) a vital step in patient care, according to Alexandra Drakaki, MD.

“I'm excited to see that drug development is shifting toward the rare tumors. Finally, we have studies for the non–clear cell histologies. When patients come to our clinic, we now have evidence and we're going to have even more evidence why we select the drugs we offer them,” Drakaki said in an interview with OncLive®.

In the interview, Drakaki , who serves as an associate professor of Medicine, Hematology/Oncology, and Urology at the University of California, Los Angeles (UCLA), UCLA Health, as well as a physician at Santa Monica Cancer Care, dove into a case study of a patient with refractory metastatic RCC harboring an ALK rearrangement to underscore the importance of NGS. She also highlighted a treatment approach for patients with sarcomatoid RCC and detailed updated findings for adjuvant pembrolizumab (Keytruda) in the treatment of patients with clear cell RCC at high risk of recurrence following nephrectomy.

OncLive: What were the key takeaways from the case study you and colleagues presented on a patient with refractory metastatic RCC harboring an ALK rearrangement?

Drakaki: Using NGS to try to understand the deregulated pathways in kidney cancer is important. For example, we published [a case study] for a patient of ours in JCO Precision Oncology.1 This was a patient with metastatic RCC who came to us for a second opinion. He was not responding to any immune checkpoint inhibitors, targeted therapies, or combinations. At that point, we decided to biopsy and see if we were going to learn something from the tumor, since repeating and recycling the same class of drugs didn't make any sense.

Surprisingly, we found that there was an ALK rearrangement in his tumor. We went back to the initial specimen, and that pathway was deregulated at the time of diagnosis. It was just missed or not searched for. We put him on alectinib [Alecensa], which was our first choice of an ALK inhibitor based on literature from lung cancer and knowing that there is some blood-brain barrier and central nervous system penetration. [At the start of treatment, the patient] had metastasis in the liver of significant size, and he had a significant response within a few months of therapy. Imaging of the lung and liver metastases showed significant improvement. This patient has been on alectinib for almost 4 years with significant clinical response and radiographic response.

[This type of case study] is a hint that we are in an era where we should and could personalize medicine. We should try to search for targetable mutations; that's how we're going to keep our patients alive.

How do you approach treatment for patients with advanced sarcomatoid RCC?

Sarcomatoid tumors are usually more aggressive. As you can imagine, when nivolumab [Opdivo] plus ipilimumab [Yervoy] received FDA approvals for different tumor types, including melanoma and kidney cancer, there were multiple studies with this combination in different subtypes of cancer. Thankfully, [a post hoc analysis of the phase 3 CheckMate 214 trial (NCT02231749)] evaluated this immunotherapy doublet vs sunitinib [Sutent] in patients with sarcomatoid tumors. Clearly, we had a significant benefit and survival benefit [with the first-line combination].2 When we see tumors with that specific histology, in my opinion, nivolumab plus ipilimumab is the way to go.

What are the implications of the updated overall survival (OS) data for adjuvant pembrolizumab in patients with clear cell RCC at high risk of recurrence after nephrectomy?

At UCLA, Allan J. Pantuck, MD, and colleagues collaborated with other institutions and designed the adjuvant phase 3 [S-TRAC] trial [NCT00375674] of sunitinib vs placebo in patients with high-risk kidney cancer after nephrectomy. That study was the first positive study where adjuvant sunitinib improved disease-free survival [DFS]. The truth is that [adjuvant sunitinib] is not commonly used because sunitinib is toxic. However, the whole idea of adjuvant therapy in kidney cancer led to more studies, like those with immunotherapy.

At the 2024 Genitourinary Cancers Symposium, we had the updated data [from the phase 3 KEYNOTE-564 trial (NCT03142334) showing an OS benefit] for adjuvant immunotherapy with pembrolizumab vs placebo in patients with clear cell RCC [at high risk of recurrence after surgery]. There is hope that we're going to start treating patients as early as possible with the right drugs in order to decrease the risk of recurrence and keep patients alive for years to come.

References

1. Kathuria-Prakash N, Lopez LP, Raman S, et al. ALK inhibition with alectinib for refractory metastatic renal cell carcinoma with ALK rearrangement: a rare case report and literature review. JCO Precis Oncol. 2024;8:e2400154. doi:10.1200/PO.24.00154
2. Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clin Cancer Res. 2021;27(1):78-86. doi:10.1158/1078-0432.CCR-20-2063
3. Choueiri TK, Tomczak P, Park SH, et al. Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2024;42(suppl 4):LBA359. doi:10.1200/JCO.2024.42.4_suppl.LBA359