Robert Galamaga, DO, reviews single-agent and combination targeted therapy advances in renal cell carcinoma for Kidney Cancer Awareness Month.
Robert Galamaga, DO, is the medical director of Outpatient Care Centers and a medical oncologist at Cancer Treatment Centers of America® (CTCA) Phoenix.
Kidney cancer accounts for just over 2% of cancer diagnoses worldwide. In the United States, we observe close to 80,000 new cases annually with close to 14,000 cancer-related deaths. Most kidney cancers arise within the renal cortex and are referred to as renal cell carcinomas (RCCs). More rare kidney cancers include transitional cell carcinomas of the renal pelvis, oncocytomas, renal sarcomas, collecting duct tumors, medullary carcinomas, and nephroblastomas (Wilms tumor).1 Data from the National Cancer Institute (NCI) suggests that at least one third of patients present with advanced-stage disease at diagnosis.2
Targeted Therapeutic Advances in RCC
The paradigm for the treatment of advanced-stage RCC has evolved tremendously over the past 3 decades with an ever-increasing pace of innovation. We have understood that the immune system plays a key role in kidney cancer management for many years. This has been underscored by evidence that removing the primary kidney tumor in a patient with metastatic disease can lead to spontaneous regression of metastatic deposits. With this in mind, interleukin 2 (IL-2) and interferon alpha were among early therapies approved for patients with metastatic disease, but response rates were low, and tolerability was difficult.
Research and clinical experience paved the way to target the VEGF pathway, which continues to represent a focus of therapy following the approval of sorafenib (Nexavar), an oral tyrosine kinase inhibitor, in 2005. Since that time, several more oral agents have won approval for the same indication along with bevacizumab (Avastin), which is also approved as a single agent or in combination with oral therapies.
The mTOR pathway has also been investigated in kidney cancer with everolimus, gaining approval in 2009 for patients who progressed after initial therapy with a VEGF-targeted oral therapy. Everolimus is now approved in combination with one of the newest oral tyrosine kinase inhibitors (TKIs), lenvatinib (Lenvima), as a second line option. For more than a decade, the standard of care was to start with a VEGF TKI and switch to mTOR inhibitor or vice versa.
A new era in treatment of RCC began with the exploration of immune checkpoints, alterations of CTLA-4 and PD-1 expression. Discovery of these targets and inhibition via monoclonal therapies now offers patients with advanced disease a whole new outlook on survival. Following results of the CheckMate 025 trial (NCT01668784), where nivolumab (Opdivo) showed an overall response rate of 25% versus best available second-line therapy at 5%, this drug was approved in 2015 for patients with advanced disease who progressed after VEGF-directed therapy.3 This approval opened the door for exploration of combination strategies for patients with metastatic disease.
When asked about the last decade of progress in kidney cancer in an interview forTargeted OncologyTM, Alan Tan, MD, stated, “Until 10 years ago, melanoma and kidney cancer used to be the only cancers that seemed to respond to immunotherapy. Interferon and IL-2 showed limited efficacy in these cancers with significant toxicities. This changed when Steven O’Day presented ‘Improved Survival with Ipilimumab in Patients with Metastatic Melanoma’ at the 2010 American Society of Clinical Oncology Annual Meeting in Chicago. This would open the flood gates to more advances in immunotherapy for a wide array of indications for many cancers.” Dr Tan is the director of genitourinary medical oncology at Rush University Medical Center in Chicago.
Combinations for RCC Treatment
Dual-inhibition of CTLA-4 and PD-1 pathway with ipilimumab (Yervoy) and nivolumab demonstrated outstanding results in the setting of melanoma, and the CheckMate 214 trial (NCT02231749) sought to show similar findings. This trial did show a 50% improvement in tumor response compared with best available first-line therapy, especially in those with intermediate or poor prognosis. This therapy was approved in 2018 for RCC and remains a viable option for first-line therapy.4
The KEYNOTE-426 trial (NCT02853331) studied sunitinib (Sutent) versus a newer generation TKI, axitinib in combination with pembrolizumab (Keytruda). This trial demonstrated clear superiority of the combination regimen with a response rate of close to 60% compared with 36% in the sunitinib arm.5 Similarly, nivolumab partnered with newer TKI, cabozantinib showed a 56% response rate with comparator sunitinib at 27% in the CheckMate 9ER trial (NCT03141177).6 Additional approved combination regimens include lenvatinib with pembrolizumab as well as axitinib (Inlyta) with avelumab (Bavencio).
Immunotherapy is now also indicated in the adjuvant setting for patients with intermediate or high risk of recurrence following nephrectomy. Pembrolizumab was studied in the KEYNOTE-564 trial (NCT03142334) and was found to reduce risk of recurrence or death by 32% compared with placebo.7
Yet another pathway of exploration in kidney cancer treatment is the HIF-2α pathway. Patients with von Hippel-Lindau (VHL) disease are at risk for developing RCC due to molecular alterations in the VHL gene. In patients with VHL-associated RCC, inhibition of the HIF-2α pathway yielded a response rate of close to 50% with the novel oral agent belzutifan (Welireg), which was approved in 2021, giving this subset of patients an attractive therapeutic option compared with previously available therapies.8
Emerging studies are evaluating the potential to use neoadjuvant combination therapy with avelumab and axitinib in patients with localized RCC who are at high risk of relapse after nephrectomy via the NeoAvAx trial (NCT03341845).9 This may change the paradigm of surgical management of limited-stage disease.
The Future of Treating Clear Cell RCC and Less Common Subtypes
It is important to note that the trials mentioned above studied predominantly clear cell variety RCC, the most common type. We continue to make significant advances in non–clear cell RCC as well. Combination immunotherapy and TKI therapies are now advancing survival in subtypes such as sarcomatoid RCC, which was previously associated with dismal outcomes. Dr Tan is enthusiastic about the future of research among the rarer subtypes and feels, “…more studies are needed, and referral for clinical trials are always encouraged to improve outcomes in this difficult population.”
For community medical oncologists, a wide range of therapies exists for patients diagnosed with kidney cancer. We continue to look for guidance on sequencing of therapies for patients with advanced stage disease as data from long-term trials continue to mature. The treating oncologist now uses careful patient selection for single or dual immune-targeted therapy, combination immunotherapy with a TKI, or single-modality TKI in the first-line metastatic setting. Dr Tan indicates, “While the frontline space has improved outcomes significantly, more than half of patients will have died of their disease. CheckMate 214 now has the longest follow-up for any phase 3 trial of immunotherapy combination in RCC and the 5-year survival rate is 48%. We still have work to do and the Litespark 6482-012 trial [NCT04736706] is looking to raise the bar with the introduction of belzutifan in combination with immune checkpoint inhibitors and lenvatinib.”
For patients with kidney cancer, a diagnosis previously associated with few viable treatment options, the future appears bright. Emerging therapies and maturing data continue to drive an increasing pace of practice change.
1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. doi:10.3322/caac.21708
2. Cancer stat facts: kidney and renal pelvis cancer. SEER. Accessed March 22, 2022. https://bit.ly/3iuHoXv
3. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803-1813. doi:10.1056/NEJMoa1510665
4. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277-1290. doi:10.1056/NEJMoa1712126
5. Rini BI, Plimack ER, Stus V, et al; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1116-1127. doi:10.1056/NEJMoa1816714
6. Choueiri TK, Apolo AB, Powles T, et al. A phase 3, randomized, open-label study of nivolumab combined with cabozantinib vs sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC; CheckMate 9ER). J Clin Oncol. 2018;36(suppl 15). doi:10.1200/JCO.2018.36.15_suppl.TPS4598
7. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391
8. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel–Lindau Disease. N Engl J Med.2021;385:2036-2046. doi:10.1056/NEJMoa2103425
9. Bex A, Abu-Ghanem Y, van Thienen JV, et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx). J Clin Oncol. 2022;40(suppl 6):289. doi:10.1200/JCO.2022.40.6_suppl.289