Kidney cancer (KC) ranks 14th in the most common cancers with 431,288 cases in 2020 and an estimated 179,368 deaths globally (1), with incidence on the rise. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of this disease, accounting for over 75-80% of cases.
The survival of patients with RCC has improved over recent years thanks to the advent and expansion of treatment options for patients with various stages of disease. Driven by a deeper understanding of the underlying genetic mechanisms of this tumor type, the past decade has witnessed an increase in more potent therapies including targeted therapies and immunotherapy. Despite such progress, RCC remains a highly aggressive and lethal cancer – particularly for patients with advanced/metastatic disease.
While immune-based therapies continue to step up as more potent treatment options across an increasing number of tumor types, including kidney cancer, these novel contenders do not benefit all patients nor do they necessarily achieve durable response despite initial clinical activity.
Results of exploratory analysis in patients with previously untreated advanced or metastatic renal cell carcinoma in the randomized multicenter phase III international CheckMate 9ER trial, presented on the ground during this week’s ASCO 2022 by VHIO’s Cristina Suárez (2), now show patients receiving the combination of first-line therapy with PD-1 inhibitor nivolumab plus targeted therapy with cabozantinib, achieved deeper responses compared to those treated with standard treatment sunitinib.
CheckMate 9ER: the continued promise of a novel immune-based combination
Previously reported data of this phase III study (3), co-led by Cristina Suárez, a Clinical Investigator of VHIO’s Genitourinary, CNS Tumors, Sarcoma & Cancer of Unknown Primary Site Group, showed that patients with previously untreated advanced renal cell carcinoma (aRRC) who received the novel nivolumab and cabozantinib combination had significantly better progression-free survival (PFS) and overall survival (OS) compared with those patients who were assigned to sunitinib.
Most recently, the CheckMate 9ER investigators subsequently reported patient-reported outcomes (PRO) in the 328 patients who were randomized to receive the immune-based combination or standard treatment (4). “Our data showed that patient-reported outcome scores were either maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, this novel combination significantly delayed time to deterioration of PROs,” says Cristina Suárez, a senior author of both of these CheckMate 9ER studies.
“Building on these investigations, results from present exploratory analysis presented here at the 2022 ASCO Annual Meeting, show that more patients receiving the combinatorial therapy achieved deeper responses, which associated with improved progression-free survival and overall survival,” observes Cristina Suárez, a Medical Oncologist at the Vall d’Hebron University Hospital’s Medical Oncology Department, headed by VHIO’s Director, Josep Tabernero.
Present findings reveal that the group receiving the treatment combination achieved superior response rates versus sunitinib, and that in both arms, increasingly deeper responses led to better overall survival. “These results support magnitude of response as a good prognostic indicator of medium- and long-term treatment outcomes in this particular patient population,” concludes Cristina Suárez, Discussant of this study at ASCO 2022.
The CALYPSO exploration of novel combinations in VEGF-refractory ccRCC
Also reflective of her expertise in the kidney cancer field, Cristina Suárez is a senior author of the CALYPSO phase II study of PD-L1 inhibitor, durvalumab, alone or with MET inhibitor, savolitinib, or monoclonal antibody against CTLA-4, tremelimumab, in previously treated advanced clear cell renal cancer (ccRCC).
The MET gene encodes a hepatocyte growth factor receptor. Mutations in this gene increase the risk of developing kidney cancer subtype papillary carcinoma. In ccRCC, this gene is involved in disease progression and may be implicated in cancer drug resistance. While the association of MET mutations with the development of this tumor type has been well described, the effect of specifically targeting MET is unclear.
To address this, the CALYPSO investigators assessed the combination of savolitinib, a potent MET inhibitor, plus immunotherapy durvalumab which is already used to treat several tumor types but not approved in renal cancer. They also explored the efficacy of durvalumab with a CTLA-4 inhibitor, tremelimumab, that had not been widely tested in this setting.
Enrolling 139 ccRCC patients who were refractory to prior vascular endothelial growth factor (VEGF) targeted therapy, patients were randomized to four study arms, each with different dosing schedules. The investigators compared the results of savolitinib as monotherapy or in combination with durvalumab, with durvalumab as monotherapy or combined with tremelimubab. They also explored the role of MET, PD-L1 and other relevant biomarkers with these targeted and immune agents.
Presented during the same Oral Abstract Session (5) by lead investigator Thomas Powles, Barts Cancer Institute, Queen Mary University of London (UK), data showed that in the papillary renal cell carcinoma cohort those patients with alterations in MET obtained greater benefit with the combination of durvalumab and savolitinib. These results were not however observed in patients with ccRCC.
“Despite the fact that all four regimens appeared safe and tolerable, they disappointingly failed to improve response rates or progression-free survival in this patient population,” says Cristina Suárez.
“While results did not show improved clinical activity compared with the standard of care in any of the study arms, they provide insights into the pairing of matched targeted therapies with immunotherapy that could now be avoided, sparing patients’ exposure to ineffective treatment approaches,” concludes Cristina Suárez.
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