Potential New Immunotherapy-TKI Combo for Advanced RCC

Treatment options for managing advanced clear cell renal cell carcinoma (RCC) are evolving rapidly, and immune checkpoint inhibitors (ICIs) have recently shifted the standard-of-care first-line therapy to include either dual immune checkpoint inhibition (e.g. nivolumab plus ipilimumab) or a combination of ICI with tyrosine kinase inhibitors (e.g. pembrolizumab or avelumab plus axitinib, or nivolumab plus cabozantinib). These combinations have demonstrated superiority over sunitinib.

Data from clinical trials of novel combination strategies are accumulating. At the 2021 Genitourinary Cancer Symposium, updated results from the randomized, open-label, phase III CLEAR trial, which evaluated the efficacy and safety of lenvatinib in combination with pembrolizumab or everolimus versus sunitinib as first-line therapy for patients with advanced RCC, were presented and simultaneously published in theNew England Journal of Medicine. Among 1069 patients randomized to receive lenvatinib plus pembrolizumab, lenvatinib plus everolimus, or sunitinib, the majority of patients had an intermediate or favorable prognosis according to Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification. The primary endpoint of the trial was progression-free survival (PFS), and key secondary endpoints were overall survival (OS) and objective response rate (ORR), all as assessed by an independent review committee. Median PFS was significantly longer in the lenvatinib plus pembrolizumab group versus the sunitinib group: 23.9 versus 9.2 months (hazard ratio [HR], 0.39; P<0.001). The PFS benefits of lenvatinib plus pembrolizumab were seen across all patient subgroups, including all MSKCC/IDMC risk groups and regardless of PD-L1 expression. PFS was also longer with lenvatinib plus everolimus versus sunitinib: 14.7 versus 9.2 months (HR, 0.65; P<0.001). With respect to overall survival (OS), median OS was not reached in any treatment arm; however, OS was significantly longer in the lenvatinib plus pembrolizumab group versus sunitinib (HR, 0.66; P=0.005). This is in contrast to lenvatinib plus everolimus, where no OS benefit was seen. Notably, at 24 months, 79.2% of patients in the lenvatinib plus pembrolizumab group were alive compared with 66.1% and 70.4% in the lenvatinib plus everolimus and sunitinib arms, respectively. Both lenvatinib plus pembrolizumab and lenvatinib plus everolimus had significantly higher confirmed ORRs than sunitinib (71.0%, 53.5%, and 36.1%, respectively). Furthermore, complete response rate was highest in the lenvatinib plus pembrolizumab group (16.1%, 9.8%, and 4.2%, respectively). The safety profiles were consistent with those previously reported for the single agents and the combinations. Adverse events of grade ≥3 of any cause were reported in 82.4%, 83.1%, and 71.8% of patients in the lenvatinib plus pembrolizumab, lenvatinib plus everolimus, and sunitinib groups, respectively, with hypertension, diarrhea, elevated lipase levels, and hypertriglyceridemia occurring in at least 10% of patients. Adverse events that emerged or worsened during treatment were managed effectively with interruptions, dose reductions, and supportive care. However, treatment discontinuations due to adverse events occurred in 37.2%, 27.0%, and 14.4% of patients in the lenvatinib plus pembrolizumab, lenvatinib plus everolimus, and sunitinib groups, respectively.

In their discussion, the investigators of the trial highlight that these results compare favorably with other immunotherapy trials and support lenvatinib plus pembrolizumab as a potential new option for patients with advanced RCC. Alain Ravaud, MD, PhD (Hospital Saint-André, University Hospital Center Bordeaux, France),the author of an accompanying editorial, agrees but notes that for intermediate-/poor-risk patients with advanced RCC, survival benefits should be evaluated after longer follow-up. Additionally, he emphasizes the need for biomarker-driven studies to better predict treatment efficacy for individual patients.

References

Motzer R, et al N Engl J Med. 2021; Feb 13. [Online ahead of print].

Ravaud A, et al. N Engl J Med. 2021; Feb 13. [Online ahead of print].