CLEAR Trial Update - ESMO 2022
The CLEAR trial investigated the combination of the TKI lenvatinib and pembrolizumab in patients with treatment-nai advanced clear cell renal cell cancer. Initially published in NEJM in 2021, CLEAR randomly assigned 1069 patients 1:1:1 to receive lenvatinib + pembrolizumab; lenvatinib + everolimus; or sunitinib. The primary endpoint was progression-free survival, with secondary endpoints including overall survival and safety.
At the time of initial publications, both PFS and OS were superior in the lenvatinib + pembrolizumab compared to sunitinib:
mPFS: 23.9 vs. 9.2 months; HR 0.39; P<0.001
mOS: NR vs NR; HR 0.66; P=0.005
ORR: 71% vs 36%
At the ESMO Annual Congress in 2022, study author Dr Camillo Porta provided an update on the study results in all IMDC risk groups, with a median follow-up of 33.7 months:
mPFS: 23.3 vs. 9.2 months; HR 0.42
mOS: NR vs NR; HR 0.72
ORR: 71% vs 36%
The PFS benefit of lenvatinib + pembrolizumab over sunitinib was demonstrated across all risk groups. OS benefit was limited to those in the intermediate and poor risk groups, as the favourable risk group had very few events.
These results roughly align CLEAR with other TKI-IO combination trials in the advanced ccRCC space. In the subsequent discussion, results from CLEAR, Checkmate 9ER (cabozantinib + nivolumab), KEYNOTE-426 (axitinib + pembrolizumab) and Checkmate-214 (ipilimumab + nivolumab) were compared. Results for PFS, OS, objective response rate (ORR), complete response rate (CR) and median duration of response (mDOR) were compared across trials (see below).
Source: ESMO
Available from: https://www.urotoday.com/conference-highlights/esmo-2022/esmo-2022-kidney-cancer/139456-esmo-2022-invited-discussant-1449mo-and-1450mo.html
It is worth noting that the combination of lenvatinib and pembrolizumab had a higher rate of G3 toxicities and TKI dose reductions compared to the other regimens
G3 TRAEs (%): 82 (CLEAR); 61 (Checkmate 9ER); 63 (KEYNOTE-426); 48 (Checkmate-214)
DR (%): 69 (CLEAR); 56 (Checkmate 9ER); 20 (KEYNOTE-426)
The Bottom Line…
There is no current consensus regarding the optimum combination of TKI and IO in patients with advanced renal cell cancer. This is a question that is unlikely to be conclusively answered until definitive overall survival data are available across all studies. As ever, it remains important to consider potential toxicities, tailor therapeutics to the individual patient as much as possible, and work within existing access frameworks.
Sources:
https://www.nejm.org/doi/full/10.1056/NEJMoa2035716
https://www.urotoday.com/conference-highlights/esmo-2022/esmo-2022-kidney-cancer/139456-esmo-2022-invited-discussant-1449mo-and-1450mo.html
https://twitter.com/tompowles1/status/1630510376000401410?s=20
