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Page 8 of 12 Porta et al. J Cancer Metastasis Treat 2021;7:49 https://dx.doi.org/10.20517/2394-4722.2021.86

As far as OS, no statistically significant difference was evidenced. Indeed, deaths from any cause were
recorded in 63 patients (14.3%) who received the combination vs. 75 patients (16.9%) who received
Sunitinib monotherapy (HR = 0.78; 95%CI: 0.55-1.08; P = 0.14).

A subgroup analysis showed a significant PFS benefit for the immune-based combination across the three
IMDC risk categories: indeed, HR for progression or death was 0.50 (0.26-0.97), 0.64 (0.47-0.88), and 0.53
(0.30-0.93) for good-, intermediate-, and poor-risk patients, respectively.

As far as safety, adverse events of any grade occurred in 99.5% and 99.3% of patients who received the
immune-based combination and Sunitinib, respectively; adverse events of grade 3 or higher during
treatment occurred 71.2% and 71.5% of the patients in the respective groups. Furthermore, adverse events
leading to discontinuation of both Avelumab and Axitinib or of single-agent Sunitinib were 7.6% and 13.4%,
respectively.

A recent publication updated the results of the JAVELIN Renal 101 trial, after a minimum follow-up of 13
[16]
months . Again, PFS was significantly longer in those patients with PD1-positive tumors treated with the
combination, as compared to monotherapy arm (13.8 months vs. 7.0 months; HR = 0.62; 95%CI: 0.490-
0.777; P < 0.0001). In the overall patient population, median PFS was 13.3 months for the combination, and
8.0 months for Sunitinib (HR = 0.69; 95%CI: 0.574-0.825; P < 0.0001). HR for OS was 0.828 (95%CI: 0.596-
1.151; P = 0.1301) for the PD-L1-positive population, and of 0.796 (95%CI: 0.616-1.027; P = 0.0392) for the
overall population.

As a whole, the results of the four trial which yielded an OS benefit are summarized in Table 1; results from
JAVELIN Renal 101 were not included in the table, due to the lack of OS benefit, which makes - in our
opinion - the Avelumab + Axitinib option less intriguing.

DISCUSSION
Given all the data above presented, how can we navigate between them? Or, in other words, how can we
make treatment choices in real world?

First of all, we should avoid making direct comparisons between studies which are extremely different in
terms of: agents used, study endpoints, primary efficacy patient populations, different follow-up (meaning
that there are still many immature data), distribution of patients between the three IMDC prognostic
groups, and, as a consequence, also results.

Despite all the above, it is almost impossible not to do some general considerations.

First, the Pembrolizumab + Lenvatinib combination seems to be the more potent, having achieved
astounding PFS benefit, the largest ever observed in mRCC, together with an unprecedented disease control
rate (90%) and percentage of complete responses (16%) . However, we should beware of patient selection.
[4]
Indeed, among the discussed trials, CLEAR has enrolled the lower amount of IMDC poor risk patients
[4]
(9%) and, together with Checkmate 214 , the larger amount of intermediate risk patients (60%).
[1]
A high treatment activity has also been observed in Keynote 426 (with almost the same issue relative to
patient selection as in CLEAR) , as well as in Checkmate 9ER , where there is probably a better balance in
[3]
[2]
terms of patient selection.