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Page 4 of 12 Porta et al. J Cancer Metastasis Treat 2021;7:49 https://dx.doi.org/10.20517/2394-4722.2021.86

response, patients could discontinue treatment.

The dual primary end points were OS and PFS according to blinded, independent central review, while key
secondary end points were ORR, duration of response, and safety.

[2]
In this first report with a median follow-up of 12.8 months, the median OS was not reached in either
group, the estimated percentage of patients who were alive at 12 months was 89.9% (95%CI: 86.4-92.4) in
the combination arm, and 78.3% (95%CI: 73.8-82.1) in the monotherapy arm.

Median PFS was 15.1 months (95%CI: 12.6-17.7) in the combination arm and 11.1 months (95%CI: 8.7-
12.5) in the control arm; the HR for disease progression or death was 0.69 (95%CI: 0.57-0.84; P < 0.001).

The above survival benefits of the immune-based combination were observed in all the three IMDC risk
categories.

ORR was 59.3% (95%CI: 54.5-63.9) in the immune-based combination group, where 5.8% of patients
experienced a complete response, and 35.7% (95%CI: 31.1-40.4) in the monotherapy group (P < 0.001),
where just 1.9% of the patients had a complete response.

As far as safety, adverse events of any cause occurred in 98.4% of the patients randomized to receive the
combination, and in 99.5% of Sunitinib-treated patients, with grade 3 or higher TRAEs occurring in 62.9%
and 58.1% of the patients, respectively.

Finally, in the Pembrolizumab + Axitinib group, adverse events of any cause leading to discontinuation of
either drug, discontinuation of both drugs, interruption of either drug, or dose reduction of Axitinib
occurred in 30.5%, 10.7%, 69.9%, and 20.3% of patients, respectively; on the contrary, in the Sunitinib group,
adverse events of any cause led to discontinuation in 13.9% of patients, interruption in 49.9%, and dose
reduction in 30.1%.

[14]
At the second study update , at a median follow-up of 30.6 months, the immune-based combination
continued to yield superior clinical outcomes over Sunitinib. Indeed, the estimated OS rate at 24 months
was 74.4% (95%CI: 69.9-78.2) in the Pembrolizumab + Axitinib group and 65.5% (95%CI: 60.8-69.8) in the
Sunitinib group. In IMDC good risk patients, however, 12 and 24 months OS rates were 95.6% (95%CI:
90.5-98.0) and 85.3% (95%CI: 78.1-90.2) for the combination therapy, and 94.6% (95%CI: 89.0-97.4) and
87.7% (95%CI: 80.6-92.2), clearly indicating no added benefit from the combination, as compared to
monotherapy, in this subgroup of patients.

Median PFS was 15.4 months (95%CI: 12.7-18.9) with the combination, vs. 11.1 months (95%CI: 9.1-12.5)
with Sunitinib monotherapy (HR = 0.71; 95%CI: 0.60-0.84; P < 0.0001).

ORR was 60% (95%CI: 55.4-64.8) with Pembrolizumab + Axitinib, compared with 40% (95%CI: 35.2-44.7)
with Sunitinib (P < 0.0001); 38 (9%) of 432 patients in the combination arm and 13 (3%) of 429 patients in
the monotherapy arm had a complete response .
[14]
Finally, neither new safety signals, nor new treatment-related deaths, were observed with a longer follow-up,
compared with the first study report.