Keynote 4265/21/2023 ![]() In the pembrolizumab plus axitinib arm, 50% of patients that discontinued therapy started a second line of treatment, most of which with an anti-angiogenic therapy (44.3%). One of the first questions that arises is if it is better to start with a combination directed against both targets (immune system and angiogenesis) upfront or if it could be beneficial to use it sequentially. So, what is left to other treatment strategies such as TKIs monotherapy? And when should we use the ICI plus TKI combination or the ICI plus ICI combination? The results of these three combination trials are adding new standards of care in I line treatment of mRCC and will probably be incorporated in future guidelines. Differently, the study Javelin-Renal 101 restricted the evaluation of the primary endpoints PFS and OS to the 63.2% of patients with PD-L1 positivity, thus narrowing the field in which this combination could be used moreover, it should be underlined that the method of evaluation of PD-L1 is not standardized in RCC thus different methods were used in each trial. Pembrolizumab plus axitinib proved its efficacy in all the risk categories according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria ( 6), differently to nivolumab plus ipilimumab combination that has been approved only for intermediate and poor risk categories, and independently to PD-L1 expression. Nonetheless, it should be underlined that in the Keynote-426 a higher percentage of favorable risk patients than in the Javelin-Renal 101 was enrolled (31.9% and 21.7% in the overall population, respectively). The only combination to achieve a better rate of complete response is nivolumab plus ipilimumab in the CheckMate-214 (9% in the intermediate and poor risk population) ( 5). The percentage of complete response with pembrolizumab plus axitinib were also higher than those obtained with avelumab plus axitinib, both in the PD-L1 positive population (4.4%) and the overall population (3.4%). After a median follow-up of 12.8 months, pembrolizumab plus axitinib resulted in better overall survival (HR 0.53, P<0.0001), median progression free survival (15.1 months in the combination arm versus 11.1 months in the sunitinib arm, HR 0.69, P<0.001) and objective response rate (59.3% in the combination arm versus 35.7% in the sunitinib arm), with a higher percentage of complete response (5.8% in the combination arm versus 1.9% in the sunitinib arm). The primary endpoints of the Keynote-426 were overall survival and progression-free survival in the intention-to-treat population. The results of two studies investigating combination of ICI and anti-angiogenic therapy compared to sunitinib have been recently published, proving the benefit of the combination over the anti-angiogenic therapy alone: Keynote-426 ( 3), investigating the combination of pembrolizumab, an anti-PD1, plus axitinib, a VEGFR inhibitor, and Javelin-Renal 101 ( 4), investigating the combination of avelumab, an anti-PD-L1, plus axitinib. This could result in a synergistic effect of the blockade of PD-1/PD-L1 and VEGFR, leading to an enhanced effect of both therapies ( 1, 2). The biological rationale of this combination lies on the known effect of anti-angiogenic therapies of normalizing tumor vascularization and activating endothelial cells, leading to a higher infiltration of intra-tumoral T-cells. ![]() The treatment scenario for patients with metastatic renal cell carcinoma (mRCC) is witnessing its third revolution: the first was the advent of anti-angiogenic targeted therapies, consisting in tyrosine-kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) the second was the introduction of immunotherapy, consisting in immune checkpoint inhibitors (ICI), like anti-programmed death 1 (PD-1) receptor or anti-programmed death ligand 1 (PD-L1) the third and current revolution is the advent of ICI and TKIs combination. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. Email: This is an invited article commissioned by the Guest Section Editor Kaiping Zhang (PhD, AME College, AME Group, Hangzhou, China).Ĭomment on: Rini BI, Plimack ER, Stus V, et al. Orsola-Malpighi Hospital, Via Albertoni n 15, 40138 Bologna, Italy. Interviews with Outstanding Guest EditorsĬorrespondence to: Francesco Massari, MD.Policy of Dealing with Allegations of Research Misconduct.Policy of Screening for Plagiarism Process. ![]()
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