At the first interim analysis of the phase 3 KEYNOTE-426 trial, first-line pembrolizumab plus axitinib showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) over sunitinib for advanced renal cell carcinoma (RCC). To assess long-term durability of clinical outcomes and elucidate predictive biomarkers for RCC, we performed efficacy and prespecified exploratory biomarker analyses from KEYNOTE-426 with ≥5 years of follow-up. Pembrolizumab plus axitinib showed sustained benefits in OS (hazard ratio: 0.84; 95% confidence interval: 0.71-0.99), PFS (hazard ratio: 0.69; 95% confidence interval: 0.59-0.81) and ORR (60.6% versus 39.6%) compared to sunitinib. An 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) was positively associated with OS (P = 0.002), PFS (P < 0.0001) and ORR (P < 0.0001) within the pembrolizumab plus axitinib arm. An angiogenesis signature was positively associated with OS (P = 0.004) within the pembrolizumab plus axitinib arm and with OS (P < 0.0001), PFS (P < 0.001) and ORR (P = 0.002) within the sunitinib arm. Across arms, programmed cell death ligand 1 combined positive score was only associated (negatively) with OS within the sunitinib arm (P = 0.025). Additionally, PBRM1 (polybromo-1) mutation had a positive association with ORR (P = 0.002) within the pembrolizumab plus axitinib arm. Within the sunitinib arm, OS was positively associated with VHL (von Hippel-Lindau tumor suppressor gene) (P = 0.040) and PBRM1 (P = 0.010) mutations and was negatively associated with BAP1 (BRCA1-associated protein 1) mutation (P = 0.019). Results showed a sustained clinical benefit with pembrolizumab plus axitinib over sunitinib and provide valuable information on biomarkers for immunotherapy-based treatment combinations in advanced RCC. Prospective clinical investigations are needed for biomarker-directed treatment for advanced RCC. ClinicalTrials.gov identifier: NCT02853331 .

• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Four approved immune-based combinations for untreated metastatic renal carcinoma have demonstrated survival benefits. The ARON-1 study (NCT05287464) analyzed real-world data of patients with metastatic renal cell carcinoma receiving first-line immuno-oncology combinations. This sub-analysis is focused on the nivolumab plus cabozantinib effectiveness. METHODS: We conducted a retrospective study across 52 centers in 17 countries, including patients with metastatic renal carcinoma treated with first-line nivolumab plus cabozantinib, regardless of histologic characteristics, performance status, or risk by IMDC prognostic model. Patients with incomplete medical data were excluded. The primary objective of this sub-analysis of the ARON-1 study was to evaluate the real-world effectiveness and safety. RESULTS: A total of 333 patients were treated with nivolumab plus cabozantinib, clinical characteristics included ECOG performance status ≥2 20%, non-clear cell histology 16%, sarcomatoid de-differentiation 12%, and poor-risk by IMDC 28%. At a median follow-up of 15.9 months (95%CI 11.2-44.0), the median overall survival was not reached (40.0-NR), the probability of survival at 2 years was 75%, while median progression free survival was 33.7 months (95%CI 21.1-38.9). In the entire cohort, an objective response was observed in 58%, with 6% complete responses, and a median duration of response of 38.9 months (95%CI 33.7-NR). At multivariate analysis, adverse prognostic factors for overall survival included ECOG performance status ≥2, sarcomatoid de-differentiation, brain and bone metastases, and poor IMDC group. In the safety analysis, the incidence of grade 3 or higher toxicity was 37%, with hypertension and hand-foot syndrome being the most frequent adverse events. CONCLUSION: The findings in the present real-world study reaffirm the clinical benefits and safety of the nivolumab plus cabozantinib combination across all subgroups, including populations that are generally excluded from clinical trials for whom data is often missing. Poor performance status, sarcomatoid de-differentiation, bone or central nervous system metastases and IMDC poor risk group were confirmed as negative prognostic factors.

• Klíčová slova
• clear cell renal cell carcinoma, metastatic renal cell carcinoma, nivolumab plus cabozantinib, non-clear cell renal cell carcinoma, real-world evidence,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Pembrolizumab plus lenvatinib is a treatment option for metastatic Renal Cell Carcinoma (mRCC). In the ARON-1 study we investigated we the real-world experiences gained from the use of this combination for mRCC. METHODS: We retrospectively investigated real-world clinical outcomes of mRCC patients receiving pembrolizumab plus lenvatinib within the ARON-1 study. Overall survival (OS) was calculated from the start of pembrolizumab plus lenvatinib to death for any cause. Progression-Free Survival (PFS) was defined as the time from the start of pembrolizumab to progression or death from any cause. Duration of response (DoR) was defined as the time from the start of pembrolizumab to disease progression or death, whichever occurred first, in patients who achieved complete remission (CR) or partial response (PR). Overall Response Rate (ORR) was defined as the proportion of patients who achieve a CR or PR per RECIST criteria. Adverse events were retrospectively collected from electronic and paper charts and categorized by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS: Overall, we included 202 mRCC patients treated with pembrolizumab plus lenvatinib. The median follow-up time was 15.1 months. The median OS was not reached (NR), with a median PFS of 25.6 months and an Overall Response Rate (ORR) of 59%. The median Duration of Response (DoR) was 26.2 months. G3-G4 adverse events (AEs) were observed in 92 patients (46%), with hypertension being the most common AE (13%). CONCLUSIONS: Pembrolizumab plus lenvatinib is an effective and tolerable treatment for mRCC also in the real-world setting.

• Klíčová slova
• ARON- 1, Immune-combinations, Lenvatinib, Pembrolizumab, Real-world data, Renal cell carcinoma, Survival,
• MeSH
• chinoliny * terapeutické užití   aplikace a dávkování   farmakologie   MeSH
• dospělí MeSH
• fenylmočovinové sloučeniny * terapeutické užití   aplikace a dávkování   farmakologie   MeSH
• humanizované monoklonální protilátky * terapeutické užití   aplikace a dávkování   farmakologie   MeSH
• karcinom z renálních buněk * farmakoterapie   mortalita   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory ledvin * farmakoterapie   patologie   mortalita   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chinoliny * MeSH
• fenylmočovinové sloučeniny * MeSH
• humanizované monoklonální protilátky * MeSH
• lenvatinib MeSH Prohlížeč
• pembrolizumab MeSH Prohlížeč

Lenvatinib plus pembrolizumab significantly improved efficacy versus sunitinib in treatment of advanced renal cell carcinoma (aRCC) in the phase 3 CLEAR study. We report results of an exploratory post hoc analysis of tumor response data based on baseline metastatic characteristics of patients who received lenvatinib plus pembrolizumab versus sunitinib, at the final overall survival analysis time point of CLEAR (cutoff: July 31, 2022). Treatment-naïve adults with aRCC were randomized to: lenvatinib (20 mg PO QD in 21-day cycles) plus pembrolizumab (n = 355; 200 mg IV Q3W); lenvatinib plus everolimus (not reported here); or sunitinib (n = 357; 50 mg PO QD; 4 weeks on/2 weeks off). The most common (lenvatinib plus pembrolizumab; sunitinib, respectively) metastatic site was lung (71.0%; 63.9%), followed by lymph node (45.6%; 43.7%), bone (22.5%; 24.9%), and liver (17.7%; 19.6%). Across treatment arms, ≥65% had two or more metastatic organs/sites involved, >80% of patients had nontarget lesions, and ~45% had baseline sums of diameters of target lesions ≥60 mm. Lenvatinib plus pembrolizumab demonstrated greater progression-free survival, objective response rate, and duration of response versus sunitinib across evaluable subgroups regardless of site or size of baseline metastasis or number of metastatic sites at baseline. Overall survival generally trended to favor lenvatinib plus pembrolizumab versus sunitinib; and tumor shrinkage was greater across sites (lung, lymph node, liver, and bone) for patients in the lenvatinib-plus-pembrolizumab arm versus the sunitinib arm. These results further support lenvatinib plus pembrolizumab as a standard-of-care in patients with aRCC regardless of site or size of baseline metastasis or the number of metastatic sites.

• Klíčová slova
• lenvatinib, lenvatinib plus pembrolizumab, pembrolizumab, renal cell carcinoma,
• MeSH
• chinoliny * aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• fenylmočovinové sloučeniny * aplikace a dávkování   terapeutické užití   MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   terapeutické užití   MeSH
• karcinom z renálních buněk * farmakoterapie   patologie   mortalita   sekundární   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory ledvin * farmakoterapie   patologie   mortalita   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• senioři MeSH
• sunitinib * aplikace a dávkování   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• chinoliny * MeSH
• fenylmočovinové sloučeniny * MeSH
• humanizované monoklonální protilátky * MeSH
• lenvatinib MeSH Prohlížeč
• pembrolizumab MeSH Prohlížeč
• sunitinib * MeSH