Patients with advanced renal cell carcinoma (RCC) who received frontline nivolumab (Opdivo) plus cabozantinib (Cabometyx) achieved a longer treatment-free survival (TFS) duration vs sunitinib (Sutent), according to findings from an analysis of the phase 3 CheckMate 9ER trial (NCT03141177) presented during the 

Over the 48-month period following random assignment, patients in the intention-to-treat (ITT) population who received the combination (n = 323) experienced a mean TFS of 7.0 months compared with 4.6 months in the sunitinib arm (n = 328), for a difference of 2.4 months (95% CI, 0.8-3.9). Patients without a grade 2 or higher treatment-related adverse effect (TRAE) experienced a mean TFS of 3.0 months vs 2.3 months, respectively; those who experienced a grade 2 or higher TRAE experienced a mean TFS of 3.9 months vs 2.3 months. The 48-month mean overall survival (OS) was 35.1 months in the doublet arm vs 30.7 months in the sunitinib arm. The mean times on protocol treatment were 22.6 months compared with 14.1 months, respectively.

Additionally, the 48-month OS rates were 49.2% in the nivolumab plus cabozantinib arm vs 40.2% in the sunitinib arm, and the 48-month TFS rates were 33.3% compared with 12.9%, respectively.

“There are multiple immunotherapy-based combination treatments with similar efficacies approved for first-line treatment of advanced RCC. Therefore, it’s important to characterize patient survival time after treatment initiation,” Charlene Mantia, MD, a medical oncologist at Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School in Boston, Massachusetts, said during a presentation of the findings. “Over the 4-year period since first-line protocol therapy initiation, [patients treated with] nivolumab plus cabozantinib achieved a 1.5-times longer mean TFS vs sunitinib.”

CheckMate 9ER was an open-label study that enrolled patients with histologically confirmed untreated advanced or metastatic clear cell RCC who did not receive prior systemic therapy for RCC. However, treatment with 1 prior adjuvant or neoadjuvant therapy was permitted for patients with completely resectable disease if the agent was not VEGF-targeted and if recurrence occurred at least 6 months following treatment.

Patients were randomly assigned 1:1 to receive intravenous nivolumab 240 mg every 2 weeks in combination with oral cabozantinib 40 mg daily or sunitinib 50 mg daily for 4 weeks in 6-week cycles. Treatment in both arms continued until disease progression or unacceptable toxicity, and the maximum duration of nivolumab therapy was 2 years.

The primary end point was progression-free survival by blinded independent central review per RECIST 1.1 criteria. Secondary end points included OS, objective response rate, and safety.

In the ITT population, the baseline characteristics were well balanced between the combination and sunitinib arms; the median age was 62 years (range, 29-90) vs 61 years (range, 28-86), respectively. Most patients in both arms were not from North America or Europe (51.1% vs 50.9%), had a Karnofsky performance status (KPS) of 90 or 100 (79.6% vs 73.5%), underwent prior nephrectomy (68.7.% vs 71.0%), and had tumors without sarcomatoid features (89.1% vs 87.1%).

Additional findings from the TFS analysis showed that patients with IMDC favorable-risk disease in the combination (n = 74) and control (n = 72) arms achieved a 48-month mean TFS of 6.1 months vs 4.3 months, respectively, for a difference of 1.8 months (95% CI, –1.1 to 4.6). The mean OS during this time frame was 38.2 months in the nivolumab plus cabozantinib arm vs 38.6 months in the sunitinib arm. Patients spent a mean time of 25.2 months vs 19.9 months on protocol treatment, respectively.

Further, patients with IMDC intermediate- or poor-risk disease in the combination (n = 249) and sunitinib (n = 256) arms achieved a 48-month mean TFS of 7.2 months vs 4.7 months, respectively, for a difference of 2.5 months (95% CI, 0.8-4.3). The 48-month mean OS was 34.2 months vs 28.5 months, respectively, and patients spent a mean time of 21.8 months in the combination arm vs 12.5 months in the sunitinib arm on protocol treatment.

Results from a TFS subgroup analysis showed that the benefit with nivolumab plus cabozantinib vs sunitinib was observed across prespecified subgroups. The largest differences in 48-month mean TFS in favor of the combination were reported among patients with a KPS of 80 or less (5.3 months [95% CI, 2.1-8.5]), IMDC poor-risk disease (4.0 months [95% CI, 0.5-7.5]), and a PD-L1 expression of at least 1% (3.5 months [95% CI, 0.8-6.1]).

“Mean TFS differences were similarly longer for nivolumab plus cabozantinib vs sunitinib across most baseline subgroups analyzed,” Mantia said in conclusion. “TFS was more frequently observed after patients stopped therapy due to adverse effects, study drug toxicity, or prespecified other reasons with nivolumab plus cabozantinib vs sunitinib. We believe that future studies should continue to investigate the impact of having a defined treatment duration for patients. This partitioned OS analysis highlights important aspects of patient survival time that can be considered in making decisions when choosing a first-line treatment for patients.”

Mantia C, Jegede O, Viray H, et al. Partitioned overall survival: Comprehensive analysis of survival states over 4 years in CheckMate 9ER comparing first-line nivolumab plus cabozantinib versus sunitinib in advanced renal cell carcinoma (aRCC). 

 2024;42(suppl 16):4507. doi:10.1200/JCO.2024.42.16_suppl.4507

Powles T, Burotto M, Escudier B, et al. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. 

. 2024;9(5):102994. doi:10.1016/j.esmoop.2024.102994

A study of nivolumab combined with cabozantinib compared to sunitinib in previously untreated advanced or metastatic renal cell carcinoma (CheckMate 9ER). ClinicalTrials.gov. Updated January 17, 2024. Accessed June 4, 2024. https://clinicaltrials.gov/study/NCT03141177

Articles

Patients with advanced renal cell carcinoma (RCC) treated with nivolumab plus cabozantinib achieved longer treatment-free survival (TFS) and overall survival (OS) compared to those treated with sunitinib, according to the CheckMate 9ER trial. Over 48 months, the combination therapy showed a mean TFS of 7.0 months versus 4.6 months with sunitinib. The 48-month OS rates were 49.2% for the combination therapy versus 40.2% for sunitinib. The study highlights the importance of characterizing patient survival time post-treatment initiation for advanced RCC.

Partition overall survival data indicated that nivolumab plus cabozantinib extended treatment-free survival vs sunitinib in advanced renal cell carcinoma.

Nivolumab/Cabozantinib Combination Prolongs Treatment-Free Survival in Advanced RCC

Higher T-cell inflamed gene expression profile (GEP) values were positively associated with clinical outcomes for pembrolizumab (Keytruda) plus axitinib (Inlyta), and angiogenesis had a positive association with clinical outcomes for sunitinib (Sutent), in patients with clear cell renal cell carcinoma (RCC), according to an exploratory biomarker analysis of the phase 3 KEYNOTE-426 trial (NCT02853331) presented at the 

There was a significant positive association of a higher T-cell inflamed GEP with objective response rate (ORR; 

 < .0001), progression-free survival (PFS; 

 = .002) for pembrolizumab plus axitinib; there was no significant association of higher T-cell inflamed gene expression score with outcomes for sunitinib. Higher angiogenesis was positively associated with OS (P = .004) but not PFS or ORR for pembrolizumab/axitinib and was positively associated with ORR (

 < .0001) for sunitinib. Additionally, PD-L1 combined positive score (CPS) was negatively associated with OS (

 = .013) for sunitinib and not significant for the other outcome measures or with any outcome measures for the doublet therapy.

“PD-L1 continues to underperform as a biomarker in kidney cancer [and] was not associated with clinical outcomes for pembrolizumab plus axitinib,” Brian Rini, MD, said in a presentation of the data. “We saw an improved response rate across molecular subtypes for the combination regimen and, more interestingly, the highest response rate within the immune/proliferative subtype for pembrolizumab plus axitinib and the highest response rate within the angiogenetic subtype for sunitinib.”

Patients with angiogenesis below the median in the pembrolizumab plus axitinib arm (n = 190) experienced a median PFS of 15.2 months vs 9.5 months for those in the sunitinib arm (n = 175; HR, 0.62; 95% CI, 0.48-0.79); the median OS was 42.9 months vs 32.6 months, respectively (HR, 0.69; 95% CI, 0.54-0.89). In patients with angiogenesis at or above the median who received the combination therapy (n = 179) the median PFS was 18.0 months vs 15.0 months for those treated with sunitinib (n = 186; HR, 0.73; 95% CI, 0.57-0.94). The median OS was 57.6 months vs 54.2 months, respectively (HR, 0.94; 95% CI, 0.71-1.24).

The median PFS for patients with a low T-cell inflamed GEP in the pembrolizumab plus axitinib arm (n = 129) was 12.4 months compared with 16.3 months in the sunitinib arm (n = 114; HR, 0.91; 95% CI, 0.67-1.23); the median OS was 44.3 months vs 47.1 months, respectively (HR, 0.90; 95% CI, 0.65-1.23).
Among patients with a non-low T-cell inflamed GEP, those treated with pembrolizumab plus axitinib (n = 240) experienced a median PFS of 20.2 months vs 9.8 months for those given sunitinib (n = 247; HR, 0.58; 95% CI, 0.47-0.72). The median OS was 53.3 months compared with 40.8 months, respectively (HR, 0.77; 95% CI, 0.61-0.96).

Rini, who is chief of Clinical Trials, Ingram Professor of Cancer Research, and a professor of medicine at Vanderbilt Ingram Cancer Center in Nashville, Tennessee, also added that “Most importantly, additional correlative data is needed. We need to translate these findings and [conduct] prospective clinical investigations to turn these biomarkers into useful biomarkers to select treatment for patients.”

Enrollment Criteria and Baseline Patient Characteristics

KEYNOTE-426 enrolled patients with newly diagnosed or recurrent stage IV clear cell RCC who did not receive prior systemic treatment for advanced disease and stratified them by International Metastatic RCC Database Consortium (IMDC) risk group (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs rest of world). Patients who received at least 1 dose of treatment and had an evaluable RNA-sequencing or whole-exome sequencing sample were included in the biomarker-analysis. In KEYNOTE-426 patients were randomly assigned 1:1 to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles plus axitinib 5 mg twice daily or sunitinib 50 mg daily for the first 4 weeks of each 6-week cycle. The dose of axitinib could be increased to 7 mg then 10 mg twice daily if safety criteria were met and could also be reduced to 3 mg then 2 mg twice daily to manage toxicities; sunitinib could be decreased to 37.5 mg then 25 mg once daily for the first 4 weeks of each 6-week cycle.

Angiogenesis, 18-gene T-cell inflamed GEP, non-T-cell inflamed GEP signatures, and molecular clusters were evaluated via RNA sequencing. VHL, PBRM1, SETD2, and BAP1 were examined via whole-exome sequencing, and PD-L1 CPS was evaluated via the PD-L1 IHC 22C3 pharmDx assay. Rini noted that angiogenesis, 18-gene T-cell inflamed GEP, and PD-L1 CPS were the primary end points of the biomarker analysis.

“We used standard statistical methods to look at the association between each of these biomarkers and clinical outcomes both within and across the pembrolizumab/axitinib and sunitinib arms, importantly, with adjustment for IMDC criteria and adjustment for multiplicity. These translational data are based on the last clinical cutoff of the minimum 5-year follow-up—the most recent clinical data that have been presented,” Rini said.

Baseline characteristics were well balanced across the doublet and monotherapy arms for those who received whole-exome sequencing as well as RNA sequencing. The median age of those who received RNA sequencing was 62 years (IQR, 14) in the pembrolizumab plus axitinib arm (n = 369) and 61 years (IQR, 15) in the sunitinib arm (n = 361). Most patients were male (70.7% vs 74.5%), had intermediate/poor disease by IMDC risk category (69.9% vs 70.4%), and a PD-L1 CPS of at least 1 (61.2% vs 62.6%), respectively. Patients included in the biomarker analysis also had sarcomatoid features (12.5% vs 13.0%) and were enrolled in North America (25.5% vs 25.2%), Western Europe (27.1% vs 26.0%), and the rest of the world (47.4% vs 48.8%), respectively.

Additional Findings From the Biomarker Analysis

“Pembrolizumab/axitinib had a superior ORR over sunitinib across molecular subtypes,” Rini explained. “The angiogenic [subtype had] the least difference in response rates between the arms and that’s because that’s the molecular cluster in which sunitinib performed the best in terms of response rate. If you then look at cluster 4, you see the greatest difference between the arms and that’s because the pembrolizumab/axitinib response rate in this subset was nearly 80%. Differential response according to molecular cluster [is seen as well].”
Additionally, the only significant DNA result was seen with the PBRM1 subtype, according to Rini. The ORR for patients with mutated PBRM1 treated with the combination (n = 154) was 71.4% compared with 52.3% for those treated with sunitinib (n = 193; 

When examining non–T-cell inflamed GEP signatures and clinical outcomes without adjustment for T-cell inflamed GEP, investigators found that myeloid derived suppressor cell (MDSC), glycolysis, RAS, stomal/EMT/TGF-β, and WNT did not show significance in either treatment arm.

Rini explained that “There was some association with the MDSC signature and clinical outcomes in the pembrolizumab/axitinib arm. However, this was not significant after adjusting for the T-cell [inflamed] GEP. The other non–T-cell GEP signatures are generally not significant, although there were some negative associations between the MYC and proliferative subsets and some of the clinical outcomes in the sunitinib arm.”

Rini BI, Plimack ER, Stus V, et al. Biomarker analysis of the phase 3 KEYNOTE-426 study of pembrolizumab (P) plus axitinib (A) versus sunitinib (S) for advanced renal cell carcinoma (RCC). 

. 2024;42(suppl 16):4505. doi:10.1200/JCO.2024.42.16_suppl.4505

Higher T-cell inflamed gene expression profile (GEP) values correlate with better clinical outcomes for pembrolizumab plus axitinib in clear cell renal cell carcinoma (RCC). Angiogenesis is positively associated with clinical outcomes for sunitinib. The KEYNOTE-426 trial showed significant associations between higher T-cell inflamed GEP and improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for pembrolizumab/axitinib. Angiogenesis was linked to better OS for pembrolizumab/axitinib and improved ORR, PFS, and OS for sunitinib. PD-L1 combined positive score (CPS) was not a reliable biomarker for clinical outcomes.

Higher T-cell inflamed GEP values were positively associated with clinical outcomes for pembrolizumab plus axitinib in advanced clear cell RCC.

Higher T-Cell Inflamed GEP Values Are Positively Associated with Outcomes For Pembrolizumab/Axitinib in ccRCC

Treatment with lenvatinib (Lenvima) plus pembrolizumab (Keytruda) led to a trend towards later tumor progression in all organs vs sunitinib (Sutent) in patients with advanced renal cell carcinoma (RCC), according to findings from an analysis of the phase 3 CLEAR trial (NCT02811861) presented during the 

Findings from the analysis showed that the time to disease progression was favorable for patients who received the combination vs sunitinib among those with tumors of the bone (HR, 0.40; 95% CI, 0.25-0.63), central nervous system (CNS; HR, 0.47; 95% CI, 0.19-1.19), kidney (HR, 0.65; 95% CI, 0.37-1.14), liver (HR, 0.52; 95% CI, 0.32-0.84), lung (HR, 0.48; 95% CI, 0.36-0.62), and lymph nodes (HR, 0.63; 95% CI, 0.46-0.85). The median time to disease progression was not estimable (NE; 95% CI, NE-NE) in both arms of the bone, CNS, kidney, and liver tumor organ groups. In the lung tumor group, the median time to disease progression was 47.9 months (95% CI, 43.3-NE) in the combination arm vs 16.6 months (95% CI, 11.1-24.0) in the sunitinib arm; in the lymph node tumor subgroup, the median time to disease progression was NE (95% CI, 41.6-NE) vs NE (95% CI, 24.0-NE), respectively.

“Our analysis showed that the time to progression was later with the use of lenvatinib and pembrolizumab compared with sunitinib,” Viktor Grünwald, MD, PhD, professor of Interdisciplinary Genitourinary Oncology at the University Hospital Essen in Germany, said during a presentation of the findings. “Also, when we look at the overall disease progression pattern, meaning the analysis of the tumor burden at the time of tumor progression, we [saw] a larger fraction of patients who had a larger change [regarding tumor burden of target lesions] with lenvatinib and pembrolizumab at the time of progression than with sunitinib.”

CLEAR enrolled adult patients with treatment-naive advanced clear cell RCC. Eligible patients needed to have measurable disease, adequate organ function, and a Karnofsky performance score of at least 70. The primary end point was progression-free survival (PFS) by RECIST 1.1 criteria. Secondary end points included objective response rate (ORR), overall survival (OS), and safety.

Patients were randomly assigned 1:1:1 to receive lenvatinib 20 mg orally daily in 21-day cycles plus pembrolizumab 200 mg intravenously every 3 weeks on day 1 of each 21-day cycle, lenvatinib 18 mg orally daily plus oral everolimus (Afinitor) 5 mg daily, or sunitinib 50 mg orally daily for 4 weeks on and 2 weeks off.

Data from the final prespecified OS analysis of CLEAR demonstrated that the median OS in the lenvatinib plus pembrolizumab arm was 53.7 months (95% CI, 48.7-NE) vs 54.3 months (95% CI, 40.9-NE) in the sunitinib arm (HR, 0.79; 95% CI, 0.63-0.99; nominal 

 = .0424). The median PFS was 23.9 months (95% CI, 20.8-27.7) vs 9.2 months (95% CI, 6.0-11.0), respectively (HR, 0.47; 95% CI, 0.38-0.57; 

 < .0001). The ORRs were 71.3% (95% CI, 66.6%-76.0%) vs 36.7% (95% CI, 31.7%-41.7%), respectively, including respective complete response rates of 18.3% vs 4.8%.

Additional findings from the patterns of progression analysis demonstrated that the median change in sums of targeted lesions vs baseline in all patients who received lenvatinib plus pembrolizumab (n = 355) and sunitinib (n = 357) was –48.1% vs –17.4%, respectively. At baseline, the median sum of target lesions was 56.7 mm (range, 10.0-348.3) for those who received the combination vs 56.7 mm (range, 10.6-357.9) for those who received sunitinib. At progression, the median sum of target lesions was 29.8 mm (range, 0.0-301.9) vs 42.8 mm (range, 0.0-313.4), respectively.

During survival follow-up, 181 patients in the combination arm received a subsequent anticancer medication compared with 246 patients in the sunitinib arm; the median time to treatment discontinuation was 10.6 months vs 10.9 months, respectively. Seventy patients in the combination arm received cabozantinib (Cabometyx) as the first subsequent anticancer agent during follow-up compared with 25 patients in the sunitinib arm; the median time to cabozantinib discontinuation among these patients was 13.2 months vs 7.1 months, respectively. Axitinib (Inlyta) was given as the first subsequent therapy during follow-up to 20 patients vs 14 patients in the respective arms; the median time to axitinib discontinuation among these patients was 23.7 months vs 12.6 months, respectively.

“In the second-line analysis [on] the use of axitinib or cabozantinib, it appears that patients who were previously exposed to treatment with lenvatinib plus pembrolizumab had a longer time on those therapies than the group of patients who received sunitinib,” Grünwald said in conclusion. “Overall, our results continue to support the use of lenvatinib and pembrolizumab as a current standard treatment option in the first-line treatment of [patients with] kidney cancer.”

Grünwald V, Motzer RJ, Keizman D, et al. Lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in advanced renal cell carcinoma (aRCC): patterns of progression and subsequent therapy in the CLEAR trial. 

. 2024;42(suppl 16):4524. doi:10.1200/JCO.2024.42.16_suppl.4524

Motzer RJ, Porta C, Eto M, et al. Lenvatinib plus pembrolizumab versus sunitinib in first-line treatment of advanced renal cell carcinoma: final prespecified overall survival analysis of CLEAR, a phase III study. 

. 2024;42(11):1222-1228. doi:10.1200/JCO.23.01569

Lenvatinib/everolimus or lenvatinib/pembrolizumab versus sunitinib alone as treatment of advanced renal cell carcinoma (CLEAR). ClinicalTrials.gov. Updated July 10, 2023. Accessed June 4, 2024. 

https://classic.clinicaltrials.gov/ct2/show/NCT02811861

The combination of lenvatinib and pembrolizumab demonstrated a trend towards delayed tumor progression across various organs compared to sunitinib in advanced renal cell carcinoma (RCC) patients, as per the phase 3 CLEAR trial. The combination therapy showed favorable progression-free survival (PFS), overall survival (OS), and objective response rates (ORR). Additionally, patients treated with lenvatinib and pembrolizumab had a more significant reduction in tumor burden at progression and longer durations on subsequent therapies like cabozantinib and axitinib compared to those treated with sunitinib.

Lenvatinib/pembrolizumab offered a significant benefit in terms of time to disease progression in all organs vs sunitinib in advanced RCC.

Lenvatinib Plus Pembrolizumab Delays Tumor Progression in All Organs vs Sunitinib in Advanced RCC

Regardless of patient biomarker subtype, lenvatinib (Lenvima) plus pembrolizumab (Keytruda) produced greater clinical benefit vs sunitinib (Sutent) in advanced clear cell renal cell carcinoma (RCC) when the primary end point of progression-free survival (PFS) and secondary end point of objective response rate (ORR) of the phase 3 CLEAR trial (NCT02811861) were examined.

Findings from a biomarker analysis of CLEAR presented at the 

 revealed that PFS consistently favored lenvatinib plus pembrolizumab vs sunitinib regardless of mutation status of RCC driver genes. A PFS benefit was observed in patients with mutated 

 (HR, 0.48; 95% CI, 0.24-0.98),which were the most frequently mutated genes.

Additionally, patients with wild-type disease also experienced a PFS benefit with the combination vs sunitinib, including those with wild-type 

“We initially reported as part of the study [PFS by] PD-L1 immunohistochemistry [IHC] using the combined positive score [CPS] cutoff of 1 and at that time the benefit was consistent. But here we looked at PD-L1 [IHC CPS] as a continuous variable in the lenvatinib/pembrolizumab arm [n = 219; 

 = .2301] vs the sunitinib arm [n = 222; 

 = .0670] and there is no difference; we cannot use PD-L1 here to pick 1 treatment vs another,” Toni Choueiri, MD, said in a presentation of the findings. Choueiri is director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, co-leader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center, and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

Additionally, gene signature scores were not associated with PFS outcomes for the lenvatinib plus pembrolizumab arm. However, Choueiri noted that “when we look at single-agent sunitinib, not surprisingly, 2 out of 3 angiogenesis signatures—notably the angiogenesis (

 < .1)—were associated with better outcomes to the VEGF TKI sunitinib, and this is another validation, one of many. On the other hand, 2 other signatures—proliferation (

 < .1)—were associated with worse outcomes with sunitinib and worse prognosis.”

PFS by gene signature scores in each treatment arm were examined by 1 T-cell inflamed (GEP), 2 immuno-oncology (monocytic myeloid-derived suppressor cells and granulocytic myeloid-derived suppressor cells), 3 angiogenesis (angiogenesis, microvessel density, and Angio36), and 7 pan-cancer signatures. The signatures for pan-cancer were proliferation, 

, stroma/epithelial-mesenchymal transition/

Patients treated with combination of lenvatinib plus pembrolizumab also experienced a longer PFS vs sunitinib regardless of having a high or low signature. The most prominent benefit was reported in the angiogenesis-low (HR, 0.39; 95% CI, 0.27-0.57), GEP-low (HR, 0.41; 95% CI, 0.24-0.68), 

-high (HR, 0.42; 95% CI, 0.30-0.60), Angio36-low (HR, 0.44; 95% CI, 0.31-0.63), 

 -low (HR, 0.44; 95% CI, 0.30-0.64), and hypoxia-low (HR, 0.44; 95% CI, 0.30-0.65) subgroups.

“[Regarding] the primary end point of PFS, the combination is active irrespective of PD-L1 IHC. It’s active and improved PFS and response rates vs sunitinib regardless of RCC driver gene mutation status or gene signature subgroups,” Choueiri said.

CLEAR enrolled adult patients with advanced clear cell RCC who did not receive prior systemic anticancer therapy for RCC. Patients had a Karnofsky performance of at least 70 and were stratified by geographic region (Western Europe and North America vs rest of the world) and Memorial Sloan Kettering Cancer Center (MSKCC) risk category (favorable, intermediate, or poor). Patients were then randomly assigned 1:1 to receive lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 weeks vs lenvatinib 18 mg daily plus everolimus (Afinitor) 5 mg daily vs sunitinib 50 mg daily given for 4 weeks on and 2 weeks off. This biomarker analysis of the study solely focused on the lenvatinib plus pembrolizumab and sunitinib arms.

At baseline, PD-L1 expression was evaluated in 441 patients via the IHC pharmDx assay, gene alteration was evaluated in 380 patients via the whole-exome sequencing ImmunoID NeXT platform, and gene expression was evaluated in 388 patients via the RNA-sequencing ImmunoID NeXT platform.

“[When examining] the full analysis set [of] 355 [patients in] the combination [arm] and 357 [patients receiving] sunitinib and comparing it with the PD-L1, whole exome sequencing DNA,and RNA sequencing [analysis sets], there wasn’t a major difference in baseline characteristics [regarding] risk factor by MSKCC or International Metastatic RCC Database Consortium [(IMDC) criteria] or PD-L1 [CPS]. Even more importantly, when you look at activity in terms of PFS and response rate, there is also no difference between the total clinical set and the biomarker set.”

In the full analysis set, regarding clinical outcomes, patients achieved a median PFS of 23.9 months (95% CI, 20.8-27.7) in the lenvatinib plus pembrolizumab arm vs 9.2 months (95% CI, 6.0-11.0) in the sunitinib arm (HR, 0.48; 95% CI, 0.39-0.58). The ORR was 71% vs 37%, respectively. Additionally, by MSKCC risk evaluation, patients had favorable- (27%), intermediate- (64%), and poor- (9%) risk disease in both the lenvatinib plus pembrolizumab and sunitinib arms. By IMDC risk evaluation, patients had favorable- (31% vs 35%), intermediate- (59% vs 54%), and poor- (9% vs 10%) risk disease in the combination vs sunitinib arms, respectively. Patients had a PD-L1 CPS less than 1 (32% vs 29%), 1 or greater (30% vs 33%), or not available (38% vs 38%), respectively.

Trends observed with ORR were similar to those seen with PFS, as the ORR was higher for the combination vs sunitinib irrespective of the 5 gene mutations examined and gene signatures across high/low subgroups.

Lenvatinib plus pembrolizumab led to a superior ORR vs sunitinib among patients with mutated

(85.7% vs 37.9%), respectively. The ORRs also favored the combination vs sunitinib in patients with wild-type 

Molecular subtypes included in the CLEAR analysis were informed by analyses of RCC datasets from Merck as well as analyses of the phase 3 JAVELIN Renal 101 study (NCT02684006) and phase 3 IMmotion 151 study (NCT02420821), which Choueiri noted were both examining VEGF/immunotherapy combinations vs sunitinib.

“Tumors of patients with IMDC favorable- and intermediate- risk [disease] were enriched in the angiogenesis and angiogenesis/stromal clusters,” Choueiri highlighted. “On the other hand, the poor-risk [tumors] were enriched in the proliferative cluster and [tumors that were] PD-L1–positive were enriched in the immune proliferative cluster. But does that mean that the combination of lenvatinib/pembrolizumab would be better in some clusters or perhaps the same as sunitinib? The answer is no. Looking at response rates, PFS, and this RCC specific cluster signature, the combination of lenvatinib/pembrolizumab remains superior to sunitinib in all the clusters tested.”

Across all molecular subtype clusters, the median PFS in the combination arm (n = 192) was 24.3 months (95% CI, 18.6-28.6) compared with 9.4 months (95% CI, 6.0-11.1) in the sunitinib arm (n = 196). Numerically higher tumor responses and longer PFS were observed across all 5 molecular subtypes: angiogenesis/stromal, angiogenesis, immune/proliferative, proliferative, and stromal/proliferative.

“The combination of lenvatinib/pembrolizumab showed clinical benefit over sunitinib in patients with first-line advanced clear cell RCC regardless of all the biomarkers we tested; this is the first test,” Choueiri said. “PFS analysis confirmed the superiority of the combination irrespective of PD-L1 IHC. When we look at the top gene mutations [and] the signature the [results show the] same [trend] whether the signatures are cancer signatures in general or kidney cancer-specific molecular subtypes.”

Motzer RJ, Porta C, Eto M, et al. Biomarker analyses in patients with advanced renal cell carcinoma (aRCC) from the phase 3 CLEAR trial. 

. 2024;42(suppl 16):4504. doi:10.1200/JCO.2024.42.16_suppl.4504

Lenvatinib plus pembrolizumab demonstrated superior clinical benefits over sunitinib in advanced clear cell renal cell carcinoma (RCC) across various biomarker subtypes, as evidenced by the phase 3 CLEAR trial. Progression-free survival (PFS) and objective response rate (ORR) were consistently better with the combination therapy, regardless of RCC driver gene mutations or gene signature subgroups. PD-L1 immunohistochemistry and gene signature scores did not significantly influence outcomes, reinforcing the combination's efficacy across diverse patient profiles.

Lenvatinib plus pembrolizumab displayed a superior clinical benefit vs sunitinib irrespective of patient biomarker subtype in advanced clear cell RCC.

Lenvatinib/Pembrolizumab Yields Greater Clinical Benefit vs Sunitinib Regardless of Biomarker Subtypes in ccRCC 

Pre-treatment levels of CD8-positive, PD-1-positive, TIM3-negative, and LAG3-negative tumor infiltrating lymphocytes (TILs) were not associated with improved clinical outcomes for patients with metastatic clear cell renal cell carcinoma (RCC) treated with nivolumab (Opdivo) and ipilimumab (Yervoy), according to a post-hoc analysis of the phase 3 CheckMate-214 trial (NCT02231749) presented at the 

Among patients with intermediate- and poor-risk disease and available multiplex immunofluorescence (mIF) data treated with nivolumab plus ipilimumab (n = 136), the density of CD8-positive, PD-1-positive, TIM3-negative, and LAG3-negative TILs measured as continuous variable showed a trend for a positive association with overall response rate ORR (ORR; OR, 1.23; 

 = .1162). However, there was no association observed regarding progression-free survival (PFS; HR, 0.97; 

Additionally, in patients with available mIF data who received sunitinib (Sutent) in CheckMate-214 (n = 119) the density of CD8-positive, PD-1-positive, TIM3-negative, and LAG3-negative TILs measured as continuous variable showed a trend for a positive association with ORR (OR, 1.32; 

 = .0726) and a significant positive association with PFS (HR = 0.78, 

However, lead study author Sayed Matar, MBBChB, a postdoctoral research fellow at Brigham and Women’s Hospital in Boston Massachusetts, and colleagues noted in a poster presentation of the data that “Given that [patients treated with] sunitinib with available mIF data were enriched for responders, results obtained in the sunitinib group should be interpreted with caution.” They added that the association between outcomes and CD8-positive, PD-1-positive, TIM3-negative, and LAG3-negative TILs with sunitinib treatment require further investigation.

“These results suggest that the baseline levels of intratumoral T-cell inflammation do not represent a strong determinant of response to anti-CTLA4-based therapy in metastatic clear cell RCC, which is consistent with the knowledge that anti-CTLA4 therapy [ipilimumab] can recruit new T cells into the tumor,” Matar and coauthors added.

Efficacy data from CheckMate-214 previously presented at the 

 demonstrated that patients treated with nivolumab plus ipilimumab (n = 550) experienced a median overall survival (OS) of 52.7 months (95% CI, 45.8-64.5) vs 37.8 months (95% CI, 31.9-43.8) among those who received with sunitinib (n = 546; HR, 0.72; 95% CI, 0.62-0.83) at a median follow-up of 8 years. The ORRs were 39% (95% CI, 35%-44%) compared with 33% (95% CI, 29%-37%), respectively.

To conduct the current analysis of the performance of CD8-positive, PD-1-positive, TIM3-negative, and LAG3-negative TILs as a biomarker of response to nivolumab/ipilimumab combination therapy in CheckMate-214, pre-treatment, formalin fixed paraffin embedded tumor samples from the trial were stained with an mIF assay. A Vectra 3 Automated Quantitative Pathology Imaging System was used to perform the multispectral scanning. Additionally, IF signals were unmixed using InForm V.2.4.2 software and Halo image was used to measure the density of CD8-positive, PD-1-positive, TIM3-negative, and LAG3-negative TIL. Cox proportional hazards and logistic regression models with a significance level set at 5% (2-sided) were used to evaluate the correlation between outcomes and CD8-positive, PD-1-positive, TIM3-negative, and LAG3-negative TIL density.

Additional findings revealed that patients who received sunitinib achieved a higher ORR vs patients without available data, at 33% vs 24%, respectively. Investigators noted that in the nivolumab plus ipilimumab combination arm, there was no imbalance regarding ORR or PFS when comparing patients with available data with those without.

Disclosures: Dr Matar did not have relationships to disclose.

Matar S, Jegede O, Denize T, et al. Intratumoral T-cell infiltration and response to nivolumab plus ipilimumab in patients with metastatic clear cell renal cell carcinoma from the CheckMate-214 trial. 

. 2024;42(suppl 16):4536. doi:10.1200/JCO.2024.42.16_suppl.4536

Tannir NM, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab (NIVO+IPI) vs sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC): Long-term follow-up data from the phase 3 CheckMate 214 trial. 

. 2024;42(suppl 4):363. doi:10.1200/JCO.2024.42.4_suppl.363

Pre-treatment levels of CD8-positive, PD-1-positive, TIM3-negative, and LAG3-negative TILs were not linked to improved clinical outcomes in metastatic clear cell RCC patients treated with nivolumab and ipilimumab. While a trend for a positive association with ORR was observed, no significant correlation with PFS was found. Conversely, in patients treated with sunitinib, these TILs showed a significant positive association with PFS. The findings suggest that baseline intratumoral T-cell inflammation is not a strong predictor of response to anti-CTLA4-based therapy in this patient population.

Using CD8-positive, PD-1-positive, TIM3-negative, and LAG3-negative TILs as a biomarker was not associated with improved clinical outcomes for patients with mccRCC treated with nivolumab plus ipilimumab.

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