Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.

BACKGROUND: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy. CONCLUSIONS: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

Impact of renal cell carcinoma molecular subtypes on immunotherapy and targeted therapy outcomes.

Saliby et al. show that a machine learning approach can accurately classify clear cell renal cell carcinoma (RCC) into distinct molecular subtypes using transcriptomic data. When applied to tumors biospecimens from the JAVELIN Renal 101 (JR101) trial, a benefit is observed with immune checkpoint inhibitor (ICI)-based therapy across all molecular subtypes.

Characterization of Responses to Lenvatinib plus Pembrolizumab in Patients with Advanced Renal Cell Carcinoma at the Final Prespecified Survival Analysis of the Phase 3 CLEAR Study.

In the phase 3 CLEAR trial, lenvatinib plus pembrolizumab (L + P) showed superior efficacy versus sunitinib in treatment-naïve patients with advanced renal cell carcinoma (aRCC). The combination treatment was associated with a robust objective response rate of 71%. Here we report tumor responses for patients in the L + P arm in CLEAR, with median follow-up of ∼4 yr at the final prespecified overall survival (OS) analysis. Tumor responses were assessed by independent review using Response Evaluation Criteria in Solid Tumors v1.1. Patients with a complete response (CR; n = 65), partial response (PR) with maximum tumor shrinkage ≥75% (near-CR; n = 59), or PR with maximum tumor shrinkage <75% (other PR; n = 129), were characterized in terms of their baseline characteristics. The median duration of response was 43.7 mo (95% confidence interval [CI] 39.2-not estimable) for the CR group, 30.5 mo (95% CI 22.4-not estimable) for the near-CR group, and 17.2 mo (95% CI 12.5-21.4) for the other PR group. The 36-mo OS rates were consistently high in the CR (97%), near-CR (86%), and other PR (62%) groups. Robust objective response rates were observed across International Metastatic RCC Database Consortium favorable-risk (69%, 95% CI 60-78%), intermediate-risk (73%, 95% CI 67-79%), and poor-risk (70%, 95% CI 54-85%) subgroups. The robust response to L + P supports this combination as a standard-of-care first-line treatment for patients with aRCC. PATIENT SUMMARY: The CLEAR trial enrolled patients with advanced kidney cancer who had not previously received any treatment for their cancer. Here we report results for tumor shrinkage observed in the group that received lenvatinib plus pembrolizumab combination treatment during the trial. Shrinkage of target tumors with this combination was long-lasting and was observed in patients irrespective of their disease severity. This trial is registered on ClinicalTrials.gov as NCT02811861.

Impact of smoking status on clinical outcomes in patients with metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based regimens.

BACKGROUND: Current tobacco smoking is independently associated with decreased overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) treated with targeted monotherapy (VEGF-TKI). Herein, we assess the influence of smoking status on the outcomes of patients with mRCC treated with the current first-line standard of care of immune checkpoint inhibitor (ICI)-based regimens. MATERIALS AND METHODS: Real-world data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were collected retrospectively. Patients with mRCC who received either dual ICI therapy or ICI with VEGF-TKI in the first-line setting were included and were categorized as current, former, or nonsmokers. The primary outcomes were OS, time to treatment failure (TTF), and objective response rate (ORR). OS and TTF were compared between groups using the log-rank test and multivariable Cox regression models. ORR was assessed between the 3 groups using a multivariable logistic regression model. RESULTS: A total of 989 eligible patients were included in the analysis, with 438 (44.3%) nonsmokers, 415 (42%) former, and 136 (13.7%) current smokers. Former smokers were older and included more males, while other baseline characteristics were comparable between groups. Median follow-up for OS was 21.2 months. In the univariate analysis, a significant difference between groups was observed for OS (P = .027) but not for TTF (P = .9), with current smokers having the worse 2-year OS rate (62.8% vs 70.8% and 73.1% in never and former smokers, respectively). After adjusting for potential confounders, no significant differences in OS or TTF were observed among the 3 groups. However, former smokers demonstrated a higher ORR compared to never smokers (OR 1.45, P = .02). CONCLUSION: Smoking status does not appear to independently influence the clinical outcomes to first-line ICI-based regimens in patients with mRCC. Nonetheless, patient counseling on tobacco cessation remains a crucial aspect of managing patients with mRCC, as it significantly reduces all-cause mortality.

Clinical outcomes and safety of immune checkpoint inhibitors in patients with solid tumors and paraneoplastic syndromes.

BACKGROUND: Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce. METHODS: In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT). RESULTS: Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58-74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7-3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4-3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS. CONCLUSIONS: Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.

Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects.

One of the major hurdles that has hindered the success of chimeric antigen receptor (CAR) T cell therapies against solid tumors is on-target off-tumor (OTOT) toxicity due to sharing of the same epitopes on normal tissues. To elevate the safety profile of CAR-T cells, an affinity/avidity fine-tuned CAR was designed enabling CAR-T cell activation only in the presence of a highly expressed tumor associated antigen (TAA) but not when recognizing the same antigen at a physiological level on healthy cells. Using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution, and flow cytometry, we identified high carbonic anhydrase IX (CAIX) density on clear cell renal cell carcinoma (ccRCC) patient samples and low-density expression on healthy bile duct tissues. A Tet-On doxycycline-inducible CAIX expressing cell line was established to mimic various CAIX densities, providing coverage from CAIX-high skrc-59 tumor cells to CAIX-low MMNK-1 cholangiocytes. Assessing the killing of CAR-T cells, we demonstrated that low-affinity/high-avidity fine-tuned G9 CAR-T has a wider therapeutic window compared to high-affinity/high-avidity G250 that was used in the first anti-CAIX CAR-T clinical trial but displayed serious OTOT effects. To assess the therapeutic effect of G9 on patient samples, we generated ccRCC patient derived organotypic tumor spheroid (PDOTS) ex vivo cultures and demonstrated that G9 CAR-T cells exhibited superior efficacy, migration and cytokine release in these miniature tumors. Moreover, in an RCC orthotopic mouse model, G9 CAR-T cells showed enhanced tumor control compared to G250. In summary, G9 has successfully mitigated OTOT side effects and in doing so has made CAIX a druggable immunotherapeutic target.

Integrative Analysis of Germline Rare Variants in Clear and Non-clear Cell Renal Cell Carcinoma.

Background and objective: Previous germline studies on renal cell carcinoma (RCC) have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification, which might have led to an inaccurate estimation of genetic risk. Here, we aim to analyze the major germline drivers of RCC risk and clinically relevant but underexplored germline variant types. Methods: We first characterized germline pathogenic variants (PVs), cryptic splice variants, and copy number variants (CNVs) in 1436 unselected RCC patients. To evaluate the enrichment of PVs in RCC, we conducted a case-control study of 1356 RCC patients ancestry matched with 16 512 cancer-free controls using approaches accounting for population stratification and histological subtypes, followed by characterization of secondary somatic events. Key findings and limitations: Clear cell RCC patients (n = 976) exhibited a significant burden of PVs in VHL compared with controls (odds ratio [OR]: 39.1, p = 4.95e-05). Non-clear cell RCC patients (n = 380) carried enrichment of PVs in FH (OR: 77.9, p = 1.55e-08) and MET (OR: 1.98e11, p = 2.07e-05). In a CHEK2-focused analysis with European participants, clear cell RCC (n = 906) harbored nominal enrichment of low-penetrance CHEK2 variants-p.Ile157Thr (OR: 1.84, p = 0.049) and p.Ser428Phe (OR: 5.20, p = 0.045), while non-clear cell RCC (n = 295) exhibited nominal enrichment of CHEK2 loss of function PVs (OR: 3.51, p = 0.033). Patients with germline PVs in FH, MET, and VHL exhibited significantly earlier age of cancer onset than patients without germline PVs (mean: 46.0 vs 60.2 yr, p < 0.0001), and more than half had secondary somatic events affecting the same gene (n = 10/15, 66.7%). Conversely, CHEK2 PV carriers exhibited a similar age of onset to patients without germline PVs (mean: 60.1 vs 60.2 yr, p = 0.99), and only 30.4% carried somatic events in CHEK2 (n = 7/23). Finally, pathogenic germline cryptic splice variants were identified in SDHA and TSC1, and pathogenic germline CNVs were found in 18 patients, including CNVs in FH, SDHA, and VHL. Conclusions and clinical implications: This analysis supports the existing link between several RCC risk genes and RCC risk manifesting in earlier age of onset. It calls for caution when assessing the role of CHEK2 due to the burden of founder variants with varying population frequency. It also broadens the definition of the RCC germline landscape of pathogenicity to incorporate previously understudied types of germline variants. Patient summary: In this study, we carefully compared the frequency of rare inherited mutations with a focus on patients' genetic ancestry. We discovered that subtle variations in genetic background may confound a case-control analysis, especially in evaluating the cancer risk associated with specific genes, such as CHEK2. We also identified previously less explored forms of rare inherited mutations, which could potentially increase the risk of kidney cancer.

Clinical Outcomes Among Immunotherapy-Treated Patients With Primary Cardiac Soft Tissue Sarcomas: A Multicenter Retrospective Study.

Background: Primary cardiac soft tissue sarcomas (CSTS) affect young adults, with dismal outcomes. Objectives: The aim of this study was to investigate the clinical outcomes of patients with CSTS receiving immune checkpoint inhibitors (ICIs). Methods: A retrospective, multi-institutional cohort study was conducted among patients with CSTS between 2015 and 2022. The patients were treated with ICI-based regimens. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates were determined according to Response Evaluation Criteria in Solid Tumors version 1.1. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events version 5.0. Results: Among 24 patients with CSTS, 17 (70.8%) were White, and 13 (54.2%) were male. Eight patients (33.3%) had angiosarcoma. At the time of ICI treatment, 18 patients (75.0%) had metastatic CSTS, and 4 (16.7%) had locally advanced disease. ICIs were administered as the first-line therapy in 6 patients (25.0%) and as the second-line therapy or beyond in 18 patients (75.0%). For the 18 patients with available response data, objective response rate was 11.1% (n = 2 of 18). The median PFS and median OS in advanced and metastatic CSTS (n = 22) were 5.7 months (95% CI: 2.8-13.3 months) and 14.9 months (95% CI: 5.7-23.7 months), respectively. The median PFS and OS were significantly shorter in patients with cardiac angiosarcomas than in those with nonangiosarcoma CSTS: median PFS was 1.7 vs 11 months, respectively (P < 0.0001), and median OS was 3.0 vs 24.0 months, respectively (P = 0.008). Any grade treatment-related adverse events occurred exclusively in the 15 patients with nonangiosarcoma CSTS (n = 7 [46.7%]), of which 6 (40.0%) were grade ≥3. Conclusions: Although ICIs demonstrate modest activity in CSTS, durable benefit was observed in a subset of patients with nonangiosarcoma, albeit with higher toxicity.

Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma.

The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and an abundance of innate immune subsets in the A+Ax arm. Treatment with A+Ax led to greater T-cell repertoire modulation and less change in T-cell numbers versus sunitinib. In the A+Ax arm, patients with tumors harboring mutations in ≥2 of 10 previously identified PFS-associated genes (double mutants) had distinct circulating and tumor-infiltrating immunologic profiles versus those with wild-type or single-mutant tumors, suggesting a role for non-T-cell-mediated and non-natural killer cell-mediated mechanisms in double-mutant tumors. We provide evidence for different immunomodulatory mechanisms based on treatment (A+Ax vs. sunitinib) and tumor molecular subtypes. SIGNIFICANCE: Our findings provide novel insights into the different immunomodulatory mechanisms governing responses in patients treated with avelumab (PD-L1 inhibitor) + axitinib or sunitinib (both VEGF inhibitors), highlighting the contribution of tumor biology to the complexity of the roles and interactions of infiltrating immune cells in response to these treatment regimens. This article is featured in Selected Articles from This Issue, p. 384.

Comparison of outcomes for Hispanic and non-Hispanic patients with advanced renal cell carcinoma in the International Metastatic Renal Cell Carcinoma Database.

BACKGROUND: Existing data on the impact of Hispanic ethnicity on outcomes for patients with renal cell carcinoma (RCC) is mixed. The authors investigated outcomes of Hispanic and non-Hispanic White (NHW) patients with advanced RCC receiving systemic therapy at large academic cancer centers using the International Metastatic Renal Cell Carcinoma Database (IMDC). METHODS: Eligible patients included non-Black Hispanic and NHW patients with locally advanced or metastatic RCC initiating systemic therapy. Overall survival (OS) and time to first-line treatment failure (TTF) were calculated using the Kaplan-Meier method. The effect of ethnicity on OS and TTF were estimated by Cox regression hazard ratios (HRs). RESULTS: A total of 1563 patients (181 Hispanic and 1382 NHW) (mostly males [73.8%] with clear cell RCC [81.5%] treated with tyrosine kinase inhibitor [TKI] monotherapy [69.9%]) were included. IMDC risk groups were similar between groups. Hispanic patients were younger at initial diagnosis (median 57 vs. 59 years, p = .015) and less likely to have greater than one metastatic site (60.8% vs. 76.8%, p < .001) or bone metastases (23.8% vs. 33.4%, p = .009). Median OS and TTF was 38.0 months (95% confidence interval [CI], 28.1-59.2) versus 35.7 months (95% CI, 31.9-39.2) and 7.8 months (95% CI, 6.2-9.0) versus 7.5 months (95% CI, 6.9-8.1), respectively, in Hispanic versus NHW patients. In multivariable Cox regression analysis, no statistically significant differences were observed in OS (adjusted hazard ratio [HR], 1.07; 95% CI, 0.86-1.31, p = .56) or TTF (adjusted HR, 1.06; 95% CI, 0.89-1.26, p = .50). CONCLUSIONS: The authors did not observe statistically significant differences in OS or TTF between Hispanic and NHW patients with advanced RCC. Receiving treatment at tertiary cancer centers may mitigate observed disparities in cancer outcomes.

NCCN Guidelines® Insights: Kidney Cancer, Version 2.2024.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with advanced RCC and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Kidney Cancer.

Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model.

One of the major barriers that have restricted successful use of chimeric antigen receptor (CAR) T cells in the treatment of solid tumors is an unfavorable tumor microenvironment (TME). We engineered CAR-T cells targeting carbonic anhydrase IX (CAIX) to secrete anti-PD-L1 monoclonal antibody (mAb), termed immune-restoring (IR) CAR G36-PDL1. We tested CAR-T cells in a humanized clear cell renal cell carcinoma (ccRCC) orthotopic mouse model with reconstituted human leukocyte antigen (HLA) partially matched human leukocytes derived from fetal CD34+ hematopoietic stem cells (HSCs) and bearing human ccRCC skrc-59 cells under the kidney capsule. G36-PDL1 CAR-T cells, haploidentical to the tumor cells, had a potent antitumor effect compared to those without immune-restoring effect. Analysis of the TME revealed that G36-PDL1 CAR-T cells restored active antitumor immunity by promoting tumor-killing cytotoxicity, reducing immunosuppressive cell components such as M2 macrophages and exhausted CD8+ T cells, and enhancing T follicular helper (Tfh)-B cell crosstalk.

Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients.

BACKGROUND: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. METHODS: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. RESULTS: Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. CONCLUSIONS: This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

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.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final prespecified overall survival (OS) analysis of the open-label, phase III CLEAR study in treatment-naïve patients with advanced renal cell carcinoma (aRCC). With an additional follow-up of 23 months from the primary analysis, we report results from the lenvatinib plus pembrolizumab versus sunitinib comparison of CLEAR. Treatment-naïve patients with aRCC were randomly assigned to receive lenvatinib (20 mg orally once daily in 21-day cycles) plus pembrolizumab (200 mg intravenously once every 3 weeks) or sunitinib (50 mg orally once daily [4 weeks on/2 weeks off]). At this data cutoff date (July 31, 2022), the OS hazard ratio (HR) was 0.79 (95% CI, 0.63 to 0.99). The median OS (95% CI) was 53.7 months (95% CI, 48.7 to not estimable [NE]) with lenvatinib plus pembrolizumab versus 54.3 months (95% CI, 40.9 to NE) with sunitinib; 36-month OS rates (95% CI) were 66.4% (95% CI, 61.1 to 71.2) and 60.2% (95% CI, 54.6 to 65.2), respectively. The median progression-free survival (95% CI) was 23.9 months (95% CI, 20.8 to 27.7) with lenvatinib plus pembrolizumab and 9.2 months (95% CI, 6.0 to 11.0) with sunitinib (HR, 0.47 [95% CI, 0.38 to 0.57]). Objective response rate also favored the combination over sunitinib (71.3% v 36.7%; relative risk 1.94 [95% CI, 1.67 to 2.26]). Treatment-emergent adverse events occurred in >90% of patients who received either treatment. In conclusion, lenvatinib plus pembrolizumab achieved consistent, durable benefit with a manageable safety profile in treatment-naïve patients with aRCC.

Outcomes of Patients with Brain Metastases from Renal Cell Carcinoma Receiving First-line Therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Patients with brain metastases (BrM) from renal cell carcinoma and their outcomes are not well characterized owing to frequent exclusion of this population from clinical trials. We analyzed data for patients with or without BrM using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). A total of 389/4799 patients (8.1%) had BrM on initiation of systemic therapy. First-line immuno-oncology (IO)-based combination therapy was associated with longer median overall survival (OS; 32.7 mo, 95% confidence interval [CI] 22.3-not reached) versus tyrosine kinase inhibitor monotherapy (20.6 mo, 95% CI 15.7-24.5; p = 0.019), as were intensive focal therapies with stereotactic radiotherapy or neurosurgery (31.4 mo, 95% CI 22.3-37.5) versus whole-brain radiotherapy alone or no focal therapy (16.5 mo, 95% CI 10.2-21.1; p = 0.028). On multivariable analysis, IO-based regimens (HR 0.49, 95% CI 0.25-0.97; p = 0.040) and stereotactic radiotherapy or neurosurgery (HR 0.48, 95% CI 0.29-0.78; p = 0.003) were independently associated with longer OS, as was IMDC favorable or intermediate risk (HR 0.40, 95% CI 0.24-0.66; p < 0.001). Intensive systemic and focal therapies were associated with better prognosis in this population. Further studies should explore the clinical effectiveness of multimodal strategies. PATIENT SUMMARY: In a large group of patients with advanced kidney cancer, we found that 8.1% had brain metastases when starting systemic therapy. Patients with brain metastases had significantly poorer prognosis than those without brain metastases. Receipt of combination immunotherapy, stereotactic radiotherapy, or neurosurgery was associated with longer overall survival.

The Relationship Between Health-Related Quality of Life and Overall Survival in Patients With Advanced Renal Cell Carcinoma in CheckMate 214.

BACKGROUND: In CheckMate 214 (median follow-up, 25.2 months), nivolumab plus ipilimumab yielded greater overall survival (OS) benefit than sunitinib in patients with intermediate-/poor-risk advanced renal cell carcinoma (aRCC). Health-related quality of life (HRQoL) assessed by the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19) was also more favorable for the nivolumab plus ipilimumab group than the sunitinib group. We investigated whether HRQoL scores can predict OS of patients with 5 years follow-up in CheckMate 214. PATIENTS AND METHODS: CheckMate 214 was an open-label, phase III trial in previously untreated aRCC (N = 1096). Patients with intermediate-/poor-risk disease (International mRCC Database Consortium prognostic score ≥ 1; n = 847) were randomized to either nivolumab plus ipilimumab or sunitinib monotherapy. Pooled data for OS and FKSI-19 total and subscales (disease-related symptoms [DRS], DRS-physical [DRS-P], and function/well-being [FWB]) were analyzed. Relationships between HRQoL and OS were assessed using Cox proportional hazard models with baseline and longitudinal scores. Associations between HRQoL changes and OS were assessed by landmark analyses. RESULTS: Patients with higher FKSI-19 total and subscale scores at baseline had longer OS than patients with lower scores (HR ≤ 0.834; P < .0001). Longitudinal models indicated stronger associations between HRQoL and OS (HR ≤ 0.69; P < .001 for each). At 3 months after randomization, patients with stable/improved HRQoL versus baseline had longer median OS than patients with worsened/unobserved HRQoL versus baseline (55.9 and 26.0 months, respectively; HR = 0.56; 95% CI, 0.46-0.67; P < .0001). Results at 6-, 9-, and 12-month landmarks were consistent with these findings. CONCLUSION: In aRCC, patient-reported outcomes are important for HRQoL and prognostic evaluation. CLINICALTRIALS.GOV IDENTIFIER: NCT02231749; https://clinicaltrials.gov/ct2/show/NCT02231749.

PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients.

PURPOSE: Programmed cell death protein 1 (PD-1) expression on CD8+TIM-3-LAG-3- tumor-infiltrating cells predicts positive response to PD-1 blockade in metastatic clear-cell renal cell carcinoma (mccRCC). Because inhibition of PD-1 signaling in regulatory T cells (Treg) augments their immunosuppressive function, we hypothesized that PD-1 expression on tumor-infiltrating Tregs would predict resistance to PD-1 inhibitors. EXPERIMENTAL DESIGN: PD-1+ Tregs were phenotyped using multiparametric immunofluorescence in ccRCC tissues from the CheckMate-025 trial (nivolumab: n = 91; everolimus: n = 90). Expression of CD8, PD-1, TIM-3, and LAG-3 was previously determined (Ficial and colleagues, 2021). Clinical endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). RESULTS: In the nivolumab (but not everolimus) arm, high percentage of PD-1+ Tregs was associated with shorter PFS (3.19 vs. 5.78 months; P = 0.021), shorter OS (18.1 vs. 27.7 months; P = 0.013) and marginally lower ORR (12.5% vs. 31.3%; P = 0.059). An integrated biomarker (PD-1 Treg/CD8 ratio) was developed by calculating the ratio between percentage of PD-1+Tregs (marker of resistance) and percentage of CD8+PD-1+TIM-3-LAG-3- cells (marker of response). In the nivolumab (but not everolimus) arm, patients with high PD-1 Treg/CD8 ratio experienced shorter PFS (3.48 vs. 9.23 months; P < 0.001), shorter OS (18.14 vs. 38.21 months; P < 0.001), and lower ORR (15.69% vs. 40.00%; P = 0.009). Compared with the individual biomarkers, the PD-1 Treg/CD8 ratio showed improved ability to predict outcomes to nivolumab versus everolimus. CONCLUSIONS: PD-1 expression on Tregs is associated with resistance to PD-1 blockade in mccRCC, suggesting that targeting Tregs may synergize with PD-1 inhibition. A model that integrates PD-1 expression on Tregs and CD8+TIM-3-LAG-3- cells has higher predictive value.

The 5th Kidney Cancer Research Summit: Research Accelerating Cures for Renal Cell Carcinoma in 2023.

The 5th Kidney Cancer Research Summit was a hybrid event hosted in Boston, MA in July 2023. As in previous editions, the conference attracted a wide representation of global thought leaders in kidney cancer spanning all stages of clinical and laboratory research. Sessions covered tumor metabolism, novel immune pathways, advances in clinical trials and immunotherapy, and progress toward biomarkers. The abstract presentations were published as a supplement in The Oncologist (https://academic.oup.com/oncolo/issue/28/Supplement_1). Aiming to be more concise than comprehensive, this commentary summarizes the most important emerging areas of kidney cancer research discussed and debated among the stakeholders at the conference, with relevant updates that have occurred since.