Sumanta Pal, MD, FASCO, explained the rationale for evaluating atezolizumab vs placebo for the treatment of patients with high-risk localized RCC.

Dr Pal on the Rationale for Evaluating Atezolizumab in High-Risk Localized RCC

“The IMmotion010 study is a randomized phase 3 trial comparing atezolizumab [with] placebo in patients at high risk for recurrence with high-risk localized kidney cancer. In this particular trial, there weren’t any improvements seen in disease-free survival with atezolizumab.”

Sumanta Pal, MD, FASCO, the codirector of the Kidney Cancer Program and a professor in the Department of Medical Oncology & Therapeutics Research at the City of Hope, detailed the design of the phase 3 IMmotion010 trial (NCT03024996) that evaluated adjuvant atezolizumab (Tecentriq) compared with placebo for the treatment of patients with high-risk localized renal cell carcinoma (RCC).

Patients included in the IMmotion010 analysis all had high-risk localized RCC, Pal began. Specifically, patients included on the study had T2 grade 4 disease, T3a grade 3/4 disease, T3b/c or T4 any-grade disease, and M1 with no evidence of disease. Patients included on the study also had a clear cell histology and/or a sarcomatoid component. Patients were then stratified based on their disease stage, PD-L1 expression on tumor-infiltrating immune cells, and geographical region. Patients who were enrolled (n = 778) were randomly assigned 1:1 to be treated with either atezolizumab at 1200 mg intravenously every 3 weeks for 16 cycles or 1 year or placebo every 3 weeks for 16 cycles or 1 year.

Results from the trial revealed that there were no improvements regarding disease-free survival with atezolizumab compared with placebo, Pal continued. Nevertheless, data from the study were valuable, particularly those stemming from the specimens that were collected, he asserted. At baseline, there were specimens derived from tissue, and blood samples were also collected at baseline as well as the time of recurrence, he explained. Previous data from the study suggested that KIM-1 is a unique biomarker that could help predict outcomes with immunotherapy, specifically in the adjuvant setting, he added. Furthermore, the study included a detailed genomic analysis that evaluated the tumor at baseline and whether its potential evolution over time was associated with KIM-1, according to Pal.

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Dr Pal on Future Research Directions With Adjuvant Immunotherapy in High-Risk Resected RCC

“We are looking to conduct trials that enrich for patients who truly need adjuvant therapy. The data that we have produced offer a suggestion that down the line we can do trials that are focused in these subsets of individuals who we [believe are] at the highest risk for recurrence.”

Sumanta Kumar Pal, MD, FASCO, chair of the Kidney and Bladder Cancer Disease Team, co-director of the Kidney Cancer Program, and a professor and vice chair of Academic Affairs in the Department of Medical Oncology & Therapeutics Research at City of Hope, discussed future directions using genomic data from the phase 3 IMmotion010 trial (NCT03024996).

, Pal presented data from a genomic analysis of IMmotion010, which evaluated adjuvant atezolizumab (Tencentriq) vsplacebo in patients with high-risk localized renal cell carcinoma (RCC). Although primary findings from IMmotion010 showed that adjuvant atezolizumab did not prolong disease-free survival (DFS) vs placebo, data from the genomic analysis demonstrated that patients with certain molecular characteristics experienced a benefit with the agent.

Specifically, patients with high KIM-1 expression who received adjuvant atezolizumab (n = 151) achieved a median DFS that was not estimable (NE) compared with 21.16 months in the placebo arm (n = 149; HR, 0.72; 95% CI, 0.52-0.99). Comparatively, patients with low KIM-1 expression in the atezolizumab (n = 229) and placebo (n = 223) arms experienced a median DFS of 57.23 months and NE, respectively (HR, 1.12; 95% CI, 0.88-1.63).

In the future, investigators can use these data to design clinical trials that enrich for patient subgroups who will benefit from adjuvant therapy, Pal said. This includes creating future trials that are focused on patients with KIM-1–high or T-effector–high disease, he added. According to data from the genomic analysis, these patient subsets are at the highest risk of disease recurrence and would benefit the most from adjuvant therapy, he noted. Overall, the data collected by Pal and his coauthors will be useful in terms of tailoring therapy for patients, he concluded.

Sumanta Kumar Pal, MD, FASCO, discusses future directions using genomic data from the phase 3 IMmotion010 trial.

Dr Pal on the Predictive Utility of KIM-1 Expression in High-Risk Resected RCCC

Dr Pal on the Predictive Utility of KIM-1 Expression in High-Risk Resected RCC

"When we look at baseline specimens, we can identify, for instance, patients that have an angiogenic profile or a T-effector profile, which...is associated with immunotherapy sensitivity. We don't necessarily see a direct association with benefit from atezolizumab."

Sumanta Kumar Pal, MD, FASCO, chair of the Kidney and Bladder Cancer Disease Team, co-director, Kidney Cancer Program, professor, Department of Medical Oncology and Therapeutics Research, City of Hope, discusses the potential use of serum KIM-1 levels as a biomarker for clinical benefit or recurrence risk in patients with high-risk, resected renal cell carcinoma (RCC).

Findings from comprehensive tissue and blood biomarker analyses from the phase 3 IMmotion010 trial (NCT03024996), a randomized study evaluating adjuvant atezolizumab (Tecentriq) vs placebo, were presented during the 

 and indicated that serum KIM-1 levels may hold prognostic and predictive value. In the KIM-1–high subgroup (n = 151 for atezolizumab; n = 149 for placebo), disease-free survival (DFS) was longer with atezolizumab vs placebo (not estimable [NE] vs 21.16 months; HR, 0.72; 95% CI, 0.52-0.99). No DFS benefit was observed in the KIM-1–low subgroup (n = 229 for atezolizumab; n = 223 for placebo).

According to Pal, these results represent the first comprehensive biomarker dataset from an adjuvant immunotherapy study in kidney cancer, offering important context for patient stratification. Analysis of immune and angiogenic signatures revealed that most patients exhibited an angiogenic profile, with a subset displaying a T-effector immune-related signature.

Access to tumor samples from patients at the time of progression allowed for additional mechanistic insights, including the downregulation of major histocompatibility complex class I (MHC-I) pathways observed at recurrence, suggesting potential resistance to immunotherapy.

Pal emphasized that integrating baseline genomic characteristics, serum biomarkers such as KIM-1, and molecular profiling of recurrent tumors could guide future strategies to identify patients most likely to benefit from adjuvant therapy and to develop approaches that overcome immune resistance in high-risk RCC.

Sumanta Kumar Pal, MD, FASCO, discusses data supporting KIM-1 as a potential biomarker to inform adjuvant immunotherapy use in high-risk resected RCC. 

Dr Pal on Genomic Activity With Adjuvant Atezolizumab vs Placebo in High-Risk Resected RCC

"[Since we have access to patients with tumors that have progressed], I think we can really make some far-reaching conclusions around [the underlying mechanisms of adjuvant atezolizumab in this population]. We, for instance, [identified] that MHC-I pathways appear to be downregulated at the time of recurrence, and that’s a putative mechanism for resistance."

Sumanta Kumar Pal, MD, FASCO, chair of the Kidney and Bladder Cancer Disease Team, co-director of the Kidney Cancer Program, and a professor and vice chair of Academic Affairs in the Department of Medical Oncology & Therapeutics Research at City of Hope, discussed the significance of genomic findings from the phase 3 IMmotion010 trial (NCT03024996), a randomized study evaluating adjuvant atezolizumab (Tecentriq) vs placebo in patients with high-risk resected renal cell carcinoma (RCC).

The trial featured the first large-scale genomic and transcriptomic evaluation of both pre- and post-immunotherapy tumor tissue in the adjuvant RCC setting, Pal began. Among baseline samples, a range of molecular profiles were identified, including angiogenic signatures and a subset of tumors exhibiting high T-effector cell immune gene expression. Within the KIM-1–high subgroup (n = 151 for atezolizumab; n = 149 for placebo), patients with tumors that had a high T-effector cell signature had longer disease-free survival (DFS) with atezolizumab compared with placebo, suggesting the predictive value of this molecular subset, he said.

Within the KIM-1–high population, the median DFS was not estimable (NE) in the atezolizumab arm compared with 21.16 months in the placebo arm. Treatment with atezolizumab resulted in a hazard ratio (HR) for DFS of 0.72 (95% CI, 0.52-0.99), indicating a 28% reduction in the risk of recurrence or death in this biomarker-defined population.

In contrast, among patients in the KIM-1–low subgroup (n = 229 for atezolizumab; n = 223 for placebo), no DFS benefit was observed with atezolizumab vs placebo. The median DFS was 57.23 months for patients receiving atezolizumab and was NE in the placebo arm. The HR was 1.12 (95% CI, 0.88-1.63), indicating no significant difference in DFS between treatment arms in this subgroup.

In patients with available post-progression tissue, recurrent tumors showed increased stromal and proliferation gene signatures regardless of treatment, and tumors treated with atezolizumab showed downregulation of MHC-I expression. According to Pal, these findings suggest a potential immune evasion mechanism via impaired antigen presentation, which could contribute to resistance to PD-L1 blockade in the adjuvant setting.

Serum KIM-1 emerged as the strongest individual biomarker for predicting outcomes with atezolizumab. Although certain molecular subsets, such as high T-effector cell–expressing tumors, may provide context regarding immune responsiveness with atezolizumab, KIM-1 levels consistently correlated with clinical benefit and risk of recurrence across the cohort.

Sumanta Kumar Pal, MD, FASCO, discusses the genomic activity of adjuvant atezolizumab vs placebo in patients with high-risk resected RCC.

Sumanta Kumar Pal, MD, FASCO,  discusses outcomes with the use of zanzalintinib in patients with relapsed/refractory clear cell renal cell carcinoma.

Dr Pal on Outcomes With the Use of Zanzalintinib in Relapsed/Refractory ccRCC

Sumanta Kumar Pal, MD, FASCO, chair, Kidney and Bladder Cancer Disease Team, co-director, Kidney Cancer Program, professor, Department of Medical Oncology and Therapeutics Research, City of Hope, discusses outcomes with the use of zanzalintinib (XL092) in patients with relapsed/refractory clear cell renal cell carcinoma (ccRCC).

At the 2023 International Kidney Cancer Symposium, Pal shared results from the expansion cohort of the phase 1b STELLAR-001 trial (NCT03845166) assessing the next-generation TKI, zanzalintinib, in patients with previously treated ccRCC and other locally advanced or metastatic solid tumors. Findings demonstrated that at a median follow-up of 8.3 months, patients with ccRCC (n = 32) achieved an objective response rate (ORR) of 38% and a disease control rate (DCR) of 88%. Notably, anti-tumor activity was observed in patients who had progressed on a prior VEGF TKI, including cabozantinib (Cabometyx), with evaluable patients (n = 26) experiencing an ORR and DCR of 35% and 92%, respectively. Notably, 81% of all patients had intermediate-risk disease. The safety profile was consistent across cohorts, with manageable adverse effects (AEs).

In this trial, patients were administered zanzalintinib orally at a daily dose of 100 mg until disease progression or the development of intolerable toxicities, Pal begins. The study yielded an impressive ORR and, notably, when examining patients without prior exposure to cabozantinib (n = 14), the ORR was 57%.

Pal details that the results from the ccRCC cohort are notable for 2 key reasons. Firstly, the ORR exceeded typical expectations for a refractory disease study, Pal explains. Secondly, an ORR approaching 60% is unprecedented, especially among patients with previous cabozantinib exposure, he states.

Looking to safety, the agent had a favorable toxicity profile similar to other TKIs, particularly in terms of limited incidences of stomatitis and hand-foot syndrome, Pal continues, saying that these are toxicities that pose significant challenges. Pal concludes by saying that these findings align with his personal clinical experience, where patients who struggled with standard agents have shown positive outcomes with zanzalintinib, providing a source of encouragement.

Sumanta Kumar Pal, MD, FASCO, discusses outcomes with the use of zanzalintinib in patients with relapsed/refractory clear cell renal cell carcinoma.

Sumanta K. Pal, MD

Articles

Dr Pal on the Rationale for Evaluating Atezolizumab in High-Risk Localized RCC

Dr Pal on Future Research Directions With Adjuvant Immunotherapy in High-Risk Resected RCC

Dr Pal on the Predictive Utility of KIM-1 Expression in High-Risk Resected RCC

Dr Pal on Genomic Activity With Adjuvant Atezolizumab vs Placebo in High-Risk Resected RCC

Dr Pal on Outcomes With the Use of Zanzalintinib in Relapsed/Refractory ccRCC