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.

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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 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