Sumanta Kumar Pal, MD, FASCO
Comprehensive tissue and blood biomarker analyses from the phase 3 IMmotion010 trial (NCT03024996) showing a consistent correlation between serum KIM-1 levels and clinical benefit or recurrence risk in patients with high-risk, resected renal cell carcinoma (RCC) highlight a potential path toward more precisely selecting patients most likely to benefit from adjuvant immunotherapy in future trials, according to Sumanta Kumar Pal, MD, FASCO.
Findings from a biomarker analysis of IMmotion010, a randomized study evaluating adjuvant atezolizumab (Tecentriq) vs placebo, were presented during the 2025 ASCO Annual Meeting. In the subset of patients with high KIM-1 expression (n = 151 for atezolizumab; n = 149 for placebo), patients had longer disease-free survival (DFS) with atezolizumab compared with placebo, at not estimable (NE) vs 21.16 months, respectively (HR, 0.72; 95% CI, 0.52-0.99). Conversely, no DFS benefit was observed with atezolizumab vs placebo for patients in the KIM-1–low subgroup (n = 229 for atezolizumab; n = 223 for placebo). The median DFS was 57.23 months with atezolizumab and was NE in the placebo arm (HR, 1.12; 95% CI, 0.88-1.63).
“At the end of the day, these data serve to tailor studies that would be very useful for guiding future therapy,” Pal, chair of the Kidney and Bladder Cancer Disease Team, codirector 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 in Duarte, California, shared with OncLive®.
In the interview, Pal discussed prior findings from IMmotion010 that spurred this genomic analysis, the emerging predictive value of the serum biomarker KIM-1 and baseline immune/angiogenic signatures based on these analyses, and how longitudinal genomic analyses of pre- and post-recurrence tissue may inform future biomarker-driven adjuvant trial enrichment strategies.
OncLive: What was the rationale for investigating the activity of adjuvant atezolizumab vs placebo in patients with resected RCC and high T-effector cell immune gene expression?
Pal: IMmotion010 was a randomized phase 3 trial comparing atezolizumab to 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 DFS with atezolizumab. That being said, we had a trove of valuable data coming from all the specimens that we included. We had specimens derived from tissue at baseline, and we had blood collection at baseline, and the same at the time of recurrence. With this very valuable resource, last year, one of my colleagues presented data suggesting that KIM-1 is a unique biomarker that can predict benefit with immunotherapy in the adjuvant setting. It was the first time we saw that.
Now we’ve enriched the study with a lot of detailed genomic analyses that really show what happens with the tumor both at baseline and whether or not it’s associated with KIM-1, and also show how it evolves. Our findings included the fact that when you look at baseline tissue and look at the tumor at the time of recurrence, there is an evolution in the genomics, and it’s not always a predictable evolution as you go from one patient to the next.
What should be known about the trial design, objectives, and patient population?
In this specific analysis, patients included in the IMmotion010 analysis were all high-risk patients with RCC. As we think about the population that we presented at the 2025 ASCO annual meeting, the key to bear in mind is that we had access to tissues that were collected at the time of recurrence. This is a hugely valuable resource, and something that we don’t see in a lot of clinical trials today.
One of the main takeaways from the data is that when we look at baseline specimens, we can identify, for instance, patients that have an angiogenic profile, or patients who have what we call a T-cell effector profile, which we’ve shown in the past through other studies is associated with immunotherapy sensitivity. What we don’t necessarily see is a direct association with the benefit from atezolizumab. One of the things that we noticed is still the strongest predictor [of benefit] was the serum-based biomarker KIM-1. We can complement that a little bit if we add to it an in-base signature. Our tissue-based studies also demonstrated that, over time, there’s some evolution in genomic signatures, but again, not in a very predictable fashion.
What did the analysis reveal about the predictive utility of KIM-1 in patients with high-risk resected RCC?
The key to keep in mind as we consider the results of the trial is that this is the first comprehensive data set in one of our adjuvant studies of immunotherapy in kidney cancer. When we factor that into the equation, the various immune profiles that we’ve identified and angiogenic profiles serve to suggest what a population of patients with high-risk RCC might possess. There is still a dominance of an angiogenic profile, and there is a subpopulation of patients with a T-effector immune-related signature as well. What we see among patients who recur is that it looks as though they may have this unique profile called a small nuclear RNA profile. Putting all that together, the baseline characteristics of this population and their genomics are key.
Also, since we have access to patients who have tumors that have progressed, we can make some far-reaching conclusions about what those underlying mechanisms might be. For instance, we identify that MHC-I pathways appear to be downregulated at the time of recurrence. That’s a putative mechanism for resistance and is something important for us to keep in mind moving forward.
What next steps are planned for genomic and transcriptomic evaluation of both pre- and post-immunotherapy tumor tissue from IMmotion010?
We’re looking to do trials that enrich for patients who truly need adjuvant therapy. The data that we’ve produced offers some suggestion that, perhaps down the line, we can do trials that are focused on patients who [express] high KIM-1, high T-cell effector, all of these subsets of individuals that we think might be at the highest risk for potential recurrence and who might benefit from adjuvant immunotherapy.
Down the line, we may incorporate some of these tools, complemented by some elements of the genomic signature, to pick patients who would benefit most from immunotherapy.
Reference
Pal S, Albiges A, Bex A, et al. Genomic characterization of baseline and post-progression tumors in IMmotion010, a randomized, phase 3 study of adjuvant (adj) atezolizumab (atezo) vs placebo (pbo) in patients (pts) with high-risk localized renal cell carcinoma (RCC). J Clin Oncol. 2025,43(suppl 16):4510. doi:10.1200/JCO.2025.43.16_suppl.4510