Molecular Testing, New Biomarkers on Horizon for Immunotherapy in RCC

Mark Ball, MD

Nivolumab (Opdivo) produced exceptional responses in patients with renal cell carcinoma (RCC), which may pave the way for further treatment breakthroughs, according to Mark Ball, MD.

Nivolumab was approved by FDA for the treatment of patients with advanced RCC in November 2015. The approval was based off of findings from the phase III CheckMate-025 trial, in which efficacy of nivolumab showed a significant survival benefit when compared with standard therapy everolimus (Afinitor).

Results showed that the median overall survival in the overall study population was 25.0 months with nivolumab versus 19.6 months with everolimus (HR, 0.73; 98.5% CI, 0.57-0.93; P = .002). Median progression-free survival was 4.6 and 4.4 months in the nivolumab and everolimus arms, respectively (HR, 0.88; 95% CI, 0.75-1.03; P = .11).

OncLive: Can you give an overview of your recent study regarding nivolumab?

In an interview with OncLive, Ball, chief urology resident, Johns Hopkins University School of Medicine, discusses the clinical, pathological, and genomic profiles of exceptional responders to anti—PD-1 therapy in RCC, the future of immunotherapy, and what significance genomic testing may hold.Ball: Our study looked at exceptional responders of patients with RCC to nivolumab, which is an anti—PD-1 therapy. Exceptional response is a pretty rare event; about 1% has these long-term, durable responses. In our study, we defined it as greater than 2 years with a complete or near-complete response. What we did is we characterized those patients by comparing them with patients with primary refractory disease or disease that progressed rapidly on therapy.

What we found are several differences. We found a higher number of somatic mutations in exceptional responders and, corresponding with that, we found a higher number of neoantigens. The thought is that with more neoantigens, there are more opportunities for T cells to recognize these cancers as different enough to attack them.

How can these findings be applied down the line? Will there be testing done beforehand to identify these patients?

Going along with that idea, we found higher numbers of CD8-positive lymphocytes in exceptional responders. Most interestingly, we found differences in RNA-expression patterns. We found 31 different genes in exceptional responders versus primary refractory disease, and these were genes associated with T-cell activation and acute inflammation that were upregulated in the exceptional responders.For a preliminary study like this, it is hard to generalize, but what we hope is that if this were validated in large multi-institutional studies, we could eventually target those patients with these characteristics and they may be eligible for an anti—PD-1 therapy in the first-line setting.

Where does the role of PD-L1 fit in, if at all?

Do you think there may be a shift moving away from using PD-L1 testing?

Overall, do you feel that there should be more molecular testing done upfront?

Right now, it's approved as a second-line agent. However, perhaps for patients with higher somatic mutation burden, where we anticipate having genetic data going into treatment, we may be able to identify who is more likely to respond either in the first- or second-line setting.Interestingly, what we found is that PD-L1 expression did not correlate with response. This is in contrast to some early studies showing that patients with higher PD-L1 expression may respond better to anti—PD-1 therapy. It was supported in a recent phase III trial published in the New England Journal of Medicine, which also found that expression of PD-L1 did not correlate with response.We may not be moving away, but what I think what we're learning is that it is a more complex picture. PD-L1 may or may not be a part of that selection process in the future. It's too early to say at this point.Molecular testing upfront makes a lot of sense, particularly in RCC where we have multiple targeted therapies using different pathways. We've got TKIs that are targeting VEGF, we have MTOR inhibitors, and now we have checkpoint blockades. Knowing what mutations we're dealing with upfront will make a lot of sense in selecting sequencing of these agents.

Will immunotherapy continue to show potential in RCC?

I think the biggest factor for this becoming more common in the clinic is going to be cost. We are in the era of the $1000 genome where that is going to become a lot more realistic.Immunotherapy is here to stay. Checkpoint blockades with anti—PD-1 is just the start, and there are a lot of other exciting areas of investigation, such as other checkpoints—LAG3 and CTLA4 are still being tested in addition to PD-1. This idea of combination checkpoint blockade is really intriguing.

Are there next steps planned for your study?

Then, there are predictive biomarker studies, and these studies will only help us to determine who to select for which sequence of therapies.Yes. We are fortunate enough to have collaborators at other institutions, and we're actively pooling our data to have 1 larger study looking at predictive biomarkers response to anti—PD-1 therapy in RCC. We hope to share those results in the future.

Motzer RJ, Sharma P, McDermott DF, et al. CheckMate 025 phase III trial: Outcomes by key baseline factors and prior therapy for nivolumab (NIVO) versus everolimus (EVE) in advanced renal cell carcinoma (RCC). J Clin Oncol. 34, 2016 (suppl 2S; abstr 498).

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