Expert Shares Insight on Analyses From S-TRAC Trial in RCC

Daniel J. George, MD

Findings from the phase III S-TRAC trial led to the FDA approval of sunitinib (Sutent) in November 2017 as an adjuvant therapy for patients with renal cell carcinoma (RCC) who are at high risk for recurrence. In a prospective study presented at the 2018 ASCO Annual Meeting, Daniel J. George, MD, reported on the disease-free survival (DFS) of patients at the highest risk of recurrence from S-TRAC.¹

DFS analyses showed that the treatment benefit by independent review for sunitinib versus placebo in this group (HR, 0.73; 95% CI, 0.54-0.97; P = .03) was consistent with the hazard ratio previously reported in the S-TRAC trial for patients with T3 or higher disease. The hazard ratio for T3 or higher was (HR, 0.74; 95% CI, 0.55-0.99; P = .044).

George said that these findings, paired with a consistent safety profile between the groups, support the assessment of sunitinib as a viable adjuvant treatment option for patients with RCC who are at high risk of recurrence following nephrectomy.

In another analysis on S-TRAC presented at the 2018 ASCO Annual Meeting, investigators evaluated neutrophil-to-lymphocyte ratio as a prognostic factor of DFS in patients with high-risk RCC.² George said that a lower neutrophil-to-lymphocyte ratio may be a prognostic factor of shorter DFS.

OncLive: Can you share some background on the rationale for the S-TRAC study?

In an interview with OncLive, George, professor of Medicine at Duke Cancer Center, discussed the analysis of RCC patients in the S-TRAC trial with the highest risk of recurrence, and potential prognostic factors of DFS that emerged from the study.George: S-TRAC was a phase III, prospective, multicenter study looking at the effectiveness of sunitinib versus placebo in patients at high risk for disease recurrence, particularly T3 or node-positive kidney cancer. In that prospective study, what we found [in the overall population] was that treatment with sunitinib for up to 1 year delayed DFS by about 24% with a hazard ratio of 0.76 and a P value of .03. This was a 615-patient study.

We wanted to look at higher-risk patients because these patients are more likely to relapse sooner, and because those at higher risk may benefit by a greater proportion to adjuvant therapy. We identified high-risk as patients with T3 or higher grade, node-positive T4, or a decreased performance status of 1 or less. In those subgroups, we saw a greater overall benefit associated with 1 year of sunitinib with a hazard ratio of 0.73, so a 27% reduction in the risk of disease recurrence. Like the overall population, that was a sustained benefit up to 5 years or more.

What is the significance of these findings?

Were these findings expected?

As we enrich for patients at greater risk for disease recurrence, the benefit of sunitinib doesn't go away—if anything, it increases. To me, it reinforces that in our high-risk patients, particularly those T4 node-positive patients, we see a benefit. Even though those numbers are decreased, the statistical significance was sustained. That is really important. Clinically, when we are thinking about who to treat with sunitinib, we want to pick the patients who we think are most likely to benefit. By enriching for these highest-risk patients, we can focus further on the patients wo are most likely to benefit. When I see a patient in my clinic who has node-positive disease, T4 disease, or poor-performance status, that is going to be a patient who I am more inclined to offer sunitinib to, even if I think they might be on the fence medically. This means that they are older, or have other issues that question whether they can tolerate sunitinib for 1 year. That is a patient who I still want to have a conversation with, because there is a greater risk of them recurring and a greater benefit associated with that adjuvant therapy. [It was only expected in] that this is consistent with the overall population. We are not saying that this is the only subset that is benefitting—we are seeing the overall population benefit—but we are seeing an enrichment in the higher-risk patients. We're not pigeonholing the drug to only those patients, we are saying especially in those patients.

You also discussed neutrophil-to-lymphocyte ratio as a potential prognostic factor of DFS in high-risk RCC. Can you give an overview of this analysis of the S-TRAC trial?

Overall, the population was high-risk to begin with. The only thing that is a little bit surprising is the node-positive patients, because they are the most likely to be metastatic, and if we think about this as a metastatic disease progressive-population, those are the patients who are the most likely to progress in the first 1 to 2 years. Even there, we see the benefit with sunitinib, suggesting that early use of this drug within the first 3 months after surgery can make a big difference. In S-TRAC, we saw an overall benefit with the population that we enriched for. This was the high-risk population T3 or node-positive patients treated with sunitinib or placebo for 1 year. Overall, we saw about a 24% reduction in the risk of disease recurrence.

We wanted to look at factors that might help us prognosticate that benefit. In particular, looking for factors that might be a predictor for who is likely to relapse sooner. We know that the neutrophil-to-lymphocyte ratio is one of the factors in metastatic kidney cancer that is prognostic, especially in patients with a neutrophil-to-lymphocyte ratio greater than 3. These are the patients at highest risk for disease progression and early death from metastatic RCC.

In the adjuvant setting, we wanted to look at this marker, as well. What was surprising to us is that when we looked at this marker, it was flipped. The patients who had a low neutrophil-to-lymphocyte ratio actually had a worse prognosis than those who had a high one. This was confusing to us at first—and it was irrespective of placebo or sunitinib treatment.

If you think about it, what is driving the neutrophil-to-lymphocyte ratio in the adjuvant setting is different than what is driving it in the metastatic setting. In the metastatic setting, it is the tumor burden that is driving it, and that inflammatory profile associated with the tumor is a poor prognostic indicator.

In the adjuvant setting, what might be driving the neutrophil-to-lymphocyte ratio is the post-inflammatory process after surgery. After surgery, there are some proinflammatory growth factors that are part of that healing process that also might be stimulating the immune system. If you have that persistent stimulation and persistently high neutrophil-to-lymphocyte ratio not associated with tumor burden, but its associated with your engagement of the immune system, that might be protective from disease recurrence. Whereas, the patients who do not generate that and maintain a low neutrophil-to-lymphocyte ratio, they might not be getting that situation or protective effect and are relapsing sooner.

Are there any other factors that could be prognostic and worth investigating?

In retrospect, we can understand why this ratio may work differently in the adjuvant setting than the metastatic setting.The other interesting factor was the change in neutrophil-to-lymphocyte ratio over time. In the placebo group, it did not change often, but maybe 15% to 20% of the time. It either went down or up, and the ones that went up did worse. You can imagine that a rising neutrophil-to-lymphocyte ratio is associated with an increasing tumor burden and an inflammatory tumor burden. The ones that go down over time are doing better.

What is the takeaway message from this analysis?

What was interesting was that after 4 weeks on therapy, treatment with sunitinib was more likely to drive down that neutrophil-to-lymphocyte ratio. When it did that, it was associated with a better outcome. Over time though, a drop in that ratio is better. The baseline has some prognostic significance, and the on-treatment changes have prognostic significance, as well.It is confusing, but our immune systems are dynamic in this adjuvant setting. They are being stimulated by that surgical inflammatory profile, and that is a good thing. They are also being somewhat manipulated by the presence of sunitinib. This drug, and its effect of neutrophil-to-lymphocyte ratios and that innate inflammatory profile, is a good thing. It is helping the body react to, hopefully delay, and maybe prevent disease recurrence in the future. It is an interplay between sunitinib, its effects, and the immune system. That is important.

We think of sunitinib as primarily targeting angiogenesis, but it also plays a role in our immune system in stimulating that immune recognition, potentially affecting other cells in the immune system that play a role in blunting our immune recognition of cancer. Sunitinib may be releasing some of that and allowing that reaction to occur.

References

1. Ravaud A, George DJ, Motzer RJ, et al. Disease-free survival in patients at highest risk of recurrent renal cell carcinoma in S-TRAC. J Clin Oncol. 2018;36 (suppl; abstr 4565).
2. Patel A, Ravaud A, Motzer RJ, et al. Neutrophil-to-lymphocyte ratio as a potential prognostic factor of disease-free survival in high-risk renal cell carcinoma: analysis of the S-TRAC trial. J Clin Oncol. 2018;36 (suppl; abstr 4562).