Daniel J. George, MD, professor of medicine and surgery at Duke Cancer Institute, discussed the results from these 2 analyses in this high-risk patient population with RCC compared to metastatic RCC. He also shares his own insights on what to take away from this data.
Daniel J. George, MD
The phase III S-TRAC trial randomized more than 600 patients with renal cell carcinoma (RCC) to receive either sunitinib (Sutent) or placebo in the adjuvant setting. In an analysis of disease-free survival (DFS) looking at a subgroup of patients considered highest risk for recurrence, this patient population seemed to benefit more from maintenance treatment with sunitinib immediately following surgery.
Sunitinib benefited the overall population of patients in the trial, but patients in this particular subgroup, which included patients with T3/T4 or node-positive disease, experienced a 27% reduction in the risk of recurrence, compared to a 24% reduction in the overall population. These results were significant, as they showed not only can this therapy be beneficial to the overall population, but results were also statistically significant for high-risk patients that are more likely to relapse, according to Daniel J. George, MD.
In another analysis, the neutrophil-to-lymphocyte ratio proved to be a reliable prognostic factor for those patients that would do well on an adjuvant sunitinib treatment. Interestingly, results showed that those patients who had a low neutrophil-to-lymphocyte ratio benefitted more in the adjuvant setting, George said. Sunitinib is able to stimulate the immune system during the healing process after surgery and can ultimately become a protective barrier to recurrence.
During the 2018 ASCO Annual Meeting, George, professor of medicine and surgery at Duke Cancer Institute, discussed the results from these 2 analyses in this high-risk patient population with RCC compared to metastatic RCC. He also shares his own insights on what to take away from this data.
TARGETED ONCOLOGY: You discussed an analysis of DFS in patients at highest risk of recurrent RCC in the S-TRAC trial. Can you discuss the background on this analysis?
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 kidney cancer or patients with node-positive kidney cancer. In that prospective study, what we found was that treatment with sunitinib up to a year delayed disease recurrence by about 24% with a hazard ration of 0.76 and aPvalue of 0.03.
This was a 615-patient study. We wanted to look at higher-risk patients because patients at higher risk are more likely to relapse sooner, and because patients at higher risk may benefit by a greater proportion to adjuvant therapy. We identified high-risk patients either with a higher grade of disease, so 2- to 4-grade, or a decreased performance, meaning a performance status of 1 or less.
In that group of patients, node-positive or T4, we actually saw a greater overall clinical benefit associated with a year’s worth of sunitinib with a hazard ratio of 0.73, so it was actually a 27% reduction in the risk of disease recurrence. Like the overall population, there was a sustained benefit out to 5 years or more. It really suggests that as we enrich for patients with greater risk for disease recurrence, the benefit of sunitinib doesn’t go away. If anything, it increases.
To me, it really enforces that in our highest risk patients, particularly those T4, node-positive patients, we’re seeing a benefit associated with this. Even though those numbers decrease, the statistical significance was sustained. That’s really important.
TARGETED ONCOLOGY: What was the significance of these results?
George:Clinically, when we are thinking about who to treat with sunitinib, we want to pick the patients we think are most likely to benefit. By enriching for these highest-risk patients, we can focus even further on those patients most likely to benefit. When I see a patient in my clinic who has node-positive disease or a patient with T4 disease, or even really high-grade or poor performance status disease, that’s a patient that I’m going to be more inclined to offer sunitinib to, even if medically I think they might be a little more on the fence. If they are older or if they can really tolerate sunitinib for a year, I really don’t know, but that’s a patient I have a conversation with because there’s an even greater risk of them recurring and an even greater benefit associated with that adjuvant therapy.
TARGETED ONCOLOGY: Was there anything else you found striking in these results?
George:This is consistent with the overall population. We’re not seeing this is the only subset benefiting. We’re seeing the overall population benefit. We’re just seeing an enrichment in even the highest-risk patients. Not to pigeon-hole the drug to only those patients, but to say we especially want to treat those patients with sunitinib.
TARGETED ONCOLOGY: Was anything surprising about these results?
George:They were expected. For overall, the population was high-risk to begin with, so we kind of expected that. If anything, it’s a little bit surprising in node-positive patients because they’re the most likely to be metastatic and if we think about this as a metastatic disease-progression population, those patients are probably most likely to progress within the first year or 2. Yet, even there, we still see the benefit of sunitinib. Early use of this drug, so not delaying it a year or 2 years, but right after surgery within the first 3 months can really make a big difference.
TARGETED ONCOLOGY: Another analysis of S-TRAC looked at neutrophil-to-lymphocyte ratio as a potential prognostic factor of DFS in high-risk RCC. Can you give us some background on that?
George:Again, in S-TRAC, we saw an overall benefit with a population we enriched for. This is the high-risk T3 or node-positive patients treated with sunitinib or placebo for a 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 more likely to relapse sooner.
We know that the neutrophil-to-lymphocyte ratio is 1 of the factors in metastatic kidney cancer that’s prognostic. In particular, patients that have a high neutron-phil-to-lymphocyte ratio greater than 3 or 5, these are the patients that are at higher risk for disease progression and early death for metastatic disease, so in the adjuvant setting we wanted to look at this marker as well.
What was surprising to us was when we looked at this marker was that it was flipped. The patients that had a low neutrophil-to-lymphocyte ratio actually had a worse prognosis than those who had a high neutrophil-to-lymphocyte ratio. This was confusing to us at first because this was flipped, and it was irrespective of placebo or sunitinib treatment. This was all comers. If you think about it, what was 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’s the tumor burden that’s driving that neutrophil-to-lymphocyte ratio, and that inflammatory profile associated with tumor may be a poor prognostic indicator. In the adjuvant setting, what might be driving that neutrophil-to-lymphocyte ratio is the post-inflammatory process after surgery. If you think about what happens after surgery, there is some pro-inflammatory growth factors that are part of that healing process and may be stimulating the immune system. However, if you have that persistent stimulation and persistently high neutrophil-to-lymphocyte ratio, where it’s not associated with tumor burden but it is associated with your engagement of the immune system and the pro-inflammatory healing process, that may actually be protective from these recurrences. For the patients that don’t generate that and maintain a low neutrophil-to-lymphocyte ratio, maybe they are not getting that stimulation, they’re not getting that protective, and [that is why] they’re relapsing sooner.
In retrospect, we can understand kind of why ratio may work differently in the adjuvant setting than in the metastatic setting, but that was interesting to us.
TARGETED ONCOLOGY: Were there any other prognostic factors you found?
George:The other factor that was interesting was the change in neutrophil-to-lymphocyte ratio over time. If we look at that in the placebo group, it didn’t change often. There was a change in that ratio maybe 15% to 20% of the time. It went down over time or it went up over time. Particularly, the ones that went up did worse, and you can imagine that a rising neutrophil-to-lymphocyte ratio associated with an increasing tumor burden and increasing inflammatory burden. That’s bad. The ones that go down over time are actually doing better.
What was really interesting to us was that 4 weeks on treatment, 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. Short-term after surgery, the neutrophil-to-lymphocyte ratio is the higher the better, because it’s in a post-operative inflammatory profile. Longer-term, over time, a drop in that ratio is better. For those patients that are healing, that’s going away. For those patients that are on sunitinib, they are responding to that therapy. Those are both good prognostic indicators. That’s what we see in our study, that the baseline has some prognostic significance and the on-treatment changes have prognostic significance as well.
TARGETED ONCOLOGY: What would you say is the takeaway from all of this?
George:It’s confusing, but I think the takeaway for me is that our immune systems are dynamic in the adjuvant setting. They are being stimulated by that surgical inflammatory profile. They’re also being manipulated somewhat by the presence of sunitinib. This drug and its effect on neutrophil-to-lymphocyte ratio and that innate inflammatory profile is a good thing, in that it’s helping the body react, and hopefully, will delay and prevent disease recurrence in the future.