Finally, adjuvant renal cancer treatment shows OS benefit

8 minute read

After decades of negative results, adjuvant pembrolizumab demonstrates a significant survival benefit for clear cell renal cell carcinoma patients at risk of recurrence after nephrectomy.

Patients given adjuvant pembrolizumab had a 38% lower risk of death than those in the placebo group at nearly five years after treatment.

“This further supports adjuvant pembro as a standard of care after surgery in this disease setting,” study author Professor Toni K. Choueiri from Dana-Farber Cancer Institute at Harvard Medical School announced to those gathered at the 2024 ASCO Genitourinary Cancers Symposium.

The Phase 3 Keynote-564 study was the first to show any survival benefit after 17 random controlled trials with over 12,000 patients conducted since 1973, Professor Choueiri pointed out.

About 80% of all renal cell cancer diagnoses are clear cell renal cell carcinomas. The five-year survival rate for clear cell renal cell carcinoma is 50-69%, but 10% when the disease has metastasised. Currently about half of all patients with high risk features have disease recurrence.

The study included almost 1000 patients with mainly oligometastatic disease, resected within a year of surgery. They were all at intermediate-high or high risk of recurrence and started on the trial no more than 12 weeks after surgery. They received either pembrolizumab or placebo for almost a year. Most of the patients, 85%, were in the intermediate-high risk group, and they had a 41% lower risk of death than the placebo group. Benefit was seen regardless of sarcomatoid features or high or low PD-L1 expression. Patients on the treatment had a 28% lower risk of disease recurrence in the study period than those on placebo (161 patients vs 210).

Safety results showed no increase in adverse effects from previous results at 30 months.

Subsequent therapy was given to about 85% of patients during the five years. About 70% had checkpoint inhibitors, and around 25% had radiation or surgery.

“I think this does raise the question about the biology of the tumours that end up progressing,” said Dr Pedro Barata from University Hospitals Seidman Cancer Center in Ohio, who was invited to discuss these findings at the oral abstract session, along with those of the Phase 3 CheckMate 914 study, presented immediately prior.

The CheckMate 914 study had very different results. This trial found no disease free survival benefit for either nivolumab plus ipilimumab versus placebo (in Part A of the study) and none for nivolumab monotherapy versus placebo (Part B) in the adjuvant setting for patients with localised RCC at high risk of recurrence after nephrectomy.

“The primary endpoint of the study was DFS … for nivo versus placebo. This primary endpoint was not met,” said author Dr Robert Motzer from Memorial Sloan Kettering Cancer Center, who presented the findings.

In Part B of the study, 825 patients randomised to receive either nivo (411), placebo (208) or nivo plus ipi (206) for a median of 5.1 months. Most patients had a radical nephrectomy. Around 80% had pT3 tumours, 7-8% had sarcomatoid features and 10%  had PD-L1 expression greater than 1%. They were followed up for a median of 27 months.

At 18 months, DFS was seen in the same proportion of the nivo group as in the placebo group (78% vs 75%). But there was a trend favouring nivo in patients with sarcomatoid features, PD-L1 expression greater than 1%, and a baseline haemoglobin level at the lower limit.

Around 80% of the nivo monotherapy group completed their treatment with only 11% dropping out due to toxicity, compared with 58% of the nivo plus ipi group completing theirs and 31% discontinuing treatment for the same reason.

“I do think this is a very important study. It allows us to test the activity of an active regimen, ipi/nivo, evaluates individual contribution of nivolumab and ipilimumab, and explores a shorter duration of immunotherapy,” said Dr Barata.

“Interestingly enough, the two-year disease-free survival with the control group seems to be around 73%, which seems to be higher than what we see in the control group for the Keynote-564, pembro. If you think about the most active regimen in this trial, the ipi/nivo, you also see more … significant side effects, more use of high-dose steroids, and more discontinuation rates. And perhaps, that might have impacted the results of this regimen.”

Local significance

Dr Mark Voskoboynik, medical oncologist and head of Genito-Urinary Oncology at the Alfred Hospital in Melbourne, told Oncology Republic the excitement around the KEYNOTE-564 trial results was to be expected. “There’s been a string of many negative adjuvant trials in that space, not just with immunotherapy, but with various targeted therapies, from the point of view of overall survival. Having one that’s shown an overall survival benefit, not surprisingly, has sparked some interest,” he said.

“I think the data from this Keynote-564 trial has already changed practice in the US and has received FDA approval. The issue in Australia is obviously PBS reimbursement. Irrespective of this, however, although there was an overall survival benefit, it’s relatively modest. It’s not a huge benefit, but it’s there and clearly a very important advance.”

Dr Voskoboynik said that whether the treatment was funded or not, adjuvant pembrolizumab should be part of the conversation with patients where it could be of benefit.

“It is important that we frame the conversation with patients correctly. None of these treatments, including pembrolizumab, are without side effects. Although it’s generally well tolerated, there are a significant minority of patients that experience serious side effects, and sometimes these side effects are permanent or even life threatening. It’s not without risk and not everyone benefits from the treatment. In fact, most people don’t benefit from these adjuvant treatments,” he said.

Predicting which individuals would benefit was not currently possible, he said. “We need to be careful to only have this discussion with patients that would have been eligible for this trial as well. This was a very carefully selected patient population. If we start to stray from that, then the benefit may not be there.”

Outcomes may also be different in Australia because of modern access to treatments on relapse, said Dr Voskoboynik. “We don’t know if everyone in the trial, conducted several years ago, necessarily had what would be considered the current best standard of care on relapse, so that might impact that modest overall survival benefit.”

Dr Voskoboynik said it wasn’t clear why the adjuvant nivolumab trial was negative and the pembrolizumab was positive as the two drugs were very similar. “In melanoma we can almost use them interchangeably,” he pointed out. “It might be partly explained by the shorter duration of treatment in the adjuvant nivolumab trial. The patient population might be slightly different. Is it different enough? We’ll never know. They’ll never be compared head-to-head.”

Changing practice

Dr Barata told symposium attendees that quality of life, patient preferences and availability of the drug were all factors in deciding for or against the use of adjuvant pembrolizumab where appropriate. “However, I would argue that after this morning, I think the scale tilts towards favouring adjuvant pembrolizumab, as we found out those patients live longer,” he told his colleagues.  

He said in his own practice, in the US, when patients come to him after surgery with clear cell RCC, he looks at staging and generally offers localised treatment for oligometastatic disease followed by a discussion around adjuvant pembrolizumab, and he uses a risk calculator for those without metastatic disease. Low risk patients tend to be offered observation. “I do the same for sarcomatoid features. And I should say that I actually don’t normally order PD-L1 staining in my clinic, so I do not use PD-L1 status to make decisions,” he said.

“Why do I do this? Well, we can use the example of sarcomatoid RCC. We know that checkpoint inhibitors are very active in the metastatic setting, either with a dual immunotherapy combo, like ipi/nivo, or even with immunotherapy as monotherapy… But I’m also going to point out that in the CheckMate 214 trial, it’s interesting to see that actually in … sarcomatoid RCC, there’s an enrichment for PD-L1 positive as well.”

In those for whom there is recurrence even after adjuvant pembrolizumab, which is around 40% of patients, Dr Barata recommended using an algorithm published earlier this year to determine next steps.

Patients’ thoughts on whether to use adjuvant therapy or not were very important, said Dr Barata. “For any stage, patients think there’s a higher risk of recurrence compared to their doctors. And when you ask them what factors matter in the decision to get adjuvant therapy? Number one reason ― risk of dying from cancer. And that actually trumps the side effect profile or even cost of treatment.”

Dr Barata said improving patient selection was the next step and could be optimised by using ctDNA, methylomes, looking at whole exome and whole transcriptome sequencing to try to identify tumours likely to benefit from immunotherapy, or strategies such as neoantigen vaccination.

Meanwhile, many trials were currently looking at different approaches such as the combination of CTLA-4 with PD-L1; combining pembrolizumab with an alpha inhibitor, using pembrolizumab in papillary renal cell carcinoma, and “even exploring IO/TKI,” said Dr Barata.

“The story is not over,” he said.

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