CHICAGO-A subgroup of patients with previously untreated advanced clear cell renal cell carcinoma with sarcomatoid histology who were treated with combination immune checkpoint blockade had markedly better outcomes than those in a control group receiving standard therapy. These results were from the multicenter randomized, open-label, phase III CheckMate 214 study reported at the 2019 ASCO Annual Meeting (Abstract 4513).
Patients were randomized to treatment with a combination of the PD-1 targeted checkpoint inhibitor nivolumab plus the CTLA-4 antibody ipilimumab or to monotherapy with the VEGF tyrosine kinase inhibitor (TKI) sunitinib.
"In this subgroup of patients, [there] was clear superiority of the combination immune checkpoint blockade compared to the standard therapy on all the efficacy endpoints: response, long-term progression-free survival, overall survival," said lead study author David F. McDermott, MD, Director of the Biologic Therapy and Cutaneous Oncology Programs, Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center in Boston.
Not only was the favorable impact of the combined therapy seen in tumors that expressed PD-L1, it was also found in those that did not. "So this is a big win for the patients with the worst [type] of metastatic kidney cancer," McDermott told Oncology Times.
In what he said was "a first look at combination immune checkpoint blockade," the study looked for sarcomatoid histology in kidney cancers: "a dedifferentiated state of kidney cancer where the tumor looks more aggressive under the microscope and behaves more aggressively in patients." These patients generally had far worse prognoses and were "typically resistant" to standard therapy, McDermott said.
Study Details
A total of 842 patients in the CheckMate 214 study had local pathology reports and from among these 116 were found to have renal cell carcinoma with sarcomatoid features (sRCC). From these, all but four had risk scores categorized as intermediate or poor. From the remaining 112 patients, 60 entered the investigational arm and 52 went on to have standard sunitinib.
Nivolumab plus ipilimumab combined therapy was given intravenously with four doses 3 weeks apart followed by nivolumab maintenance. The standard control group regimen was sunitinib administered in a "4 weeks on, 2 weeks off" schedule, said McDermott.
The baseline characteristics of patients with sRCC were balanced between the two arms and about half of the patients in each arm had PD-L1 expression of at least 1 percent-which turned out to have little effect on outcomes.
At 30 months follow-up, overall response rate, complete response (CR) rate, overall survival (OS), and progression-free survival (PFS) were all improved in patients treated with combined checkpoint inhibition compared with those on standard sunitinib therapy. And no new safety signals were seen.
The median OS was 31.2 months in the combination immunotherapy arm and 13.6 months in patients treated with sunitinib-a hazard ratio of 0.55. The probability of surviving 1 year was 80 percent among patients on the combination but only 56 percent for those on sunitinib treatment. Fifty-three percent of patients were alive at 30 months in the investigational arm compared with only 29 percent of patients in the control arm. PFS was nearly doubled for patients treated with the combination-8.4 months, compared with 4.9 months on the control arm.
While 18 percent of patients (all with sarcomatoid features and who were categorized as having intermediate or poor risk) receiving checkpoint blockade had CRs, none of the patients on sunitinib therapy had a CR.
McDermott said they had looked at depth of response. "One of the exciting things about the depth of response is that the CR rate in this group was 18 percent. Complete responses are very important because they often lead to long-term survival and opportunities for remission: living with advanced cancer off treatment."
Standard therapies like VEGF blockade worked less well in this type of kidney cancer then in standard clear cell cancer, he noted. "What's exciting about the newer approaches (based on immune checkpoint blockade in this study and, importantly, several other studies have shown the same thing) is [that] if you add PD-1 blockade to [treatment of] a sarcomatoid kidney cancer [the patients] do better."
He was not able to explain why this should be. But he speculated that one of the likely relationships that existed was that these very aggressive tumors probably generated immune responses at the time they were diagnosed. "We often see them infiltrated by immune cells. And they are defending themselves with PD-L1. So when you come in with a PD-L1 blocking drug, you allow those in and the cells kill the tumor. But if you don't, the tumor kills the patient."
McDermott said they hadn't yet been able to say whether or not the CTLA-4 component of the checkpoint blockade had added to the benefit. Further studies would be needed.
Patient Benefits
When he was asked to comment on the magnitude of the benefit to patients treated with checkpoint inhibition, McDermott said the most important number coming out of the trial had been the improvement of PFS from 5 to 8 months.
"But, more importantly, the percentage of patients who are progression-free at over 3 years is close to 40 percent," he noted. "So that means that almost four out of 10 patients who received the combination immune therapy had yet to progress over 3 years after starting treatment."
He also said that, not only were these patients living longer, they had yet to require other therapy. He held out the prospect that maybe they had entered states of remission of their disease.
McDermott was also bullish about the potential of this approach in kidney and other cancers after these encouraging results for some of the "worst, most difficult patients with aggressive disease." Clinicians should consider immunotherapy even in patients with faster-growing symptomatic disease, he said. "You don't need to have an indolent tumor. And in fact some of the more aggressive ones responded.
"And that's the story in other places in cancer-not just in kidney cancer. Some of our most aggressive mutated tumors tend to respond to checkpoint blockade. Whereas the more indolent tumors are less likely to respond."
Different Side Effects
When he was asked about the toxicity of this immunotherapy, McDermott explained the incidence of grade 3-4 toxicity had been lower in the checkpoint inhibitor arm than with VEGF TKIs, and that this was encouraging.
"But the side effect profiles are very different. With VEGF blockade. you get fatigue, diarrhea, hypertension-side effects that are chronic and often annoying but don't often require urgent intervention. Whereas most patients tolerate immune checkpoint therapy better-which is good, they can occasionally have severe side effects."
Up to 20 percent of patients in the experimental arm had to have their treatment discontinued because of treatment-related toxicity. And the list of possible side effects was very long, said McDermott.
"Most commonly you can get inflammation of the gut, the liver, the skin. But you can also get inflammation of the myocardium, the pancreas. Any body organ can be impacted. So it requires a lot of patient education [and] a lot of education of the team that's taking care of the patients. But with early intervention you can make a big impact."
McDermott saw the potential of reducing immunotherapy side effects by reducing exposure to CTLA-4 blockade. But he said this was still to be investigated.
The message for cancer doctors was that PD-1 based combination therapy had become the new standard therapy for advanced kidney cancer for all untreated patients unless they had a specific contraindication, such as autoimmune disease. "It is here to stay as our baseline," he concluded.
Peter M. Goodwin is a contributing writer.