Findings from the noncomparative, phase 2, biomarker-driven BIONIKK trial demonstrated clinical evidence to support the use of molecularly-directed frontline therapy as means to enrich responses in patients with metastatic clear cell renal cell carcinoma.
Findings from the noncomparative, phase 2, biomarker-driven BIONIKK trial demonstrated clinical evidence to support the use of molecularly-directed frontline therapy as means to enrich responses in patients with metastatic clear cell renal cell carcinoma (ccRCC).
According to the results, which were presented during the 2020 ESMO Virtual Congress, among evaluable patients in the target cohort (TCE; n = 154), the objective response rate (ORR) was 39.3% with nivolumab (Opdivo) monotherapy (Arm A), 44.5% with nivolumab plus ipilimumab (Yervoy; Arm B), and 50% with a TKI (Arm C). The ORRs among evaluable patients in an additional cohort (ACE; n = 33) were 41.7%, 54%, and 25%, respectively.1
The study randomized 4 groups of patients with distinct tumor microenvironment compositions and outcomes with sunitinib (Sutent) to 1 of the 3 aforementioned treatments. These subtypes were identified through previous analysis of transcriptomic data from frozen ccRCC specimens.2,3
Groups 1 (ccrcc1) and 4 (ccrcc4) were “immune-low” and “immune-high,” respectively, and were associated with poor outcomes with sunitinib. Conversely, patients in Groups 2 (ccrcc2) and 3 (ccrcc3) had “angio-high” and “normal-like” tumors, respectively, and were associated with favorable outcomes with sunitinib.
Groups 1 and 4 were randomized to receive nivolumab (Opdivo) alone or nivolumab in combination with ipilimumab. Groups 2 and 3 were randomized to receive the combination regimen or physician’s choice of TKI with either sunitinib or pazopanib (Votrient).
In Group 1, the ORR was 20.7% with nivolumab alone (n = 29). The ORR was 39.4% with nivolumab and ipilimumab (n = 33); 6.1% of these were complete responses (CRs), and 33.3% were partial responses (PRs).
The ORR in Group 4 was 50.0% with nivolumab alone (n = 14) versus 53.0% with the combination of nivolumab and ipilimumab (n = 17). The CR rates were 7.1% and 11.8%, respectively. The PR rates were 42.9% and 41.2%, respectively.
In Group 2, the ORR was 53.8% with a TKI (n = 26) compared with 48.3% with the combination regimen (n = 29). Additionally, 13.8% of patients who received the combination derived CRs.
Finally, the ORR among patients in Group 3 who received a TKI (n = 2) was 0% compared with 25.0% with nivolumab/ipilimumab (n = 4). No patients on either regimen derived a CR.
“[The] BIONIKK trial provides evidence on the best candidates to receive TKI, nivolumab alone, or nivolumab/ipilimumab,” said lead study author Yann-Alexandre Vano, MD, PhD, a medical oncologist at Hôpital Européen Georges-Pompidou in Paris, France, during a virtual
presentation of the data. “We see the highest response rates with nivolumab alone in patients with ccrcc4 tumors, with durable responses.”
“The poor prognosis of these highly infiltrated tumors seems to be reversed by anti–PD-1 treatment,” added Vano. “In patients with ccrcc1 tumors, combination ipilimumab and nivolumab seems to be needed. In patients with ccrcc2 tumors, TKIs provide very high response rates…at 16 months of follow-up.”
Eligible patients had to have metastatic RCC with clear cell histology, though patients with translocation carcinoma were allowed to enroll. Additionally, patients had to be previously untreated in the metastatic setting, have an ECOG performance status of 2 or less, and have frozen tumor tissue available for testing.
A quantitative reverse transcription PCR with a 35-gene signature was performed on frozen tissue samples to classify patients into the 4 molecular groups. Following classification, patients were randomized to their respective treatments.
Single-agent nivolumab was dosed at 240 mg and given intravenously every 2 weeks. The combination regimen consisted of 3 mg/kg of intravenous (IV) nivolumab plus 1 mg/kg of IV ipilimumab given every 3 weeks for 4 doses, followed by 240 mg of nivolumab alone. Sunitinib or pazopanib were given as per recommended doses.
Patients were treated until progression as defined by RECIST 1.1 criteria, death, unacceptable toxicity, or study conclusion at 18 months.
Between June 2017 and July 2019, 15 centers in France screened 308 patients for potential enrollment on the study. In total, 106 patients were excluded from the trial due to not meeting inclusion criteria (n = 43), not having available frozen tissue and/or insufficient quality of specimen (n = 57), declining to participate (n = 4), or patient death during screening (n = 2).
In the target cohort (TC), baseline characteristics were similar between all randomized patients. Common sites of metastases included the lung, lymph node, bone, liver and brain. Additionally, the majority of patients (>50%) had intermediate or poor–risk disease by International Metastatic RCC Database criteria.
At a median follow-up of 16 months, the median progression-free survival (PFS) in Group 1 was 8.0 months with the combination of nivolumab and ipilimumab versus 4.6 months with nivolumab alone. In Group 4, the median PFS was 12.2 months versus 7.8 months, respectively.
The median PFS in Group 2 was not reached in the TKI arm compared with 10.4 months with nivolumab plus ipilimumab. In Group 3, the Kaplan-Meier curve was not shown due to the limited number of patients enrolled in the cohort.
At the median follow-up time, 16% of overall survival (OS) events were observed, which translated to immature OS findings.
No statistical tests were performed due to the noncomparative design of the BIONIKK trial.
The median duration of response (DOR) in Group 1 was 6.7 months with nivolumab alone versus 13.9 months with the combination. The median time to response (TTR) was 2.5 months and 2.2 months, respectively. Comparatively, the median DOR in Group 4 was 15.0 months with nivolumab versus 12.3 months with the combination. The median TTR was 2.2 months and 3.5 months, respectively.
The DOR with the combination was 12.0 months in Group 2 versus 20.2 months in Group 3. With a TKI, the DOR was 8.4 months in Group 2; the DOR was not evaluable (NE) in Group 3. The median TTR with the combination was 2.3 months in Group 2 versus 2.2 months in Group 3. With a TKI, the median TTR was 3.1 months and NE, respectively.
“The main findings are that the vast majority of patients responded at the first CT scan,” said Vano, referencing a swimmer plot that was presented with the data. “This is particularly the case for [treatment with] nivolumab [alone] in group 4. In Group 2, around 30% of patients responded very late—after 10 months—which is very uncommon with TKIs.”
Notably, there were no new safety signals among all randomized patients compared with previously published data. In arm A (n = 61), grade 3 or 4 treatment-related adverse effects (TRAEs) were observed in 18% of patients. In Arm B, grade 3 or 4 TRAEs were observed in 44% of patients. Finally, in Arm C (sunitinib, n = 33; pazopanib, n = 7), grade 3 or 4 TRAEs were observed in 55% of patients.
Treatment-related deaths occurred in 0 patients in Arm A, 1 patient in Arm B, and 2 patients in Arm C.
Though early, a transcriptomic analysis of immune cells distribution showed that tumors in Group 4 have the highest level of infiltration by immune cells, particularly cytotoxic lymphocytes.
“A huge biomarker program including transcriptomic analyses, in situ protein expression, and analyses of circulating immune cells is currently ongoing,” concluded Vano.