In an interview with Targeted Oncology, Yann-Alexandre Vano, MD, discussed the implications of the findings from the phase 2 BIONIKK trial of second-line treatment for patients with metastatic RCC.
Treatment with nivolumab (Opdivo) in combination with ipilimumab (Yervoy) in metastatic renal cell carcinoma (RCC) is effective, according to updated findings from the phase 2 BIONIKK trial (NCT02960906).
In the multicenter, randomized, phase 2 study, a total of 99 patients with metastatic RCC were randomized and treated with either nivolumab (n = 58), nivolumab and ipilimumab (n = 101), or an or anti-VEGFR tyrosine kinase inhibitor (TKI; n = 40) in the frontline.
At a median follow-up of 42.1 months, patients in the nivolumab arm had a median overall survival of 43.4 months (95% CI, 31.4-not reached [NR]), while rates were 52.7 months with nivolumab and ipilimumab (95% CI, 46-NR), and 38.1 months (95% CI, 33.2-NR) with a TKI.
Regarding safety, a total of 86 patients (43%) died, including 27 who were treated with nivolumab (46.5%), 39 given nivolumab and ipilimumab (39%), and 20 (50%) with TKI.
In an interview with Targeted OncologyTM, Yann-Alexandre Vano, MD, Georges-Pompidou European Hospital, Paris, France, discussed the implications of the findings from the phase 2 BIONIKK trial of second-line treatment for patients with metastatic RCC.
Targeted Oncology: Can you explain the importance of the BIONIKK study?
Vano: The BIONIKK trial is a randomized phase 2 trial performed in France in 16 centers. It is a biomarker-based trial because the patient has to be randomized to a molecular grouping of the tumor tissue. It's first-line metastatic kidney cancer, and patients were randomized according to the molecular group of the tumors. We are developing certified gene signatures, and patients are classified as tumors. Patients are classified between 1 to 4. Patients in groups 1 and 4 were randomized to receive nivolumab or nivolumab/ipilimumab. Patients in groups 2 and 3 were randomized to receive nivolumab/ipilimumab or an anti-VEGFR TKI.
Randomization is not balanced because in a prior study, we showed that groups 2 and 3 were sensitive to a VEGFR TKI, but it was the opposite for groups 1 and 4, they were not sensitive to the VEGFR TKI. That's why groups 1 and 4 were randomized between 2 I/O-based therapies groups 2 and 3 were randomized between a double I/O and a VEGFR TKI. This is a non-comparative phase 2 trial, and we already published the results last year, but we had a limited follow-up of 18 months. Now, we have presented the updated results with a more prolonged follow up with 46 months follow-up, and results, according to the molecular group, and regarding overall survival and as a second-line treatment, after progression.
What are the key findings from the study?
The main findings discussed overall survival. At the time of the publication last year, we had a median follow-up of 18 months. So, we had only 20% appearance. Now with mature data, we have over 43% appearance. If we look at overall survival by treatment arm, the median was not reached with nivolumab/ipilimumab, and it was 35 months with nivolumab, clearly inferior to nivolumab/ipilimumab. It was 45 months with VEGFR TKI, which is quite high.
When we look at it by molecular group tumor, we saw that in group 1, nivolumab/ipilimumab provided a higher overall survival, 45 months for nivolumab/ipilimumab and 35 months for nivolumab alone. In group 4, the difference is bigger. With nivolumab/ipilimumab the median OS was not reached and was 35 again for nivolumab alone, and in group 2, this group that was sensitive to VEGFR TKI, both treatment arms, TKI and nivolumab/ipilimumab, the median was not reached, and the curve looked like very similar. That's the first result.
The second result is the update of overall response rate. Again, we showed that nivolumab/ipilimumab provided a higher response rate in group 4, better than nivolumab, where we reached 55% objective response and in group 2, we had a high response rate, almost the same, at 54% with nivolumab/ipilimumab, and 58% with VEGFR TKI. Again, we confirmed that VEGFR TKI is a very effective treatment in ccRCC-2, and nivolumab/ipilimumab is very effective in ccRCC-4, but also in ccRCC-2.
The second part is treatment progression because we recorded the second-line treatment after progression. Nearly 67% of patients receive the second-line treatment and almost all 80% of these patients received the TKI, which is quite interesting to look at because most of these TKI’s are cabozantinib in 54% of the patients, which is the most effective TKI in the second-line or later. We see that the efficacy of the TKI seems to be higher plus nivolumab and ipilimumab in group 4 vs with nivolumab alone with a 33% objective response rate plus nivolumab/ipilimumab in group 4, and an 11% response rate with nivolumab in group 4.
Clearly there are some things that happened with nivolumab and ipilimumab with the TKI, particularly in group 4. In group 1, we had the same results. The median PFS was also consistent with a higher median PFS post nivo/ipi group for nearly 12 months vs 8 or 9 months in group 4. For group 2, the TKI plus TKI performed extremely well with more than 60% objective response rate, and the TKI plus nivolumab and ipilimumab group performed extremely well, also with a very high response rate and median PFS are nearly 12 months. These results suggest that the second-line is influenced or impacted by the first-line treatments and by the molecular group defined at the beginning. These are hypothesis generating data, but it demonstrates the feasibility of these kinds of biomarker driven trials, and it opens a new way to think about new designs with biomarker-based clinical trials.
What are the implications of these results and what can oncologists learn from them?
First, is it feasible? Is it possible to make some smaller trials than phase 3 trials and big phase 3 trials launched by the industry? Is it possible to make a hypothesis and to verify this hypothesis with [a] limited randomized phase 2 trial. This is the first thing. Second, this approach seems to me more clever, to select treatments based on [on the] biomarker. I think it's what we need, because in first-line metastatic RCC we have plenty of options [and] we have a lot of combinations. We don't know clearly what to do [or] what to use, and this biomarker-based approach, I think, is a new way to improve the efficacy of this treatment in [a] subgroup of patients. I think it's very important.
The drawback of that is that is, this is based on transcriptomic data. I think we have to be simpler to go on the real-life population. It's not ready for primetime now for medical oncologists to use in the clinic. We are working on the ancillary program to make these complex transcriptomic signatures simpler. more understandable, with in situ biomarkers and protein biomarkers and some biomarkers that we could do the clinic daily routine to be applicable to a broader population.
What other practice changing RCC data can you discuss?
We have some biomarker data from CheckMate-9ER and we have updates from CheckMate-9ER of cabozantinib/nivolumab vs sunitinib [Suntent] which confirms the efficacy of this combination, but again, we have plenty of combinations in the first-line and we do not know how to use it. The biomarker parts of this trial are quite negative. We have data on the triplet of cabozantinib, nivolumab, and ipilimumab. We already know that this triplet is positive on PFS, negative on overall survival for the moment, and we know also that in 2 risk patients, the triplet is not too bad. It would be a problem for this combination in the near future for the approval of this combination if these results are confirmed. Then, another study is showing the efficacy of different treatments in case of brain metastases. We see that brain metastasis is associated with a very poor prognosis and we have no clear efficacy of any treatments right now.