Toni K. Choueiri, MD
Over the last decade, there have been several breakthroughs made in the treatment of patients with renal cell carcinoma (RCC), as checkpoint inhibitors, targeted agents, and combination regimens received approvals from the FDA. Although the outlook is bright for patients, said Toni K. Choueiri, MD, refining what is now a complex treatment paradigm will be challenging.
For example, in the pivotal CheckMate-214 trial, the frontline combination of the checkpoint inhibitors nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated a clear survival advantage over sunitinib (Sutent) in patients with previously untreated RCC.
In the subgroup of intermediate- and poor-risk patients, the overall response rate (ORR) was 42% versus 27% in favor of the checkpoint inhibitor combination (P
<.001). However, in the favorable-risk population, the nivolumab/ipilimumab combination led to significantly worse progression-free survival (HR, 2.18; 99.1% CI, 1.29-3.68; P
<.0001) and ORR (29% vs 52%; P
=.0002) compared with sunitinib. Therefore, the current FDA approval is for use only in those who with intermediate- and poor-risk disease.
Biomarkers continue to be explored in the RCC paradigm. Although PD-L1 expression ≥1% tended to be associated with superior outcomes in CheckMate-214, it was only of prognostic value in patients treated with nivolumab alone versus everolimus (Afinitor) in the CheckMate-025 trial, Choueiri said. PD-L1 expression has been inconsistent in terms of predicting immune response.
In an interview with OncLive
, Choueiri, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, Jerome and Nancy Kohlberg Associate Professor of Medicine at Harvard Medical School, Dana-Farber Cancer Institute, discussed recent progress in RCC and where future research is heading in the field.
OncLive: What is the current role of immunotherapy in RCC?
: Immunotherapy has made its way back into RCC. We had cytokine, VEGF, and mTOR inhibitors for over 10 years. Now, immunotherapy is coming back in the form of checkpoint inhibitors, drugs that target PD-1 and CTLA-4. Initially, nivolumab was approved by the FDA as a single agent for patients who progress on a VEGF-targeted agent. This [approval] was based on an overall survival benefit [demonstrated in] CheckMate-025. Now, we have a frontline combination therapy of nivolumab and ipilimumab that showed a survival advantage over sunitinib, which was the standard of care for a decade.
[There are] different combination therapies of checkpoint inhibitors and VEGF TKIs that are making headway [in the space]. We had phase I results with TKIs that showed impressive response rates and tolerability, particularly with axitinib (Inlyta). We also had several positive phase III trials [read out].
The treatment landscape of RCC is going to remain pretty complex. Most importantly, there will be many unanswered questions. We do not yet have clear biomarkers to help us make treatment decisions. We might end up with more than 5 possible combinations in the frontline setting, all compared with sunitinib. We do not know how to sequence all of these options. We continue to investigate these questions.
What are some factors to consider when combining checkpoint inhibitors and VEGF TKIs?
We have to be careful. We have enough phase I data with agents such as axitinib and cabozantinib (Cabometyx) to suggest that these [agents] will be taken to the next stage. We also have data with bevacizumab (Avastin), which is probably the least toxic VEGF inhibitor.
Pneumonitis [is seen] with checkpoint inhibitors, but not in VEGF inhibitors. Although diarrhea is something we commonly see with both, they have different mechanisms of action and different approaches for treatment. [For example], with immunotherapy, you have to treat diarrhea with steroids. With VEGF TKIs, you usually halt therapy. As we proceed with these combinations, we have to be careful. [This area is] pretty unclear at this time.
Could you expand on the current state of biomarkers in RCC?
It is a good question, but we do not have a good answer at this stage. The biomarker story, especially with PD-L1 status, went up and down a lot in RCC. We have evidence that patients with PD-L1–positive tumors do worse with VEGF systemic therapy. In CheckMate-025, nivolumab won hands-down based on survival benefit and response rate. Patients derived benefit irrespective of PD-L1 status, although PD-L1 positivity was associated arm to arm with worse outcome.
Having said that, what we saw in CheckMate-214 was something different. OS was achieved irrespective [of PD-L1 status], but this was different. If you look at the hazard ratio, it was much higher in patients with PD-L1–positive tumors. Therefore, for now, we have to just use clinical trial data to decide which treatment to use. It is an interesting story.
With all of these treatments now available in the RCC space, what are some other challenges?
It is a very good challenge actually [because we have so many agents available]. What is going to happen is we are going to go with the preferred first-line therapy. We do not have a standard frontline therapy right now. In intermediate- and poor-risk patients, we know that there is a survival benefit with checkpoint inhibitors, so that is what we should go with generally speaking.
However, all of these combinations were tested against sunitinib. Pembrolizumab (Keytruda) and axitinib were also proven to have an advantage over sunitinib. Therefore, which one do we go with? What will probably happen is once patients progress on one frontline combination, another combination will be the next best [option] to use. However, most, if not all, of these combinations have frontline indications, but they do not, to my knowledge, have any second- or third-line data.
What is your take-home message?
The take-home message is that this is all great news for patients. Having more options is always better. Next, we have to keep working hard to customize therapy for each patient, and this includes [identifying clear] biomarkers. Tolerability of these agents is going to be an important [factor to consider] along with cost. I do not deal directly with cost, but it is obviously very important from a patient perspective. Importantly, the magnitude of difference between these agents in terms of cost is not too much. The field is continuing to evolve, and checkpoint inhibitors are here to stay.
Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Eng J Med. 2018;5(14):1277-1290. doi: 10.1056/NEJMoa1712126.