Mario Sznol, MD
With the combination of PD-1 inhibitors and VEGF TKIs now poised to move into the frontline setting for patients with metastatic renal cell carcinoma (mRCC), the field has significantly evolved over the last decade. However, the next steps in achieving even more durable responses are unclear, said Mario Sznol, MD.
The CheckMate-214 study, which compared nivolumab (Opdivo) and ipilimumab (Yervoy) with single-agent sunitinib (Sutent) in the frontline setting, led to the proof-of-concept for combination immunotherapy in this space. After the anti–PD-1/CTLA-4 combination received FDA approval for the frontline treatment of intermediate- and poor-risk patients with advanced RCC, research was released on combining VEGF TKIs with checkpoint inhibitors in this space.
At the 2019 Genitourinary Cancers Symposium, results from the KEYNOTE-426 trial showed that this novel approach has the potential to be practice changing. In that study, the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) resulted in a 47% reduction in the risk of death versus sunitinib (HR, 0.53; 95% CI, 0.38-0.74; P
These data led to the FDA’s decision to grant a priority review designation to a supplemental biologics license application for the combination in February 2019, for use as a frontline treatment for patients with advanced RCC.
A similar combination, avelumab (Bavencio) plus axitinib, is also moving through the pipeline. At the 2018 ESMO Congress, data from the JAVELIN Renal 101 study showed that the combination significantly improved progression-free and overall survival (OS) compared with TKI monotherapy in patients with treatment-naïve mRCC.2 This benefit was observed across all subgroups, irrespective of PD-L1 expression. As such, this combination also received a priority review designation by the FDA.
For both combinations, the FDA is expected to make a final decision by June 2019.
In an interview with OncLive
, Sznol, professor of medicine and co-director of the Cancer Immunology Program and the Yale SPORE in Skin Cancer at Yale Cancer Center, highlighted recent advances made with immunotherapy in RCC and shed light on what the future may hold.
OncLive: What are the key data supporting an immunotherapy approach in mRCC?
: There are 2 or 3 key trials. CheckMate-214 compared ipilimumab and nivolumab to sunitinib, showing that at least in a subset of mRCC—the intermediate- and poor-risk group—the combination improved survival compared with TKI monotherapy. That is probably the major trial in our field. It's clear that anti–PD-1 alone is active in this setting, but it isn't clear yet whether or not the combination is better than anti–PD-1 by itself. The randomized trial data are clearly [in favor of] the combination. We also have a dosing schedule that is really well tolerated.
The other major advance is the combination of anti–PD-1 with VEGF TKIs. There are 2 key trials in that space. One is a randomized trial of pembrolizumab plus axitinib and the other is avelumab plus axitinib; both are being compared with sunitinib. The one that has survival data available is KEYNOTE-426, and it showed that across all subgroups, there appeared to be an advantage with the combination. Right now, the major decision to make for someone who comes into the clinic with mRCC is whether they should receive ipilimumab plus nivolumab or a checkpoint inhibitor with a VEGF TKI. We do not have clear data to guide us yet, although we can probably make some determination based on subgroup analyses, such as PD-L1 expression.
The other key data that have recently been presented is the activity of these agents in non–clear cell RCC. Anti–PD-1 is clearly active in non–clear cell disease—in about 25% of these patients. Actually, many more patients probably get some level of tumor regression. We actually now have a treatment that works for that subgroup of patients. Before, neither the VEGF TKIs nor the mTOR inhibitors gave us substantial activity in that non–clear cell subgroup.
With these new advances, how do you decide which therapies to use in which patients?
Since ipilimumab/nivolumab has not yet been compared with anti–PD-1/VEGF TKI, we don't really know which one will be better. If you actually look at the demographics of those studies, they aren't exactly identical. You can't say that, because the 1-year OS is better in one study, that one combination is clearly better than the other. You have to look at individual subgroups of patients—the good-risk, the intermediate-risk, and the poor-risk patients, based on either the International Metastatic Renal Cell Carcinoma Database Consortium or Motzer criteria. You probably even have to look at PD-L1 expression within those subgroups. However, the data have not been presented that way, so at this point you can't make the decision of which combination is best.