Sznol Highlights Immunotherapy Advances in RCC

Mario Sznol, MD, highlights recent advances made with immunotherapy in renal cell carcinoma and sheds light on what the future may hold.

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 <.0001).1 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.

OncLive: What are the key data supporting an immunotherapy approach in mRCC?

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.Sznol: 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.

With these new advances, how do you decide which therapies to use in which patients?

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.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.

What are some factors to consider when combining VEGF TKIs with immunotherapy?

I have my own biases, and based on the data, I would treat a good-risk, PD-L1—negative patient with a VEGF TKI and checkpoint inhibitor. Although, in all other groups, I would probably give nivolumab plus ipilimumab first for a variety of reasons. There is the reasonable toxicity of that combination and the fact that you could always rescue patients with VEGF TKIs if they don't respond to the immunotherapies.Surprisingly, the toxicity of the combination seems to be that of the individual agents. There doesn't seem to be any added or synergistic toxicity. Most of the toxicity that you see is really from the VEGF TKIs. It is going to be confusing when a patient develops diarrhea, whether it's related to nivolumab, pembrolizumab, or avelumab, or whether it's related to 1 of the VEGF TKIs. Most of the time when you use a TKI, if you stop therapy for a few days, the diarrhea goes away.

What are some other unanswered questions with immunotherapy in mRCC?

However, that's not true for the immunotherapy toxicities. There are some VEGF TKIs that you would not want to combine with anti—PD-1 therapies. Pazopanib (Votrient) is an example because it can cause severe liver toxicity. Sunitinib got a very bad rap with the initial trial, but anecdotally, I have seen that you can combine this drug fairly well with anti–PD-1. Any of the agents, except perhaps pazopanib, is suitable to be combined with anti–PD-1.There are many. For example, we don't have good predictive biomarkers; that is a clear unanswered question. We also don't know what the mechanisms of resistance are when a patient doesn't respond to immunotherapy. RCC is a disease with a low to moderate number of mutations, so why it is so responsive to immunotherapy is still a bit of a mystery. There are some potential answers like the expression of endogenous retroviruses or more indels. However, RCC is almost as responsive as melanoma to these therapies, which again, is still a mystery.

Now that we have effective immunotherapies, how has the outlook changed for patients with RCC?

I do have to say that in RCC, we do see fewer durable responses than in melanoma. Therefore, the key question is, “If a patient receives these therapies and doesn't respond, what is the reason?” It could be 20 or 30 different reasons, for which there would be 20 or 30 different combinations you might choose. One combination for all nonresponding patients is obviously not going to work. In fact, when you do those phase II trials, that signal may be so low that it could be active, but we don't detect it in a phase II trial.It's really amazing. If you go back just over a decade, all we had was interleukin-2. Then, we had VEGF TKIs, which are clearly effective agents but don't cure patients. Then, we had anti—PD-1 therapies, which provide a subset of patients with good responses and some durable responses. Then came ipilimumab plus nivolumab. Now, we have the combinations of anti–PD-1 with a VEGF TKI. The OS is going to be improved, although it is going to be hard to prove that in a randomized trial because these are therapies you are going to be giving sequentially. However, for any individual patient who comes into the clinic, their overall prognosis is much better than it would have been 10 or 15 years ago. We have 2 clear, very active approaches that we can use in almost every patient.

However, I'm not sure that we know what the next steps should be. We don't know what that next agent or next therapy should be. We don't know what to add to nivolumab plus ipilimumab or anti—PD-1 agents plus VEGF TKIs to make those combinations even more effective. You might imagine we'll see triplets coming down the road comprised of ipilimumab, nivolumab, and a VEGF TKI, and my guess is that [this approach] would be well tolerated. However, is that going to be more effective than giving these therapies sequentially? That isn't clear. There are new agents, such as the cytokines, that are coming down the road and being combined with anti–PD-1 agents. Some of the preliminary data there look exciting, but, again, how much is that going to add to what we already know?


  1. Powles T, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) vs sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. J Clin Oncol. 2019;37(suppl 7; abstr 543). doi: 10.1200/JCO.2019.37.7_suppl.543.
  2. Motzer RJ, Penkov K, Hannen JBAG, et al. JAVELIN Renal 101: a randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). Ann Oncol. 2018;29(suppl 8; abstr LBA6_PR). doi: 10.1093/annonc/mdy424.036.