Biomarkers Needed to Refine Use of Novel Combos in mRCC

Neeraj Agarwal, MD

The combination of PD-1 inhibitors and VEGF TKIs has emerged as a promising option for the frontline treatment of patients with metastatic renal cell carcinoma (mRCC), but the lack of biomarkers and refined guidelines for patient selection remain as challenges, said Neeraj Agarwal, MD.

In February 2019, the FDA granted a priority review designation to a supplemental biologics license application for the combination of pembrolizumab (Keytruda) plus axitinib (Inlyta) as a frontline treatment for patients with mRCC. The regulatory decision came on the heels of phase III data from the KEYNOTE-426 study, which demonstrated a 47% reduction in the risk of death with the combination versus sunitinib (Sutent) and a 31% reduction in the risk of disease progression or death.¹

Specifically, data showed a median progression-free survival (PFS) of 15.1 months in patients treated with the combination versus 11.1 months for patients who received sunitinib. Median overall survival (OS) had not been reached in either arm at the time of the announcement.

Further, 12- and 18-month OS rates were both in favor of the combination, at 89.9% versus 78.3% and 82.3% versus 72.1%, respectively, according to data presented at the 2019 Genitourinary Cancers Symposium. In terms of PFS, the 12-month rates were 59.6% with the combination versus 41.1% with sunitinib, while the 18-month PFS rates were 46.2% versus 32.9%, respectively.

Beyond pembrolizumab/axitinib, the combination of avelumab (Bavencio) and axitinib has also been granted a priority review designation by the FDA in this setting. In the phase III JAVELIN Renal 101 trial, results showed that the combination significantly improved PFS and objective response rates versus sunitinib in patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.²

Agarwal, a professor of medicine, physician and an investigator at the Huntsman Cancer Institute, University of Utah, said that although there are certain patient factors that should be considered in order to inform the right treatment approach for patients with mRCC, clear guidelines have yet to be established.

In an interview with OncLive, Agarwal discussed the recent encouraging data reported in mRCC and highlighted the next steps needed to move the needle forward in this space.

OncLive: What were your biggest takeaways in mRCC data at the 2019 Genitourinary Cancers Symposium?

Agarwal: In the frontline mRCC setting, the results of the KEYNOTE-426 study were presented. That study accrued more than 800 patients and randomized them to receive the pembrolizumab plus axitinib combination or sunitinib. The PFS benefit was clearly superior with the combination therapy compared with sunitinib, with a hazard ratio of 0.69 and an absolute increase in PFS of about 4 months in the overall population. Even objective responses were higher with the combination, at about 60% compared with 39% with sunitinib. The OS was also superior in the combination arm compared with the sunitinib arm in a significant fashion. This is a very promising combination as a new option.

I would like to emphasize on the complete response (CR) rates. We know that these patients usually have long-term responses. CRs were in the range of 5% to 6%, which is clearly not as good as what we see with nivolumab (Opdivo) plus ipilimumab (Yervoy), with which we have seen CR rates of around 11%. That is probably the only concern I have with this combination. Having said that, this is a very valid option for patients who have newly diagnosed mRCC.

Another study that was updated at this meeting and originally presented at the 2018 ESMO Congress is the JAVELIN Renal 101 trial. That trial also randomized more than 800 patients to axitinib plus avelumab (Bavencio) versus sunitinib. In terms of PFS in the overall population, we saw a difference of about 5 months, very similar to what we see with the KEYNOTE-426 study. In the control arm, the PFS was approximately 8 months. It was about 13 months in the experimental arm. Response rates were, again, similarly improved in the combination arm by about 25%. However, again, I would like to come back to CRs. With this combination, CRs were about 3%.

These combinations are all promising options, but the biggest challenge for us now, which is good news for our patients, is how to best use [these agents]. We have a myriad of options now. Starting with sunitinib, which was our standard 2 years ago, we now have cabozantinib (Cabometyx), pembrolizumab plus axitinib, axitinib plus avelumab, and ipilimumab plus nivolumab. There are also more drugs coming down the line, such as lenvatinib (Lenvima) plus pembrolizumab and, hopefully, cabozantinib-based combinations.

What factors should you look at to determine patient selection?

That's a great question. It is very hard to tell right now with so many options out there, none of which have been compared with each other. For all of them, sunitinib is the control arm. In general, if patients have rapidly progressive, high-volume disease and I'm really concerned about primary progressive disease as the best response, they usually don't get to see the subsequent lines of therapy. If the concern is disease control and we need to worry about responses and PFS benefit, I would either go with the targeted therapy alone, such as cabozantinib, or with a combination such as pembrolizumab plus axitinib.

On the other hand, and this is my own clinical decision making, if I see a patient with more indolent disease where we don't have to worry about immediate disease control and we at least have time to worry about CRs, ipilimumab plus nivolumab would be my preferred option.

In terms of checkpoint inhibitor/TKI combinations, are there unforeseen challenges in terms of toxicity?

The good news is that all of these combinations are pretty well tolerated. We are not seeing any overwhelming discrepancy or difference in adverse events (AEs). The toxicity profile of these drugs seems pretty good, but it will be a learning curve to manage these AEs. How would we manage diarrhea, for example? We would need to determine if it's immune-related diarrhea or axitinib-related diarrhea, just for the sake of discussion. The first thing we can easily do is stop axitinib; it is a short half-life. If diarrhea is happening because of axitinib, it should resolve pretty quickly. If diarrhea is happening because of checkpoint inhibitors, it won't resolve. Then, we can go ahead with the management of diarrhea according to its severity and the standard guidelines. In this context, it's not that challenging.

However, I spoke about diarrhea because it's probably the most challenging AE that we see with these agents; this is an overlapping AE. With hypertension, for example, you know it's related to axitinib. Similarly, with liver enzyme elevation, which is relatively rare with axitinib, you can always stop the drug. The good thing about VEGF-related AEs is that you can stop the drug first and see if the event improves.

How has the outlook of patients with mRCC improved in recent years?

Five years ago, we had very limited options available. First-line therapy was mostly sunitinib or pazopanib (Votrient). We have much better options in the form of cabozantinib, the combination of ipilimumab/nivolumab, axitinib/pembrolizumab, and axitinib/avelumab. I would say this is an embarrassment of riches, and I wouldn't be wrong. This is great news for our patients.

Where does future research need to focus in this space?

I always come down to this conclusion: how do we select patients for a given therapy? We have so many options now, which is great, but it also makes selection very challenging for us. For that, we will need biomarkers. Right now, we don't have them. I am really looking forward to having clinically validated biomarkers in the near future.

References

1. Powles T, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus 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). Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA6_PR.