Long-Term KEYNOTE-426 Data Support Pembrolizumab/Axitinib as Frontline Standard in Advanced RCC

Elizabeth R. Plimack, MD

Pembrolizumab (Keytruda) plus axitinib (Inlyta) continued to significantly improve efficacy over sunitinib (Sutent) in patients with previously untreated metastatic renal cell carcinoma (mRCC), according to updated results from the phase 3 KEYNOTE-426 trial.

The randomized, open-label trial evaluated the efficacy and safety of pembrolizumab in combination with axitinib versus sunitinib monotherapy as a first-line treatment in 861 patients with newly diagnosed or recurrent stage IV clear cell RCC who were classified as

International Metastatic RCC Database Consortium (IMDC) favorable, intermediate, or poor risk. Results showed that pembrolizumab plus axitinib improved overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).

Results showed that in the intent-to-treat (ITT) population, the OS rate at 24 months was 74% with the combination versus 66% with sunitinib alone (HR, 0.68; 95% CI, 0.55-0.85; P <.001). The PFS rates at 24 months in this population were 38% and 27% with the combination versus sunitinib, respectively (HR, 0.71; 95% CI, 0.60-0.84; P <.0001). Additionally, the confirmed ORR was 60.2% with pembrolizumab plus axitinib (95% CI, 55.4-64.8) versus 39.9% (95% CI, 35.2-44.7) with sunitinib (P <.0001).

When broken down by IMDC risk groups, the OS rates in the favorable-risk subgroup were 85% versus 88% with the combination versus sunitinib, respectively (HR, 1.06; 95% CI, 0.60-1.86); the PFS rates were 45% and 35%, respectively (HR, 0.79; 95% CI, 0.57-1.09), and the ORR was 69.6% versus 50.4%, respectively. In the IMDC intermediate-/poor-risk subgroup, the OS, PFS, and ORR all favored the combination. Specifically, the OS rates were 69% versus 56% with the combination and sunitinib respectively (HR, 0.63; 95% CI, 0.50-0.81); the PFS rates were 34% versus 23%, respectively (HR, 0.69; 95% CI, 0.56-0.84); and the ORRs were 55.8% versus 35.2%, respectively.

An exploratory analysis was also conducted in which investigators examined the depth of response with the combination and its relationship to OS in the subgroup of patients who reached the 6-month mark.

“We saw that, with pembrolizumab plus axitinib, there was a relationship between depth of response and survival: The deeper the response, the longer patients lived,” said lead study author Elizabeth R. Plimack, MD. “That relationship wasn't really clear in the sunitinib arm. From a clinical perspective, that means that a patient with a near complete response (CR) or a deep response is likely to do very well on pembrolizumab plus axitinib; this is helpful to know when we are counseling patients.”

In an interview with OncLive, Plimack, who is also the chief of the Division of Genitourinary Medical Oncology, the director of Genitourinary Clinical Research, and a professor in the Department of Hematology/Oncology at Fox Chase Cancer Center, further discussed results from the updated phase 3 KEYNOTE-426 trial and the implications of these data on clinical practice.

OncLive: Could you provide some background to the KEYNOTE-426 trial? What were the significance of those data?

Plimack: [Data from the] KEYNOTE-426 [trial were] presented over 1 year ago at the Genitourinary Cancers Symposium. The trial evaluated the combination of pembrolizumab plus axitinib versus sunitinib in frontline RCC. Both primary end points of the trial—OS and PFS—were met, which was very exciting. [The combination was since] approved and we've been using it in the clinic. However, one of the key questions when we consider this combination has been, ‘What are the long-term results?’ This is actually one of the most important questions in our field because we want to care for patients over the long-term and we want to [extend benefit with the combination] for as long as possible.

The updated results presented during the 2020 ASCO Virtual Scientific Program showed that we're maintaining the benefit of pembrolizumab plus axitinib over sunitinib with time. What's interesting to me though are the landmark analyses. At 1 and 2 years, we're really hitting the high watermark for OS in the overall population. Many factors contribute to that, but it's certainly encouraging that we're seeing a much higher percentage of patients reach those meaningful landmarks.

In this study, some of the interesting findings with time are that, in the favorable-risk group, we have yet to see the OS curves split. We hope to see that with time, but it’s possible that we may not; this is a group of patients who do very well overall, which is great. As such, whether the combination makes a difference over a single agent for that group remains to be seen. For the intermediate- and poor-risk groups, however, the difference [between the combination and the comparator] is clear with regard to OS, PFS, and response rate.

Do you believe these data will better inform how to decide amongst different available frontline treatment options?

What's interesting in oncology is that whatever comes first tends to be something that's hard for people to give up. That being said, ipilimumab (Yervoy)/nivolumab (Opdivo) came first, and people still like to use that combination. It's not a bad regimen, but I haven't seen data that tells me that any given patient should preferentially receive ipilimumab plus nivolumab over pembrolizumab plus axitinib. One point that is often brought is up is that we have longer follow-up with ipilimumab plus nivolumab and some people are doing really well on this regimen long term. These data support that this will hopefully, and probably, also be the case for pembrolizumab plus axitinib.

I'll bring up a poster presentation delivered at this year's ASCO; it was follow-up [data] from the phase 1 experience with pembrolizumab plus axitinib. While not randomized, and certainly in a select phase 1 population, those data have the benefit of much longer follow-up by many years, and those survival curves continue to look excellent. I believe these benefits will be seen with time and hopefully we can be flexible to incorporate this relatively new combination into our treatment paradigm for RCC. The data with avelumab (Bavencio) plus axitinib (Inlyta) are similar but the randomized trials didn't show a survival benefit, so it's slightly weaker in terms of data.

Is biomarker work being done in KEYNOTE-426 to further understand which patients will benefit most from this regimen?

A lot of biomarker research efforts are going, but nothing is yet ready for primetime. I would refer everyone to the presentation on biomarkers in kidney cancer that was delivered by Martin H. Voss, MD, of Memorial Sloan Kettering, at the Genitourinary Cancers Symposium. It’s just hard to find markers that really predict response, so I don’t see that happening based on what we know to date. That being said, we continue to look to look for that. Randomized trials are a treasure trove of data for which to seek those biomarkers out.

Has the ongoing COVID-19 pandemic impacted the way you are giving pembrolizumab and axitinib?

COVID-19 made us change [how we approach treatment] really quickly over the past several months. A month ago, I may have given a different answer. However, here, at Fox Chase Cancer Center, our peak has declined. We are figuring out how to stay COVID negative through the continual usage of testing and masks. I’m hopeful. In our current paradigm, we are going to treat everyone as we would have prior to the pandemic. Patients are more anxious, especially since they can't come with visitors. However, we are bringing treatment decision-making back to the usual standard. Hopefully, this will be the case at all centers soon. Cancer is a life-threatening condition as well, so our patients still need therapy. We hope we can continue to deliver that treatment to them safely.

Reference

Plimack ER, Rini BI, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma: updated analysis of KEYNOTE-426. J Clin Oncol. 2020;38(suppl 15):5001. doi:10.1200/JCO.2020.38.15_suppl.5001