Rini Remarks on Remaining Questions With Pembrolizumab/Axitinib in Frontline Advanced Clear Cell RCC

Partner | Cancer Centers | <b>Vanderbilt-Ingram Cancer Center</b>

At a median follow-up of 42.8 months, frontline pembrolizumab plus axitinib continued to yield improved outcomes over sunitinib in patients with advanced clear cell renal cell carcinoma.

At a median follow-up of 42.8 months, frontline pembrolizumab (Keytruda) plus axitinib (Inlyta) continued to yield improved outcomes over sunitinib (Sutent) in patients with advanced clear cell renal cell carcinoma (RCC), according to Brian Rini, MD, who added that remaining questions in the field are focused on how durable responses will be after the PD-1 inhibitor is stopped and what the optimal duration of treatment will be in this population.

Results from the final analysis of the phase 3 KEYNOTE-426 study (NCT02853331), which were presented during the 2021 ASCO Annual Meeting, showed that pembrolizumab plus axitinib resulted in a median overall survival (OS) of 45.7 months (95% CI, 43.6–not reached) in the intent-to-treat population vs 40.1 months (95% CI, 34.3-44.2) with sunitinib (HR, 0.73; 95% CI, 0.60-0.88; P < .001). The median progression-free survival (PFS) in the investigative and control arms was 15.7 months (95% CI, 13.6-20.2) and 11.1 (95% CI, 8.9-12.5), respectively (HR, 0.68; 95% CI, 0.58-0.80; P < .0001).

Moreover, the confirmed objective response rate (ORR) was 60.4% (95% CI, 55.6%-65.1%) with the combination vs 39.6% (95% CI, 35.0%-44.4%) with sunitinib (P < .0001); the complete response (CR) rates in these arms were 10.0% and 3.5%, respectively.

“This [regimen] is a clear standard of care in RCC. The data have held up over time, with advantages in OS, PFS, ORR, and CR rates. Importantly, we are still seeing those benefits even after pembrolizumab has stopped,” Rini said. “There is clearly more follow-up and work that needs to be done, but [what we have seen thus far] is encouraging.”

In an interview with OncLive®, Rini, a professor of medicine and inaugural chief of Clinical Trials at Vanderbilt-Ingram Cancer Center, discussed results from the KEYNOTE-426 trial and the potential for pembrolizumab and axitinib as a first-line therapy for patients with advanced clear cell RCC.

OncLive®: What was the rationale for examining pembrolizumab plus axitinib in the KEYNOTE-426 trial?

Rini: Immunotherapy/TKI combos have [emerged] in kidney cancer over the past 5 years. The basic rationale [for these regimens] is 2-fold. It is known that biology is important in kidney cancer, and [we know] from many studies over the years, including recent [work with] RNA expression, that the inflammatory pathways are important; VEGF pathways are also important. Data are also available regarding VEGF immunosuppression. [We know] VEGF is immunosuppressive; therefore, by inhibiting VEGF, you allow immunotherapy to work better. [Based on] both of those rationales, many phase 3 trials, including this one, sprung up and have [shown this combination approach to be] successful compared with VEGF-targeted monotherapy.

What was the design of the trial? What did it examine?

KEYNOTE-426 was a large, randomized phase 3 trial that enrolled more than 800 patients with previously untreated clear cell metastatic RCC. Participants were randomized 1:1 to receive either pembrolizumab plus axitinib or sunitinib at 50 mg, which is the standard of care and [serves as] the standard control arm in many of these trials. The co-primary end points [of the trial] are OS and PFS in the intent-to-treat population.

What were the results at 42 months of follow-up?

At the 2021 ASCO Annual Meeting, the second long-term follow-up data [from the trial were presented]. Long-term follow up is important—especially for these combinations. The other main combination therapy in RCC is ipilimumab [Yervoy] and nivolumab [Opdivo], a dual-immunotherapy combination. The trial [examining that regimen] was conducted about 2 years before this trial, so it has longer follow-up. Long follow-up, duration of response, and durability is all clearly important.

The data that we presented at the meeting are starting to get to that longer-term range [that we like to see], which is a minimum of 3 years of follow-up and approximately 3.5 years of median follow-up. We are not quite long-term [at this point], but we are starting to get out there, in terms of [seeing] how durable responses are going to be [with this approach].

In this trial, pembrolizumab was stopped after 35 doses, or 2 years. How durable responses will be after stopping pembrolizumab is a big remaining question in the field. What will the required duration of therapy be? Can we stop the treatment, and what happens if we do? The data are mostly important [because we are starting to see] what happens to patients [in the long-term], and we [are figuring out how we] can compare this [doublet] with other regimens in with respect to long-term outcomes.


  1. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(suppl 15):4005. doi:10.1200/JCO.2021.39.15_suppl.4500