Data from the phase 3 KEYNOTE-426 continue to support pembrolizumab plus axitinib as a standard of care for patients with clear cell renal cell carcinoma.
In the phase 3 KEYNOTE-426 trial (NCT02853331), treatment with pembrolizumab (Keytruda) plus axitinib (Inlyta) continued to improve overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) over sunitinib (Sutent) monotherapy in patients with treatment-naïve clear cell renal cell carcinoma (ccRCC), according to data from a 5-year analysis data presented at the 2023 ASCO Annual Meeting.1
At a median follow-up of 67.2 months (range, 60-75), the median PFS in the intention-to-treat (ITT) population who received the doublet (n = 432) was 15.7 months (95% CI, 13.6-20.2) vs 11.1 months (95% CI, 8.9-12.5) with the monotherapy (n = 429), translating to a 31% reduction in the risk of disease progression or death (HR, 0.69; 95% CI, 0.59-0.81). The 60-month PFS rates were 18.3% vs 7.3%, respectively.
Moreover, the median OS with pembrolizumab plus axitinib was 47.2 months (95% CI, 43.6-54.8) vs 40.8 months (95% CI, 34.3-47.5) with sunitinib alone, translating to a 16% reduction in the risk of death (HR, 0.84; 95% CI, 0.71-0.99). The 60-month OS rates in the investigative and control arms were 41.9% and 37.1%, respectively.
The doublet induced an ORR of 60.6% in the ITT population, which was comprised of a complete response (CR) rate of 11.6%, a partial response (PR) rate of 49.1%, and a stable disease (SD) rate of 22.7%; 11.6% of patients experienced disease progression. In the sunitinib arm, the ORR was 39.6%, with a 4.0% CR rate, a 35.7% PR rate, and a 35.7% SD rate; in this group, 17.0% had progressive disease. The duration of response (DOR) with the doublet was 23.6 months (range, 1.4+ to 68.6+) vs 15.3 months (range, 2.3-68.3) with the monotherapy, with 26.0% and 14.4% of patients, respectively, remaining in response at 60 months.
“[These improvements with the combination] are observed despite the high percentage of subsequent therapy [received] in both arms, but especially in the sunitinib arm,” Brian I. Rini, MD, lead study author and professor of medicine in the Division of Hematology Oncology at Vanderbilt University Medical Center, said in a presentation of the data. “There was a substantial percentage of patients who made it to that 2-year mark, who completed 35 cycles of pembrolizumab, and they have very good long-term outcomes as you might expect. These data continue to support pembrolizumab plus axitinib as a standard of care for [this population].”
Patients with newly diagnosed or recurrent stage IV ccRCC were enrolled to KEYNOTE-426. To be eligible for enrollment, patients could not have received prior systemic treatment for advanced disease, and they needed to have measurable disease by RECIST v1.1 criteria.
A total of 861 patients were randomly assigned 1:1 to receive intravenous pembrolizumab at 200 mg every 3 weeks for up to 35 cycles plus oral axitinib at a twice-daily dose of 5 mg (n = 432) or oral sunitinib at a once-daily dose of 50 mg for the first 4 weeks of every 6-week cycle (n = 429). Key stratification factors included International Metastatic RCC Database Consortium (IMDC) risk group (favorable vs intermediate vs poor) and geographic region (North America vs Western Europe vs rest of world).
The co-primary end points for the pivotal trial were PFS by RECIST v1.1 criteria and OS in the ITT population. Important secondary end points included ORR by RECIST v1.1 criteria and blinded independent central review (BICR) in the ITT population. Other end points of interest comprised DOR by BICR and RECIST v1.1 criteria, as well as safety.
Data from the first interim analysis, which had a median follow-up of 12.8 months, showed significant improvements with the doublet over the monotherapy with regard to PFS, OS, and ORR. The median PFS was 15.1 months vs 11.1 months in the investigative and control arms, respectively (HR, 0.69; 95% CI, 0.57-0.84; P < .001). The median OS had not yet been reached in either arm (HR, 0.53; 95% CI, 0.38-0.74; P < .0001). The doublet induced an ORR of 59.3% vs 35.7% with the monotherapy (P < .001). These data supported the April 2019 FDA approval of the doublet for use as frontline treatment in patients with advanced RCC.2
With extended follow-up, a median follow-up of 42.8 months, pembrolizumab plus axitinib continued to provide PFS and OS benefits over sunitinib monotherapy, with hazard ratios (HRs) of 0.71 and 0.68, respectively.3 Data from the protocol-specified final analysis, which had a median follow-up of 42.8 months, showed HRs of 0.68 and 0.73 for PFS and OS, respectively.4
At the 2023 ASCO Annual Meeting, Rini presented efficacy in all patients randomly assigned to treatment.1 Notably, there was no formal hypothesis testing “because statistical significance for all the end points was met at that very first analysis,” he explained.
At the time of the data cutoff date, which was January 23, 2023, 7.0% of those on the investigative arm were still receiving treatment vs 4.5% of those on the control arm. In the pembrolizumab/axitinib arm, 88.8% of patients had discontinued treatment due to radiographic disease progression (n = 227), toxicity (n = 92), clinical disease progression (n = 14), physician decision (n = 14), and CR (n = 9), among other reasons.
Baseline characteristics were as previously published and presented. “They’re very representative of an advanced clear cell population, with a median age in the early sixties and predominantly male,” Rini said. “Accrual was about one-quarter North America, one-quarter Western Europe, and half the rest of the world. About 30% of patients [had] favorable[-risk disease] by IMDC criteria, about 12% had sarcomatoid features, and just over 80% had undergone prior nephrectomy.”
Additional data showed that in those with favorable-risk disease, the median OS in the investigative arm was 60.3 months (95% CI, 49.6-not evaluable [NE]) vs 62.4 months (95% CI, 54.1-NE; HR, 1.10; 95% CI, 0.79-1.54). The 60-month OS rates were 50.0% and 52.2%, respectively. “There’s a PFS advantage to the combination therapy for favorable-risk patients,” Rini noted. The median PFS with the doublet was 20.7 months (95% CI, 15.2-28.9) vs 17.9 months (95% CI, 12.5-20.7) with the monotherapy (HR, 0.76; 95% CI, 0.57-1.02), with 60-month PFS rates of 19.3% and 8.0%, respectively. “Response rates are high in both arms but continue to favor pembrolizumab plus axitinib,” he added. The doublet elicited an ORR of 68.8%, with a CR rate of 13.0%. With sunitinib, the ORR was 50.4%. with a CR rate of 6.1% in this group.
In those with intermediate- or poor-risk disease, “there was a strong OS signal,” Rini said. The median OS with pembrolizumab plus axitinib was 42.2 months (95% CI, 36.5-47.9) vs 29.3 months (95% CI, 23.7-34.3) with sunitinib (HR, 0.76; 95% CI, 0.62-0.93). The 60-month OS rates were 38.0% and 30.4%, respectively. The median PFS “favored pembrolizumab plus axitinib,” he added, at 13.8 months (95% CI, 12.3-18.0) and 8.3 months (95% CI, 6.6-10.0), respectively (HR, 0.68; 95% CI, 0.56-0.82). The 60-month PFS rates were 17.9% and 7.1%, respectively. The ORRs in the investigative and control arms were 56.8% and 34.9%, respectively, with CR rates of 10.9% and 3.0%, respectively.
Rini also shared findings from an ad-hoc, hypothesis-generating analysis that was conducted for OS utilizing the 2-stage estimation method to assess the potential impact of subsequent anticancer therapy on survival.
“The vast majority of patients have discontinued treatment, at nearly 90% and 95% in the arms, respectively,” Rini said. “As you would expect in kidney cancer with multiple available regimens, most of these patients will receive subsequent anticancer therapy.”
In the doublet arm, 62.2% of patients went on to receive subsequent treatment, which included a PD-1/PD-L1 inhibitor (26.6%) or a VEGF/VEGFR inhibitor (86.9%). In this group, 99.6% received at least 1 subsequent line of therapy, 50.2% received at least 2 lines, and 25.3% received 3 or more subsequent lines. In the monotherapy arm, 73.9% of patients received subsequent treatment, with 80% receiving a PD-1/PD-L1 agent and 72.0% receiving a VEGF/VEFGR inhibitor. In this arm, all patients received at least 1 line of subsequent treatment, 57.3% received at least 2 lines, and 31.3% received 3 or more lines. “[This] reflects the field of kidney cancer with active drugs, and I think, in part, [accounts] for the prolonged survivals that are seeing in this and other trials,” Rini noted.
In the analysis of OS adjusted by subsequent therapy using the 2-stage estimation method, the median OS with pembrolizumab plus axitinib was 38.8 months (95% CI, 34.6-43.6) vs 25.3 months (95% CI, 22.5-28.6) with axitinib (adjusted HR, 0.67; 95% CI, 0.52-0.84).
Additionally, PFS, OS, and ORR was evaluated for all patients who completed 35 cycles, or 2 years, of pembrolizumab. Rini referred to this effort as the completer analysis, which looked at 120 patients (27.8% of the total population) who completed treatment.
The median age in this group was 61.5 years (range, 30-89), and 72.5% were male. Regarding IMDC risk category, 37.5% had favorable risk and the remainder had intermediate or poor risk. Moreover, 14.2% of patients had sarcomatoid features, and 61.7% had at least 2 metastatic sites. The majority (87.5%) underwent prior nephrectomy.
“Not surprisingly, these patients had somewhat more favorable features [than the ITT population],” Rini noted. “Largely, a higher percentage of patients had IMDC favorable-risk [disease]; a higher percentage of patients had sarcomatoid features, which would be favorable in the context of getting immunotherapy; a lower percentage had 2 metastatic sites…and a slightly higher percentage had prior nephrectomy.”
In the completer group, the ORR with treatment with the doublet was 85.0%, with a CR rate of 18.3% and a PR rate of 66.7%. The median OS was not yet reached (95% CI, 70.6-not reached), and the 36- and 60-month OS rates were 94.2% and 70.7%, respectively. Lastly, the median PFS was 37.4 months (95% CI, 32.3-43.7); the 36- and 60-month PFS rates were 55.2% and 32.8%, respectively.
1. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma. J Clin Oncol. 2023;41(suppl 17):LBA4501. doi:10.1200/JCO.2023.41.17_suppl.LBA4501
2. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA. April 19, 2019. Accessed June 5, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-plus-axitinib-advanced-renal-cell-carcinoma
3. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;31(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8
4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced renal cell carcinoma (ccRCC): results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500