Progression-free and overall survival in patients with previously untreated, advanced renal cell carcinoma continued to show improvements with the combination of pembrolizumab and axitinib versus sunitinib in the phase 3 KEYNOTE-426 trial.
Progression-free and overall survival (OS) in patients with previously untreated, advanced renal cell carcinoma (RCC) continued to show clinically meaningful improvements with the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) versus sunitinib (Sutent). Efficacy of the combination was demonstrated in the phase 3 KEYNOTE-426 trial whose results were presented during the 2020 American Society of Clinical Oncology Virtual Scientific Program.1
Results showed that, at a minimum follow-up of 23 months, the median OS was not reached with pembrolizumab plus axitinib versus 35.7 months with sunitinib, leading to a 32% reduction in the risk of death in the intent-to-treat (ITT) population (HR, 0.68; 95% CI, 0.55-0.85; P <.001). The 1- and 2-year OS rates were 90% and 74% with pembrolizumab/axitinib and were 79% and 66% with sunitinib, respectively.
The median progression-free survival (PFS) in the ITT population was 15.4 months with pembrolizumab/axitinib compared with 11.1 months with sunitinib, leading to a 29% reduction in the risk of disease progression or death (HR, 0.71; 95% CI, 0.60-0.84; P <.0001). The 1-year and 2-year PFS rates were 60% and 38% with pembrolizumab/axitinib versus 48% and 27% with sunitinib, respectively.
“These results continue to support pembrolizumab plus axitinib as a standard of care for patients with previously untreated advanced RCC,” lead study author Elizabeth R. Plimack, MD, MS, chief of the Division of Genitourinary Medical Oncology and director of Genitourinary Clinical Research at Fox Chase Cancer Center, said in a presentation during the meeting.
In April 2019, the FDA approved the combination of pembrolizumab and axitinib for the frontline treatment of patients with advanced RCC, based on earlier findings of KEYNOTE-426. In these data, the combination significantly improved overall response rates (ORRs), progression-free, and OS versus sunitinib in this patient population.2
Those data showed that, at a median follow-up of 12.8 months, pembrolizumab/axitinib led to a 47% reduction in the risk of death versus sunitinib (HR, 0.53; 95% CI, 0.38-0.74; P <.0001), and the median OS was not reached in either arm. Moreover, there was a 31% reduction in the risk of disease progression or death with pembrolizumab/axitinib over sunitinib (HR, 0.69; 95% CI, 0.57-0.84; P <.001), and a higher ORR with combination, at 59.3%, versus 35.7% with sunitinib, respectively (P <.001).
The approval marked the first time that an anti–PD-1 therapy became available as part of a combination regimen that significantly improved OS, progression-free survival (PFS), and ORR compared with sunitinib in this patient population.
In the open-label KEYNOTE-426 study (NCT02853331), 861 patients with newly diagnosed or recurrent stage IV clear cell RCC were randomized 1:1 to receive pembrolizumab at 200 mg intravenously every 3 weeks for up to 35 cycles plus axitinib at 5 mg orally twice daily (n = 432) or sunitinib at 50 mg orally once daily for the first 4 weeks of each 6-week cycle (n = 429). Treatment was administered until disease progression, unacceptable toxicity, or if patients dropped out of the trial.
To be eligible for enrollment, patients had no prior systemic treatment for advanced disease, had a Karnofsky performance status of ≥70, measurable disease per RECIST v1.1 criteria, provision of a tumor sample for biomarker assessment, and adequate organ function.
The median age was 62 years; 73% of patients were male and 27% were female. Patients were stratified by geographic region (North America vs western Europe vs rest of world), and by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group as having favorable-, intermediate-, or poor-risk disease.
Roughly half of patients were from the rest of world (51.7%), 24.4% of patients were from western Europe, and 24.1% of patients were from North America. A total 31.2% of patients had favorable-risk disease, 56.2% of patients had intermediate-risk disease, and 12.6% had poor-risk disease. Additionally, 18.2% of patients had sarcomatoid features, 60.7% had a PD-L1 combined positive score of 1 or higher, and three-fourths of patients (75.1%) had 2 or more metastatic sites. A total 83.4% of patients underwent prior nephrectomy. The coprimary end points of the trial were OS and progression-free survival (PFS) in the ITT population; secondary end points were ORR in the ITT population, as well as duration of response (DOR) and safety.
At the first planned interim analysis, the data cutoff date was August 24, 2018, with a minimum of 7 months of follow-up. In the analysis presented at the 2020 ASCO Virtual Scientific Program, the data cutoff date was 23 months of minimum follow-up. Because the trial’s objectives were previously met, P values used throughout the updated data set are nominal, Plimack explained.
In the pembrolizumab/axitinib arm, updated results showed that 22.8% of patients were continuing treatment while 72.7% of patients had discontinued therapy; in the sunitinib arm, these rates were 17.9% and 82.1%, respectively.
For those on the pembrolizumab/axitinib arm who discontinued treatment (n = 312), 54.5% received subsequent therapy versus 69.3% of those who discontinued sunitinib (n = 349). These treatments included any PD-1/PD-L1 inhibitor (8.0%), any VEGF-directed agent (49.0%), and other (15.1%) for those who were previously on pembrolizumab/axitinib. For patients on the sunitinib arm, 48.4% were subsequently on a PD-1/PD-L1 inhibitor, 45.6% were on a VEGF inhibitor, and 15.5% were on a treatment labeled as other.
“An important point to make about this data set is that patients may have not received subsequent therapy for a multitude of reasons,” Plimack said. “They could have not needed it, they could have been in deep response, had maintained [response] off of therapy, or were on a treatment break. They may have been too ill to receive it, or they may have been in a health care system where they didn’t have access to adequate subsequent therapy.”
Additional results with the longer follow-up showed that the confirmed ORR in the ITT population was 60.2% with pembrolizumab/axitinib compared with 39.9% with sunitinib. The pembrolizumab/axitinib arm comprised an 8.8% complete response (CR) rate, 51.4% partial response (PR) rate, a 23.1% stable disease (SD) rate, and an 11.3% progressive disease (PD) rate. In the sunitinib arm, the CR rate was 3.0%, and the PR rate was 36.8%; the SD rate was 35.0%, and the PD rate was 17.2%. The median DOR was 23.5 months (range, 1.4+ to 34.5+) and 15.9 months (range, 2.3 to 31.8+) with pembrolizumab/axitinib and sunitinib, respectively.
“We see with extended follow-up that the curves remain separated. The difference in OS remains statistically significant,” Plimack explained of the OS data in the ITT population. “An important point to make about the 24-month landmark is that this is the point at which patients on the study ceased receiving infusions of pembrolizumab, and were allowed per protocol to either continue off both therapies or on axitinib alone. Further evaluation of data beyond this cutoff will be critical in understanding the implications of infusional treatment-free survival in this patient population.”
The updated findings also included OS, PFS, and ORR by IMDC risk groups. In favorable-risk patients, no benefit was yet seen with pembrolizumab/axitinib. The median OS was not reached with pembrolizumab/axitinib nor sunitinib (HR, 1.06; 95% CI, 0.60-1.86); the median PFS was 20.8 months with pembrolizumab/axitinib and 18.0 months with sunitinib (HR, 0.79; 95% CI, 0.57-1.09). The ORR was 69.6%, including an 11% CR rate, with pembrolizumab/axitinib versus a 50.4% ORR and a 6% CR rate with sunitinib.
“There are several reasons for this; one is perhaps patients with favorable-risk disease don’t benefit from the addition of [immune-based] therapy,” said Plimack. “However, another potential explanation is that patients with favorable risk have just that: favorable-risk disease, and a known excellent OS. It’s possible that, with time, these curves may split.”
In the IMDC intermediate-/poor-risk subgroup, the benefit with pembrolizumab/axitinib was more pronounced; the median OS was not reached with pembrolizumab/axitinib and 28.9 months with sunitinib (HR, 0.63; 95% CI, 0.50-0.81). Additionally, the median PFS was 12.7 months and 8.3 months with pembrolizumab plus axitinib and sunitinib, respectively (HR, 0.69; 95% CI, 0.56-0.84); the ORR and CR rate was 55.8% and 8% with pembrolizumab/axitinib versus 35.2% and 2% with sunitinib.
Regarding safety, treatment-related adverse events (TRAEs) of any grade occurred in 96.3% and 97.6% of patients on pembrolizumab/axitinib compared with sunitinib, respectively, the most common of which in both arms were diarrhea, hypertension, hypothyroidism, fatigue, palmar-plantar erythrodysesthesia, decreased appetite, nausea, increase in alanine aminotransferase level, and increase in aspartate transaminase levels.
Grade 3 to 5 TRAEs were slightly higher in the pembrolizumab/axitinib arm at 66.9% versus 62.4% of sunitinib-treated patients, respectively. Four deaths were reported on the pembrolizumab/axitinib arm and 6 deaths were reported on the sunitinib arm. The most common adverse events (AEs) of interest were mainly immunotherapy related, and included hypothyroidism and hyperthyroidism; the rate of grade 3 to 5 of these AEs were around 15% with pembrolizumab/axitinib, which is consistent with earlier reports.
Furthermore, 94% of patients on pembrolizumab/axitinib experienced a reduction in tumor burden versus 86% of those on sunitinib.
A post hoc 6-month exploratory landmark analysis was designed to explore the relationship between depth of response and survival with the updated KEYNOTE-426 findings. Investigators pooled all randomized patients, and then selected those who survived to 6 months (n = 745). Patients were then divided into subgroups based on maximum sum target lesion reduction from baselines up to the 6-month landmark.
At 6 months, patients who achieved a CR had good outcomes in both the pembrolizumab/axitinib and sunitinib arms. However, in pembrolizumab/axitinib-treated patients who achieved a near CR, considered to be 80% tumor shrinkage, had nearly comparable outcomes to those who had a CR; this comparison was not the same for those who received sunitinib, Plimack concluded.