Tony Berberabe, MPH

The latest results of the phase 3 KEYNOTE-426 study offered further insight into the extent of the benefitof pembrolizumab (Keytruda) plus axitinib (Inlyta) over single-agent sunitinib (Sutent) in patients with clear cell renal cell carcinoma (ccRCC).

The findings, which showed a benefit for the immunotherapy/TKI regimen in adjusted overall survival (OS) as well as in the type and timing of subsequent therapy, were shared in a poster during the 2021 ESMO Congress by principal investigator Rustem Gafanov, MD, Russian Scientific Center of Roentgenoradiology, and his coinvestigators. 

Using a 2-stage estimation (TSE) model, investigators determined the effect, called the acceleration factor, of subsequent anticancer therapy for patients in KEYNOTE-426 (stage 1). In stage 2, survival time was determined after patients received the combination treatment of pembrolizumab and axitinib vs sunitinib. Survival time was adjusted multiplicatively by the acceleration factor that was determined in stage 1 of the trial. The investigators report that patients were assumed to be at a similar stage of disease in stage 1, ie, TSE model without recensoring.

At the data cutoff of January 21, 2021, 861 patients were randomly assigned to receive either pembrolizumab plus axitinib or sunitinib. There were 432 patients assigned to the combination arm and 429 were treated; there were 429 patients assigned to the monotherapy arm, with 425 patients receiving treatment.

In the combination arm, 18 (4.2%) patients completed treatment, 62 (14.5%) patients had ongoing treatment, and 349 (81.4%) patients discontinued. In the monotherapy arm, 40 (90.4%) patients had ongoing treatment and 385 (90.6%) had discontinued.

At the median follow-up of 42.8 months (range, 35.6-50.6), 204 patients in the combination arm received subsequent treatment with 3 who completed the regimen; there were 201 patients who discontinued treatment. Among those who discontinued, 150 patients demonstrated radiographic progressive disease (PD), 31 reported adverse events (AEs), and 8 patients decided to discontinue. There were 225 patients who did not receive subsequent treatment, with 15 completing the regimen, 62 had ongoing treatment, and 148 patients who discontinued. Reasons for discontinuing included radiographic PD (n = 64), AEs (n = 52), and 11 patients decided to discontinue.

In the monotherapy arm, 281 patients received subsequent treatment. Among those, 280 discontinued treatment. There were 192 patients who discontinued because of radiographic PD, 48 patients discontinued due to AEs, and 14 patients decided to discontinue. In this arm, 145 patients did not receive subsequent treatment, with 40 patients receiving ongoing treatment and 105 patients who discontinued. Reasons for discontinuing included radiographic PD (n = 51), AEs (n = 30), and patient’s decision (n = 11).

In the combination arm, median OS was 45.7 months (95% CI, 43.6-not reached) and in the monotherapy arm, median OS was 40.1 months (95% CI, 34.3-44.2). Patients in the combination arm had a 27% lower risk of death compared with the monotherapy arm (HR, 0.73; 95% CI, 0.60-0.88). Median PFS was 15.7 months in the combination arm (95% CI, 13.6-20.2) compared with 11.1 months in the monotherapy arm (95% CI, 8.9-12.5). Patients in the combination arm had a 32% lower risk of death (HR, 0.68; 95% CI, 0.58-0.80). Patients in the combination arm had an overall response rate (ORR) of 60.4% (95% CI, 55.6%-65.1%) compared with the monotherapy arm of 39.6% (95% CI, 35.0%-44.4%).

Baseline characteristics were similar for both arms. Average age was 61 years and 71.6% of participants were male in the combination arm (n = 204) compared with 77.6% in the monotherapy arm (n = 281). Regarding PD-L1 status, combined positive score (CPS) greater than 1 was 58.3% in the combination arm vs 61.6% in the monotherapy arm. CPS less than 1 was 38.7% in the combination arm vs 34.2% in the monotherapy arm. Overall, 47.6% of patients who received the combination treatment went on to receive subsequent systemic treatment of any type compared with 66.1% of patients who received monotherapy.

Among patients who received subsequent anticancer therapy with a PD-1/PD-L1 inhibitor, 21.6% were treated with the combination (N = 432) and 74.4% were treated with monotherapy (N = 429). In the combination arm, 88.2% of patients received any VEGF/VEGFR inhibitor compared with 68.7% in the monotherapy arm. Treatment with an agent other than PD-1/PD-L1 or VEGF/VEGFR inhibitors included everolimus (Afinitor; combination arm, 26.0% vs monotherapy arm, 13.%), ipilimumab (Yervoy; 3.9% vs 7.5%, respectively), and other (7.4% vs 5.3%).

In all patients who received subsequent therapy, median time to first subsequent therapy was 15.4 months (range, 0.8-44.9) in the combination arm compared with a median of 11.6 months (range, 0.2-45.3) in the monotherapy arm. Time to receive any PD-1/PD-L1 checkpoint inhibitor was a median of 25.2 months (range, 1.6-43.7) in the combination arm compared with a median of 14.0 months (range, 0.5-45.6) in the monotherapy arm. Time to receive any VEGF/VEGFR inhibitor was a median of 15.3 months (range, 0.8-44.9) in the combination arm compared with 14.6 months (range, 0.2-44.0) in the monotherapy arm. Time to any other treatment was 19.6 months (range, 3.5-46.5) in the combination arm compared with 16.0 months (range, 1.4-38.9) in the monotherapy arm.

The investigators concluded that patients in the combination arm received less frequent PD-1/PD-L1 inhibitor therapy vs the patients in the monotherapy arm. Patients who received the combination received more frequent VEGF/VEGFR therapy vs patients in the monotherapy arm. They noted that long-term OS with adjusted analysis was similar to the first interim analysis,

 in which few patients received subsequent therapy. These results, along with the first interim analysis, continue to support the use of pembrolizumab/axitinib over sunitinib in the first-line setting.

1. Gafanov R, Powles TB, Bedke J, et al. Subsequent therapy following pembrolizumab + axitinib or sunitinib treatment for advanced renal cell carcinoma (RCC) in the phase III KEYNOTE-426 study. Presented at: 2021 European Society of Medical Oncology. September 16-21, 2021. Abstract 669P.

2. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. 

. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714

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The findings showed a benefit for the immunotherapy/TKI regimen over sunitinib in adjusted overall survival as well as in the type and timing of subsequent therapy.

Pembrolizumab/axitinib benefit in kidney cancer further detailed in pivotal trial update

Findings from cohort 2 of the EV-201 trial showed that enfortumab vedotin (Padcev) achieved a 52% confirmed objective response rate (ORR) in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who had prior exposure to a PD-1/PD-L1 immune checkpoint inhibitor.

The noncomparative phase 2 EV-201 trial included 2 cohorts. Previously reported data from cohort 1 of the study led to the December 2019 FDA accelerated approval of enfortumab vedotin for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy.

“What I'll discuss today are data from cohort 2, which specifically focused on cisplatin-ineligible patients who received immunotherapy in the frontline setting, and who were ineligible for cisplatin-containing chemotherapy at the time of study enrollment,” Arjun V. Balar, MD, said when presenting the findings during the 2021 Genitourinary Cancer Symposium.

Cisplatin-based chemotherapy is considered the standard of care in advanced disease and is associated with some survival benefit, but approximately half of all of patients are ineligible for cisplatin-containing chemotherapy. Objective responses occur in about 20% to 30% of patients unselected for PD-L1 expression.. After progression on immunotherapy, these patients have limited treatment options.

Eighty-nine patients were enrolled in cohort 2. They received 1.25 mg/kg enfortumab vedotin IV on days 1, 8, and 15 of each 28-day cycle. The primary end point was centrally confirmed ORR and the secondary end points were duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and tolerability.

Eligible patients had locally advanced unresectable or metastatic urothelial carcinoma who were previously treated with a PD-1/PD-L1 inhibitor. These patients were ineligible for cisplatin-containing chemotherapy and had no prior exposure to platinum-containing chemotherapy in the locally advanced or metastatic setting. Exclusion criteria were ongoing or sensory motor neuropathy that was grade 2 or higher, active central nervous system metastases, and uncontrolled diabetes mellitus.

At the data cutoff of September 8, 2020, 91 patients had enrolled and 89 were treated, said Balar, who is director of the genitourinary medical oncology program at New York University Langone’s Perlmutter Cancer Center in New York. Eighty-two percent of patients discontinued treatment; the most common reason for discontinuing treatment was because of progressive disease in 51% of patients. The second most common reason was the development of an adverse event (AE) in 24% of patients.

Baseline characteristics showed that patients were a median age of 75, male (74%), and 15% were obese. Two-thirds (67%) of patients exhibited a moderate decrease in kidney function. Looking at the primary site of tumor, 43% had a tumor in the upper tract. “This is somewhat expected because these are patients who may have had prior surgery and also have kidney dysfunction,” Balar said.

Regarding metastatic sites, 79% had visceral disease and 24% had liver involvement, demonstrating the overall poor prognosis of patients enrolled in the trial, added Balar.

Levels of Nectin-4 overexpression were very high in the population, obviating the need for testing prior to treatment.

The confirmed ORR was 52%. “What’s notable is a 20% rate for complete responses and only 9% of patients had progressive disease as their best response to treatment,” Balar said.

Balar noted in the subgroup analysis that responses were observed across all subgroups including patients with primary tumor sites in the upper tract (ORR = 61%), with liver metastasis (ORR = 48%), and those who did not respond to prior PD-1/PD-L1 inhibitors (ORR = 48%).

“We identified a trend toward better responses in patients who had previously done well and responded to immunotherapy, which suggests 2 potential hypotheses underlying this observation. One is simply that patients who respond to treatment are the ones who will then respond to the next course of treatment, which highlights those patients who have a generally good prognosis.

“The other, more tantalizing explanation for this observation, is that there might be the presence of synergy between both enfortumab vedotin and immunotherapy,” Balar said. “This is being actively explored in randomized studies that are currently ongoing.”

Regarding secondary end points, the median time to response was 1.81 months with some patients who have durable responses that extend beyond a year or more. Median DOR was 10.9 months.

At a median follow-up of 13.4 months, the median PFS was 5.8 months and median OS was 14.7 months.

In terms of safety, any grade overall treatment-related adverse events (TRAEs) occurred in 97% of patients and grade 3 or higher TRAEs occurred in 55% of patients. TRAEs led to discontinuations in 16% of patients, and peripheral sensory neuropathy was the most common in 4%.

Balar noted that there were 4 deaths that were considered to be treatment related by the investigator and these were a result of acute kidney injury, metabolic acidosis, multiple organ dysfunction syndrome, and pneumonitis.

“The first 3 deaths occurred within 30 days of the first dose of enfortumab vedotin. The only common denominator that is jumping out right now is a body mass index of 30 or greater. All these patients were older than 75 years and had other comorbidities, which is very common in this population,” Balar said.

TRAEs specific to enfortumab vedotin include skin reactions, peripheral neuropathy, and hyperglycemia. Median onset for skin reactions and hyperglycemia was 15 days, with median onset of peripheral neuropathy at 2.4 months.

“We observed in this study and in clinical practice that dose reduction and interruptions can lead to resolution and improvement of symptoms. What we also find particularly helpful is physical therapy to help with these toxicities. In general, these AEs are quite management,” Balar said.

Based on the data from cohort 2 of EV-201, a supplemental Biologics License Application has been filed with the FDA to expand enfortumab vedotin’s approval to include patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor and are ineligible for cisplatin.

1. Balar AV, McGregor BA, Rosenberg JE, et al. EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol. 2021;39(suppl 6).394. doi: 10.1200/JCO.2021.39.6_suppl.394

2. FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. Press release. December 18, 2019. Accessed February 12, 2021. https://bit.ly/3aYylKk

Based on these findings, an application has been filed with the FDA to expand enfortumab vedotin’s approval to include cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor.

Tony Berberabe, MPH

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Pembrolizumab/axitinib benefit in kidney cancer further detailed in pivotal trial update

Enfortumab Vedotin highly active in cisplatin-ineligible urothelial cancer