In the KEYNOTE-045 and KEYNOTE-052 trials, pembrolizumab continued to led to durable responses with no new safety signals after 5 years.
At 5 years of follow-up for both the KEYNOTE-045 (NCT02256436) and KEYNOTE-052 studies (NCT02335424), pembrolizumab (Keytruda) alone continued to elicit durable efficacy with no new safety signals when used to treat patients with platinum-resistant metastatic urothelial carcinoma (UC) and as first-line therapy in cisplatin-ineligible patients.
A total of 542 patients, including 270 to the pembrolizumab arm and 273 to the chemotherapy arm, were enrolled and randomly assigned to receive treatment in KEYNOTE-045. With a data cutoff date of October 1, 2020, the median follow-up was 62.9 months (range 58.6-70.9 months).
At 48 months, overall survival rates were 16.7% for pembrolizumab vs 10.1% for chemotherapy. The progression-free survival (PFS) rates were 9.5% and 2.7%, respectively, and the median duration of response (DOR) was 29.7 months (range 1.6+ to 60.5+ months) for pembrolizumab and 4.4 months (range 1.4+ to 63.1+ months) for chemotherapy. At 3 6months, the DOR rates in the pembrolizumab and chemotherapy groups were 44.4% and 28.3%, respectively.
In the KEYNOTE-052 study, 370 patients were enrolled, and the median follow-up was 56.3 months (range 51.2-65.3 months) at the data cut-off date of September 26, 2020. Among those enrolled, the confirmed objective response rate was 28.9% (95% CI, 24.3-33.8), and the median DOR was 33.4 months (range 1.4+ to 60.7+ months). The 36-month DOR rate was 44.8%.
Looking at safety in both studies, most treatment-related adverse events (AEs) for pembrolizumab were grade 1 or 2, and manageable, which was consistent with what has been previously reported.
“After 5 years of follow-up, pembrolizumab use in KEYNOTE-045 and KEYNOTE-052 continued to demonstrate durable responses and tolerability with no new safety signals. Consistent with prior results, pembrolizumab continued to demonstrate OS benefit versus chemotherapy in the second-line setting for patients with metastatic UC whose disease progressed on platinum-containing chemotherapy,” wrote the study authors in findings published in the Annals of Oncology.
The randomized, open-label, phase 3, KEYNOTE-045 trial evaluated pembrolizumab vs cytotoxic chemotherapy in patients with metastatic UC that progressed on platinum-containing chemotherapy. Patients were randomly assigned in a 1:1 fashion to receive pembrolizumab at 200 mg intravenously (IV) every 3 weeks or investigator’s choice of paclitaxel 175 mg/m2 IV every 3 weeks, docetaxel 75 mg/m2 IV every 3 weeks, or vinflunine 320 mg/m2 IV every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, investigator decision, after pembrolizumab was given to patients for 2 years.
Patients were eligible for enrollment in the study if they were aged 18 years and older with histologically or cytologically confirmed transitional cell–predominant UC, experienced disease progression after first-line platinum-containing chemotherapy, had ≥1 measurable lesion as per RECIST version 1.1, and had an ECOG performance status of 0-2.
The primary end points of the study were PFS and OS. Secondary end points were ORR and safety. Patient demographics and baseline characteristics were similar between treatment arms.
In the nonrandomized, open-label, phase 2 KEYNOTE-052 trial, cisplatin-ineligible patients with metastatic UC were treated with first-line pembrolizumab. Patients were required to have a histologically or cytologically confirmed diagnosis of advanced/unresectable or metastatic UC, be ineligible for cisplatin-based chemotherapy, and have not previously received systemic therapy for their disease. Additional inclusion criteria required patients to have measurable disease per RECIST version 1.1 and an ECOG performance status of 0-2.
Those enrolled received pembrolizumab at a dose of 200 mg IV every 3 weeks, also until RECIST-defined disease progression, unacceptable toxicity, withdrawal of consent, investigator decision, or completion of 2 years of pembrolizumab treatment.
The primary end point of the study was ORR with the secondary end points of DOR, PFS, OS, and safety. Additional efficacy and safety end points were analyzed among all enrolled patients who received ≥1 dose of treatment.
Patient demographics and baseline characteristics were also consistent with previous reports in this trial.
Within both trials, patients who discontinued pembrolizumab with a response or SD were eligible for up to 1 additional year of pembrolizumab therapy if they had investigator-confirmed radiographic disease progression after first-course discontinuation. Patients had to have been treated with pembrolizumab for at least 24 weeks before first-course discontinuation and were required to have had 2 or more treatments with pembrolizumab after the initial complete response (CR) date.
Patients who had stable disease (SD), partial response (PR), or CR had to have stopped pembrolizumab after finishing 24 months of treatment for reasons other than disease progression or intolerability. In this part of the study, patients must have had an ECOG performance status of 0 or 1.
Additional findings from KEYNOTE-045 showed that among the 266 patients treated with pembrolizumab and 255 treated with chemotherapy, 11 patients (4.1%) in the pembrolizumab arm and 1 patient (0.4%) in the chemotherapy arm discontinued treatment after they achieved a CR. Also, the hazard ratios for OS consistently favored pembrolizumab in subgroup analyses.
For those who received pembrolizumab, the ORR was 21.9% (95% CI, 17.1%-27.3%). A total of 27 patients (10.0%) achieved CR and 32 patients (11.9%) achieved PR. This compared with an ORR of 11.0% (95% CI, 7.6%-15.4%) with 8 patients (2.9%) who achieved CR and 22 patients (8.1%) who achieved PR in the chemotherapy arm. Additionally, 2 patients achieved CR in the pembrolizumab arm since the last analysis.
Looking at safety, 62.0% of patients receiving pembrolizumab and 90.6% of patients receiving chemotherapy experienced treatment-related AEs, with the most common being pruritus, fatigue, and nausea. For patients receiving chemotherapy, the most common treatment-related AEs were alopecia, fatigue, and anemia. Grade 3-5 treatment-related AEs were seen in 16.9% of patients in the pembrolizumab arm and 50.2% of patients in the chemotherapy arm, and 7.1% and 12.5% of patients discontinued treatment due to their treatment-related AEs in each arm, respectively.
Immune-mediated AEs or infusion reactions were observed in 19.5% of patients in the pembrolizumab arm and in 6.7% of patients in the chemotherapy arm. Most were grade 1-2 and the most common immune-mediated AEs in patients receiving pembrolizumab were hypothyroidism, pneumonitis, and hyperthyroidism. Moreover, there were 4 deaths in each arm from treatment-related AEs, as previously reported. No additional deaths occurred.
In the KEYNOTE-052 study, 370 patients were enrolled and treated with pembrolizumab, and a total of 11 patients (3.0%) discontinued pembrolizumab after reaching CR. Thirty-five patients (9.5%) achieved CR and 72 patients (19.5%) achieved PR. Another 18 patients achieved CR since the first analysis.
Patients with lymph node–only metastases treated with pembrolizumab in this study had a confirmed ORR of 46.0% (95% CI, 31.8%-60.7%), and 25.7% (95% CI, 21.0%-30.9%) for patients with visceral disease. Additionally, the median OS was 11.3 months (95% CI 9.7-13.1 months) overall, and the estimated 48-month OS rate was 19.0%. The median PFS in this trial was 2.5 months (95% CI, 2.1-3.4 months; 48-month rate, 10.3%).
There were no new safety signals reported with longer follow-up or with second-course treatment and the incidence of treatment-related AEs over time was similar for up to 1 year following treatment initiation in both the KEYNOTE-045 and KEYNOTE-052 studies. Of the 10 patients who received a second course of pembrolizumab in KEYNOTE-052, 4 (40.0%) had treatment-related AEs. Further, there were no reports of grade 4 or 5 events.
During the second course of treatment, the treatment-related AEs that occurred were diarrhea (grade 3) in 1 patient, and pruritus, hypothyroidism, decreased white blood cell count, joint stiffness, and stasis dermatitis in 1 patient each (all grade 1 or 2).