Grivas P, et al. ESMO 2017:857P

Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: Outcomes from KEYNOTE-052 in senior patients with poor performance status

Background

Previous results from the phase II KEYNOTE-052 study exhibited clinically meaningful anti-tumour activity following pembrolizumab treatment in cisplatin-ineligible patients with advanced urothelial cancer (UC), with an objective response rate (ORR) of 29% and an unmet median duration of response (DOR) after a median follow-up of 8 months.1 Subset analyses of the anti-tumour activity and safety of pembrolizumab treatment in senior patients (aged ≥65 years and ≥75 years) with poor Eastern Cooperative Oncology Group performance status (ECOG PS) were presented at the ESMO 2017 Annual Congress.2

Study design

  • KEYNOTE-052 was a phase II, open-label trial.
  • Eligibility criteria included:
    • Histologically or cytologically confirmed advanced, unresectable, or metastatic UC of the renal pelvis, ureter, bladder, or urethra (with transitional and mixed transitional/non-transitional cell histologies);
    • Cisplatin ineligibility;
    • Lack of prior systemic chemotherapy for advanced or metastatic UC;
    • ECOG PS of 0–2;
    • Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; and
    • Obtainable tumour sample for biomarker analysis.
  • Detailed inclusion and exclusion criteria can be found at https://clinicaltrials.gov/ct2/show/NCT02335424.
  • Patients received intravenous infusions of 200 mg pembrolizumab every 3 weeks for 24 months or until confirmed disease progression, intolerable toxicity, or withdrawal as per physician/patient choice.
  • Response assessment was conducted at Week 9, then every six weeks for the first year and every 12 weeks thereafter.
  • The primary endpoint was ORR assessed by central imaging vendor review according to RECIST version 1.1.
  • Secondary endpoints were DOR, overall survival (OS), progression-free survival (PFS), and safety.
    • Secondary efficacy endpoints were assessed by central imaging vendor review according to RECIST version 1.1.
  • Tumour programmed death-ligand 1 (PD-L1) expression was defined as having a combined positive score (CPS) of ≥10.
    • This cutoff was established based on the first 100 patients enrolled, and validated by determining ORR in all subsequent patients.
  • Efficacy and safety analyses were conducted on the following four patient groups:
    • Aged ≥65 years;
    • Aged ≥75 years;
    • Aged ≥65 years with an ECOG PS of 2; and
    • Aged ≥75 years with an ECOG PS of 2.

Key findings

Baseline characteristics and disposition

  • Of the 370 patients that were treated, 82% were aged ≥65 years, 48% were aged ≥75 years, 32% were aged ≥65 years with an ECOG PS of 2, and 21% were aged ≥75 years with an ECOG PS of 2.
  • The percentage of patients receiving ongoing treatment as of the data cut-off date (March 9, 2017) was comparable among the patient groups, with 24%, 17%, 21%, and 19% of patients aged ≥65 years, ≥75 years, ≥65 years with an ECOG PS of 2, and ≥75 years with an ECOG PS of 2, respectively, continuing treatment.
  • Baseline characteristics were comparable among the patient groups, with the exception of reasons for cisplatin ineligibility.
    • Renal dysfunction and ECOG PS of 2 were the majority of reasons for cisplatin ineligibility for patients aged ≥65 years (80%) and ≥75 years (80%), whereas ECOG PS of 2 and the combination of ECOG PS of 2 and renal dysfunction were the majority of reasons for patients aged ≥65 years with an ECOG PS of 2 (91%) and ≥75 years with an ECOG PS of 2 (89%).
  • The median follow-up for all patients was 10 months.

Efficacy

  • ORRs were comparable among all patient groups and with that of the total patient population, indicating that increased age or poor PS does not impact the ORR to pembrolizumab. (Figure 1)
    • Median ORRs were 29%, 27%, 29%, and 32% in patients aged ≥65 years, ≥75 years, ≥65 years with an ECOG PS of 2, and ≥75 years with an ECOG PS of 2, respectively.
    • An informal analysis of ORR in a small group of patients aged ≥85 years demonstrated a similar rate of 28%.
  • Higher ORRs were demonstrated by patients with a CPS ≥10, similar to results from the total patient population. (Figure 2)
    • Median ORRs were 52%, 50%, 52%, and 55% in patients with a CPS ≥10 and aged ≥65 years, ≥75 years, ≥65 years with an ECOG PS of 2, and ≥75 years with an ECOG PS of 2, respectively.
  • Across all patient subsets, a similar proportion of patients exhibited a reduction in tumour size.
  • The median time to response and DOR were comparable among all patient groups.
    • All groups exhibited a median time to response of 2.1 months.
    • The response duration was not reached for patients aged ≥65 years, ≥75 years, and ≥65 years with an ECOG PS of 2, though patients aged ≥75 years with an ECOG PS of 2 had a median DOR of 9.7 months (range: 2.8–19.6).
    • The proportion of patients with responses lasting ≥6 months was 83%, 77%, 76%, and 72% for patients aged ≥65 years, ≥75 years, ≥65 years with an ECOG PS of 2, and ≥75 years with an ECOG PS of 2, respectively.
  • OS and PFS of all patient groups were similar to those of the total study population, indicating that poor PS or advanced age did not impact these factors.
    • OS rates of 67%, 64%, 56%, and 55% were demonstrated at Month 6 by patients aged ≥65 years, ≥75 years, ≥65 years with an ECOG PS of 2, and ≥75 years with an ECOG PS of 2, respectively.
    • PFS rates of 34%, 32%, 33%, and 32% were exhibited at Month 6 by patients aged ≥65 years, ≥75 years, ≥65 years with an ECOG PS of 2, and ≥75 years with an ECOG PS of 2, respectively.

Figure 1. Objective response rate

Figure 2. Objective response rate in patients with CPS ≥10 (validation set)

Safety

  • The safety profile of pembrolizumab in patients with poor ECOG PS and advanced age was comparable to that of the total patient population. (Table 1)
    • Similar incidences of Grade 3–5 treatment-related adverse events (TRAEs) were exhibited by patients aged ≥65 years (20%), ≥75 years (18%), ≥65 years with an ECOG PS of 2 (20%), and ≥75 years with an ECOG PS of 2 (19%) as the total study population (19%).
    • Though the most common TRAEs were shared between the patient subgroups, the incidence of some AEs differed with ECOG PS. (Table 2)

Table 1. Summary of adverse events

Table 2. Treatment-related AEs occurring in ≥5% of patients

Key conclusions

  • Results from this subgroup analysis confirm that first-line pembrolizumab generates a well-tolerated, clinically meaningful anti-tumour response in cisplatin-ineligible, senior patients with advanced UC and poor ECOG PS.
    • Notably, these results are consistent with those of the overall patient population.
  • Pembrolizumab provides a new treatment option for senior patients with advanced UC and poor ECOG PS, who are usually only offered best supportive care.

References: 1. O’Donnell PH, Grivas P, Balar AV, et al. Biomarker findings and mature clinical results from KEYNOTE-052: First-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC). J Clin Oncol (ASCO Annual Meeting) 2017;35(Suppl):abstr 4502. 2. Grivas P, Plimack ER, Balar AV, et al. Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: outcomes from KEYNOTE-052 in senior patients with poor performance status. ESMO Annual Congress Abstracts 2017:857P.