ECC 2015. News in Lung Cancer: KEYNOTE-001 Trial


European Cancer Congress (ECC) 2015
Presented by the European Society for Medical Oncology

ECC 2015. LBA 33: Efficacy and Safety of Pembrolizumab (Pembro; MK-3475) for Patients (Pts) With Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Enrolled in KEYNOTE-001

J.C. Soria et al. (France)

Background: Among the first 394 pts with previously treated NSCLC treated in KEYNOTE-001 (NCT01295827), the anti-PD-1 antibody pembro was associated with an 18.0% ORR in all pts and a 41.0% ORR in 61 pts in the validation cohort with PD-L1 expression in ≥50% of tumor cells (PD-L1 tumor proportion score [TPS] ≥50%). We evaluated the efficacy and safety of pembro in the 449 pts with previously treated NSCLC enrolled in KEYNOTE-001.

Methods: Pts received pembro 2mg/kg Q3W (n = 55), 10mg/kg Q3W (n = 238), or 10mg/kg Q2W (n = 156) until confirmed progression, intolerable toxicity, or investigator decision. PD-L1 expression was assessed by immunohistochemistry using a clinical trial assay. Only slides prepared within 6 mo of staining were eligible for PD-L1 assessment. Response was assessed every 9 wk per RECIST v1.1 by central review. Pharmacokinetics were assessed at cycles 1 and 2, then every 12 wk for the first 12 mo, and every 6 mo thereafter.

Results: As of the 23 Jan 2015 data cutoff, median follow-up duration was 7.7, 16.1, and 15.5 mo, respectively, for pts treated at 2mg/kg Q3W, 10mg/kg Q3W, and 10mg/kg Q2W. Treatment-related AEs of grade 3–4 severity occurred in 10.5% of patients, and 4.0% of patients discontinued because of a treatment-related AE. There were 3 treatment-related deaths (cardiorespiratory arrest, interstitial lung disease, and respiratory arrest). In the 124 previously treated pts with PD-L1 TPS ≥50%, ORR was 35.5%, median duration of response (DOR) was 23.3 mo (range, 2.1+ to 23.3), median PFS was 5.8 mo (95% CI, 2.2–10.2), and median OS was 14.0 mo (95% CI, 10.5-NR). ORR was 18.7% in all pts and was generally similar across doses/schedules: 14.5% at 2mg/kg, 20.6% at 10mg/kg Q3W, and 17.3% at 10mg/kg Q2W (Table; Fisher exact test, P = .55). DOR, PFS, and OS were also generally similar across doses/schedules (Table). No relationship was observed between pembro exposure and antitumor response at 18 wk.


Table 1 (abstract 33LBA): Efficacy by dose/schedule


Figure 2.  Maximum Change from Baseline Tumour Size

Figure 1. Overall Response Rate


Conclusion: Pembro provides robust, durable antitumor activity in pts with previously treated advanced NSCLC, particularly those with PD-L1 TPS ≥50%. The lack of a significant exposure-response relationship and similar efficacy across doses and schedules support the use of 2mg/kg Q3W in NSCLC.


CARE Faculty Canadian Perspective:

The world of checkpoint inhibitors in NSCLC continues to evolve. Pembrolizumab a PD-l antibody shows efficacy in both squamous and non-squamous histology. Unlike many chemotherapy trials, where dose finding is determined by the maximal tolerated dose, with immune oncology checkpoint inhibitors for the PD-1 pathway, the maximum dose was never found. Thus the dose that will go forward in future trials will be lower at 2mg/kg every three weeks rather than 10 mg/kg.

Most importantly, a biomarker has been identified. In Keynote 001, the response rate among patients with high tumor PD-L1 expression defined as TPS>50%, the response rate was nearly double (35.5% vs 18.7%). In those responding patients, an impressive median duration of response was almost two years!

We expect the approval of pembrolizumab in the United States with this biomarker definition PD-L1 TPS >50% any day. Hopefully, Canada regulatory boards will follow shortly thereafter.

- Dr. Barbara Melosky on behalf of the CARE Oncology Faculty


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