Besse B, et al. ESMO 2017:1309P

Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with stage IV NSCLC


Part A (dose-escalating) of an expansion cohort study investigating necitumumab (an epidermal growth factor receptor [EGFR] inhibitor) in combination with a standard dose of pembrolizumab for patients with stage IV non-small cell lung cancer (NSCLC) was completed without dose-limiting toxicities (DLTs) and with no additive adverse events (AEs) observed. At the European Society of Medical Oncology (ESMO) 2017 Congress, the efficacy and safety results from Part B of the study were reported.1

Study Design

Study design

  • This ongoing phase Ib, multicentre, single-arm expansion cohort study is examining the safety, tolerability, and preliminary efficacy of necitumumab combined with pembrolizumab in patients with stage IV NSCLC who have progressed after one line of platinum-based therapy.
  • The primary objective was overall response rate (ORR).
    • Tumour response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
    • Initial tumour imaging was performed within 21 days of the first dose of treatment and every 6 weeks thereafter.
  • Secondary objectives included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) by RECIST version 1.1, safety, overall survival (OS), immunogenicity, and pharmacokinetics (PK) of necitumumab in the presence of pembrolizumab.
  • The null hypothesis is based on the assumption that the ORR is 20% and the alternative response rate of the combination treatment on ORR is 35%.
  • Statistical power was 83%, with a nominal one-sided alpha level of 0.10, based on a sample size of 54 evaluable patients (27 squamous and 27 nonsquamous) in Part B.
  • An interim safety analysis was performed after the first 15 evaluable patients in part B (including patients in part A who received the part B dose) completed 2 cycles of study treatment (or otherwise discontinued treatment).
  • Programmed death-ligand 1 (PD-L1) was retrospectively assessed at a central location using the immunohistochemistry 22C3 pharmDx assay.
  • PD-L1 expression was defined as follows:
    • Negative, <1% stained tumour cells;
    • Weak positive, 1%–49% stained tumour cells; and
    • Strong positive, ≥50% stained tumour cells.

Key findings

  • A total of 64 patients of squamous (n = 30) and non-squamous (n = 34) histology were enrolled (Parts A and B).
  • Overall, three patients received necitumumab 600 mg, 61 patients received necitumumab 800 mg, and all patients received pembrolizumab 200 mg.
  • The median age of patients was 65 years (range: 43–81), 71.9% of patients were male, and 43.7% had two or more prior lines of therapy.
  • In the population studied, 32 patients (50%) had PD-L1 negative status, 12 (18.8%) had weak positive status, and 10 (15.6%) had strong positive status.
  • PD-L1 status was unknown in 10 patients (15.6%).
  • At the time of data cutoff (January 26, 2017), 15 patients remained on treatment.


  • The median DOR was 10.9 months (95% CI: 4.2–NR).
  • One squamous (PD-L1 negative) and one non-squamous (PD-L1 weak positive) patient achieved a complete response.
  • In all evaluable patients, ORR was 23.4%, DCR was 64.1%, median PFS was 4.1 months, and the 6-month OS rate was 74.7%. (Table 1)
  • ORR was comparable in patients with squamous and non-squamous histology (20.0% vs. 26.5%, respectively); however, PFS was better in non-squamous versus squamous histology groups (median PFS 6.9 months vs. 2.79 months, respectively). (Figure 1)
  • Efficacy appeared to be associated with PD-L1 status.
    • In patients with a strong positive, weak positive, and negative status, ORR was 40.0%, 25.0%, and 12.5%, respectively; and median PFS was 7.6 months, 5.4 months, and 2.7 months, respectively. (Table 1)

Table 1. Efficacy results by PD-L1 status and histology

Figure 1. Progression-free survival by histology


  • Part A was completed without DLTs (9 patients; 2 squamous, 7 non-squamous).
  • Treatment-related AEs (TRAEs) of any grade were observed in 60 patients (94%), 20 patients (31%) experienced grade ≥3 TRAEs, 11 patients (17%) experienced serious TRAEs, and 2 patients (3%) experienced AEs leading to death (both grade 5 respiratory tract infections).
  • Treatment-emergent AEs occurring in 10% or more patients are presented in Table 2.

Table 2. Treatment-emergent adverse events in ≥10% of patients

Key conclusions

  • The results suggest that the combination of necitumumab and pembrolizumab has activity in a pretreated NSCLC population with a relatively high proportion of PD-L1 negative patients.
  • The safety profile observed corresponded to the individual profiles for necitumumab and pembrolizumab, with no additive toxicities.
  • The strategy to target both the programmed cell death-1 and EGFR pathways may be beneficial in extending treatment response and delay resistance in the biomarker-selected population.
  • Additional exploratory biomarker analyses are ongoing.

Reference: 1. Besse B, Garrido P, Puente J, et al. Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with stage IV non-small cell lung cancer (NSCLC). ESMO Annual Congress Abstracts 2017:1309P.