Borghaei H, et al. ESMO 2017:LBA49

Updated results from KEYNOTE-021 cohort G: A randomized phase II study of pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced, non-squamous non-small cell lung cancer

Background

Previous analyses from cohort G of the phase II KEYNOTE-021 trial have reported significant improvements in overall response rate (ORR) and progression-free survival (PFS) for pembrolizumab plus pemetrexed and carboplatin (PC) versus PC alone in patients with previously untreated, advanced, nonsquamous non-small cell lung cancer (NSCLC), as well as a manageable safety profile for this combination therapy.1,2 An updated analysis of these results were presented at the ESMO 2017 Annual Congress.3

Study design

  • Cohort G of the KEYNOTE-021 study was a phase II, randomized, open-label trial of PC plus pembrolizumab versus PC alone in patients with previously untreated, advanced, non-squamous NSCLC with no activating epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations.
  • The primary endpoint of the study was ORR (by Response Evaluation Criteria in Solid Tumors version 1.1 per blinded, independent central review).
  • The key secondary endpoint was PFS.
    • Other secondary endpoints included overall survival (OS), safety, and the relationship between antitumour activity and programmed death-ligand 1 (PD-L1) tumour proportion score.
  • There was no alpha allocated for the updated analysis; all p-values are nominal (one-sided p <0.025).

Study Design

Key findings

  • At the time of data cutoff (May 31, 2017), the median follow-up was 18.7 months (range: 0.8–29.0).
  • After screening (219 patients), 60 patients were allocated to the pembrolizumab plus PC arm (59 patients treated) and 63 patients were allocated to the PC alone arm (62 patients treated).
  • In the pembrolizumab arm, 14 patients remain on trial, 3 patients have completed the trial, and 42 have discontinued therapy.
    • Of the patients discontinuing therapy, 48% of patients (29/60) in the intent-to-treat (ITT) population received subsequent therapy (64% [29/45] received subsequent therapy excluding those ongoing in the trial or not treated).
  • In the PC alone arm, nine patients remain on trial and 53 have discontinued therapy.
    • Twenty-five patients crossed over to the pembrolizumab arm on study and 15 patients received anti–PD-(L)1 therapy outside of the crossover, totalling 63% of patients (40/63) in the ITT population and 75% of patients (40/53), excluding those ongoing or not treated, who have received an anti–PD-(L)1 therapy.
  • There were no major imbalances in baseline characteristics between treatment arms.

Efficacy

  • ORR was 56.7% in the pembrolizumab plus PC arm and 31.7% in the PC alone arm (Δ24.8%, 95% CI: 7.2–40.9; p = 0.0029 [p-value is descriptive, one-sided p <0.025]).
  • Compared with the prespecified analysis,1 there was a similar between-arm difference in ORR and a similar pattern of response across PD-L1 distribution.
  • The median duration of response was not reached in either of the treatment arms.
  • Fifty percent of responders in the pembrolizumab arm, and 40% of responders in the PC alone arm had an ongoing response, defined as being alive without subsequent disease progression.
  • The median PFS was longer in the pembrolizumab plus PC arm (19.0 months, 95% CI: 8.5–NR) versus the PC alone arm (8.9 months, 95% CI: 6.2–11.8). (Figure 1)
  • The median OS was not reached (95% CI: 22.8–NR) in the pembrolizumab plus PC arm versus 20.9 months (95% CI: 14.9–NR) in the PC alone arm. (Figure 2)

Figure 1. Progression-free survival*

Figure 2. Overall survival

Safety

  • The median exposure to treatment was 10.1 months (range: 0–25.0) and 4.9 months (range: 0–25.0) in the pembrolizumab plus PC and PC alone arms, respectively.
  • Treatment-related adverse events (AEs) for the pembrolizumab plus PC arm and PC alone arm, respectively, were:
    • Any grade, 93% and 92%;
    • Grade 3–5, 41% and 29%;
    • Leading to discontinuation, 15% and 15%; and
    • Leading to death, 2% and 3%.
  • Treatment-related AEs and AEs with possible immune etiology are presented in Figures 3 and 4.

Figure 3. Treatment-related AEs with incidence ≥15%

Figure 4. AEs with possible immune etiology

Key conclusions

  • Upon longer follow-up, the hazard ratio (HR) for OS continues to improve for pembrolizumab plus PC versus PC alone.
    • In this analysis, the HR for OS was 0.59 after a median follow-up of 18.7 months, compared to the primary analysis where the HR for OS was 0.90 (median follow-up 10.6 months),1 and a previous update where HR for OS was 0.69 (median follow-up 14.5 months).2
  • In the current analysis, pembrolizumab plus PC continued to demonstrate significant improvements in ORR and PFS compared to PC alone.
  • The combination of pembrolizumab with PC continued to show a manageable safety profile.

References: 1. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous nonsmall-cell lung cancer: a randomised, phase 2, cohort of the open-label KEYNOTE-021 study. Lanct Oncol 2016;17(11):1497–1508. 2. Papadimitrakopoulou V, Gadgeel SM, Borghaei H, et al. First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: Updated results of KEYNOTE-021 cohort G. J Clin Oncol (ASCO Annual Meeting) 2017;35(Suppl): abstr 9094. 3. Borghaei H, Langer CJ, Gadgeel S, et al. Updated results from KEYNOTE-021 cohort G: A randomized, phase II study of pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous non-small-cell lung cancer. ESMO Annual Congress Abstracts 2017:LBA49.