Nivolumab plus ipilimumab plus chemo vs pembrolizumab plus chemo in PD-L1 negative metastatic NSCLC patients: comparative effectiveness using the target trial emulation framework.

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Effectiveness study (incl. comparative)

  Method development or testing
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Study drug International non-proprietary name (INN) or common name:
  NIVOLUMAB

  IPILIMUMAB

  PEMBROLIZUMAB

  CARBOPLATIN

  CISPLATIN

  PACLITAXEL

  PEMETREXED
• Anatomical Therapeutic Chemical (ATC) code:
  (L01FF01) nivolumab

  nivolumab

  (L01FX04) ipilimumab

  ipilimumab

  (L01FF02) pembrolizumab

  pembrolizumab

  (L01XA02) carboplatin

  carboplatin

  (L01XA01) cisplatin

  cisplatin

  (L01CD01) paclitaxel

  paclitaxel

  (L01BA04) pemetrexed

  pemetrexed
• Medical condition to be studied:
  Non-small cell lung cancer stage IV

Population studied

• Short description of the study population:
  Adults with newly diagnosed metastatic NSCLC and PD-L1<1%
• Age groups:
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)

Study design details

• Study design:
  Retrospective new user active comparator cohort study
• Main study objective:
  To estimate the difference in average overall survival (OS) if all adults with stage IV, PD-L1 < 1% NSCLC had initiated nivolumab, ipilimumab and chemotherapy compared to if they all had initiated pembrolizumab and chemotherapy.
• Setting:
  Adults (≥18 years) with newly diagnosed metastatic NSCLC, a PD-L1<1%, ECOG PS ≤ 1, no prior systemic anticancer therapy, prior radiotherapy to the lung within 6 months of trial-treatment initiation, and no major surgery or traumatic injury within 21 days before enrollment -; who are registered in both the Dutch Medication Audit (DMA) and Dutch Lung Cancer Audit (lungcarcinoma) DLCA-L - will be followed from the moment of first administration of either the exposure (nivolumab+ipilimumab+chemotherapy) or the comparator (pembrolizumab+chemotherapy) until the outcome or the end of their observed data, whichever occured first.
• Comparators:
  (pembrolizumab plus carboplatin + paclitaxel) OR (pembrolizumab plus cisplatin or carboplatin + pemetrexed);
• Outcomes:
  Primary: Death, Secondary: time to next treatment, treatment duration, healthcare utilization.
• Data analysis plan:
  Primary analysis.; A flexible parametric survival model will be used, due to their ease-of-use when it comes to confounding adjustment and predicting the counterfactuals (using the g-formula) to estimate the restricted mean survival time (RMST) from treatment initiation to death up to 3 years, with supplementary cutoffs at 4 and 5 years. Secondary, a Cox proportional hazards model will be used to estimate the proportional hazards over time.; When excluding the unobserved confounders, the adjustment set exists of the following covariates: age, sex, smoking history, ECOG PS, histology, the treating hospital, TNM stage, and the presence of CNS, bone and liver metastases. These will be used in the parametric Royston-Parmar model and semi-parametric Cox Proportional Hazards regression. There are two censoring events: (1) last observation / L2FU (indistinguishable) and (2) end of data collection. These censoring events are assumed to be administrative, therefore no IPCW is required. ; ; For details regarding missing data methods, see the study protocol. For secondary and exploratory analyses, see the study protocol.
• Summary results:
  Not available.