Key information on check-point inhibitors

  • Three drugs that have been used in NSCLC, with evidence greatest for use after first line chemotherapy
  • Nivolumab, pembrolizumab (both PD1 ligand receptor blockers) and atezolizumab (PDL-1 - ligand blockers)
  • Evidence exists for all three agents to prolong overall survival (but not progression free survival) when compared to continuing first line chemotherapy, therefore at progression this is a good option
  • There is no significant difference between targeted chemotherapy (TKI) vs immunotherapy, therefore if the patient has a driver mutation then standard of care would be to Rx with targeted chemotherapy as first line
  • Nivolumab and atezolizumab can be used regardless of PDL-1 receptor expression, pembrolizumab requires PD-L1 >1%. Trialsused various cut-offs
  • note that presence of EGFR and ALK are not correlated with PD-L1 expression
  • For nivolumab, if patient had adenocarcinoma, there was a strong correlation between PD-L1 expression and OS
  • For pembrolizumab, there is a correlation between PD-L1 expression and survival (1 - 49%, HR 0.76)
  • Blood TMB levels are a potential biomarker for response

Using checkpoint inhibitors as first line

  • Currently in US there is approval for use of pembrolizumab in combo with platinum doublet chemotherapy in first line setting provided no EGFR or no ALK
  • KEYNOTE-024 trial for pembrolizumab - an enriched population of patients who had no prior exposure to chemotherapy and had PDL1 >50% tissue expression, the phase 3 trial demonstrated greater overall survival, improved median progression free survival and fewer treatment related side effects compared to conventional chemotherapy
  • CheckMate 026: Looked at nivolumab, PDL1 >1%, no significant difference between conventional and nivolumab group, and there was also a decreased overall response rate for nivolumab. If blood TMB was used as a biomarker, then the data mirrored that of KEYNOTE-024 data for pembrolizumab
  • PACIFIC trial: Durvalmab in Stage 3 cancer after chemoradiotherapy: Durvalumab after chemoRad resulted in improved progression free survival, orerall response rate and treatment related adverse effects compared to placebo. greatest benefit if PDL1 >25% but response still seen if PDL1 <25

Immune effects of Immune checkpoint inhibitors: imAEs

  • Can be difficult to detect, but are almost universal ~ 90% of patients will experience it
  • No grade 1 guidelines exist because no prospectively validated protocols are found.
  • Most side effects responds to cessation of drug and initiation of corticosteroids 1 - 2mg/kg, with monitoring - length of steroid taper is dependent on how pt is responding, usually prolonged steroid taper over 6 weeks
  • Interestingly, majority of patients who have an imAE have abnormalities in thyroid function therefore it is reasonable to have baseline TFT (esp TSH) and continue monitoring TSH
  • Some centres have guidance on monitoring regimes for routine surveillance
  • Pneumonitis is not common, and the spectrum of pulmonary abnormalities is broad
    • NSIP
    • COP
    • Sarcoid like granulomas
    • Honeycombing and therefore fibrosis
  • Mx of imAEs depends on the grade of effect
    • Grade 1: continue inhibitor, no steroids
    • Grade 2: withhold inhibitor, consider steroid
    • Grade 3: withhold/ discontinue inhibitor: give steroid
    • Grade 4: discontinue inhibitor: give steroid, consider additional immunosupressant
  • After corticosteroids, second line immunosuppression evidence is only from case series. The number of steroid refractory imAE pts is low
    • Can increase dose
    • Initiate second line immunosuppression (MMF/ infliximab/ cyclophosphamide)
    • Third line not well defined, but ATG, tacro and vedolizumab have been trialled