NICE Recommends Against Frontline Osimertinib in EGFR-Mutant NSCLC

The United Kingdom’s National Institute for Health and Care Excellence will not recommend osimertinib as a frontline treatment for patients with locally advanced or metastatic EGFR-mutant non–small cell lung cancer.

The United Kingdom’s National Institute for Health and Care Excellence (NICE) will not recommend osimertinib (Tagrisso) as a frontline treatment for patients with locally advanced or metastatic EGFR-mutant non—small cell lung cancer (NSCLC).

When citing their reasoning, NICE explained that osimertinib has demonstrated an overall survival (OS) benefit compared with the first-generation EGFR TKIs erlotinib (Tarceva) or gefitinib (Iressa) in patients with treatment-naïve locally advanced or metastatic EGFR-mutant NSCLC, as demonstrated in updated findings of the phase III FLAURA trial.2 However, the agency stated the third-generation TKI was not directly compared with afatinib (Gilotrif), “which may be more effective than erlotinib and gefitinib.”

Moreover, osimertinib does not meet NICE’s criteria to be considered a life-extending treatment at the end of life, as the most plausible cost-effective estimates are higher than what NICE typically considers an acceptable use of NHS resources, the agency stated. The agent also does not meet NICE’s criteria to be included in the Cancer Drugs Fund, as it does not have the cost-effective potential at its offered price of £5770 ($7564.85) for 80 mg and 40 mg of osimertinib, which comes in a 30-tablet pack, excluding value added tax.

“The relevant comparators for this technology appraisal are erlotinib, gefitinib, and afatinib,” NICE stated in its technology appraisal guidance, adding that evidence suggests improved progression-free survival (PFS) with afatinib compared with gefitinib. “FLAURA compared osimertinib with either gefitinib or erlotinib, but not with afatinib. The Cancer Drugs Fund clinical lead noted that afatinib is currently the most prescribed EGFR tyrosine kinase inhibitor in England for this population.”

The agency stated that the decision is not intended to affect treatment with osimertinib that was started in the National Health Service (NHS) before this guidance was published. Patients who are undergoing treatment outside this recommendation may continue without change to the funding arrangements in place for them before the publishing of this guidance, until they and their NHS clinician consider it appropriate to discontinue therapy.

In April 2018, the FDA approved osimertinib as a first-line treatment for patients with NSCLC whose tumors harbor EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations). The approval is based on earlier findings from the phase III FLAURA trial.

In the FLAURA study, 556 treatment-naïve patients with EGFR-positive locally advanced or metastatic NSCLC were randomized to osimertinib (n = 279) or a standard TKI (erlotinib or gefitinib; n = 277). Patients with central nervous system metastases were allowed on the trial and all patients had exon 19 deletions or L858R mutations. Daily oral therapy was given with 80 mg of osimertinib, 250 mg of gefitinib, or 150 mg of erlotinib.

NICE also stated in the document that, while the trial eligibility criteria permitted patients with stable brain metastases, patients also must have had an ECOG performance status of 0 or 1.

Therefore, “The committee was aware that the clinical trial population may be in better health than people with stage IIIb or IV NSCLC in the NHS and that people with many comorbidities were not included in the trial. Also, it noted that afatinib was not a comparator in the standard care arm in FLAURA…and that many subsequent treatments used in the trial are not routinely used in the NHS. Despite these concerns, the clinical experts explained that the evidence from FLAURA was broadly generalizable to NHS clinical practice. The committee agreed with the clinical experts.”

Prior FLAURA findings demonstrated that frontline osimertinib reduced the risk of progression or death by 54% versus standard TKI therapy—erlotinib or gefitinib. In the double-blind study, the median PFS was 10.2 months (95% CI, 9.6-11.1) for standard therapy and 18.9 months (95% CI, 15.2-21.4) with osimertinib (HR, 0.46; 95% CI, 0.37-0.57;&#8239;P&#8239;<.001).3

In updated findings that were presented at the 2019 ESMO Congress, the median OS in the osimertinib arm was 38.6 months (95% CI, 34.5-41.8) compared with 31.8 months (95% CI, 26.6-36.0) with erlotinib or gefitinib, representing a 20% reduction in the risk of death with osimertinib (HR, 0.799; 95% CI, 0.641-0.997;&#8239;P&#8239;= .0462). At the final data cutoff for the study, 54% of patients remained alive at 36 months in the osimertinib arm compared with 44% in the erlotinib/gefitinib group.

Additionally,&#8239;the 12-month OS rate was 89% in the osimertinib arm compared with 83% in the comparator group. The 24-month OS rates were 74% and 59%, for osimertinib and erlotinib/gefitinib, respectively. At 36 months, 28% of patients remained on first-line treatment with osimertinib compared with 9% remaining on erlotinib or gefitinib.

OS was improved with osimertinib across all key patient subgroups, with the exception of Asian populations where the data were unclear. In Asian patients (n = 347), the HR for OS was 0.995; in non-Asian patients (n = 209), the HR was 0.542.

Updated safety findings showed that most common all-grade adverse events with osimertinib and first-generation TKIs, respectively, were rash or acne (59% vs 79%), diarrhea (60% vs 58%), dry skin (38% vs 37%), paronychia (32% vs 30%), stomatitis (29% vs 22%), and nausea (20% vs 20%).

In June 2018, the European Commission also approved osimertinib as a frontline treatment for patients with&#8239;EGFR-mutant locally advanced or metastatic NSCLC, based on the earlier data from the phase III FLAURA trial.


  1. Technology appraisal consultation document: Osimertinib for untreated EGFR mutation—positive non-small-cell lung cancer. National Institute for Health And Care Excellence. Published January 22, 2020. Accessed January 23, 2020.
  2. Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): final overall survival analysis. Ann Oncol. 2019;30(suppl_5):mdz394.076. doi: 10.1093/annonc/mdz394.076
  3. Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non—small-cell lung cancer.&#8239;N Engl J Med. 2018;378(2):113-125. doi: 10.1056/NEJMoa1713137.