Tagrisso vs Tarceva and Iressa: EGFR TKI Comparison

People searching “Tagrisso vs Tarceva” or “Tagrisso vs Iressa” are usually asking how osimertinib (Tagrisso) compares with the older EGFR inhibitors erlotinib (Tarceva) and gefitinib (Iressa). This guide explains how the three generations of EGFR tyrosine kinase inhibitors (TKIs) differ, what the head-to-head FLAURA trial actually reported, and where the older drugs still show up in the evidence. It describes published data and does not recommend any treatment.

Updated November 4, 2026.

What are first-, second- and third-generation EGFR TKIs?

All of these drugs are pills that block the EGFR protein in lung cancers that carry an activating EGFR mutation, most often an exon 19 deletion or the L858R point mutation. The “generation” labels describe how they bind and what they cover, as the trial papers put it:

• First generation: gefitinib (Iressa) and erlotinib (Tarceva). Gefitinib is described in the LUX-Lung 7 paper as a reversible EGFR inhibitor.
• Second generation: afatinib and dacomitinib. Afatinib is described as an irreversible ErbB family blocker, and dacomitinib as a second-generation, irreversible EGFR inhibitor.
• Third generation: osimertinib (Tagrisso), described in the FLAURA paper as an irreversible EGFR-TKI that selectively inhibits both EGFR-sensitizing mutations and the EGFR T790M resistance mutation.

The T790M point matters because a 2023 review describes T790M as the most common resistance mechanism to first- and second-generation EGFR-TKIs, which osimertinib was designed to cover (review).

What did FLAURA show: Tagrisso vs erlotinib or gefitinib?

FLAURA (NCT02296125) was a double-blind phase 3 trial that randomly assigned 556 previously untreated patients with an EGFR exon 19 deletion or L858R mutation to osimertinib 80 mg daily or to a “standard” EGFR-TKI, either gefitinib 250 mg or erlotinib 150 mg daily. According to the New England Journal of Medicine report:

• Median progression-free survival (PFS), the primary endpoint, was 18.9 months with osimertinib vs 10.2 months with the comparator (hazard ratio 0.46; 95% CI 0.37 to 0.57).
• The objective response rate was similar: 80% vs 76%.
• Median duration of response was 17.2 vs 8.5 months.
• Grade 3 or higher adverse events were less frequent with osimertinib at the first analysis (34% vs 45%).

The FDA cited this trial when it approved osimertinib for first-line use on April 18, 2018 (FDA announcement). The final overall survival (OS) analysis, published in 2020, reported a median of 38.6 months with osimertinib vs 31.8 months with the comparator (hazard ratio 0.80; 95.05% CI 0.64 to 1.00; P = 0.046), with grade 3 or higher adverse events in 42% vs 47% (NEJM overall survival report). That paper also noted that after three years 28% of osimertinib patients were still on the trial regimen vs 9% in the comparator group.

A reader comparing numbers should note two things. The comparator arm combined two drugs, so FLAURA does not separate erlotinib from gefitinib. And the OS confidence interval reaches 1.00, which is why summaries describe the survival difference as modest relative to the large PFS gap. Secondary summaries also say comparator patients could cross over to osimertinib at progression with T790M; that detail should be checked against the full paper.

Why did third-generation replace first-generation in the first line?

From a trial-evidence standpoint, FLAURA combined a large PFS advantage with a survival benefit and no increase in serious toxicity versus the older drugs. Because the regulatory label and the later FLAURA2 trial (see Tagrisso with chemotherapy) both use osimertinib as the reference point, it is now the backbone against which new first-line regimens are tested. The Tagrisso landscape article covers that competitive picture, and the market overview places it among newer entrants.

Biology is a second part of the explanation: T790M resistance is a route osimertinib is built to cover. The FLAURA ctDNA resistance analysis found no T790M-mediated resistance to first-line osimertinib (Nature Communications 2023), though other resistance routes emerge; see what comes after Tagrisso.

Where do the older drugs still appear?

Erlotinib (Tarceva), gefitinib (Iressa), afatinib and dacomitinib remain part of the evidence base mostly as comparators and as earlier-generation options in published trials:

• Afatinib vs gefitinib (LUX-Lung 7, phase 2B, 319 patients): median PFS 11.0 vs 10.9 months (hazard ratio 0.73) (Lancet Oncology 2016). Mature OS was 27.9 vs 24.5 months (hazard ratio 0.86, not statistically significant) (Annals of Oncology 2017).
• Dacomitinib vs gefitinib (ARCHER 1050, 452 patients): median PFS 14.7 vs 9.2 months (hazard ratio 0.59) (Lancet Oncology 2017).

Across these trials the older drugs produced median PFS roughly between 9 and 15 months, compared with 18.9 months for osimertinib in FLAURA. These are separate trials with different designs and populations, so the figures are not a formal head-to-head ranking. This guide does not cover current treatment-guideline positions or regional availability, which differ by country and change over time.

What should analysts keep in mind?

• Cross-trial comparisons are fragile. Only FLAURA randomized osimertinib against erlotinib or gefitinib directly.
• Endpoints differ. PFS, OS and response rate each tell a different story, and OS in FLAURA is the narrowest of the three.
• The reference point has moved. New trials in this space now compare against osimertinib, not erlotinib or gefitinib.
• Trial records help. The ClinicalTrials.gov reading guide explains how to check arms and endpoints for yourself.

Next step

Teams tracking how EGFR-inhibitor programs stack up against osimertinib can look at Oncology Resource Group’s pipeline strategies page.

This article is for informational and competitive-intelligence purposes only and is not medical advice. Approvals, labels and trial results change; verify details against current prescribing information and primary sources.