After Tagrisso: Resistance and What Comes Next in EGFR NSCLC

Searches for “Tagrisso resistance” or “after Tagrisso” reflect a plain fact about EGFR-mutated lung cancer: osimertinib (Tagrisso) controls the disease for a time, and in advanced disease it eventually stops working for most patients. This guide summarizes, as of November 4, 2026, what researchers have reported about why that happens and which regimens have been tested after progression. It describes published trial data only and does not recommend any treatment.

Updated November 4, 2026.

Why does resistance to Tagrisso develop?

Researchers sort resistance into two broad groups. A 2023 review describes EGFR-dependent mechanisms, mainly the C797S mutation in the EGFR gene itself, and EGFR-independent mechanisms, which include bypass pathways, oncogenic fusions and a change in the tumor’s cell type (review).

Two datasets give numbers. In the FLAURA trial’s analysis of tumor DNA in blood, taken from patients who started on first-line osimertinib, the most frequent mechanisms found were MET amplification (17 patients, 16%) and EGFR C797S mutations (7 patients, 6%), with no T790M-mediated resistance; the authors noted that non-genetic mechanisms still need study (Nature Communications 2023). In AURA3, where osimertinib was used second-line after T790M appeared, MET amplification and EGFR C797X were each found in 18% of 78 analyzed patients (AURA3 analysis). The percentages differ by setting and by assay. Blood tests can miss some changes: a panel discussion reported by OncLive says tissue biopsy remains important, especially for MET amplification, and that small cell transformation is hard to detect without tissue.

The same panel noted that some patients show no clearly identifiable resistance alteration, so any mechanism-by-mechanism list covers only part of the story.

What happens when Tagrisso stops working: is chemotherapy the baseline?

Platinum-based chemotherapy is the comparison arm in most recent post-osimertinib trials, so its results set the benchmark. In the randomized trials below, median progression-free survival (PFS) with platinum-pemetrexed chemotherapy was around four to five and a half months:

• MARIPOSA-2 (657 patients progressing on osimertinib): 4.2 months in the chemotherapy-alone arm (FDA approval summary via ONS).
• SAFFRON (338 patients with MET overexpression or amplification after osimertinib): 5.4 months (OncLive).
• KEYNOTE-789 (492 patients progressing on any EGFR-TKI, not only osimertinib): 5.5 months in the placebo-plus-chemotherapy arm, with median overall survival 14.7 months (JCO 2024).

These are different populations, so the numbers are indicative rather than interchangeable. Adding Keytruda (pembrolizumab) to chemotherapy did not significantly extend PFS or survival in KEYNOTE-789; see Tagrisso vs Keytruda.

What does amivantamab add after osimertinib?

Amivantamab (Rybrevant) is a bispecific antibody. On September 19, 2024 the FDA approved it with carboplatin and pemetrexed for EGFR exon 19 deletion or L858R NSCLC that progressed on or after an EGFR-TKI. In MARIPOSA-2, median PFS was 6.3 vs 4.2 months with chemotherapy alone (hazard ratio 0.48; 95% CI 0.36 to 0.64), and the confirmed response rate was 53% vs 29%. At the second interim analysis, overall survival did not differ with statistical significance (hazard ratio 0.73; 95% CI 0.54 to 0.99). Reported adverse reactions in at least 20% of patients included rash, infusion reactions, fatigue and nail toxicity (same FDA summary). An editorial noted that dose modifications for adverse events may limit uptake of the triplet regimens (Med 2024).

What does the SAFFRON trial show for MET-driven resistance?

SAFFRON, reported at ESMO 2026, is a phase 3 trial of osimertinib 80 mg plus the MET inhibitor savolitinib (Orpathys) 300 mg twice daily versus platinum-pemetrexed chemotherapy in EGFR-mutated NSCLC with high MET overexpression (IHC 3+ in at least 90% of cells) or amplification (FISH of at least 10 copies) after first- or second-line osimertinib. Per AstraZeneca and OncLive:

• Median PFS by blinded independent review: 7.6 vs 5.4 months (hazard ratio 0.55; 95% CI 0.42 to 0.72).
• Median overall survival: 17.8 vs 12.9 months (hazard ratio 0.68; 95% CI 0.50 to 0.91; P = 0.010), with OS data about 53% mature.
• Confirmed response rate: 51% vs 27%.
• Safety: grade 3 or higher adverse events 64% vs 63%; fatal adverse events occurred in 12 patients (7%) on the combination and none on chemotherapy; adverse-event discontinuations were 14% vs 8%.

AstraZeneca and OncLive both report that a US New Drug Application has been submitted (OncLive dates it September 2026); No FDA decision had been reported in the sources reviewed as of November 4, 2026. Savolitinib plus osimertinib is already approved in China for MET-amplified disease on the basis of a separate trial, SACHI. SAFFRON covers only the MET-high subset, which is one of several resistance routes.

What about antibody-drug conjugates?

Datopotamab deruxtecan (Datroway) received accelerated FDA approval in June 2025 for EGFR-mutated NSCLC progressing after EGFR-targeted therapy and platinum chemotherapy, based on pooled data from TROPION-Lung05 and TROPION-Lung01: a 45% confirmed response rate and 6.5-month median response duration in 114 patients. Warnings include interstitial lung disease, eye problems and stomatitis (CURE). Accelerated approval means confirmatory trials are still needed.

Patritumab deruxtecan (HER3-DXd) followed a different path. In May 2025 Daiichi Sankyo and Merck voluntarily withdrew their US application after the confirmatory HERTHENA-Lung02 study did not show a statistically significant overall survival result, according to CancerNetwork. A later status was not found in the sources reviewed. For the wider ADC picture, see our Enhertu landscape.

What is still investigational?

Bispecific antibodies combined with chemotherapy are being studied in this setting. Ivonescimab plus chemotherapy improved overall survival in the China-only HARMONi-A trial (16.8 vs 14.1 months; hazard ratio 0.74) after prior EGFR-TKI therapy (JAMA 2026); see the ivonescimab landscape. For the starting point of this story, see the Tagrisso landscape.

Next step

Teams that need to follow post-osimertinib readouts and filings as they happen can look at Oncology Resource Group’s Sentinel 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.