Tagrisso vs Keytruda: Targeted Therapy vs Immunotherapy in EGFR NSCLC

“Is Tagrisso immunotherapy?” and “Keytruda vs Tagrisso” are common searches, and the short answer to the first is no. Tagrisso (osimertinib) is a targeted therapy, while Keytruda (pembrolizumab) is an immunotherapy. This guide explains the difference, why immune checkpoint inhibitors have shown limited benefit in EGFR-mutated lung cancer in the trials reviewed here, what a 2019 study reported about using the two in sequence, and where newer bispecific antibodies fit. It describes published evidence and does not recommend any treatment.

Updated November 4, 2026.

Is Tagrisso immunotherapy?

No. Osimertinib is an oral, third-generation, irreversible EGFR tyrosine kinase inhibitor that selectively inhibits EGFR-sensitizing mutations and the T790M resistance mutation (FLAURA, NEJM). It acts directly on a signaling protein inside the cancer cell that is driven by the tumor’s EGFR mutation. It does not work by activating the immune system.

Keytruda belongs to a different class. Pembrolizumab is a PD-1 checkpoint inhibitor, an antibody that releases a brake on T cells, and it is the subject of our Keytruda competitive landscape. The drugs are therefore not direct substitutes. They are built for different biology: Tagrisso for tumors with a specific EGFR mutation, Keytruda across many tumor types. A matched “Keytruda vs Tagrisso” randomized trial in EGFR-mutated disease was not found in the sources reviewed; the evidence below instead asks how immunotherapy performs in people with EGFR-mutated tumors.

Does immunotherapy work in EGFR-mutated lung cancer?

The best-controlled evidence is in patients whose cancer had progressed after an EGFR inhibitor, where chemotherapy with or without a checkpoint inhibitor was compared:

• KEYNOTE-789 (phase 3, 492 patients with TKI-resistant EGFR-mutant nonsquamous NSCLC): pembrolizumab plus pemetrexed-platinum chemotherapy vs placebo plus chemotherapy. Median PFS was 5.6 vs 5.5 months (hazard ratio 0.80) and median overall survival 15.9 vs 14.7 months (hazard ratio 0.84; 95% CI 0.69 to 1.02). Neither result crossed the pre-specified efficacy boundary, and the authors concluded the addition of pembrolizumab did not significantly prolong PFS or OS. Grade 3 or higher treatment-related adverse events were 43.7% vs 38.6% (JCO 2024).
• CheckMate 722 (nivolumab plus chemotherapy): median PFS by blinded review 5.6 vs 5.4 months (hazard ratio 0.72). The trial was reduced to 270 patients from a planned 500 after accrual difficulties during COVID-19.
• IMpower150 (EGFR-positive subgroup): atezolizumab plus bevacizumab, carboplatin and paclitaxel was compared with the regimen without atezolizumab. Only 124 of 1,202 patients were EGFR-positive, the hazard ratio for survival was 0.61 (95% CI 0.29 to 1.28), and the trial was not powered for this subgroup.

The last two figures come from a 2024 review (Lung Cancer: Targets and Therapy), which frames KEYNOTE-789 as a potential “nail in the coffin” for this approach. In short, what is established is that adding a PD-1 inhibitor to chemotherapy after EGFR-TKI progression did not significantly improve outcomes in KEYNOTE-789; the IMpower150 signal that includes bevacizumab is subgroup-level and remains hypothesis-generating.

Why might checkpoint inhibitors work less well here?

The same review lists several proposed explanations. These are hypotheses from the literature, not proven causes:

• Immunologically “cold” tumors: limited T-cell infiltration, with more regulatory T cells and myeloid-derived suppressor cells.
• Low tumor mutation burden: fewer neoantigens for the immune system to recognize.
• Intrinsic immune evasion: EGFR signaling can increase PD-L1 expression and reduce MHC molecules.
• Co-occurring alterations: changes such as KRAS or BRAF may activate alternative pathways.

In KEYNOTE-789 the survival hazard ratios were similar whether PD-L1 expression was 50% or higher (0.84) or below 50% (0.85), so PD-L1 level did not separate responders in that trial.

Is there a safety concern with giving Keytruda before Tagrisso?

A retrospective study from Memorial Sloan Kettering reported one. Among 126 patients with EGFR-mutant NSCLC treated with PD-(L)1 blockade and EGFR-TKIs, 15% (6 of 41; 95% CI 7% to 29%) of those given PD-(L)1 blockade followed later by osimertinib developed a severe (grade 3 to 4) immune-related adverse event. The rate was highest when osimertinib began within three months of the PD-(L)1 drug (5 of 21, 24%). No severe events were seen when osimertinib came first (0 of 29) or when PD-(L)1 was followed by afatinib or erlotinib (0 of 27). Events appeared a median of 20 days after osimertinib started, and all needed steroids (Annals of Oncology 2019).

The severe events were described as immune-related, and the abstract does not single out pneumonitis as the only type, so it is not accurate to read the 15% as a pneumonitis rate. The study was small and retrospective, and the authors framed the finding as an association. It is one reason sequencing questions are studied carefully, and the authors’ point was that the association seemed specific to osimertinib among the EGFR-TKIs they examined.

Where do bispecific antibodies like ivonescimab fit?

Ivonescimab is a PD-1/VEGF bispecific antibody, a different idea from a plain PD-1 antibody. In the China-only HARMONi-A phase 3 trial (322 patients with EGFR-variant nonsquamous NSCLC after prior EGFR-TKI therapy), ivonescimab plus chemotherapy improved median overall survival to 16.8 vs 14.1 months with chemotherapy alone (hazard ratio 0.74; 95% CI 0.58 to 0.95), with grade 3 or higher adverse events in 67.1% vs 54.7% (JAMA 2026). The global HARMONi study is a separate matter: reporting based on Summit and Akeso releases says it met its progression-free survival endpoint but not the overall survival endpoint with statistical significance, and that the FDA has a PDUFA goal date of November 14, 2026 for Summit’s application in EGFR-mutated NSCLC after TKI therapy. No FDA decision had been reported as of November 4, 2026. See the ivonescimab landscape for the competitive picture.

For the main EGFR drug story, including the trials of osimertinib itself, see the Tagrisso landscape and the mechanism explainer.

Next step

Teams tracking how immunotherapy and targeted-therapy programs intersect in lung cancer 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.