TNO155 (batoprotafib) plus nazartinib in EGFR-mutant lung cancer: an SHP2 plus EGFR doublet ended for strategic reasons after eight years

What was tried

TNO155, also known as batoprotafib, is an oral allosteric inhibitor of the phosphatase SHP2 (ChEMBL CHEMBL4650521, small molecule, maximum reported phase 2). Novartis ran a Phase 1 dose-escalation and expansion study of TNO155 alone and in combination with the EGFR tyrosine kinase inhibitor nazartinib (EGF816) across several tumor types, including EGFR-mutant and KRAS G12-mutant non-small cell lung cancer, esophageal and head and neck squamous cell carcinoma, melanoma, and gastrointestinal stromal tumors (ClinicalTrials.gov, NCT03114319). The primary endpoints were safety, dose-limiting toxicities, and dose selection. The study enrolled 227 participants and was terminated. The posted reason was business reasons and not any safety concern (ClinicalTrials.gov, NCT03114319).

The biological hypothesis

SHP2, encoded by PTPN11 (Ensembl ENSG00000179295), is a protein tyrosine phosphatase that relays signals from receptor tyrosine kinases into the RAS to MAPK pathway. Inhibiting SHP2 was expected to block the upstream reactivation that lets tumors escape narrow single-node inhibitors. In EGFR-mutant lung cancer, cells treated with an EGFR inhibitor reactivate parallel receptor tyrosine kinase input through SHP2, so pairing an EGFR inhibitor with an SHP2 inhibitor was designed to close that adaptive resistance route (Prahallad et al., 2023). Open Targets scores the PTPN11 to non-small cell lung carcinoma association at 0.34 overall, carried by literature evidence at 0.95 and somatic mutation at 0.46, with no human genetic association at 0.00 (Open Targets Platform).

What actually happened

Novartis terminated the study for business reasons rather than for a safety signal or a documented efficacy miss, and no results were posted to the registry (ClinicalTrials.gov, NCT03114319). The trial still ran for eight years and enrolled 227 participants, which is a large Phase 1 footprint for a program that did not advance. The mechanistic context explains why a sponsor might walk away without a headline failure. SHP2 inhibitors as a class face a narrow therapeutic window, with on-target effects such as edema, thrombocytopenia, and diarrhea that limit sustained combination dosing, and the sparse post-marketing record for batoprotafib in the FDA FAERS database lists diarrhea, transaminase elevation, and electrolyte disturbances among the few reported terms (openFDA FAERS). Preclinical work also showed that tumors develop resistance to combined RAS-pathway blockade through additional pathway rewiring (Prahallad et al., 2023; Lu et al., 2024).

Failure mechanism, best guess

The most likely mechanism is a crowded and competitive landscape colliding with a hard combination-tolerability problem. Vertical blockade of the EGFR to SHP2 to RAS axis is mechanistically sound, but delivering two MAPK-pathway inhibitors together at active doses is limited by overlapping on-target toxicity, which caps the exposure needed for durable responses. At the same time, the SHP2 field became crowded, and osimertinib had become the dominant EGFR backbone with its own resistance biology (Nishihara et al., 2022), which raised the bar for any EGFR plus SHP2 doublet to show differentiated benefit. A business termination with no posted efficacy is the signature of a program that did not clear that bar decisively enough to justify continued investment. The Open Targets profile fits, since the PTPN11 to lung cancer link rests on literature and somatic mutation rather than on human genetics, which sits at zero (Open Targets Platform).

How to prevent this next time

Two quantitative tools would have front-loaded the strategic decision. The first is a competitive-landscape red-team analysis that scores the probability of differentiation against the standard of care before committing to an eight-year Phase 1. With osimertinib established as first-line therapy in EGFR-mutant disease, the realistic bar for an EGFR plus SHP2 doublet is superiority over that backbone, and a formal red-team would have set an explicit stop-if-not-differentiated threshold. The second is a Bayesian predictive probability of success updated as dose-finding and early efficacy data arrive:

PP(success)=∫θ​P(final success∣θ,interim data)⋅π(θ∣interim data)dθ

A translational validation sequence, confirming that tolerated doses of the combination actually suppressed SHP2-dependent MAPK reactivation in on-treatment samples, would have provided an early kill signal before broad expansion. The single highest leverage change would have been to gate the expansion cohorts behind a prespecified pharmacodynamic and differentiation threshold rather than enrolling 227 participants across six tumor types before the strategic call.

What this means for similar programs

SHP2 inhibition remains mechanistically attractive as a combination partner, and the field has shifted toward pairing SHP2 inhibitors with direct KRAS G12C or G12D inhibitors rather than with EGFR inhibitors, where the tolerability and differentiation problems are most acute. The Mechanism Risk Score for PTPN11 stands at 25 of 100 (yellow band), near the low end of the scale, reflecting a thin documented failure record of a single Phase 1 strategic termination together with a wide genetic-evidence gap. Open Targets records only one clinical-stage PTPN11 molecule in its known-drug set, so the crowded real-world SHP2 pipeline sits largely outside that count and outside this score.

Open questions

• Did the EGFR plus SHP2 combination reach doses that suppressed MAPK reactivation, or was tolerability the binding constraint?
• Would an SHP2 inhibitor paired with a KRAS G12C or G12D inhibitor, rather than with an EGFR inhibitor, clear the differentiation bar that this program did not?
• Will Novartis or partners release the unposted Phase 1 safety and response data so the field can separate a tolerability failure from a genuine efficacy failure?

Sources

1. • ClinicalTrials.gov, NCT03114319: https://clinicaltrials.gov/study/NCT03114319 - Open Targets Platform, PTPN11 (ENSG00000179295): https://platform.opentargets.org/target/ENSG00000179295 - ChEMBL, batoprotafib / TNO155 (CHEMBL4650521): https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL4650521/ - Prahallad A et al., 2023, Cancer research.- Lu X et al., 2024, Cancer letters.- Nishihara S et al., 2022, Cells.- openFDA FAERS drug event API: https://open.fda.gov/apis/drug/event/.