The impact of TP53 co-mutations and immunologic microenvironment on outcome of lung cancer with EGFR exon 20 insertions

BACKGROUND: EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce. PATIENTS AND METHODS: We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases. RESULTS: Platinum doublets and chemoimmunotherapy showed similar response rates (20-25%), disease control rates (80%) and median progression-free survival (mPFS, ≈7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p < 0.05). Overall survival (OS) was not dependent on the choice of first-line treatment, but related to more lines of systemic therapy (p < 0.05). TP53 mutations and brain metastases were associated with shorter PFS under platinum doublets and EGFR inhibitors (HR 3.3-6.1, p < 0.01), and shorter OS for patients receiving both treatments (p < 0.05). More tumour CD8(+) and less Th1 cells were associated with longer OS independent of brain and TP53 status (p < 0.01). No difference in outcome was noted according to the ex20ins site and use of pemetrexed (vs. other cytotoxics) or bevacizumab. Long-lasting responses (>1 year) occasionally occurred under EGFR inhibitors for both 'near-' and 'far-loop' variants. CONCLUSIONS: Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20-25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival.

• Christopoulos, P.
• Kluck, K.
• Kirchner, M.
• Lüders, H.
• Roeper, J.
• Falkenstern-Ge, R. F.
• Szewczyk, M.
• Sticht, F.
• Saalfeld, F. C.
• Wesseler, C.
• Hackanson, B.
• Dintner, S.
• Faehling, M.
• Kuon, J.
• Janning, M.
• Kauffmann-Guerrero, D.
• Kazdal, D.
• Kurz, S.
• Eichhorn, F.
• Bozorgmehr, F.
• Shah, R.
• Tufman, A.
• Wermke, M.
• Loges, S.
• Brueckl, W. M.
• Schulz, C.
• Misch, D.
• Frost, N.
• Kollmeier, J.
• Reck, M.
• Griesinger, F.
• Grohé, C.
• Hong, J. L.
• Lin, H. M.
• Budczies, J.
• Stenzinger, A.
• Thomas, M.