The impact of TP53 co-mutations and immunologic microenvironment on outcome of lung cancer with EGFR exon 20 insertions.
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Christopoulos Petros, Kluck Klaus, Kirchner Martina, Lüders Heike, Roeper Julia, Falkenstern-Ge Roger-Fei, Szewczyk Marlen, Sticht Florian, Saalfeld Felix C, Wesseler Claas, Hackanson Björn, Dintner Sebastian, Faehling Martin, Kuon Jonas, Janning Melanie, Kauffmann-Guerrero Diego, Kazdal Daniel, Kurz Sylke, Eichhorn Florian, Bozorgmehr Farastuk, Shah Rajiv, Tufman Amanda, Wermke Martin, Loges Sonja, Brueckl Wolfgang M, Schulz Christian, Misch Daniel, Frost Nikolaj, Kollmeier Jens, Reck Martin, Griesinger Frank, Grohé Christian, Hong Jin-Liern, Lin Huamao M, Budczies Jan, Stenzinger Albrecht, Thomas Michael
Аннотация
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.