Osimertinib, platinum, etoposide as initial treatment for patients with EGFR mutant lung cancers with TP53 and RB1 alterations.
Authors: Chen Monica F , Rakhade Swanand , Quintanal-Villalonga Alvaro , Lee Jake , Forsythe Britney , Moses Khadeja A. , Ahn Linda Su Hyun , Pupo Amanda , Falcon Christina J. , Rekhtman Natasha , Kris Mark G. , Rudin Charles M. , Chan Joseph Minhow , Yu Helena Alexandra 
Published: June 2024

8565

Background: EGFR-mutant lung adenocarcinomas (EGFR+LC) transform to small cell lung cancer (SCLC) in up to 14% of cases, which creates an aggressive disease phenotype that is treated like de novo small lung cancer with platinum/etoposide chemotherapy. Transformed EGFR+LC molecularly mimic de novo small cell lung cancers and harbor TP53and RB1 loss. We hypothesized that if small cell directed chemotherapy is utilized prior to histologic transformation in EGFR/TP53/RB1 mutant LC, we may eradicate any pre-existing small cell clones, prevent small cell histologic transformation, and improve patient outcomes. Methods: We administered osimertinib, platinum, and etoposide in patients with newly diagnosed EGFR+LC with TP53and RB1alterations. Patients received 3 months of osimertinib induction, then 4 cycles of osimertinib, platinum and etoposide followed by osimertinib until progression. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were assessed. Patients were required to have an on-treatment biopsy prior to initiation of chemotherapy upon which single cell RNA sequencing (scRNAseq) was performed. All patients had pre-treatment and post-progression biopsies that underwent next-generation sequencing. Patients were evaluated for acquired resistance (classified as on-target, off-target, transformation, and unknown). Among patients that transformed, markers of SCLC (ASCL1, NEUROD1, POU2F3, YAP1, synaptophysin, chromogranin, and Ki-67) were analyzed. Results: Eleven patients were enrolled [median age 58 years old range (49-81), 45% female, 73% EGFRexon 19 deletions and 27% EGFR L858R]. Three patients received cisplatin/etoposide, six patients carboplatin/etoposide, and two patients progressed two months on induction osimertinib before they could start chemotherapy. The ORR was 82%, median PFS 15.6 months and median OS was 37.9 months. All patients retained EGFR, TP53, and RB1mutations on post-treatment biopsy. Acquired on-target resistance mechanisms were identified in 9% of patients ( EGFR C797S), off-target in 9% of patients ( CDKN2A), and small cell transformation in 46% of patients. Among the transformed patients, all had high Ki-67 (70-95%) and 80% were positive for synaptophysin and chromogranin. 40% of cases were ASCL1-dominant, 40% were NEUROD1-dominant, and 20% were unknown. Additionally, we utilized copy number inference and CytoTrace to identify subclones within pre-transformed EGFR+LC that potentially harbor features of early plasticity. Further scRNAseq and whole exome sequencing data are forthcoming. Conclusions: In patients with EGFR+LCs with concurrent TP53and RB1alterations, osimertinib plus platinum and etoposide demonstrated activity and no new safety signals were seen. Early addition of small cell directed chemotherapy did not prevent histologic transformation. Clinical trial information: NCT03567642 .