Figure 5.

Heterogeneity of MET Amplification in the Development of Acquired Resistance to Osimertinib in Three Patients without Prior Therapy

(A) Treatment timeline from diagnosis to death for subject LAT001. The subject began osimertinib treatment under this study upon the diagnosis of EGFR mutant metastatic lung adenocarcinoma. Imaging at first restaging showed a treatment response in the posterior liver (green circle). Upon first progression at 7 months, the subject underwent LAT (posterior liver excision, green arrows). After a second progression on osimertinib (red arrows), the subject began a clinical trial of osimertinib plus savolitinib. The subject responded to osimertinib plus savolitinib at day 43 (red arrows). The subject subsequently progressed on day 77 (yellow circle) and was found to harbor MET D1246N mutation. Block arrows represent focal amplifications in areas without cancer-related genes. Yellow: 5q11.2; purple: 6p21.1; blue: 8q21.3; magenta: 6q24.1; green: 11p11.2, 11p24.2, 11q23.3, 12p12.1. Red text signifies anatomic sites of biopsies.

(B) Treatment timeline from diagnosis to death for subject LAT006. The subject started osimertinib therapy for metastatic EGFR mutant NSCLC. Three months after starting osimertinib, the tumor in the top-right lobe continued to respond (green circles), but the tumor in the bottom-left lobe progressed (red circles). The subject underwent LAT (bottom-left lung lobectomy, red arrow) and then osimertinib was reinitiated. At a second progression receiving osimertinib (yellow circle), the subject underwent stereotactic radiosurgery to the brain then started erlotinib followed by chemotherapy (carboplatin plus pemetrexed) followed by whole-brain radiation therapy and subsequently chemotherapy along with pembrolizumab. Upon progression (yellow circle), the subject had stereotactic radiosurgery to another brain lesion. The subject was then started on combination osimertinib and crizotinib to which the subject responded (yellow circle). Upon diagnosis of leptomeningeal disease, osimertinib was increased to 160 mg. Rapid autopsy was performed upon expiration.

(C) Treatment timeline from diagnosis to death for subject LAT021. After the diagnosis of metastatic EGFR mutant NSCLC, the subject was initiated on osimertinib. First on-trial imaging demonstrated a partial response (green circles). At first progression on osimertinib, the subject underwent LAT (proton therapy) and then reinitiated osimertinib. At a second progression while receiving osimertinib, WES of the first progressive tumor showed PDL1 amplification therefore pembrolizumab was started. There was mixed response on pembrolizumab with green arrows showing a site of response and yellow arrows showing sites of progression. The second progressive tumor had MET in addition to PDL1 amplification; therefore, the subject was treated with osimertinib and crizotinib, and the subject had resolution of PET-avid disease in multiple metastatic sites (yellow arrows). Red arrow signifies a new PET-avid site. FACETS copy-number plots from tumor exome sequencing and FISH for MET for each subject are shown. Only cancer-related genes within focal copy-number amplifications are displayed. Biological replicates at post-osimertinib resistance for individual subjects are shown. RT, radiation therapy; IO, immunotherapy; Osi, osimertinib; Criz, crizotinib; Savo, savolinitib