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And Off-Target Resistance Mutations in an EML4-ALK Positive Non-Small Cell Lung Cancer Patient Under ALK Inhibition

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And Off-Target Resistance Mutations in an EML4-ALK Positive Non-Small Cell Lung Cancer Patient Under ALK Inhibition www.oncotarget.com Oncotarget, 2021, Vol. 12, (No. 19), pp: 1946-1952 Case Report Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition Marcel Kemper1,2,*, Georg Evers1,2,*, Arik Bernard Schulze1,2, Jan Sperveslage3, Christoph Schülke4, Georg Lenz1,2, Thomas Herold5, Wolfgang Hartmann3, Hans- Ulrich Schildhaus2,5,# and Annalen Bleckmann1,2,6,# 1Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Muenster, 48149 Muenster, Germany 2West German Cancer Center, Sites Muenster & Essen, 45147 Essen, Germany 3Gerhard-Domagk-Institute of Pathology, University Hospital Muenster, 48149 Muenster, Germany 4Institute of Clinical Radiology, University Hospital Muenster, 48149 Muenster, Germany 5Institute of Pathology, University Hospital Essen, 45147 Essen, Germany 6Department of Hematology/Medical Oncology, University Medical Center Goettingen, 37075 Goettingen, Germany *Authors share first authorship #Authors share last authorship Correspondence to: Annalen Bleckmann, email: [email protected] Keywords: NSCLC; resistance mutations; ALK; KRAS; ALK inhibitors Received: June 25, 2021 Accepted: August 18, 2021 Published: September 14, 2021 Copyright: © 2021 Kemper et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Treatment of advanced stage anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) with ALK tyrosine kinase inhibitors (TKIs) has been shown to be superior to standard platinum-based chemotherapy. However, secondary progress of disease frequently occurs under ALK inhibitor treatment. The clinical impact of re-biopsies for treatment decisions beyond secondary progress is, however, still under debate. Here, we report on two novel subsequent polyclonal on- and off-target resistance mutations in a patient with ALK-fused NSCLC under ALK inhibitor treatment. A 63-year-old male patient with an advanced stage EML4-ALK fused pulmonary adenocarcinoma was initially successfully treated with the second- generation ALK inhibitor alectinib and upon progressions subsequently with brigatinib, lorlatinib and chemoimmunotherapy (CIT). Progress to alectinib was associated with a so far undescribed ALK mutation (p.A1200_G1201delinsW) which was, however, tractable by brigatinib. An off-target KRAS-mutation (p.Q61K) occurred in association with subsequent progression under second-line TKI treatment. Third-line lorlatinib showed limited efficacy but chemoimmunotherapy resulted in disappearance of the KRAS mutant clone and clinical tumor control for another eight months. In conclusion, we suggest molecular profiling of progressive tumor disease also for ALK-positive NSCLC to personalize treatment in a subgroup of ALK-positive patients. INTRODUCTION (anaplastic lymphoma kinase), ROS1 (proto-oncogene tyrosine-protein kinase ROS1), BRAF (v-Raf murine Despite new treatment options, metastatic non-small sarcoma viral oncogene homolog B) and NTRK1-3 cell lung cancer (NSCLC) continues to be associated with (neurotrophic tyrosine kinase receptors 1–3) represent the highest cancer-related mortality rates worldwide [1]. targets for personalized treatment options. Therefore, In addition to the growing landscape of immuno-oncology, molecular testing at diagnosis and at relapse is essential in a multitude of driver mutations and alterations in genes advanced NSCLC [2] and is even gaining importance in such as EGFR (epidermal growth factor receptor), ALK early tumor stages [3]. www.oncotarget.com 1946 Oncotarget Rearrangement of the ALK-gene can be detected a previously undescribed ALK-exon 23 indel mutation in 3–8% of NSCLC patients [4], with the echinoderm (p.A1200_G1201delinsW) via next-generation sequencing microtubule-associated protein-like 4 (EML4) gene being (NGS) (Figure 2). At this time, the patient rejected the the predominant genomic partner leading to the EML4- recommended treatment with lorlatinib because of its ALK fusion oncogene [5]. Aberrant ALK kinase activity potential adverse neurocognitive effects. Therefore, a can be specifically targeted with tyrosine kinase inhibitors second-line treatment with brigatinib was started leading (TKIs). The first-generation TKI crizotinib demonstrated to relief of clinical symptoms and a stable disease for four superiority over standard platinum-based chemotherapy months. Subsequently, tertiary progression of the hepatic [6]. Subsequently, second- and third-generation ALK metastases was noted while a further liquid biopsy and inhibitors such as alectinib [7], brigatinib [8] and lorlatinib liver sampling both failed to demonstrate the previous ALK [9] have shown increased benefit over crizotinib. Fourth- resistance mutation. However, the EML4-ALK fusion was generation ALK inhibitors are currently being investigated still detected in the liver specimen. Interestingly, a so far [10]. However, the ALK-targeting approach loses undescribed activating KRAS-exon 3 mutation (p.Q61K) effectiveness over time as on-target resistance mutations was identified in both the liquid and liver biopsy via of ALK or ALK gene amplifications may occur which lead NGS analysis (Figure 2). An inactivating TP53 mutation to disease progression [11–14]. (p.C238Y) was only found temporarily in a liquid Here, we report a novel ALK-exon 23 resistance biopsy but not in liver tissue at this time. Hence, therapy mutation (p.A1200_G1201delinsW) that provided was switched to the third-generation TKI lorlatinib, resistance to alectinib but was tractable by brigatinib. A which resulted in a stable disease for only two months. subsequent off-target KRAS-exon 3 mutation (p.Q61K) Due to further isolated hepatic disease progression the was associated with secondary resistance to brigatinib but patient stopped TKI treatment and underwent combined was basically sensitive to chemoimmunotherapy (CIT). chemoimmunotherapy and antiangiogenetic therapy according to the Impower150 protocol [16] based on CASE REPORT discussion in a molecular tumor board at the West German Cancer Center. After four cycles of chemoimmunotherapy A 63-year-old man with a ten pack-year history of no further disease progression was observed, and the tobacco smoking presented in our clinic with immobilizing KRAS mutation disappeared from plasma as measured in lower back pain, drenching night sweats, and a weight a liquid biopsy. Hence, four cycles of maintenance therapy loss of three kilograms over a few weeks. Radiography with atezolizumab and bevacizumab were conducted and magnetic resonance imaging (MRI) of the spine afterwards (Figure 2). Unfortunately, follow-up after four showed a pathologic fracture of lumbar vertebra 1 (L1) months revealed extensive hepatic and peritoneal disease with intrusion into the spinal canal. Follow-up computed progression, although cerebral MRI scans revealed no tomography (CT) revealed tumor mass consistent with further evidence of previously detected brain metastases lung cancer in the left upper pulmonary lobe, as well at all. Ultimately, rapid clinical deterioration resulted in as metastatic lesions in mediastinal lymph nodes, the patient’s death. liver and the left adrenal gland. 18F-fluorodeoxyglucose positron emission tomography (FDG PET), CT, and DISCUSSION cerebral MRI scans revealed additionally multiple osseous and brain metastases. Both the pathological On-target resistance mutations within the ALK examination of tissues from vertebral bone resection gene have been shown to be common under treatment and from a lung biopsy revealed a cytokeratine 7/TTF1- with second-generation ALK inhibitors such as alectinib positive pulmonary adenocarcinoma with low PD-L1 [11]. There is a plethora of published data on preclinical expression (tumor proportion score: 20%) as determined characterization of these ALK mutations, and the activity by immunohistochemistry. Molecular genetic analyses of the common ALK-TKIs against these secondary using fluorescence-in-situ-hybridization (FISH) and RNA mutations has been studied in vitro [11]. In contrast to this sequencing provided evidence of EML4-ALK fusion body of knowledge, molecular testing for ALK resistance variant 1 (exon 13/ exon 20), which is the most frequent mutations has not yet fully implemented in routine clinical (33%) variant in lung cancer [15]. practice. This is mainly due to the fact that second-line First-line treatment with the second-generation ALK-TKIs, namely brigatinib and lorlatinib, cover a TKI alectinib was initiated with concurrent stereotactic nearly comparable spectrum of resistance mutations radiotherapy of the bone and brain lesions. Treatment [11]. One exception is ALK-p.G1202R, which is the most resulted in partial remission (PR) for 20 months (Figure 1). common alteration after initial treatment with alectinib and At this timepoint worsening of clinical status occurred which is thought to be more sensitive to lorlatinib than to and a CT scan showed isolated secondary progression of brigatinib based on IC50 values [11, 13] and clinical data hepatic metastases. Liquid biopsy and tissue re-biopsy [12, 17]. However, there are no reports of any large-scale, of a liver metastasis independently yielded evidence of head-to-head, randomized, controlled trials (RCT) in ALK- www.oncotarget.com 1947 Oncotarget inhibitor-naïve NSCLC patients
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