Mutations in the KRAS gene are the most common gain-of-function mutations found in lung adenocarcinomas. The most common mutation, KRAS G12C, is present in 13% of lung adenocarcinomas. Sotorasib (AMG-510) is an irreversible small molecule inhibitor targeting KRAS G12C. In preclinical studies, treatment with sotorasib led to the regression of KRAS G12C-mutated tumors, and clinical efficacy in NSCLC was demonstrated in clinical trials. In May 2021, sotorasib received US FDA approval for treatment of KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy. In this report, we present a case with metastatic, KRAS G12C-mutated NSCLC who responded favorably to sotorasib as first-line therapy. The efficacy of sotorasib as first-line treatment in this patient was remarkable, which supports further study of sotorasib as first-line therapy for KRAS G12C-mutated NSCLC, especially in fragile patients with comorbidities.

© 2023 The Author(s). Published by S. Karger AG, Basel

Lung cancer is the leading cause of cancer-related mortality [1]. The most common bronchogenic malignancy is non-small cell lung cancer (NSCLC), representing about 85% of cases with adenocarcinoma being the most common subtype, approximately 40% of all lung cancers. Mutations in the Kirsten rat sarcoma viral oncogene (KRAS) are the most common gain-of-function mutations found in lung adenocarcinomas. KRAS G12C is the most common mutation and is present in about 13% of lung adenocarcinomas [2]. The KRAS G12C mutation results from the production of abnormal GTP-bound KRAS, leading to hyper-activation of oncogenic pathways and uncontrolled cell growth [3]. Preclinical studies established the conceptual foundation for covalent and selective KRAS G12C inhibitors, which led to the development of agents that directly inhibit mutant KRAS G12C, such as sotorasib (AMG-510), adagrasib (MRTX-849), and JNJ-74699157 [4–7]. Sotorasib is an irreversible small molecule tyrosine kinase inhibitor targeting KRAS G12C. This molecule binds to the inactive GDP-bound conformation, trapping KRAS G12C in the dormant state and inhibiting KRAS oncogenic signaling [5]. In a phase 2 clinical trial (CodeBreaK 100), sotorasib was shown to have clinical efficacy in previously treated, KRAS G12C-mutated NSCLC [8]. In May 2021, sotorasib received accelerated approval by the US Food and Drug Administration (FDA) for treatment of patients with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy [9]. In this report, we present a case of metastatic KRAS G12C-mutated NSCLC that responded well to sotorasib as first-line therapy.

The patient is an 80-year-old female, former smoker (20 pack-years, quit in 2000), and with a past medical history of chronic obstructive pulmonary disease (COPD) on home oxygen therapy (2 L per min via nasal cannula), Crohn’s disease, hypertension, and atrial fibrillation, who had a ground level fall complicated by rib fractures and pneumothorax requiring chest tube placement. On chest CT, she was incidentally found to have a 2.1 cm right lung nodule. Subsequent 18-fluorodeoxyglucose (FDG) PET/CT imaging demonstrated a 2.2 cm mass in the anterior medial right upper lobe (RUL), which was FDG avid with an SUV of 28.6 consistent with malignancy. Some small, indeterminate pleural nodules were also noted, but neoplasm could not be confirmed. A CT-guided biopsy of the RUL mass showed poorly differentiated carcinoma. Immunohistochemistry demonstrated that the malignant cells were positive for TTF-1 and CK7 and negative for P40; P63 showed nonspecific staining. The immunoprofile was consistent with poorly differentiated NSCLC. Next-generation sequencing of the tumor tissue was performed using the Lung Cancer Hotspot Gene Panel developed at Cleveland Clinic’s Robert J. Tomsich Pathology and Laboratory Medicine Institute, which showed a KRAS G12C mutation; other actionable mutations, including EGFR, ALK, ROS1, RET, BRAF, HER2, and MET, were otherwise negative. PD-L1 testing could not be performed due to insufficient tissue. She was initially felt to have early-stage disease (T1c N0 M0; AJCC stage IA3). She was not a candidate for surgery due to her underlying COPD and poor pulmonary reserve. She received stereotactic body radiotherapy (SBRT) to the RUL mass with a total dose of 5,000 cGy in 5 fractions using 6 MV photons with SBRT coplanar VMAT technique as definitive treatment.

Restaging PET/CT about 3 months after SBRT (Fig. 1a) showed an FDG-avid mediastinal, level 8 lymph node (SUV max = 9.3), scattered new FDG-avid lymph nodes in the right cardio phrenic angle up to 1.6 cm (SUV max = 12), and new right-sided pleural nodules up to 1.9 cm (SUV max = 13). The previously treated RUL mass was slightly decreased in size and FDG avidity (SUV max = 12). Due to disease progression noted on imaging, brain MRI was done to complete her restaging evaluation and no metastatic disease was found.

PET/CT imaging at baseline (a), 3 months (b), and 6 months (c) following initiation of treatment with sotorasib from left to right.

The patient was of advanced age with ECOG performance status (PS) 2 and multiple medical comorbidities. The patient was not felt to be a good candidate for platinum-based chemotherapy. The patient was not a good candidate for immunotherapy (IT) even though data have shown that KRAS G12C-mutated NSCLC responds better with IT due to the patient’s history of pre-existing Crohn’s disease, PS2, and undefined PD-L1 expression on the tumor tissue. Because of her medical comorbidities, invasive biopsy and tissue testing for PD-L1 were unlikely to change recommendations in this case. As previously noted, the tumor tissue harbored a KRAS G12C mutation. Based on this molecular finding, first-line treatment with sotorasib was the most feasible option in this clinical setting.

After obtaining authorization for use, the patient began treatment with sotorasib 960 mg by mouth daily. She tolerated the treatment well with no significant toxicities. Serial laboratory studies showed no significant abnormalities from baseline. After 3 months of treatment, PET/CT imaging was performed to evaluate treatment response (Fig. 1b). The patient had a complete response as per RECIST (response evaluation criteria in solid tumors) with complete resolution of all sites of FDG-avid disease, and the response was stable on a subsequent PET/CT scan 6 months (Fig. 1c) after initiation of sotorasib. The patient has continued on treatment with sotorasib with good clinical tolerance. Her quality of life has remained the same since the treatment except for increased oxygen use, currently using 3 L oxygen due to her advanced COPD.

Targeted therapy has revolutionized lung cancer care with precision treatment based on oncogenic driver mutations. In many clinical settings, targeted therapy is replacing conventional chemotherapy as initial treatment for patients with actionable oncogenic drivers, improving overall survival and reducing the toxicities of treatment. Sotorasib received accelerated approval by the FDA in May 2021 for previously treated NSCLC harboring a KRAS G12C based on data from the phase 2 CodeBreaK 100 trial. In longer follow-up, sotorasib treatment demonstrated a 1-year survival rate of 50.8% and 2-year survival rate of 32.5% with a median overall survival of 12.5 months [10]. Responses were seen across all PD-L1 expression levels. Sotorasib activity was also demonstrated across a spectrum of co-mutations, including TP53, STK11, and KEAP1, which are associated poor prognosis in advanced NSCLC [8]. A global, randomized phase 3 trial of sotorasib versus docetaxel (CodeBreaK 200) is ongoing. The preliminary results have favored sotorasib with significantly longer progression-free survival and higher objective response rate [11].

In this case, we have demonstrated the potential efficacy of sotorasib as first-line therapy for advanced KRAS G12C-mutated NSCLC with a complete response on imaging. Not surprisingly, sotorasib is currently under investigation as first-line therapy in the CodeBreak 201 trial (NCT04933695). This single-arm study is evaluating the use of sotorasib in stage IV, KRAS G12C-mutated NSCLC with PD-L1 <1% and/or STK11 co-mutation [12]. If history is any indication, sotorasib, like other targeted therapies, may be a highly effective first-line agent for patients with PS2, comorbidities, and not candidates for IT or surgery. We anxiously await the results of CodeBreak 201 and other trials investigating sotorasib in treating KRAS G12C-mutated NSCLC. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material at www.karger.com/doi/10.1159/000529828.

Sotorasib is an FDA-approved therapy for previously treated KRAS G12C-mutated NSCLC. In this case, the clinical potential of sotorasib as first-line therapy has been demonstrated. Our patient has demonstrated an ongoing complete response after more than 6 months of therapy and is tolerating treatment without significant toxicities. Our case supports the ongoing investigation of sotorasib as a first-line treatment for KRAS G12C-mutated NSCLC.

Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. All images comply with the journal with no identifying information of the patient to the best of our knowledge. IRB approval was not required for this case report. Ethical approval is not required for this study in accordance with local or national guidelines.

The authors have no conflicts of interest to declare.

There were no funding sources associated with this work.

S.I.: design, writing, and editing; E.W.A.: conceptualization, project supervision, and editing.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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