Lung cancer remains the most common and deadliest malignancy in China. Optimizing treatment strategies is essential for extending patient survival and improving quality of life. In the era of precision medicine, targeted therapies such as icotinib and befotertinib have provided significant breakthroughs for non-small cell lung cancer (NSCLC), demonstrating the commitment and innovation of Chinese pharmaceutical companies in the global fight against cancer.

To better summarize clinical experiences and explore personalized treatment approaches, the “The Battle of Outstanding Clinical Cases” was hosted by Oncology Frontier on December 19, 2024. The case-sharing session highlighted the exceptional efficacy of icotinib and befotertinib in real-world clinical practice while showcasing the innovative approaches of young physicians in personalized cancer treatment. This summary aims to provide valuable insights for clinical professionals and contribute to the advancement of precision and standardized lung cancer management in China.

Case Presentation

Case 1: A Journey of Resilience and Strength

Presented by  Hui Jing, Xuzhou Central Hospital

A 72-year-old male patient was admitted on April 5, 2021, due to right chest pain persisting for three months. On physical examination, a firm subcutaneous mass measuring 10 × 8 cm was palpable below the right clavicle. Chest CT revealed a right lung tumor measuring 14 × 10 cm with rib invasion. Bone scanning indicated multiple metastases to the ribs and sternum. A biopsy confirmed mucinous adenocarcinoma with genetic testing identifying an EGFR L858R mutation in exon 21. The patient was diagnosed with stage IV (T4N3M1) right lung adenocarcinoma.

Icotinib at a dosage of 250 mg three times daily was initiated as first-line therapy in combination with zoledronic acid. During treatment, the patient developed left pneumothorax, which required closed chest drainage and oxygen therapy. Despite this complication, treatment continued, and the patient achieved a partial response. In November 2023, MRI revealed brain metastases, prompting a shift in treatment strategy.

Gamma Knife radiosurgery was performed for brain lesions, and next-generation sequencing (NGS) of the blood sample detected an additional EGFR T790M mutation. The patient was started on befotertinib with a gradual dose escalation, beginning at 50 mg once daily for the first week, increasing to 75 mg in the second week, and finally reaching 100 mg daily. By March 28, 2024, follow-up MRI showed a reduction in brain lesions, while CT scans confirmed stable lung disease.

This case illustrates the effectiveness of sequential EGFR-TKI therapy. Icotinib provided initial disease control, while befotertinib successfully managed disease progression after the emergence of the T790M resistance mutation, resulting in tumor reduction and stable disease.

Case 2: Long-Term Survival in Advanced NSCLC Treated with First-Line Icotinib

Presented by Wanlan Huang , Department of Oncology, Jieyang People’s Hospital

A 74-year-old male patient with a history of hypertension and diabetes for over ten years was initially diagnosed with right upper lung adenocarcinoma and underwent thoracoscopic right upper lobectomy with mediastinal lymph node dissection on April 9, 2018. The postoperative pathology confirmed stage IA2 (pT1bN0M0) disease.

On March 24, 2022, he was admitted due to the discovery of a left cervical mass persisting for six months. Physical examination revealed an enlarged lymph node measuring approximately 2 × 1.5 cm on the left side of the neck. CT imaging of the neck, chest, and upper abdomen suggested postoperative changes in the right upper lung, with multiple enlarged lymph nodes in the left lower neck, left supraclavicular region, and mediastinum, raising concerns about metastatic progression. MRI of the brain showed signs of senile cerebral atrophy. A fine needle aspiration biopsy of the left cervical lymph node was performed under ultrasound guidance on March 25, 2022, and pathological findings confirmed metastatic papillary adenocarcinoma of pulmonary origin. Genetic testing revealed an EGFR exon 21 L858R mutation, leading to a clinical diagnosis of stage IV right upper lung adenocarcinoma with multiple lymph node metastases.

Treatment Strategy

According to the 2022 CSCO guidelines, first-line therapy for EGFR-sensitive mutation-positive stage IV NSCLC includes seven targeted agents. In the era of multiple generations of EGFR-TKIs, selecting a first-line treatment requires comprehensive consideration of efficacy, safety, resistance mechanisms, subsequent treatment options, tumor burden, metastatic sites, patient age, and comorbidities. Clinical studies have demonstrated significant benefits of EGFR-TKI therapy in advanced NSCLC patients. Global randomized controlled trials comparing the incidence of grade ≥3 adverse events (AEs) among different EGFR-TKIs indicate that first-generation TKIs exhibit superior overall safety profiles, with icotinib demonstrating the lowest incidence (9.5%).

Resistance patterns differ between first-, second-, and third-generation EGFR-TKIs. First- and second-generation EGFR-TKIs primarily induce on-target resistance mechanisms, with EGFR T790M mutations being the most common, allowing approximately 50% of patients to receive second-line targeted therapy. In contrast, first-line treatment with third-generation EGFR-TKIs tends to induce early-acquired resistance through off-target mechanisms, potentially limiting subsequent treatment options.

Given this patient’s age (74 years), underlying hypertension and diabetes, lack of visceral metastases, and absence of brain metastases at baseline, icotinib was selected as the first-line therapy due to its favorable safety profile, potential for subsequent treatment options, and manageable tumor burden.

Treatment Course

On April 4, 2022, the patient began first-line therapy with icotinib at 125 mg three times daily, achieving a partial response (PR) as the best-evaluated outcome. By February 21, 2024, follow-up CT imaging indicated progressive enlargement of multiple mediastinal lymph nodes, suggesting slow disease progression. Blood-based NGS testing did not detect an EGFR T790M mutation, but the L858R mutation persisted, prompting a continuation of icotinib therapy.

On October 17, 2024, the patient developed new brain metastases, with MRI revealing lesions in the right frontal lobe and left cerebellar hemisphere. Extracranial disease remained stable. A multidisciplinary team (MDT) consisting of specialists from radiation oncology, neurosurgery, imaging, and medical oncology provided the following treatment options:

1. Surgical resection of brain metastases followed by genetic testing
2. Stereotactic radiotherapy (SRT) combined with continued TKI therapy
3. Alternative systemic therapy, such as chemotherapy combined with anti-angiogenic treatment

The patient and family declined surgical resection, radiotherapy, chemotherapy, and genetic testing due to personal preferences and financial constraints.

The INCREASE study demonstrated that high-dose icotinib treatment for EGFR exon 21-mutated NSCLC extended PFS by 3.7 months compared to standard doses, with efficacy similar to that observed in exon 19-mutant NSCLC. Importantly, dose escalation did not significantly increase grade 3 or higher treatment-related adverse events (TRAEs) or lead to treatment discontinuation due to toxicity.

Given these findings, icotinib dosage was doubled to 250 mg three times daily starting on October 18, 2024. The patient’s dizziness improved after dose escalation, though mild diarrhea was observed and managed symptomatically.

This case highlights that icotinib as first-line therapy achieved a progression-free survival (PFS) exceeding 30 months, demonstrating significant long-term benefit. Furthermore, dose escalation of icotinib in the second-line setting showed a trend toward continued disease control, providing additional evidence for a personalized treatment approach in elderly NSCLC patients with EGFR mutations.

The patient’s MRI revealed a lesion in the right frontal lobe and a lesion in the left cerebellar hemisphere, indicating new brain metastases while extracranial disease remained stable.

Case 3: A Turn for the Better – The Treatment Journey of a Long-Surviving Lung Cancer Patient Undergoing Drug Switches

Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University –  Dan Cheng

A 55-year-old male was admitted on December 28, 2020, due to a two-month history of cough and sputum production. Laboratory tests showed an elevated serum CEA level of 38.30 ng/mL. Chest CT revealed a patchy mass and strip-like shadows in the left lung, interstitial changes in both lungs, multiple pulmonary nodules, mild enlargement of mediastinal and right hilar lymph nodes, left pleural effusion, and localized pleural thickening.

A bronchoscopy performed on December 30, 2020, showed narrowing of the left lower lobe posterior segment bronchial opening with mucosal lesions, as well as inflammatory-like changes in both bronchi. Pathological examination of bronchoscopic biopsy tissue confirmed invasive adenocarcinoma of the lung. Next-generation sequencing (NGS) of the biopsy specimen identified an EGFR exon 19 deletion (19del) mutation. The patient was diagnosed with left lung malignancy (lung adenocarcinoma, stage IVA), with metastatic lymph nodes in the left cervical region, mediastinum, and right hilum, along with left pleural effusion and interstitial pneumonia.

The patient began treatment with gefitinib (250 mg once daily) on January 21, 2021. The disease remained stable (SD), but he developed abnormal liver enzyme elevations. After nine months of gefitinib treatment, the medication was discontinued as the patient refused further examinations.

On October 27, 2021, he was switched to osimertinib (80 mg once daily). The disease remained stable (SD); however, he developed severe skin rash that did not improve despite symptomatic treatment. After three months, osimertinib was discontinued, as the patient again declined further medical evaluations.

On March 7, 2023, he was switched to icotinib (125 mg three times daily). Following this change, the skin rash gradually resolved, liver and kidney functions remained normal, and no adverse reactions were observed.

Case 4: Searching for the Right Target – The Importance of Recognizing Rare Mutations

Tianjin People’s Hospital – Yifan Zhang

A 97-year-old male with a 30-year smoking history (10 cigarettes per day) had quit smoking 40 years ago. On July 20, 2023, he was admitted due to a one-month history of cough and sputum production, which had worsened over the past two days, accompanied by fever. Chest CT revealed a mass in the upper lobe of the right lung, suspected to be malignant, with mediastinal invasion, multiple mediastinal lymph node metastases, and multiple ground-glass opacity nodules in both lungs, suggesting malignancy. A PET-CT scan further indicated a hypermetabolic mass in the upper lobe of the right lung near the hilum, highly suggestive of central lung cancer (T3N3M1) involving the adjacent right hilar and mediastinal structures, along with multiple lymph node metastases in the right cervical root, bilateral hila, and mediastinum, as well as metastases to the liver and bones. Blood-based genetic testing identified an EGFR 18G79S mutation. After a comprehensive systemic evaluation, including blood biochemistry and echocardiography, the patient was diagnosed with stage IV lung malignancy, pneumonia, respiratory failure, and cardiac dysfunction.

Starting in August 2023, the patient was prescribed befotertinib at an initial dose of 75 mg once daily (d1–21), later increased to 100 mg once daily. Follow-up imaging showed stable disease (SD) in both pulmonary and hepatic metastases. On March 18, 2024, a follow-up chest CT revealed no significant changes in the right upper lobe mass, while multiple mediastinal lymph nodes had either remained stable or decreased in size. However, new small nodules had appeared in both lungs, with some showing enlargement, indicating disease progression (PD). The first-line treatment with befotertinib achieved a progression-free survival (PFS) of nearly eight months (August 2023–March 2024).

On June 3, 2024, an abdominal ultrasound showed an increase in the size of a solid nodule in the left lateral lobe of the liver, measuring approximately 37 × 39 mm, confirming progression of hepatic metastases (PD). As of June 7, 2024, the patient was started on a combination therapy consisting of low-dose oral vinorelbine chemotherapy, anlotinib (8 mg once daily), and continued befotertinib (100 mg once daily). Follow-up assessments have indicated stable disease (SD) under this regimen.

Case 5: Breaking Through – Befotertinib Supporting an Elderly Patient’s Fight Against Cancer

Department of Internal Medicine III, Yunnan Cancer Hospital – Shu Hao

A 79-year-old female with a history of grade 2 hypertension sought medical attention in February 2022 due to over a month of chest tightness and shortness of breath. A chest CT performed on February 2, 2022, revealed a high-density mass in the apicoposterior segment of the left upper lobe measuring approximately 45 × 43 mm, with irregular margins and pleural traction. Additionally, a 27 × 23 mm nodule was observed in the posterior basal segment of the right lower lobe. The patient also exhibited left pleural thickening with multiple nodules, suggestive of pleural metastasis, and a large left pleural effusion. A CT-guided lung biopsy confirmed adenocarcinoma of the left lung, while cytology of the pleural effusion also indicated adenocarcinoma. Genetic testing identified an EGFR 21L858R mutation, leading to a diagnosis of stage IV left upper lobe lung adenocarcinoma (T2bN0M1) with malignant pleural effusion.

In March 2022, the patient started dacomitinib (30 mg once daily) as first-line therapy, achieving a partial response (PR) as the best treatment outcome over 11 months. However, a follow-up in February 2023 revealed progression (PD) with enlargement of the left upper lobe lesion and increased pleural effusion. Genetic testing at that time detected an EGFR 20 T790M mutation.

The patient was switched to furmonertinib (80 mg once daily) in February 2023 as second-line therapy. However, after four months, a follow-up in June 2023 showed tumor progression, with an increase in the size of the left upper lobe mass and a significant accumulation of pleural effusion.

From July 2023 to February 2024, she underwent third-line treatment with a combination of bevacizumab and pemetrexed. After seven months, in February 2024, brain metastases were detected. The patient declined radiation therapy and was switched to fourth-line treatment with bevacizumab and tegafur/gimeracil/oteracil (S-1). However, due to poor tolerance and grade III gastrointestinal toxicity, she discontinued treatment after one cycle. Concurrently, she developed severe hypertension (200/100 mmHg).

The patient was then initiated on befotertinib as fifth-line therapy. A follow-up in November 2024 showed a 21% reduction in the primary lung lesion and a 20% reduction in brain metastases. To date, her overall survival (OS) has reached 34 months, and her performance status remains good.

Case 6: Unveiling Precision Targeting – A Case of Advanced EGFR-Positive NSCLC Treated with Sequential First- and Third-Generation TKIs

Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University – Hu Shan

A 58-year-old female was admitted due to left-sided chest pain for nine months and a 20-day history of cough and shortness of breath. She was diagnosed with adenocarcinoma of the left lower lobe (cT4N0M1a, stage IVA), with an EGFR 21L858R mutation and a performance status (PS) of 0. Additionally, secondary pulmonary and pleural metastases were identified.

The patient initiated first-line treatment with icotinib in August 2021, achieving a progression-free survival (PFS) of nine months. However, in April 2022, disease progression (PD) was observed. Genetic testing revealed the emergence of the T790M resistance mutation.

In May 2022, she was switched to befotertinib (75 mg once daily) as second-line therapy, resulting in a partial response (PR). The combined PFS from first- and second-line treatments (1+2) reached 24 months, lasting until August 2023.

Case 7: Overcoming Lung Cancer with Comprehensive Therapy – The Role of Targeted Therapy and Interventions

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University – Rui Zhang

A 60-year-old female with a history of pulmonary tuberculosis, for which she had undergone a one-year course of anti-tuberculosis treatment, was admitted in July 2020 due to a two-month history of recurrent cough and sputum production. A chest CT scan on July 29, 2020, revealed a malignant tumor in the right upper lobe with obstructive pneumonia, measuring 9.5 × 9.6 × 5 cm at its largest section, along with enlarged hilar and mediastinal lymph nodes. A bronchoscopy and biopsy on August 3, 2020, confirmed adenocarcinoma. A whole-body bone scan showed abnormal radiotracer uptake at L3, suggestive of bone metastases. The patient was diagnosed with stage IV right lung adenocarcinoma (cT4N2M1b) with secondary bone malignancy.

First-line treatment consisted of pemetrexed, carboplatin, and bevacizumab, combined with zoledronic acid for bone protection. Genetic testing revealed an EGFR exon 19 deletion (19del) mutation, leading to the initiation of osimertinib as targeted therapy. The patient achieved a partial response (PR); however, she developed worsening interstitial pneumonia, necessitating a switch to icotinib, which led to the resolution of lung inflammation while maintaining a sustained PR. Follow-up imaging showed that bone metastases remained stable.

In April 2023, disease progression (PD) was observed in the right upper lung, prompting a switch to almonertinib. By September 2023, the lung lesions exhibited slow progression. The patient declined radiation therapy, and repeat biopsy with genetic testing revealed EGFR 19del + C797S (in trans configuration). Treatment was adjusted to icotinib combined with infusion chemotherapy.

Subsequently, the patient developed superior vena cava syndrome, requiring superior vena cava stent placement. The treatment was then intensified with increased icotinib dosage combined with radiotherapy, leading to continued disease control. As of the latest follow-up, the patient’s overall survival (OS) has reached 51 months.

Case 8: Overcoming Resistance – Befotertinib as a New Hope for Osimertinib-Resistant Lung Adenocarcinoma

Department of Traditional Chinese Medicine, The First Affiliated Hospital of Hebei North University –  Daiwei Liu

A 42-year-old female was admitted in June 2018 due to chest tightness and chest pain for six years, which had worsened over the past ten days. At admission, her ECOG performance score was 2. She had previously undergone video-assisted thoracoscopic surgery (VATS) with right upper lobectomy and hilar/mediastinal lymph node dissection on April 11, 2016. Postoperative pathology confirmed primary adenocarcinoma in situ with invasive adenocarcinoma, and the disease was staged as pT1N0M0 (stage IA).

In June 2018, a PET-CT scan showed postoperative changes in the right lung, soft tissue thickening at the bronchial stump with mild metabolic activity, and diffuse, irregular thickening of the right pleura with increased metabolism, suggesting pleural metastasis. The right supraclavicular lymph nodes also exhibited metabolic activity, raising suspicion of metastasis, while small lymph nodes in the mediastinal 2R and 4R regions showed mild metabolic uptake. Genetic testing of a biopsy sample in July 2018 identified an EGFR 21L858R mutation, and the patient was diagnosed with right lung adenocarcinoma (cT1N3M1, stage IV), with EGFR 21L858R mutation, supraclavicular lymph node metastasis, and pleural metastasis.

First-line treatment with icotinib (125 mg three times daily) began in July 2018. However, a follow-up CT in June 2019 revealed new pleural effusion, indicating disease progression (PD). From June to August 2019, the patient underwent four cycles of pemetrexed plus cisplatin chemotherapy as second-line treatment.

In August 2019, genetic testing of pleural effusion identified EGFR 21L858R and T790M mutations. By April 2020, a brain MRI showed multiple metastatic tumors, prompting a switch to third-line targeted therapy with osimertinib (80 mg once daily). The disease remained controlled until October 2021, when new bilateral lung metastases were detected. At this stage, osimertinib was combined with anlotinib (12 mg, days 1–14) to enhance efficacy.

In June 2022, follow-up brain and chest CT scans showed pulmonary disease progression (PD). The patient underwent pleural fluid drainage, and genetic testing was performed on the pleural fluid sample. Subsequently, she received albumin-bound paclitaxel (300 mg on day 1) and bevacizumab (400 mg on day 1) every 21 days.

In July 2022, pleural fluid pathology confirmed adenocarcinoma cells, and genetic testing identified EGFR 21L858R, EGFR T790M, and TP53 mutations. By August 2022, she was started on fifth-line treatment with befotertinib (75 mg once daily). The disease achieved a partial response (PR), and progression-free survival (PFS) exceeded six months under this regimen.

Case 9: A Breakthrough in Durable Treatment – First-Line Befotertinib Therapy for EGFR-Positive NSCLC

Liaoning Cancer Hospital – Tian Xin

A 48-year-old female with a history of hypertension was admitted in May 2020 due to cough, pain, shortness of breath, chest tightness, and fatigue. A chest CT scan revealed a central lung cancer in the right middle lobe, highly suggestive of malignancy, with multiple metastatic nodules in both lungs, as well as enlarged mediastinal and right hilar lymph nodes, a small right pleural effusion, and an enlarged left supraclavicular lymph node. A bronchoscopic biopsy confirmed poorly differentiated adenocarcinoma, and genetic testing identified an EGFR exon 19 deletion (19del) mutation. The patient was diagnosed with stage IV lung adenocarcinoma (cT4N3M1a) with EGFR 19del mutation.

On June 24, 2020, she initiated first-line treatment with befotertinib (75 mg once daily). By July 14, 2020, the dosage was increased to 100 mg once daily. The patient has remained on befotertinib monotherapy, achieving stable disease control with excellent tolerance. Her progression-free survival (PFS) has now exceeded 53 months, with all disease sites remaining well-controlled. From July 28, 2020, to November 25, 2024, her response has consistently been classified as partial response (PR).

Case 10: Sustained Control with Befotertinib – Second-Line Treatment for EGFR-Positive Lung Adenocarcinoma

Cancer Hospital, Chinese Academy of Medical Sciences – Haohua Zhu

A 64-year-old female with a history of mild asthma was diagnosed with lung adenocarcinoma with an EGFR exon 19 deletion (19del) mutation at an external hospital in August 2021. She was initially treated with icotinib from September 2021 to March 2022. However, a follow-up CT scan in March 2022 showed disease progression (PD). A CT-guided biopsy of the left lung tumor confirmed moderately to poorly differentiated adenocarcinoma with minimal treatment response.

Genetic testing in March 2022 identified the EGFR 19del and T790M mutations. A baseline CT scan on April 8, 2022, revealed an irregular mass in the anterior segment of the left upper lobe (4.0 × 2.3 cm), with lobulated margins, spiculations, and partial pleural traction, adjacent to the mediastinal pleura. The tumor had also caused partial bronchial obstruction and distal atelectasis. Multiple pulmonary nodules were present in both lungs, the largest located in the right lower lobe near the mediastinum (1.7 × 1.1 cm). The patient was diagnosed with stage IVA lung adenocarcinoma with multiple bilateral lung metastases and EGFR 19del/T790M mutations.

In April 2022, she was enrolled in a clinical trial for befotertinib (D-0316) and began receiving befotertinib 100 mg once daily, achieving a best overall response of partial response (PR). During treatment, she developed a skin rash, which improved with symptomatic management. Her progression-free survival (PFS) has now exceeded 31 months, with continued disease control under befotertinib therapy.