Combination therapy of apatinib with icotinib for primary acquired icotinib resistance in patients with advanced pulmonary adenocarcinoma with EGFR mutation.

Multi-targeted agents represent the next generation of targeted therapies for solid tumors, and patients with acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) may also benefit from their combination with TKI therapy. Third-generation targeted drugs, such as osimertinib, are very expensive, thus a more economical solution is required. The aim of this study was to explore the use of apatinib combined with icotinib therapy for primary acquired resistance to icotinib in three patients with advanced pulmonary adenocarcinoma with EGFR mutations. We achieved favorable oncologic outcomes in all three patients, with progression-free survival of four to six months. Unfortunately, the patients ultimately had to cease combination therapy because of intolerable adverse effects of hand and foot syndrome and oral ulcers. Combination therapy of apatinib with icotinib for primary acquired resistance to icotinib may be an option for patients with advanced pulmonary adenocarcinoma with EGFR mutations, but physicians must also be aware of the side effects caused by such therapy.

Introduction

Lung cancer is one of the most common types of cancer and the leading cause of human cancer death worldwide.1 Non‐small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases. Treatment strategies for NSCLC have evolved to emphasize molecular targeted therapy based on the genomic classification of patients.2 The increase in lung adenocarcinoma incidence, reported at 1.3% annually in Chinese men between 1990 and 2010, is a significant threat to life.3 Lung adenocarcinoma shows a significantly higher rate of gene mutation than squamous cell carcinoma, especially in non‐smoking patients with lung adenocarcinoma.4, 5 Therefore, for patients with lung adenocarcinoma with EGFR mutations, treatment with EGFR‐tyrosine kinase inhibitors (TKIs) plays an increasingly important role. However, tumors that initially respond to EGFR‐TKIs and anaplastic lymphoma kinase inhibitors eventually acquire resistance, which limits the therapeutic success of these targeted agents,6 and third‐generation targeted drugs such as osimertinib are very expensive. It is well known that tumor angiogenesis is one of the hallmarks of cancer and is an essential step in tumor growth and metastasis.7, 8 Apatinib, a small‐molecule (VEGFR‐2) TKI, is presently undergoing phase II/III clinical trials in China for the treatment of many cancer types, such as NSCLC, breast cancer, and hepatocellular carcinoma.9 Multiple trials and clinical studies have shown the potential advantages of combination therapy of EGFR and VEGF inhibitors in patients with advanced NSCLC and acquired resistance to targeted therapies.10, 11, 12 In addition, NSCLC patients with acquired resistance to EGFR‐TKIs are reported to benefit from the combination with TKI therapy by achieving months to years of disease control.13 To our knowledge, however, there are no reports of combination therapy of VEGFR‐2 with EGFR‐TKIs for primary acquired resistance to EGFR‐TKIs in patients with advanced lung adenocarcinoma with EGFR mutations. Herein, we report cases of three such patients with EGFR mutations at exon 19(+) or exons 19 and 21(+), where a partial response was achieved in one patient and stable disease in two. Therapeutic evaluation was made according to Response Evaluation Criteria in Solid Tumors version 1.1.14

Case presentation

Patient I, a 62‐year‐old male smoker, complained of repeated coughing with sputum for three years and bloody sputum for two weeks. Chest enhanced computed tomography (CT) revealed a space‐occupying lesion in the right upper lung apex and double hilum of the pulmonary lymph nodes. He underwent bronchofiberscopy at a local hospital, and the pathology report revealed adenocarcinoma. Radical video‐assisted thoracic surgery of right upper lung cancer was performed under general anesthesia on 17 November 2014. The pathology report at this time revealed the lesion to be a medium to poorly differentiated pulmonary adenocarcinoma, and EGFR examination of paraffin‐embedded slices detected an exon 19 deletion (Table 1). Four months later, whole‐body positron emission tomography‐CT (PET‐CT) showed increased metabolism in the upper right lung mass, and a slowly rising carcinoembryonic antigen (CEA) serum level. Therefore, 125 mg icotinib was administered three times a day (t.i.d.) for two months (April to June 2015) as first‐line therapy. The therapeutic evaluation indicated stable disease; however, the blood CEA level continued to increase. Icotinib combined with radiotherapy 200 cGy × 30 f and icotinib combined with pemetrexed + cisplatinum was administered for six chemotherapy cycles (June 2015 to August 2016). Chest CT then revealed multiple mediastinal lymph nodes, and his serum CEA level was 247.3 ng/mL (Fig 1), indicating progressive disease. Hence, on 7 November 2016 we began oral administration of apatinib 250 mg/d combined with icotinib 125 mg/t.i.d. Chest CT performed in January 2017 indicated stable disease (Fig 1). At this writing, the patient has achieved progression‐free survival (PFS) of six months, but intolerable grade 2–3 foot syndrome (Fig 2) and oral ulcers have emerged.

Table 1

Baseline characteristics of patients

Characteristics	Case 1	Case 2	Case 3
Age	62	66	61
Gender	Male	Female	Male
Smoking	Yes	No	Yes
Pathologic type	Medium‐poorly differentiated adenocarcinoma	Adenocarcinoma	Poorly‐differentiated adenocarcinoma
Gene type
EGFR	19(+)	19Del(+)	19Del (+) and 21 L858R (+)
ALK	Negative	Negative	Negative
ROS‐1	Negative	Negative	Negative
Metastases	Multiple lung and mediastinal node	Multiple lung and mediastinal node and bone	Multiple lung and clavicle node and bone
Stage	IV (cT4N2M0)	IV (cT4N2M1b)	IV (cT4N3M1b)
Therapy (response)
First line	Icotinib (SD)	Icotinib (SD)	Icotinib (SD)
Second line	Icotinib and Radiotherapy and Chemotherapy (PD)	Icotinib and Apatinib (PR)	Icotinib and Apatinib (SD)
Third line	Icotinib and Apatinib (SD)
CEA (μg/ml)
Pre‐apatinib	247.3	113.4	332.3
Post‐apatinib	39.4		26.9
PFS (months)	6	4	4
Adverse events
Hypertension	Grade 1		Grade 1
Hand‐foot	Grade 2–3	Grade 1–2	Grade 2–3
Diarrhea		Grade 1
Fatigue	Grade 1	Grade 1	Grade 1
Oral ulcers	Grade 1–2	Grade 2–3	Grade 1–2
Anorexia		Grade 1	Grade 2

CEA, carcinoembryonic antigen; PD, progressive disease; PFS, progression‐free survival; PR, partial response; SD, stable disease.

Figure 1

The time course of the carcinoembryonic antigen (CEA) concentrations measured in patients (a) I and (b) III.

Figure 2

One of three patients developed grade 2–3 hand‐foot syndrome.

Patient II was a 66‐year‐old woman who had never smoked. She underwent CT‐guided percutaneous needle biopsy in November 2015 for a cough with bloody sputum persisting for more than two weeks. The pathology report revealed that the obtained specimen was pulmonary adenocarcinoma, and EGFR examination of paraffin‐embedded slices detected an exon 19 deletion (Table 1). Therefore, icotinib 125 mg t.i.d was administered orally from December 2015. The therapeutic evaluation was stable disease. A whole‐body PET‐CT scan was performed about 10 months later, which showed multiple thoracic bone metastases and the therapeutic evaluation was progressive disease. Therefore, from 1 December 2016 we administered oral doses of apatinib 250 mg/d combined with icotinib 125 mg t.i.d. After more than three months of therapy, chest CT showed a partial response of the lesions (Fig 3). Presently, the patient has achieved PFS of over four months, but intolerable grade 2–3 oral ulcers have developed.

Figure 3

Computed tomographic images from patients I, II, and III show the mass(a,c,e) before apatinib treatment, and (b,d,f) after three months of apatinib therapy, respectively.

Patient III, a 61‐year‐old male heavy smoker complained of a cough with bloody sputum lasting longer than 20 days. A PET‐CT scan showed right lower lung cancer with multiple lung metastases on both sides of the clavicle and mediastinum, along with right hilar lymph node metastasis and multiple bone metastases of stage cT4N3M1b. Bronchofiberscopy was performed at our hospital, and the pathology report showed poorly differentiated cancer. An amplification refractory mutation system EGFR examination of paraffin‐embedded slices detected 19‐Del and 21L858R deletions (Table 1). Icotinib 125 mg/t.i.d was administered as first‐line targeted therapy for seven months (April to November 2016), and the therapeutic evaluation was progressive disease. Chest CT showed malignant pleural effusion and a drastic increase in his serum CEA level (Fig 3). From 8 December 2016, apatinib 250 mg/d combined with icotinib 125 mg t.i.d was administered. A chest CT performed four months later showed rapid control of the malignant pleural effusion and a rapid decrease in his serum CEA level (Figs 1, 3). Hence, the therapeutic evaluation was stable disease. Currently, the patient has achieved PFS of over four months, but as with patient I, intolerable grade 2–3 foot syndrome (Fig 2). and oral ulcers have emerged.

Late in the follow‐up period, it was discovered that suspending the medication for a week could alleviate the side effects. As a result, all patients suspended treatment for a week. However, because of the side effects and economic affordability, apatinib was only used intermittently.

Discussion

Lung cancer has the highest cancer mortality rates worldwide, and incidence increases year by year. NSCLC, usually diagnosed at advanced stage, accounts for > 70% of all lung cancer cases.15 Surgery is an effective means of treatment for early stage lung cancer; however, cancer discovered at advanced stage cannot be treated surgically. Many studies have shown that EGFR‐TKI therapy is effective as first‐line treatment against advanced NSCLC with EGFR mutations. For most advanced NSCLC patients without a genetic driver mutation, platinum‐based doublet chemotherapy is the standard treatment option.16, 17 Compared with traditional first‐line chemotherapy, EGFR‐TKI therapy has achieved statistically significantly longer PFS, a higher objective response rate, numerically longer overall survival, and lower toxicity in patients with advanced NSCLC harboring activated EGFR mutations, breaking the treatment bottleneck experienced with traditional chemotherapeutic drugs.18 Furthermore, published studies have shown that EGFR‐TKIs offer favorable safety, with the vast majority of patients able to tolerate this therapy.19 In the present study of three patients with advanced lung adenocarcinoma and exon 19 or exons 19 and 21 deletions, the lesion was soon controlled after beginning icotinib 125 mg/t.i.d. However, after several months of treatment with this EGFR‐TKI, the tumor cells began to replicate and resist apoptosis, the disease progressed, the lesion size increased, and serum CEA levels underwent a sustained rise, indicating the appearance of acquired resistance,20 and limiting the therapeutic success of these targeted agents. Several randomized, phase III clinical trials of first‐line treatments (including IPASS, WJTOG3405, NEJ002, OPTIMAL, LUXLUNG3, and EURTAC) have revealed that use of EGFR‐TKIs as a first‐line treatment for advanced NSCLC patients with active EGFR gene mutations could achieve PFS of 9.5–13.7 months.21, 22, 23, 24, 25, 26 Moreover, it was reported that NSCLC patients with acquired resistance to EGFR‐TKIs could also benefit from combined therapy with TKIs to achieve months to years of disease control.13

Angiogenesis is a key process for cell growth, especially for tumor growth, development, and metastasis.27 Serum VEGF activates VEGFR‐2, inducing a cascade of different signaling pathways to promote the endothelial cell migration and proliferation necessary for angiogenesis. Studies have revealed that anti‐angiogenesis drugs inhibit the growth of solid tumors, including NSCLC.28 Apatinib (a small molecule drug developed in China in October 2014 that targets the treatment of advanced gastric cancer) strongly inhibits VEGFR‐2 activation, which can suppress endothelial proliferation and ultimately lead to anti‐angiogenesis. Apatinib is confirmed to exert an anti‐tumor effect on various cancers.

Multi‐targeted agents represent the next generation of targeted therapies in solid tumors. Multiple trials and clinical studies have shown the potential advantages of combining EGFR and VEGF inhibitors for patients with advanced NSCLC and acquired resistance to targeted therapies; for example, the median PFS was 16.0 months with erlotinib plus bevacizumab but only 9.7 months with erlotinib alone.10, 11, 29 A report on the safety and pharmacokinetics of apatinib in advanced NSCLC indicated that apatinib could be well tolerated and showed substantial antitumor activity at a dose of 500 or 750 mg once daily.30, 31 However, in accordance with the general condition of our patients and our concern over their intolerance to toxicity, we treated them with targeted therapy comprising daily doses of apatinib at 250 mg/d combined with icotinib at 125 mg t.i.d for 28 days per cycle, with the endpoint of unacceptable toxicity or disease progression. The most frequent adverse effects were hypertension, hand‐foot syndrome, proteinuria, fatigue, anorexia, and elevated aminotransferase level.9 Two of the patients suffered intolerable grade 2–3 foot syndrome and oral ulcers, while the third patient suffered intolerable grade 2–3 oral ulcers.

In summary, the VEGFR‐2 TKI apatinib combined with the first‐generation EGFR‐TKI icotinib provided effective therapeutic action in three patients with advanced pulmonary adenocarcinoma and acquired resistance to icotinib. We treated them with daily doses of apatinib at 250 mg/d combined with icotinib at 125 mg t.i.d, and all three patients achieved long PFS, although they suffered intolerable grade 2–3 foot syndrome and/or oral ulcers. Additional clinical studies are required to clarify the guidelines for clinical treatment with this combination therapy; however, we are convinced that the future for this therapy is promising.

Disclosure

No authors report any conflict of interest.