Chemotherapy in combination with pembrolizumab and antiangiogenesis in young patients with advanced primary pulmonary mucinous adenocarcinoma: Two case reports

Abstract

Primary pulmonary mucinous adenocarcinoma is an unusual histological type of non-small cell lung cancer and has a rare prevalence at a young age. There is no standard first-line therapy for advanced primary pulmonary mucinous adenocarcinoma in children and young adults—this study reports two rare cases of primary pulmonary mucinous adenocarcinoma with wild-type anaplastic lymphoma kinase and epidermal growth factor receptor (EGFR) genes. One is a 13-year-old boy ( Case#1 ), and another is a 27-year-old male ( Case#2 ). Both two cases were treated with antibiotics for suspected pulmonary infection. In our hospital, they were diagnosed with advanced primary pulmonary mucinous adenocarcinoma, the Eastern Cooperative Oncology Group (ECGO) performance status was three scores. We chose pembrolizumab and chemotherapy plus angiogenesis inhibitors for Case#1 and Case#2 . The two patients' symptoms improved and presented with a partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria，the scores of ECOG performance status were two for Case#1 and one for Case#2 . This study illustrates a promising outcome for advanced primary pulmonary mucinous adenocarcinoma with immunotherapy and chemotherapy plus angiogenesis inhibitors at a young age.

Introduction

Lung cancer is the most common cancer and remains the leading cause of cancer death in all cancer deaths. ¹ The overall incidence of lung cancer in children is ∼0.049/100,000, sporadic in children under 15 years old. ² In comparison, the rate ranges from 0.12% to 0.20% in the age of 18–∼30 years. ³ Lung adenocarcinoma is the predominant pathological subtype of non-small cell lung cancer (NSCLC) with an increasing prevalence recently. ⁴ Primary pulmonary mucinous adenocarcinoma (PPMA) is a subtype of producing intra- or extracellular mucus in the lung adenocarcinomas. ⁵ Data showed that the insufficiency of K-ras(G12D) and Nkx2-1 could drive the PPMA. ⁶ The subtype of secreting abundant extracellular mucus is inclined to invade stromal cells, along with much shorter recurrence-free survival and overall survival (OS) than those patients with producing intracellular mucus adenocarcinoma. ⁷ Most PPMA patients were diagnosed at an advanced stage. ⁸

Currently, immunotherapy and antiangiogenesis have been recognized as a critically acclaimed option for NSCLC, including epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase (ALK) inhibitors. ⁹ However, oncogenic EGFR mutations occur in ∼16% of advanced lung adenocarcinoma, whereas ALK fusions occur in 1%–7% of NSCLC patients. ¹⁰ CAMKMT-ALK fusion also expands the spectrum of ALK fusion variants in PPMA. ¹¹ a novel somatic gene fusion, CD47-NRG1, is expressed in invasive mucinous lung adenocarcinomas of never smokers and account for approximately 1.7%. ¹² Expression of the CD47-NRG1 fusion protein was associated with K-RAS mutations. ⁶ These looked promising for a new option. ¹³ That programmed cell death 1 (PD-1)/programmed death ligand-1 (PD-L1) antibodies have prolonged the survival time in advanced NSCLC. ¹⁴ Pembrolizumab is considered the first-line therapy for lung adenocarcinoma with wild-type EGFR or ALK and PD-L1 expression ≥50%. In contrast, pembrolizumab in combination with chemotherapy is recommended for patients with low PD-L1 expression.^14,15 Pembrolizumab plus chemotherapy numerically improved OS over the combination of atezolizumab and chemotherapy plus antiangenesis. ¹⁶ As the principal regulator of antiangiogenesis, VEGF inhibitors, including anlotinib and bevacizumab, could modulate multiple pathways and an immunosuppressive mechanism that tumours hijack. Combining bevacizumab or anlotinib with chemotherapy had a survival benefit or improved quality of life in NSCLC^17–19. Pieces of evidence demonstrate the synergistic antitumor activity of the combination of anti-VEGF inhibitors and anti-PD1/PDL1, along with favourable tolerability. ²⁰ Here, we report two cases of advanced PPMA treated with pembrolizumab, chemotherapy and angiogenesis inhibitors. It is the first report to use combination therapy for PPMA patients at a young age.

Case report

Case #1: A 13-year-old boy with a history of fever at 40°C, broad red papules, recurrent cough, and yellow phlegm was admitted to the local pediatric hospital on 6 June 2018. It showed a number of increasing neutrophils and C-reactive proteins. Chest computerized tomography (CT) indicated multiple patchy lesions in the right lung and cavity formation in bilateral lobes (Figure 1(a)). Tracheoscopic biopsy indicated acute inflammatory cell infiltration in the right pulmonary lesion. Antibiotics could not improve outcomes after regular treatment. The chest showed patchy lesions in the right lung on 24 December 2018 (Figure 1(b)). He was admitted to our hospital on 17 July 2019. The patient had no history of cancer and smoking, nor alcohol consumption. The lesion in the right lung had progressed radiologically (Figure 1(c)). No pathogens were found in bronchoalveolar lavage fluid. The pathology demonstrated pulmonary mucinous adenocarcinoma (Figure 2(a)). The patient showed both negative ALK and EGFR mutation concurrent with PD-L expression of less than 1%. He was diagnosed with IVA (cT4N3M1a), and the grade of ECOG performance status was three scores. Treatment was started with Pembrolizumab (2 mg/kg), pemetrexed (10 mg/kg), bevacizumab (5 mg/kg) for the first day on 22 July 2019, 3 weeks once a cycle. On 12 September 2019, CT scan showed the tumor reduced (Figure 1(d)). After five cycles, the lesions in bilateral lobes reduced in size on 21 November 2019 (Figure 1(e)). The patient had no severe marrow suppression. Other adverse events were mild-to-moderate liver dysfunction. The ECOG performance status was two scores. It prompted a partial response according to the RECIST 1.1 criteria.

Figure 1.

CT images in Case #1. (A) The first chest CT scan in the local hospital on 6 June 2018. (B) Chest CT scan on 24 December 2018 after antibiotic treatment for 6 months. (C) Chest CT in our hospital on 17 July 2019. (D) After three cycles of combination treatment, chest CT scan showing a reduced lesion in bilateral lobes on 12 September 2019. (E) After five cycles, chest CT scan on 21 November 2019.

Figure 2.

The pathological results of the pulmonary biopsy in our hospital. (A) For Case #1. (B) For Case #2. Magnification × 400.

Case #2: A 27-year-old male with a 5-day history of Thailand tourism presented with cough, yellow sputum, and fever at 39.3°C. On 18 December 2018, he felt worse. A chest CT scan in the local hospital showed some consolidation in the left lower lobe (Figure 3(a)). The hematologic etiological examinations were negative. Four sputum pathogens indicated positive of Actinomyces, Klebsiella pneumonia, Amebic protozoa, and Albicans candida successively during the hospitalization. CT-guided puncture biopsy showed some inflammatory cells infiltration. He felt worse than ever after empiric antibiotic therapy and the pulmonary lesion aggravated on radiology on 26 February 2019 (Figure 3(b)). As of 5 March 2019, he was presented to our hospital. He was non-alcoholic and had no history of cancer and smoking. The chest showed progressed on chest CT scan (Figure 3(c)). for this time, the biopsy verified pulmonary mucinous adenocarcinoma (Figure 2(b)) with both negative ALK and EGFR gene mutation. He was classified into cT4NxMx in pathology and IV stage, and the grade of ECOG performance status was three scores. During the hospitalization, he was treated with some antibiotics because of respiratory failure and severe respiratory symptoms until 19 March 2019 (Figure 3(d)). Since 20 March 2019, he was commenced with pembrolizumab (2 mg/kg) and albumin paclitaxel (4 mg/kg) for the first day, and Anlotinib (12 mg, Q.D., P.O.) for 14 days. Twenty-one days is a cycle of treatment. After six cycles, the lesion in the left lobe had shrunk on 10 September 2019, and the ECOG performance status was one score (Figure 3(e)). The patient had mild liver and kidney dysfunction. Neutrophils decreased moderately. The ECOG performance status was one score. It indicated a partial response.

Figure 3.

CT images in Case #2. (A) The first chest CT scan on 18 December 2018. (B) Chest CT scan on 26 February 2019 after antibiotics treatment. (C) Chest CT in our hospital on 5 March 2019. (D) Chest CT scan before the first combination therapy on 19 March 2019. (E) After six cycles, chest CT scan on 10 September 2019.

Discussion

Lung adenocarcinoma in young patients was probably likely to stay at the middle–late clinic stage (e.g. stage IV was 80.6%) and was apt to have a distant metastasis (51.6%). ²¹ PPMA is an uncommon histological subtype of PPMA, rarely occurring in young patients under 40 years old. ³ Mucus production is a typical feature of PAMA. It originates in stem cells with the potential of multidirectional differentiation and secrets mucus with different properties according to the differentiation microenvironment. Generally, the mucus secreted by cancer cells can be discharged as sputum. Still, if the growth of cancer cells is uncontrolled, it may cause excessive production of mucus, which obstructs the upper airways. Pneumonia is a common complication in advanced lung cancers, even the leading causes of deterioration and death.^21,22 Lung cancer was even masqueraded as pulmonary infection under some conditions, especially accompanying elevated inflammatory cells. MRI with water-sensitive sequences was considered a tool for a patient with pulmonary infection suspected to be PPMA. ²³

In this report, we first introduce two advanced PPMA with combination therapy at a young age. Because of the tumor heterogeneity, they were misdiagnosed with pulmonary infection in the beginning. It is difficult for us to make further effective options until multiple biopsies demonstrate PPMA. Immunotherapy is a kind of anticancer way to enhance the ability of the immune system to recognize and kill tumour cells. Immunotherapy represents a paradigm shift and has been commonly used in advanced cancer, including lung cancer, melanoma, gastrointestinal cancer, lymphoma, breast cancer, prostatic cancer and leukaemia. Patients with lung cancer widely used the PD-1 or PD-L1 therapy. The common PD-1/PD-L1 inhibitors are pembrolizumab, nivolumab, and atezolizumab. Pembrolizumab, a kind of PD-1 drug, was approved for the first-line treatment of NSCLC patients with high expression of PD-L1 without EGFR mutation and ALK gene fusion. ²⁴ A study showed pembrolizumab plus chemotherapy had higher progression-free survival (PFS), OS, and objective response rate compared with chemotherapy alone in metastatic NSCLC, regardless of PD-L1 expression level, the estimated rate of OS at 12 months was 69.5% in the pembrolizumab to chemotherapy versus 49.4% in the chemotherapy alone. ²⁵ Besides, immunotherapy combined with angiogenesis inhibitors is a relatively accessible mode of combined therapy currently. An IMpower-150 study indicated that atezolizumab plus bevacizumab plus chemotherapy benefited, regardless of PD-L1 and gene mutation status. ²⁶ A network meta-analysis indirectly showed pembrolizumab to chemotherapy prolonged the OS compared with the atezolizumab chemotherapy group. ¹⁶

The suppression of the angiogenesis pathway is a well-recognized method modality in cancer therapy. VEGF inhibitors, including bevacizumab and anlotinib, is approved for advanced, metastatic, or recurrent NSCLC. Bevacizumab plus platinum-based chemotherapy increased the OS versus placebo chemotherapy. ²⁷ anlotinib, 12 mg per day, on the 2/1 schedule, have been performed and well efficacy in NSCLC. ²⁸ Numerous pieces of evidence suggests that inhibition of the VEGF pathway can stimulate the immune system. In reverse, immunotherapies can also affect antiangiogenic process. ²⁹ it has demonstrated that a combination of VEGF inhibitors and immunotherapy increased the efficacy in several studies, including ClinicalTrials.gov Identifier: NCT02039674/NCT01633970/NCT02856425. ²⁰

Selective combination therapy in PPMA was based on the guideline of nonmucinous adenocarcinoma. A report indicated that pemetrexed was chosen as a way to the treatment of PPMA and showed a radiographic response without deterioration of performance status for the treatment of 20 cycles. ³⁰ A retrospective study reported that these patients with PPMA developed metastases in 5–20 months after the surgery. ³¹ However, the IFCT-0401 Trial showed median PFS and OS for mucious pulmonary cancer in patients treated with gefitinib was 2.6 months and 10.1 months, respectively. ³² In our study, Both Case#1 and Case#2 showed a partial response after treatment for five and six cycles, respectively. It showed a radiographic response, and the ECOG performance status was two and one scores, respectively. Pembrolizumab combined with chemotherapy and angiogenesis inhibitors may present a new potential option for PPMA patients in young people.