First case report of erlotinib plus ramucirumab treatment for lung carcinosarcoma with EGFR L858R mutation

Abstract Lung carcinosarcoma is acknowledged as a rare form of lung cancer. Due to its rarity, the inability to conduct large‐scale clinical trials and interventions is currently carried out based on empirical evidence. In this study, we report the case of a 73‐year‐old female patient diagnosed with postoperative recurrence of lung carcinosarcoma. The resected tumor was diagnosed as lung carcinosarcoma, and genetic testing revealed the presence of the epidermal growth factor receptor (EGFR) exon21 L858R. Approximately 2 years postoperatively, the tumor recurred and the patient was treated with erlotinib plus ramucirumab, which were effective in controlling metastatic disease. Erlotinib plus ramucirumab is therefore a treatment option for EGFR mutation‐positive lung carcinosarcoma.


INTRODUCTION
Lung carcinosarcoma is a rare malignant lung tumor.There are no effective drugs, and empirical pharmacotherapy is currently used in cases of inoperability or recurrence.In this report, we describe the efficacy of erlotinib plus ramucirumab for postoperative recurrent lung carcinosarcoma with epidermal growth factor receptor (EGFR) exon21 L858R positivity.

CASE REPORT
A 73-year-old female patient was referred to our department after an abnormal shadow was found on a chest x-ray examination during a health checkup (Figure 1a).Computed tomography (CT) of the chest revealed a 28 mm tumor with calcification in the left upper lobe (Figure 1b,c), and positron emission tomography (PET)/CT identified [ 18 F] fluorodeoxyglucose uptake in the tumor (Figure 1d).The patient was clinically suspected of having left lung cancer according to the Union for International Cancer Control (UICC) T1cN0M0 stageIA3 and video-assisted thoracoscopic surgery (VATS) left upper lobectomy and hilar and mediastinal lymph node dissection were performed.Pathological examination revealed a maximum diameter of 35 mm and papillary adenocarcinoma components in approximately 70% of the specimen and spindle-shaped sarcoma-like components in approximately 30%.Focal areas of osteosarcomalike components were observed, confirming a diagnosis of lung carcinosarcoma and the patient was finally pathologically diagnosed with T2aN0M0 stage IB (Figure 2a-f).Genetic analysis by reverse transcription-polymerase chain reaction using tumor detected EGFR exon21 L858R mutation.The programmed death ligand 1 expression was 15% (Dako 22C3).The patient was followed up because there was no known effective adjuvant therapy for lung carcinosarcoma, and the patient did not wish to undergo adjuvant therapy.However, 2 years post-surgery, a small nodule appeared in the right lung segment 1 on chest CT and showed a progression (Figure 3a).When we diagnosed a postoperative recurrence and presented her with a treatment plan (surgical resection or drug therapy), she chose drug therapy.The diagnosis of postoperative recurrence led to the initiation of erlotinib (150 mg/day, daily) and ramucirumab (10 mg/kg, every two weeks).Adverse events were fatigue as a common terminology adverse event grade 1, skin rash as grade 2, and oral mucositis as grade 2. Erlotinib was reduced to every other day and treatment is still ongoing.The patient's subsequent clinical course has been good, with partial response (revised RESCIST guidelines version 1.1) lasting more than 16 months (Figure 3b,c).

DISCUSSION
Lung carcinosarcoma is a rare tumor, accounting for 0.2%-0.3% of all lung cancers.It is defined as a biphasic tumor with malignant components of both epithelial and mesenchymal origins. 1,2Because of its biphasic nature, only one component may be obtained in the case of small biopsy specimens.Thus, preoperative diagnosis is difficult in the case of peripheral lesions, and even tumors arising centrally may be difficult to diagnose accurately. 3,4Koss et al. reported that lung carcinosarcoma has a 5-year survival rate of 21.3%. 5On the other hand, Petrov et al. analyzed 15 cases and reported that 5-year survival rate of 49.38% postoperatively. 6Since there is no established effective drug therapy for lung carcinosarcoma, aggressive surgical resection should  be considered in clinically operable patients.If curative surgery is not possible at the time of diagnosis, platinum-based chemotherapy is primarily used, such as in non-small cell lung cancer (NSCLC).There have also been reports where cisplatin and doxorubicin have been used, following the treatment regimen for soft tissue malignancies. 7However, due to the limited number of cases and the difficulty in conducting large-scale clinical trials for effective treatment, the treatment strategy is left to the discretion of individual physicians.
Osimertinib has become the standard treatment for first-line therapy in patients with EGFR gene mutationpositive NSCLC. 8However, subgroup analysis of the FLAURA trial showed that the median progression-free survival (PFS) in the EGFR exon21 L858R mutationpositive group did not show the same marked benefit as seen in the EGFR exon19 deletion (del19) mutationpositive group (L858R: 14.4 months, del19: 21.4 months). 9Different mutations in the genes may result in varying sensitivities to tyrosine kinase inhibitors (TKIs).On the other hand, the RELAY trial (erlotinib plus ramucirumab) and CTONG1509 trial (erlotinib plus bevacizumab) were conducted using combination therapy of a TKI and angiogenesis inhibitor, and the median PFS (del19/L858R) was comparable, 19.6/19.4months for the RELAY trial and 17.7/19.5months for the CTONG1509 trial, respectively. 10,11The results based on the genetic mutations in these clinical trials cannot be easily and directly compared.However, the addition of anti-VEGFR2 antibody to a TKI can significantly reduce the number of CD31-positive blood vessels and potentiate the antitumor effect of the TKI, in addition to inhibiting angiogenesis.Furthermore, in another study, VEGFR2 expression was induced after TKI treatment, suggesting the importance of VEGFR2 inhibitor combination. 12In cases of recurrence after the use of first-and secondgeneration TKIs, sequencing therapy with osimertinib can be an option when T790M is identified. 13Simulated PFS of a representative clinical trial examining the efficacy of an EGFR TKI for NSCLC showed a PFS of 24.8 months for osimertinib to chemotherapy sequencing.Although T790M is positive in about 40% of patients when a TKI is used as first-line therapy, erlotinib plus ramucirumab treatment is predicted to have a PFS of 28.1 months, which is superior to osimertinib. 14Considering these reports and the fact that a Japanese patient was entered in the RELAY trial, we chose erlotinib plus ramucirumab therapy over erlotinib plus bevacizumab therapy for postoperative recurrence of lung carcinosarcoma with EGFR exon 21 L858R mutation.Osimertinib remained as sequence therapy after this treatment became resistant.Currently, a partial response (revised RECIST guidelines version 1.1) has been maintained for approximately 50 months, and the patient's condition is well controlled.Although there is no established effective drug therapy for lung carcinosarcoma, TKI therapy should be considered as an option in cases of EGFR gene mutation-positive tumors, and erlotinib plus ramucirumab combination therapy may be particularly effective in cases with the EGFR ezon21 L858R mutation.

F
I G U R E 1 Chest x-ray film on admission showed a tumor shadow in the left upper lung field (arrow) (a).Chest computed tomography (CT) on admission (b).CT showed a tumor with internal calcification in the left upper lobe (c).Positron emission tomography (PET) showed 18 F-fluorodeoxyglucose accumulation consistent with a lung tumor (d).

F I G U R E 2
Histological features.Hematoxylin and eosin (H&E) staining showed a carcinoma component (hypodense papillary adenocarcinoma) in about 70% and a mixed sarcoma component in about 30%.The sarcoma component contained proliferating spindle-sharped tumor cells with partial osteoid formation.Cytokeratin staining was positive for the adenocarcinoma component and negative for the sarcoma component.Vimentin staining was positive for both adenocarcinoma and sarcoma components.(a,b,c) Adenocarcinoma components, (d,e,f) sarcoma components.(a,d) H&E, (b,e) cytokeratin staining, (c,f) vimentin staining.