Prolonged survival with erlotinib followed by afatinib in a caucasian smoker with metastatic, poorly differentiated large cell carcinoma of the lung: a case report

Abstract

Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR; ErbB1) – either exon 19 deletions or exon 21 point mutations – are associated with hypersensitivity to EGFR tyrosine kinase inhibitors (TKIs). EGFR mutations are more frequently found in females, non-smokers, Asians, and patients with adenocarcinoma. We report the case of a 51-year-old Caucasian woman with metastatic NSCLC harboring an EGFR exon 19 deletion although she was a smoker and had a poorly differentiated large cell carcinoma. Following a partial response on 4 months of chemotherapy, the patient progressed and was treated with the reversible EGFR TKI erlotinib for 3 y. The patient then developed resistance to erlotinib and went on to receive the irreversible ErbB Family Blocker afatinib for 1 year, attaining a partial response at 4 months. The impressive survival time attained by our patient highlights the clinical benefit of targeting one or more members of the ErbB Family in patients with disseminated NSCLC and EGFR activating mutations.

Abbreviations

CT

computed tomography

EGFR

ErbB1, epidermal growth factor receptor

NSCLC

non-small cell lung cancer

PFS

progression-free survival

PR

partial response

RUL

right upper lobe

TKI

tyrosine kinase inhibitor.

Introduction

Non-small cell lung cancer (NSCLC) accounts for around 85% of all lung cancer.¹ Survival of patients with advanced NSCLC is poor, with <10% survival at 5 y with standard chemotherapy and a median overall survival of <14 months.^2,3

Treatment with reversible tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR; ErbB1) has resulted in responses in only a subset of NSCLC patients.^4,5 These patients have tumors harboring activating mutations within the tyrosine kinase domain of EGFR, which confer hypersensitivity to EGFR TKIs.⁵ Activating mutations are more frequent in women, non-smokers, Asians, and patients with adenocarcinoma.^4,6-9 EGFR TKI treatment in NSCLC patients harboring these mutations significantly delays disease progression.¹⁰

This article reports the case of a female smoker presenting with Stage IV, poorly differentiated, large cell carcinoma of the lung, an uncommon NSCLC histological subtype.^1,8 Despite being a smoker and not having adenocarcinoma histology, the patient responded to the reversible EGFR TKI erlotinib for more than 3 y and, following progression, attained an additional year of survival with afatinib.

Afatinib is an irreversible ErbB Family Blocker that selectively and potently blocks signaling from all relevant ErbB Family receptors (EGFR, human epidermal growth factor receptor-2 and ErbB4) and the transphosphorylation of ErbB3.^11,12 Afatinib has recently been approved in the US and Europe for the first-line treatment of EGFR mutation-positive advanced NSCLC, based primarily on the clinical efficacy observed in the Phase 3 LUX-Lung 3 trial.¹³ Later studies, including the LUX-Lung 6 trial confirmed the clinical activity of afatinib.^14,15

Case description

In March 2007, a 51-year-old white, female smoker (20 pack-years) presented with lumbar pain, which irradiated to the lower extremities. Pain had been present since October 2006 and had not evolved favorably with several prescribed treatments. No respiratory symptoms or overall syndrome was present.

The patient presented with an Eastern Cooperative Oncology Group performance status of 1. Physical assessment showed no palpable adenopathy or edema in the head and neck; heart sounds were normal; pulmonary auscultation showed decreased vesicular murmur in the right hemithorax (no additional sounds); breasts and underarm examinations were normal; no abdominal clinical findings were observed; pain was induced by left hip mobilization with functional impairment of the left lower extremity. Hemogram results were normal. Alkaline phosphatase, lactate dehydrogenase and gamma-glutamyl transferase were above normal limits. Other biochemical parameters were normal. Chest X-ray revealed infiltrate in the right upper lobe (RUL). Bronchoscopy showed mucosal inflammation of the apical RUL, which was biopsied with no evidence of neoplastic infiltration. Bronchial aspirate and broncheoalveolar lavage showed atypical cells compatible with poorly differentiated large cell carcinoma. Computed tomography (CT) revealed a 4cm mass in the RUL with atelectasis causing mediastinal shift; multiple bilateral not-well-limited nodular images were related to probable bronchial dissemination; mediastinal adenopathies of around 1cm were observed in the aortopulmonary window and pretracheal retrocaval space; pleural effusion was noted; there were lytic lesions in the left sacral ala, supra-acetabular region and left ilio- and ischio-pubic branches. Bone gammagraphy revealed pathologic accumulates in the right frontal region, 4th, 5th and 6th right ribs, left hemipelvis and in the proximal third of both femurs (latter observations uncertain). These observations suggested multiple bone metastases. Pelvis X-ray showed lytic lesion affecting the left ischial branch. A CT scan of the skull showed no clinical findings.

The patient was diagnosed with Stage IV, poorly differentiated, large cell lung carcinoma (T4N3M1b).

Treatment and evolution

On 27 March 2007, the patient initiated platinum-based first-line chemotherapy (cisplatin 75 mg/m² and docetaxel 75 mg/m², day 1 every 21 days) and received 6 cycles up to July 2007 with no serious toxicity. Due to intense pain despite opioid treatment, the patient also initiated antalgic palliative radiotherapy and monthly bisphosphonates, receiving 24Gy on the left ischio-pubic branch for 10 d. The patient showed clinical improvement, with the disappearance of asthenia and dyspnea, and a significant decrease in bone pain, and analgesic drugs were therefore withdrawn.

CT scans after the third and sixth cycles of chemotherapy showed a partial response (PR), with the disappearance of contralateral nodes but persistence of mass in the RUL and of bone metastases, plus a pathologic fracture of the left ilio-pubic branch. The fracture was managed conservatively and monthly bisphosphonate treatment was continued, except when the patient showed hypocalcemia (twice).

In January 2008, tumor progression was observed, with massive pleural effusion, complete atelectasis of the right lung, and the appearance of contralateral metastatic nodes. The patient suffered dyspnea at minimal effort, which was managed with talc pleurodesis. Pleural carcinomatosis was diagnosed.

In February 2008, the patient started second-line treatment with erlotinib (150 mg/day). She initially showed signs of Grade 1 skin toxicity but no serious later toxicity. An initial PR was followed by extended disease stability: persistence of mass in the RUL, no changes in contralateral nodes and bone metastases, pseudoarthrosis of the left ischio-pubic branch, and no pleural effusion.

The patient maintained excellent overall physical status, with no need for supportive treatment or treatment adjustment, while receiving erlotinib for more than 3 y.

In January 2011, a CT scan revealed tumor progression with the appearance of left suprarenal metastasis (Fig. 1). The patient started palliative treatment with pemetrexed 500mg/m² every 21 d and received 4 cycles from February to April 2011.

Figure 1.

CT-scan images (January 2011). Tumor progression with appearance of left suprarenal mass.

In May 2011 a CT scan showed new tumor progression and the appearance of brain metastases. Since the patient had attained prolonged progression-free survival (PFS) with an EGFR TKI, the presence of mutations in the EGFR gene was assessed on the cytological sample previously used for diagnosis and an exon 19 deletion was detected. A request was filed to use the then investigational drug afatinib for compassionate use and the patient started afatinib treatment (50 mg/day) on 16 May 2011. The patient also received concomitant palliative whole-brain cranial radiotherapy, reaching 30Gy on 6 June 2011.

In September 2011, a CT scan showed a PR with the disappearance of the suprarenal metastasis (Fig. 2). Afatinib tolerability was manageable following dose adjustment in July 2011 to 30mg/day due to persistent Grade 2 gastrointestinal toxicity. The patient also experienced mild periungeal toxicity.

Figure 2.

CT-scan image (September 2011). Partial response (disappearance of suprarenal metastasis) after initiating treatment with afatinib.

In May 2012, one year after starting afatinib, a CT scan detected tumor progression at bone level. Active treatment was therefore discontinued and the patient went on to palliative care. The patient reported worsening of her overall status and spinal pain requiring major opioids. She later suffered increasing dyspnea, which finally showed at minimal effort. The patient died at home as a consequence of her disease on 4 September 2012.

Discussion

The treatment of NSCLC has changed greatly over recent years with the use of new molecular targeted therapies. Approximately 10–15% of NSCLCs harbor EGFR activating mutations, 90% of which are exon 19 deletions or exon 21 point mutations.^4,5,16,17 These mutations are more frequent in non-smokers, females, Asians, and patients with adenocarcinoma.^4-6,8,9,18 Our female patient was a smoker and Caucasian with large cell carcinoma, yet she harbored an exon 19 deletion. EGFR activating mutations confer sensitivity to EGFR TKIs, and NSCLC patients harboring these mutations attained prolonged PFS on EGFR TKIs compared to chemotherapy.¹⁹ Gefitinib and erlotinib are the 2 most developed reversible EGFR TKIs approved for the first-line treatment of EGFR mutation-positive stage IV NSCLC.^20,21 In addition, erlotinib has shown activity in second and successive lines of treatment.²¹

EGFR mutations can be assessed in cytological samples. ¹⁶ During the clinical evolution of our patient, at the time of new tumor progression about 4 y after she originally began treatment, EGFR mutations were assessed on the cytological sample used for diagnosis allowing the patient to receive a targeted treatment and to reach longer survival.

The ErbB Family Blocker afatinib showed clinical benefit compared to standard chemotherapy in the first-line treatment of EGFR mutation-positive advanced NSCLC.^13-15 In the second-line setting, afatinib also conferred a significant PFS benefit compared to placebo following failure of erlotinib, gefitinib or both, and one or 2 lines of chemotherapy (3.3 months vs. 1.1 months; p < 0.0001) in the LUX-Lung 1 trial.²² However, in this study the objective response rate was relatively low and the primary goal of improving overall survival was not reached. Nevertheless, our case is an example of objective response with prolonged survival in NSCLC with EGFR mutation treated with a TKI with more capacity to block the EGFR, after tumor progression with a first generation TKI. Today's challenge is to elucidate the mechanisms of resistance to EGFR TKIs and to develop drugs to overcome them.²³ Currently, several studies are being carrying out with different strategies based on new generation drugs directed against the EGFR and other targets involved in the mechanisms of resistance.

Unfortunately, in our case a new biopsy was not performed at the time of progression due to the inaccessible location of the disease and the characteristics of our patient. The performance of a biopsy at progression in patients with NSCLC with EGFR mutations should be considered in order to better understand the disease at the molecular level and to develop more effective therapies.

In spite of central nervous system involvement, our patient showed a radiologically documented PR and prolonged survival on afatinib treatment after having previously progressed on 2 lines of chemotherapy followed by erlotinib. Research on the development of targeted treatments for NSCLC must continue and the participation of cooperative groups in clinical trials is indispensable if progress is to be made.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

Editorial support was funded by Boehringer Ingelheim.

Funding

Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Ogilvy Healthworld Barcelona, during the preparation of this article.