Erlotinib in non-small-cell lung cancer patients from Hospital Fernado Fonseca

INTRODUTION: The oral epidermal growth factor receptor (EGFR) tyrosine-kinase inibitor (TKI) erlotinib is an established second-line treatment for advanced non-small-cell lung cancer (NSCLC).1 Erlotinib delays disease progression and increases survival after first-line chemotherapy in patients with advanced NSCLC as second-line therapy.2 Maintenance therapy with erlotinib, when compared to placebo, could be associated with a significantly longer progression free survival and tolerability mainly in EGFR activating mutation tumours.3 However second line therapy with erlotinib is not more effective than chemotherapy (pemetrexed or other).4,5 In terms of traditional toxicities associated with chemotherapy, Erlotinib seems to have a better safety profile than chemotherapy, with no haematological toxicities, the most common event was mild to moderate skin rash which is relatively manageable.5 There is a lack of evidence regarding efficacy of Erlotinib used as second line versus third line therapy. OBJECTIVES: To compare Erlotinib effectiveness profile in Hospital Fernando Fonseca NSCLC patients when used as second or third line therapy. METHODS: We have followed up 30 NSCLC patients, who have done Erlotinib before and after other approved chemotherapies, during 14 months starting from June 2011. During this period we have collected patient’s demographics and baseline characteristics and also their EGFR mutational status. To determine Erlotinib effectiveness we calculated progression–free survival (PFS) which was defined as the time from Erlotinib therapeutic initiation to the date of documented disease progression or death. RESULTS: The median age of our 30 patients was 62,5 years. The most common pathological subtype was adenocarcinoma (66,7 %). 46,6 % of our patients had received one prior chemotherapy regimen before Erlotinib and 36,6 % had received two prior chemotherapy regimen before Erlotinib. Two patients have done Erlotinib as a first line therapy. Median PFS for second line Erlotinib patients is 18,7 weeks while for third line Erlotinib patients is 12,3 weeks. Only 50 % of our patients had available information regarding EGFR mutational status; however patients who harbor tumor-associated EGFR activating mutation seem to have higher response rates to Erlotinib. Rash was the most common treatment-related adverse event with Erlotinib, as expected. CONCLUSIONS: Our results show that maybe there could be a better disease outcome for advanced NSCLC patients if the oral epidermal growth factor receptor tyrosine-kinase inhibitor (Erlotinib) is administered as a second line therapy instead of using it as a third line therapy. As far EGFR mutational status is concerned it seems that enhanced efficacy is related with EGFR mutation-positive disease. REFERENCES: 1- Summary of product characteristics - Tarceva© 2- Shepherd FA, Pereira J, Ciuleanu T, et al. Erlotinib in previously treated Non-small-cell Lung Cancer. N Eng J Med 2005; 353:123-132. 3- Cappuzzo F, Ciuleanu T, Stelmakh l, et al. Erlotinib as maintaenance treatment in advanced non-small-cell lung cancer: a multicentre, randomized, placebo-controlled phase 3 study. Lancet Oncol 2010; 11:521-29. 4- Vamvakas L, Agelaki S, Kentepozidis NK, et al. Pemetrexed (MTA) compared with erlotinib (ERL) in pretreated patients with advanced non-small-cell lung cancer (NSCLC): results of a randomized phase III Hellenic Oncology Research Group trial. Proc Am Soc Clin Oncol 2010; 28 (suppl): abstr 7519. 5- Ciuleanu T, Stelmakh l, Cicenas S, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomized multicentre, open-label, phase 3 study. Lancet Oncol 2012; DOI:10.1016/s1470-2045(11)70395-

Long-Term and Low-Grade Safety Results of a Phase III Study (PARAMOUNT): Maintenance Pemetrexed Plus Best Supportive Care Versus Placebo Plus Best Supportive Care Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer

n/

Early pneumothorax as a feature of response to crizotinib therapy in a patient with ALK rearranged lung adenocarcinoma.

Background: Single arm phase 1 and 2 studies on Crizotinib in ALK-positive patients so far have shown rapid and durable responses. Spontaneous pneumothoraces as a result of response to anti-cancer therapy are rare in oncology but have been documented in a number of tumour types including lung cancer. This includes cytotoxic chemotherapy as well as molecular targeted agents such as gefitinib and Bevacizumab. These often require chest drain insertion or surgical intervention with associated morbidity and mortality. They have also been associated with response to treatment. This is the first report we are aware of documenting pneumothorax as response to crizotinib therapy.Case presentation: A 48-year-old Caucasian male presented with a Stage IV, TTF1 positive, EGFR wild-type adenocarcinoma of the lung. He received first line chemotherapy with three cycles of cisplatin-pemetrexed chemotherapy with a differential response, and then second-line erlotinib for two months before further radiological evidence of disease progression. Further analysis of his diagnostic specimen identified an ALK rearrangement by fluorescence in situ hybridization (FISH). He was commenced on crizotinib therapy 250 mg orally twice daily. At his 4-week assessment he had a chest radiograph that identified a large left-sided pneumothorax with disease response evident on the right. Chest CT confirmed a 50% left-sided pneumothorax on a background of overall disease response. A chest tube was inserted with complete resolution of the pneumothorax that did not recur following its removal.Conclusion: Our case demonstrates this potential complication of crizotinib therapy and we therefore recommend that pneumothorax be considered in patients on crizotinib presenting with high lung metastatic burden and with worsening dyspnoea. © 2013 Gennatas et al.; licensee BioMed Central Ltd

Is the chemotherapy era in advanced non-small cell lung cancer really over? Maybe not yet

Lung cancer is one of the most frequently diagnosed tumors in both the male and female population. In Italy it is the leading cause of cancer deaths in men and the third in women. Although the 5-year survival rate has moderately increased in the last years, the diagnosis remains associated with a very poor prognosis. However, in the last decade significant progress has been made, also in the treatment of advanced-stage non-small cell lung cancer. The advent of targeted therapies and the recent explosion of immunotherapy seem to have limited the role of chemotherapy. But is this completely true? The aim of this editorial is to discuss some of the most controversial aspects of the therapeutic scenario in non-small cell lung cancer, with particular attention to the role that chemotherapy still play

Nivolumab in the treatment of thoracic cancer — new possibilities

Immune checkpoint inhibitors have significantly changed the treatment of patients with advanced non-small cell lung cancer in recent years. The value of nivolumab was initially assessed in patients previously treated with systemic therapy. The association of nivolumab with ipilimumab and the interaction of these antibodies on different immune checkpoints have proven effective in solid tumors (melanoma and renal cell carcinoma). The CheckMate-9LA study assessed the value of dual immunotherapy combined with platinum-based chemotherapy in the first-line treatment of advanced non-small cell lung cancer. A clinical benefit – prolonged overall survival in patients receiving combination therapy – was documented. The results of the CheckMate743 trial for patients with pleural mesothelioma provide a basis for changing the current management algorithm for patients with this diagnosis. Patients diagnosed with mesothelioma of a non-epithelioid type particularly benefit from two-drug immunotherapy compared to chemotherapy. Maintaining the safety of treatment using immunotherapy targeting two immune checkpoints remains the challenge

Role of denosumab in the management of skeletal complications in patients with bone metastases from solid tumors

Skeletal-related events (SREs) including pain, fractures, and hypercalcemia are a major source of morbidity for cancer patients with bone metastases. The receptor activator of NF-κB ligand (RANKL) is a key mediator of osteoclast formation and activity in normal bone physiology as well as cancer-induced bone resorption. The first commercially available drug that specifically targets and inhibits the RANKL pathway is denosumab, a fully human monoclonal antibody that binds and neutralizes RANKL, thereby inhibiting osteoclast function. In this review, we summarize the major studies leading to the US Food and Drug Administration-approval of denosumab for the prevention of SREs in patients with bone metastases from solid tumors. Further, we discuss the role of denosumab in the prevention and treatment of SREs and bone loss in cancer patients. As a monoclonal antibody, denosumab has several advantages over bisphosphonates, including improved efficacy, better tolerability, and the convenience of administration by subcutaneous injection. In addition, as denosumab has no known renal toxicity, it may be the preferred choice over bisphosphonates in patients with baseline renal insufficiency or receiving nephrotoxic therapies. However, other toxicities, including osteonecrosis of the jaw and hypocalcemia, appear to be class effects of agents that potently inhibit osteoclast activity and are associated with both denosumab and bisphosphonate use. The data presented highlight the differences associated with intravenous bisphosphonate and denosumab use as well as confirm the essential role bone-modifying agents play in maintaining the quality of life for patients with bone metastases

Oligoprogression : Eine innovative Indikation für die Körperstereotaxie bei metastasierten Tumorsituationen

Hintergrund: Erlotinib ist beim nichtkleinzelligen Lungenkarzinom (NSCLC) in der metastasierten Situation zugelassen nach dem Versagen der Erstlinien-Chemotherapie, unabhängig vom EGFR-Mutationsstatus. Die vorliegende Phase-II-Studie untersuchte den Stellenwert einer lokalen körperstereotaktischen Bestrahlung simultan zur Erlotinib-Therapie nach Progress in der Erstlinien-Chemotherapie beim NSCLC im Stadium IV [1]. Methode: In dieser prospektiven Phase-II-Studie wurden 24 Patienten mit NSCLC im Stadium IV nach Progress der Erstlinien- (n = 15), Zweitlinien- (n = 7) und Drittlinien-Chemotherapie (n = 2) (Cisplatin-basiert 21/24) mit Körperstereotaxie (SBRT) behandelt, wenn sie an bis zu 6 Läsionen im FDG-PET progredient waren und nicht bereits mit einem EGFR-Inhibitor behandelt worden waren. Die SBRT konnte in einer Fraktion (Gesamtdosis: 19–24 Gy), 3 (27–33 Gy) oder 5 (35–40 Gy) Fraktionen appliziert werden; mit Erlotinib wurde in einer Dosierung von 150 mg/Tag eine Woche vor der SBRT begonnen und bis zur Progression weitergeführt. Primärer Endpunkt war das progressionsfreie Überleben nach 6 Monaten. Ergebnisse: Die 24 Patienten wurden zwischen 2007 und 2013 rekrutiert, und die Auswertung erfolgte nach einer medianen Nachbeobachtungszeit von 16,3 Monaten. Die bestrahlten Läsionen, insgesamt 52, waren am häufigsten in der Lunge (n = 18), im Mediastinum (n = 13) und den Nebennieren (n = 7) lokalisiert. 48/52 Läsionen konnten ohne relevante Dosisabweichung bestrahlt werden. Erlotinib wurde für eine mediane Dauer von 273 Tagen eingenommen. Ein Patient erlitt eine Grad-IV- und anschließend eine Grad-V-Toxizität (pulmonal), die möglicherweise auf die SBRT zurückzuführen ist. Das mediane Gesamtüberleben betrug 20,4 Monate und das mediane progressionsfreie Überleben 14,7 Monate. Eine Progression wurde nur selten in den bestrahlten Lokalisationen beobachtet (n = 3/21 Patienten), häufiger an neuen Lokalisationen (n = 10/21). Bei 10/21 Patienten kam es während der gesamten Nachbeobachtungzeit aber zu keiner Krankheitsprogression. Schlussfolgerung der Autoren: Mit der Kombination aus systemischer Erlotinib-Therapie und lokaler SBRT kann man eine lange Progressionsfreiheit und ein vielversprechendes Gesamtüberleben erzielen