Retrospective Study in Non Small Cell Lung Cancer (NSCLC) With Epidermal Growth Factor Receptor (EGFR)

Background :

• Lung cancer represents the leading cause of death by cancer in France. Significant advances have been made in recent years on knowledge of oncogenesis of NSCLC in particularly the discovery of specific oncogenic drivers playing major role in oncogenic addiction responsible for the occurrence of NSCLC. Activating mutations of the gene encoding the receptor tyrosine kinase EGFR appeared in a subgroup of patients with NSCLC. In 2010, the search for EGFR mutations in patients with lung cancer was performed in 16,834 patients and the mutation rate was 10.5%. The use of specific inhibitors of EGFR tyrosine kinase in patients with activating mutations of EGFR have shown a significant clinical benefit with a response rate more than 70 % ,with PFS ranging from 9 to 13,1 months and median overall survival from 20 to 30 months. Despite these very good results, all patients develop a resistance to EGFR TKI. This progression is usually defined according to RECIST criteria.

These RECIST criteria were established primarily on studies conducted in patients treated with conventional chemotherapy with few or no targeted therapies. In addition, the mode of action of TKI (blocking signalling pathways involved in cell proliferation, angiogenesis, apoptosis, metastasis ..) is very different from the mode of cytotoxic action (action during cell division). Thus, the use of RECIST does not seem to be the most appropriate way to evaluate the response in patients treated by TKI.

Despite this, the RECIST criteria have been used to demonstrate superiority of EGFR TKI compared to chemotherapy in patients with EGFR activating mutations in first line setting.

In 2010, Pr Jackman proposed a clinical definition of acquired resistance to EGFR TKI :

1. Treatment with a single agent EGFR TKI,
2. Presence of EGFR activating mutation, clinical benefit from treatment with an EGFR TKI
3. Systemic progression of disease according to RECIST or WHO criteria while on continuous treatment with EGFR TKI within the last 30 days TKI
4. No intervening systemic therapy between cessation of EGFR TKI and initiation of new therapy.

Tony Mok , in the accompanying editorial, made some criticism to this definition. He argued that it was not uncommon to find new small slow growing tumor nodules after the dramatic initial response to EGFR TKIs. He stated that in this situation, EGFR TKIs could be continued with benefit for the patients.

Since then, others clinical situations have been described, such as the emergence of one or even more new metastasis located in one single organ (like the brain or bones), which can be controlled by a loco-regional treatment. The authors found that the continuation of EGFR TKIs in these cases allowed control of the disease for a considerable length of time.

More recently, it has been suggested that even loco-regional treatment was not mandatory for EGFR TKIs continuation.

Pr Nishino studied retrospectively 56 patients with EGFR activating mutations and acquired resistance. 88% of patients continued EGFR TKI treatment for at least 2 months beyond progressive disease defined according to RECIST criteria. The median time from RECIST progressive disease to termination of TKI for these patients was 10.1 months (range 2.2 to 64.2 months) and the median overall survival was 31.8 months, which is a rather good result.

Pr Oxnard, in a similar study, found that in 45% of 42 patients with acquired resistance to EGFR TKI, alternate systemic therapy could be delayed for three months or more. These 19 patients had more frequently the exon 19 deletion and were free of cancer related symptoms at RECIST progressive disease.

Another recently published retrospective Japanese study suggested that continuous use of EGFR-TKI beyond progressive disease may prolong overall survival compared with switching to cytotoxic chemotherapy in patients with EGFR activating mutations.

A prospective ASIAN phase II study (ASPIRATION) has been recently completed. It compared the continuous use of erlotinib versus stopping erlotinib at progression according to RECIST criteria. Patients could continue erlotinib if progression was slow (> 6 months stability), asymptomatic minimal increase and/or new cerebral metastasis controlled locally. The patients switch to another systemic treatment if they had rapid progressive disease, extra brain symptomatic metastasis, deterioration of Performance Status (PS) or life threatening complications. The results of this study should be available in December 2014.

Purpose :

The purpose of our retrospective study is to describe which circumstances EGFR TKI is continued despite progression according to the usual RECIST criteria in patients with EGFR activating mutations and acquired resistance to EGFR TKI. This study concerns patients who have began a TKI treatment in first line from 1st JANUARY 2010 to 1st JUNE 2012.We'll collect their social and demographic data (age, sex), first PFS (from start of EGFR TKI: PFS 1) and second (from first progression according to RECIST 1.1 to second progression : PFS2) , OS (from diagnosis OS 1 and from first progression OS2), mutational status, and we will analyze more closely the mode of progression (site), the therapeutic approach at disease progression. We will define two subgroups: those for whom EGFR TKI was continued at least three months despite progression defined according to RECIST criteria, and those for whom a second-line treatment (chemotherapy without EGFR TKI) was chosen at disease progression. It will be individualized the subgroup of patients in whom it was continued TKI after progression.

In this subgroup, it will be searched for a correlation between delaying systemic therapy (second line) by pursuing a EGFR TKI at least 3 months and various parameters:

• Type of EGFR mutation
• Symptoms at disease progression
• Clinical characteristic
• Emergence of new metastases vs increasing size of known targets
• Speed of decay and tumour progression (% per month)
• Delivery of loco-regional treatment when relapse occurs in a single site
• PFS (PFS1 and PFS2) and OS (OS1) from the first progression in this group will be compared to the general population (population for which there was TKI stop to the progression) with EGFR activating mutations.