Background: Although erlotinib is widely used in the management of non-small cell lung cancer (NSCLC), no prior studies were conducted in Middle Eastern population. Our study aims at evaluating erlotinib prospectively in this population. Patients and Methods: This open-label, prospective, single-arm, multicenter Phase IV clinical trial of erlotinib as single agent evaluated safety and efficacy of Erlotinib in Middle Eastern patients with advanced NSCLC. Results: A total of 56 patients were enrolled in five sites in Saudi Arabia. Majority of patients were males (60%) with median age of 57 years (34–80), Stage IV (98%), and adenocarcinoma (84%). Eastern Cooperative Oncology Group performance Status III (41.1%). Epidermal growth factor receptor (EGFR) mutations were present in 24 patients out of 36 patients tested (67%). The most common reported adverse events (AEs) were rash 36 (64%), diarrhea 29 (52%), fatigue 10 (18%), and anorexia 5 (9%). Grade 4 or 5 AEs were not observed. Complete response was achieved in 2 (3.6%) and overall disease control was 60.8%. Median overall survival (OS) was significantly longer in patients with EGFR mutation than wild type (20 vs. 3 months, P = 0.002). Progression-free survival was 10 months and significantly longer in patients with EGFR mutation than wild type (16 vs. 6 months, P = 0.037). Patients with unknown EGFR status had PSF and OS better than wild-type patients and worse than patients with EGFR mutation. Cox regression analysis showed that older age (P = 0.029, HR 1.064), EGFR wild type (P = 0.014, hazard ratio [HR]: 8.497), and receiving radiation (P = 0.033, HR 6.433) significantly increase risk of death for patients receiving erlotinib. Conclusion: Erlotinib has efficacy and safety profile in Middle Eastern population similar to the reported literature. The empiric use of erlotinib in patients with unknown EGFR status in our patient population is warranted due to high prevalence of the mutation. However, it should not be used in confirmed wild-type disease.
Lung cancer is the leading cause of cancer mortality worldwide with >1.69 million deaths in 2015. About 85% of lung cancers are non-small cell lung cancer (NSCLC), comprising adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, which generally diagnosed as locally advanced or metastatic disease.
Metastatic disease remains universally fatal in spite of all recent advances in cancer therapy. For patients with advanced NSCLC, platinum-based chemotherapy has historically been the cornerstone of systemic treatment, although it offers modest improvement in overall survival (OS). However, a better understanding of the biology of cancer and the ability to identify driver mutation that can be targeted did bring forward a better cancer therapy that changed radically the landscape of lung cancer management. It was found that epidermal growth factor receptor (EGFR) is a potent oncogenic driver that can be targeted.[4, 5]
The activation of EGFR kinase domain mutation results in increased and sustained duration of receptor activation by the ligands compared with wild-type EGFR.
Multiple tyrosine kinase inhibitors (TKIs) targeting EGFR mutation are one of the best success stories in precision medicine that introduced multiple approved agents: erlotinib, gefitinib, afatinib, and others.[6–12]
These agents produce higher objective response rate and longer progression-free survival (PFS) with better tolerability and quality of life and fewer side effects, in addition to the convenience of oral medication compared with standard chemotherapy.
Unfortunately, almost all these patients will develop disease progression due to acquired resistance by different mechanisms including T790 mutation.[13, 14] New agents targeting T790 mutation to overcome resistance were studied and osimertinib was approved or that disease progression initially then approved for treatment-naïve patient with EGFR driver mutations. [15, 16]
Erlotinib is one of these TKIs that is approved and used worldwide which was initially approved for all subtypes of NSCLC to be limited only to EGFR mutation disease, and the efficacy and safety profile of erlotinib is well studied in the Western and for Eastern population.[12, 17–20] However, there are no data published about Middle Eastern population.
Our study aimed at evaluating erlotinib in a prospective fashion in our patient population in terms of its safety and efficacy in the management of NSCLC.
Patients and Methods
The study was an open-label, prospective, single-arm, multicenter Phase IV clinical trial in patients with advanced (inoperable Stage III or IV) NSCLC who had failed standard treatment, or in patients who could not receive other systemic anticancer therapy, or patients who were not medically suitable for chemotherapy or because of either unavailability or ineligibility for other clinical trials with erlotinib.
The first dose of erlotinib was given within 7 working days after registration. All enrolled patients received erlotinib (150 mg/day). No dose escalation of erlotinib was permitted. In the event of toxicity (e.g., diarrhea and rash) that was not controlled by optimal supportive care or not tolerated due to any reason, regardless of severity, the daily dose of erlotinib was decreased to 100 mg/day.
Patients remained on treatment until withdrawal due to toxicity, disease progression, or withdrawal of consent. The study was terminated after every living patient had a follow-up of at least 6 months after stopping Erlotinib.
This study in patients with Stage IIIB or Stage IV NSCLC who met the selection criteria described below:
Patients must be 18 years of age or older with Eastern Cooperative Oncology Group (ECOG) performance of 0–3, life expectancy of at least 12 weeks, normal organ functions, and had histological or cytological documented diagnosis of inoperable, locally advanced, recurrent, or metastatic (Stage IIIB or Stage IV) NSCLC. Although patients can be enrolled if they had received one or two previous lines of systemic chemotherapy and had recovered from any toxic effects, they can also be enrolled to receive erlotinib as first line if they had positive EGFR mutation, poor performance status of 3, severe comorbidities and illness which make the patient not candidate for standard systemic chemotherapy. Prior radiotherapy is allowed too. Regarding female subjects of childbearing potential, a negative pregnancy test must be obtained. Patients should be able to comply with study, follow-up procedures.
Subjects were excluded from the study if they have any severe comorbidities, uncontrolled brain metastasis, or spinal cord or any other malignancies within 5 years except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer.
In addition, patients with prior therapy with systemic antitumor therapy with HER1/EGFR inhibitors are also excluded from the study.
Patients are disqualified for the study if they have any significant ophthalmologic abnormality. Nursing mothers are excluded too.
Ethical approval in this study was approved by the Institutional Review Board and all the patients provided written informed consent to participate in the study.
According to the schedule of assessments, subjects were assessed for ECOG performance status, tumor measurement according to RECIST version 1, serious adverse events (SAEs), adverse events (AEs) leading to premature withdrawal, unexpected erlotinib-related AEs, and erlotinib-related rash. AEs were graded according to the National Cancer Institute Common Terminology Criteria, version 5.
For responding patients, a confirmatory evaluation was repeated at least 4 weeks after the initial determination of response.
Laboratory assessments were completed according to the schedule of assessments. Such assessments included complete blood count and differential liver and kidney function test, pregnancy test for females of childbearing potential, and international normalized ratio for patients receiving warfarin or coumadin derivative. EGFR testing was performed using real-time polymerase chain reaction.
RECIST version 1–0 had been used to evaluate best response during the treatment as per investigators decision.
Time to progression
The time to progression is defined as the time from enrollment to the date of the first documented progression or the date of death from any reason.
All deaths had been recorded. At the end of the study, a survival follow-up report for each patient is required. OS had been assessed by analyzing time from enrollment to death or lost to follow-up.
After discontinuation of erlotinib treatment, patients had been followed per institutional standards. Any serious erlotinib-related toxicity was continued to be reported until resolution or until no further change is expected.
SAS V9.2 (SAS institute, NC, USA) was used for data analysis. Both descriptive and analytic inferential statistics were conducted. A two-tailed P ≤ 0.05 was accepted as significant for all statistical tests. All variables are analyzed descriptively for their demographic, clinical, and pathological characteristics.
All patients who receive at least one dose of Tarceva™ will be included in the safety analyses. Efficacy analysis will include evaluable patients’ interim of response. PFS and OS will be analyzed using Kaplan–Meier method. Descriptive summary tables will be presented for patients’ characteristics, safety and efficacy parameters, and reasons for study drug discontinuation.
Cox regression analysis was used to identify significant factors predicting survival.
Patients and disease characteristics
Between December 2009 and April 2015, a total of 56 patients had been enrolled from five sites in Riyadh, Jeddah, Al-Ahsa, and Madinah, Saudi Arabia. The characteristics of the patients are summarized in Table 1. Majority were Saudi (88%), nonsmokers (60.7%), male (60%) with median age of 57 years (34–80), and ECOG PS of III (41.1%). Almost enrolled patients had Stage IV represent (98%). The most common NSCLC histological types were adenocarcinoma (83.9%) and squamous cell carcinoma (5%).
Overall, 36 (64%) patients were tested for EGFR mutations. EGFR mutations were identified in 24 (66.7%) patients. The most frequent mutations were exon 19 (50.1%), exon 21 (33%), and exon 18 (8.3%).
The most common reported AEs were rash 36 (64%), diarrhea 29 (52%), dry skin 21 (38%), vomiting 15 (27%), and cough 14 (25%). All AEs reported in 5% or more of our cohort are presented in Table 2 in total and categorized according to the grade. Majority of the AEs are in the Grade I and II categories.
The most common SAE was inpatient hospitalization 12 (21%) for vomiting, chest pain, diarrhea, and dyspnea. At the time of the study closure, reasons for discontinuation were disease progression (70%) [ Table 3].
The efficacy results of this study are summarized in Table 3. Overall disease control rate for all patients was 60.8% and for EGFR mutant was >87%, and it was 40% and 42% in unknown and wild-type patients.
All 56 patients in the study were included in the survival analysis, and the minimum follow-up time was 6 months. At the time of the analysis, 16 (28.6%) patients remained alive. The median PFS was 10 months (95% confidence interval [CI]: 3.93–16.07) [Figure 1] and PFS was 16 months, 7 months, and 6 months in EGFR-mutant, unknown, and wild type, respectively, with statistically significant different between groups (log rank test P = 0.037). The median OS was 12 months (95% CI: 8.5–15.4) [Figure 2]; OS was significantly different between three groups which was 20, 13, and 3 months in EGFRMut, unknown, and wild type, respectively (log rank test P = 0.002).
Cox regression analysis showed older age (P = 0.029, hazard ratio [HR]: 1.064), EGFR wild type (P = 0.014, HR 8.497), and receiving radiation (P = 0.033, HR: 6.433) significantly increased risk of death for the patients in this study [Table 4].
Our study confirmed that, in our patient population, erlotinib is safe and effective in the management of patients with NSCLC, especially those with EGFR mutation status.
Similar to published literature, erlotinib most common AEs included rash and diarrhea. No major unsuspected AE was identified in our patient population.
It is noteworthy that most of these AEs are Grade I and II with Grade III and IV AEs are generally <5%.
Since we started using doxycycline as prophylactic treatment for our patients for the first 2 months, we did not encounter any Grade III skin toxicity or higher.[ 22]
As for disease response rate, the patients with EGFR mutation had significantly better response rate and disease control than EGFR wild type. The same is true for PFS and OS. Expectedly, patients with EGFRmut did much better than the patients with wild-type tumor. However, patients with unknown EGFR mutation status did fairly well compared to patients with wild type and this is important concept to illustrate for our patients population. If for whatever reason, patients did not have the test performed, they should not be deprived of a potentially very effective treatment.
There are many reasons that patients would not have the biopsy done which may be as high as quarter of the patients. These reasons including insufficient initial biopsy and refusal of patient to undergo a second biopsy or the second biopsy are not feasible due to medical or technical reasons. We are not advocating to default to empiric therapy without a serious attempt to obtain EGFR status whether by tissue biopsy. If tissue is not available, liquid biopsy is an important and feasible alternative to be explored. What we are proposing here, that in case, we do not have EGFR status, empiric therapy with TKI is worth considering which may be due to the high prevalence of mutation in our patient population which maybe up to third of the patients. However, patients with confirmed wild-type EGFR should not receive TKI.
Although one of our study limitations is small sample size, the prospective design of the study and the consistency of the findings with what reported in the literature give our study a strength of delineating an experience in new population that was not previously reported.
We included in our study indication of second-line treatment of lung cancer irrespective of histology or EGFR status which was approved indication by USFDA initially and therefore, EGFR status was not mandatory requirement for enrollment in the study. Therefore, the high prevalence of EGFRMut in this cohort is not reflective of EGFRMut in our population which is in the range of 30%. It is much higher in our study because many patients were selected due to the presence of EGFR mutation.
In summary, erlotinib is safe and effective in our patient population, especially those with tumors harboring EGFRmut. All efforts should be done to obtain EGFR testing including liquid biopsy, but if EGFR status is not available or unknown for whatever reason, TKI use should be considered in our patient population due to high prevalence of the mutation. However, patients with EGFRWT tumor should not receive TKI.
Financial support and sponsorship
This study was supported by funding from King Abdullah International Medical Reseach Center, Ministry of National Guard Health Affairs.
Conflicts of interest
The authors declared no conflicts of interest.
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