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Third-line therapy in the epidermal growth factor receptor mutation-positive advanced nonsmall-cell lung cancer

Introduction: The treatment of lung cancer is not defined in the third-line setting and remains an unanswered question. Erlotinib is the only drug approved in the third-line setting. With the introduction of effective first- and second-line therapies, more and more patients warrant an effective third-line therapy. We did a post hoc analysis of our randomized trial for the epidermal growth factor receptor (EGFR)-positive patients who received third-line therapy. Materials and Methods: The present series is of 85 patients who received third-line therapy. Demographic data were collected which included age, performance status, gender, stage, comorbidities, and sites of metastasis. Data were collected for the type of systemic treatment patients received and number of cycles received. Information related to the impact of treatment on the symptoms of patients and the imaging done for response evaluation was collected. Results: Of the 85 patients, there were 13 patients (15%) who achieved a partial response and 34 patients (40%) who had stable disease as best response. There were no complete response and 20 patients (24%) had disease progression at the time of first assessment. The median overall survival (OS) was 8.36 months (95% confidence interval [CI] 6.8–9.8 months) and median progression-free survival was 4.4 months (95% CI 3.3–4.9 months). Grade 3 or 4 toxicities were seen in 42.5% (n = 36) of the total patients. Conclusions: The study provides the patterns and outcomes of systemic treatment in metastatic EGFR-mutated lung adenocarcinoma in patients who have progressed on two or more lines of systemic therapies. This data suggest that third-line systemic therapy may provide meaningful outcomes in these patients.


Introduction
The treatment for advanced nonsmall-cell lung cancer (NSCLC) is fairly well-defined in the first-line and second-line settings. [1,2] There are very few studies regarding third-line therapy as compared to that of the first and second line. This may be because at the best very few patients make it to third-line treatment and even fewer with good performance status (PS) tolerate third-line therapy. A large randomized trial evaluated the use of erlotinib as third-line treatment for advanced NSCLC and resulted in its approval for same, making it the only agent approved for the same. [2] With the introduction of effective first-and second-line therapies, more and more patients are now alive and in good PS to warrant consideration of third-line therapy. In the epidermal growth factor receptor (EGFR)-negative patients, erlotinib remains an accepted option in the third-line setting, but in the EGFR-positive patients, data are more limited. Relevant data in this setting are important to guide clinicians in clinical practice.
We did a post hoc analysis of our randomized trial for EGFR-positive patients who received third-line therapy. We analyzed their outcomes, different regimens used, and toxicities.

Materials and Methods
The current study is a post hoc analysis of the patients evaluating the use of tyrosine kinase inhibitor (TKI) (gefitinib) versus platinum doublet in the first line conducted in the outpatient department of the thoracic medical oncology unit at a tertiary care oncology center in Mumbai, India. [3] The patient inclusion criteria included the following: 1. Pathologically-proven NSCLC patients who were Stage IIIB or IV at the time of diagnosis and were EGFR mutation-positive using reverse transcription-polymerase chain reaction This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

Discussion
Third-line therapy in NSCLC has been marred with controversies and it remains inconclusive whether third-line therapy should be offered to patients. Erlotinib became the only agent approved in this setting after a large trial found benefit compared to the best supportive care. [2] With the current improvement in regimens and the introduction of targeted therapies and immunotherapy, there remains a significant proportion of patients after the failure of first two lines of therapy who maintain a good PS and would warrant further therapy. There are also studies to show that many patients choose chemotherapy for a small benefit in health outcomes

Results
There were 290 patients randomized to receive either pemetrexed-platinum or gefitinib as the first-line therapy in the primary study with 145 in each arm. A total of 214 (74%) of them had progressive disease. 169 of these 214 (79%) received second-line therapy.
There were 85 patients with metastatic EGFR-mutated adenocarcinoma progressions who had received third-line therapy were analyzed. Fifty-two (61%) were male and 33 (39%) were female in this cohort [ Table 1]. The most common EGFR mutation was Exon 19 mutation 61 (72%) and Exon 21 being the second most common 21 (25%). All patients had received gefitinib before starting the third line with majority receiving pemetrexed (59%) as the first line.
The treatment details are mentioned in Table 2. Taxanes as single agents (paclitaxel (n = 43, 51%) docetaxel (n = 15, 17.6%) were given in 68% of the total patients. Gefitinib was continued beyond progression in 10 (12%) of the patients. Single-agent gemcitabine was used in 6 (7%) of the total patients [ Table 2]. These constituted the bulk of treatment options in the third line which were based on treating physicians' discretion after a thorough assessment.
There were 13 patients (15%) who achieved a partial response and 34 patients (40%) who had stable disease as best response. There were no complete response and 20 patients (24%) had disease progression at the time of first assessment [ Table 3]. Patients receiving weekly paclitaxel had OS of 10.6 months (95% confidence interval [CI] 6.7-14.4) as compared to 9.8 months (95% CI − 7.5-12.0) when other agents were used (P = 0.5), suggesting that there was no survival difference as compared to other lines [ Figure 1]. The other treatment options exercised are mentioned in Table 2.
The median OS was 8.36 months (95% CI 6.8-9.8 months) [ Figure 2], and median PFS was 4.4 months (95% CI 3.3-4.9 months) [ Figure 3]. Grade 3 or 4 toxicities were seen in 42.5% (n = 36) of the total patients [ Table 4].  even after the adverse effects have been explained and hence would be more accepting to third-line therapy. [4] The EGFR mutation-positive patients are a unique group who can be started on first-line TKI and usually remain in good PS and tolerate subsequent line of therapy very well.
The introduction of newer generation TKI-like osimertinib is an alternative second line in T790M-positive patients making chemotherapy a possible alternative in third line, but this is so only in 60% of patients. Our post hoc analysis of gefitinib against pemetrexed platinum chemotherapy was done when osimertinib was not available in India. This leaves subsequent chemotherapy as the only option in the third line as they have already failed on first-generation oral TKI.
We had a significant 85 (30%) patients of the original 290 who were fit for third-line therapy which although <40% in the Phase III trial of pemetrexed versus docetaxel in the second-line setting was >14% in a large retrospective Austrian analysis for third-line therapy. [5,6] Weekly paclitaxel at 80 mg/m 2 was the most common regimen used in the present study. This regimen stems from the use of taxanes in the second line and beyond in various trials. Docetaxel weekly has been demonstrated to be both effective and less toxic regimen in multiple trials. [7][8][9] Gefitinib beyond progression and gemcitabine were the other common regimens used in this study which is keeping with the global trends for the treatment of NSCLC in the third line. [10] The response rates in this study was 15% and disease control rate of 55% which compares similarly with another retrospective analysis examining docetaxel or pemetrexed alone in the third line. [11] The PFS in this study was 4.3 months which appears better than 2.6 months with pemetrexed and 3.8 months with docetaxel in a retrospective study. [11] The OS was, however, lower in this study at 8.3 months, but weekly paclitaxel in this study had an OS of 10.6 months.
In another retrospective analysis, the median OS after the beginning of third or fourth line was only 4 months. [12] Two other single institution retrospective analysis one in Germany [13] with chemotherapy and another in France [14] with TKI as the third line showed an OS of 3.8 and 5.9 months, respectively.
The data for toxicity in third-line therapy are not forthcoming with very little data in the literature. We had neutropenia in approximately 11% of patients and anemia and thrombocytopenia in another 7% of patients as compared to 14% when pemetrexed was used in the third line in a retrospective analysis. [11]

Conclusions
The study provides the patterns and outcomes of systemic treatment in metastatic EGFR-mutated lung adenocarcinoma in patients who have progressed on two or more lines of systemic therapies. This data suggest that third-line systemic therapy may provide meaningful outcomes in these patients. We suggest a prospective clinical trial to develop level 1 clinical evidence.

Financial support and sponsorship
Nil.

Conflicts of interest
There are no conflicts of interest.