The emerging landscape of EFGR tyrosine kinase inhibitors in lung adenocarcinoma—successes and challenges

Epidermal growth factor receptor (EGFR) is a member of the erbB tyrosine kinase receptor family found to be mutated and/or overexpressed lung adenocarcinoma (LADC). Mutations in EGFR result in activation of the MAPK pathway leading to increases in cell proliferation and survival (1). EGFR mutations are present in about 15 percent of LADCs and are most prevalent in Asian populations, women, never- or previous light smokers (2). EGFR tyrosine kinase inhibitors (TKIs) have emerged as a successful class of targeted therapeutics in LADC and have revolutionized the management of patients whose tumors harbor a mutation in the EGFR gene locus.

In 2003, gefitinib became the first EGFR TKI to receive FDA approval for use in the United States in the post-platinum setting irrespective or EGFR mutation status (3). Multiple subsequent trials demonstrated superiority in progression free survival (PFS) over platinum-doublet in the first line in patients with EGFR mutated LADC, moving this class of targeted therapeutics to the frontline for these patients (4-7). Since the initial studies and approvals of the first-generation EGFR TKIs, our knowledge of this class of antineoplastics and their survival implications in LADC has grown exponentially. A multitude of second, third and fourth generation EGFR TKIs have since been developed and are in clinical use or being evaluated in clinical trials in the United States and across the globe (Table 1).

Table 1. EGFR TKIs in clinical use in the United States (3,8).

Name	Indications	Year of approval
First generation
Gefitinib	Second line for advanced or metastatic NSCLC (withdrawn)	2003
	First line in metastatic NSCLC with exon 19 (del) or exon 21 (L858R) mutations	2015
Erlotinib	First line and after progression on platinum chemotherapy for metastatic NSCLC with exon 19 (del) or exon 21 (L858R) mutations	2004
	Maintenance therapy in locally advanced metastatic disease	2010
Second generation
Afatinib	First line in metastatic disease harboring nonresistant EGFR mutations	2013
	Metastatic squamous NSCLC after progression on platinum-based therapy
Dacomitinib	First-line therapy for metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations	2018
Third generation
Osimertinib	Metastatic NSCLC with EGFR T790M who have progressed on, or after EGFR TKI therapy	2015
	First line in EGFR mutant advanced or metastatic disease	2018

EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; NSCLC, non-small cell lung cancer.

Globally, the current treatment paradigm for EGFR mutant LADC incorporates the use of either first, second or third generation TKIs in the first line setting for advanced metastatic disease. However, in the United States, the 3^rd generation osimertinib is the preferred first line agent based on the results of the FLAURA study that showed overall survival of 39 months in osimertinib treated group compared to 32 months in the erlotinib and gefitinib groups [hazard ratio (HR) =0.80, 95% confidence interval (CI), 0.64 to 1.00] (9). The PFS was also superior with osimertinib at 19 months compared to 10 months with erlotinib and gefitinib [HR =0.46; 95% CI, 0.37 to 0.57] (10). The case report by Jia et al. serves as a good validation of the superiority of osimertinib in the first line setting for metastatic LADC through in vitro sensitivity testing (11). The authors report the case of a 66-year-old male who had recurrent LADC with metastatic disease three years after curative surgery for early-stage disease. Pathology of a biopsied lesion confirmed the presence of EGFR L858R and TP53 R110L mutations. Using patient derived organoids in a personalized approach, the efficacy of five EGFR TKIs including osimertinib, afatinib, erlotinib, gefitinib and icontinib were compared. Osimertinib demonstrated superiority over all other TKIs, reaffirming the results of the FLAURA trial. The patient was then treated with osimertinib and enjoyed a PFS of about 9 months. The relatively shorter PFS in this patient is likely due to concomitant TP53 mutation, which is known to confer a poorer prognosis when co-mutated with EGFR (12).

The differences in global practice in relation to EGFR TKIs is in part attributable to local availability, or lack thereof, of these TKIs which likely affects recommended practices. This is reflected in the case report by Song et al. in which a patient with known EGFR mutation was subjected to an initial 4 cycles of platinum doublet therapy due to local unavailability of TKI (13). This is also underscored in the case report by Zheng et al. in which another patient with recurrent metastatic LADC with brain metastases was found on biopsy to harbor EGFR L858R mutation (14). She was started on gefitinib with subsequent progression of the brain metastasis after a year of therapy. The authors report that the patient declined repeat biopsy of the pulmonary or brain lesions and therefore could not confirm the presence of T790M mutation. This led to initiation of second line anlotinib, a non-EGFR multitargeting TKI, rather than osimertinib since the latter could only be prescribed at this practice if there was a documented T790M mutation. While a blood-based next generation sequencing (NGS) might be helpful in assessing for resistance mechanisms in the United States today, the technology may not have been available at the patient’s treating institution. Anlotinib was discontinued a month later due to intolerable side effects and osimertinib was commenced after the patient consented to biopsy with subsequent confirmation of T790M. It is important to note that among all approved EGFR TKIs, osimertinib is the only agent with activity in T790M mutated LADC and the only one that has optimal CNS penetration (9). Therefore, the treating physicians could have used that argument to support initiation of osimertinib in the presence of a brain metastasis. In another case report by Zang et al., the patient with recurrent metastatic LADC harboring EGFR L858R mutation was initially treated with gefitinib. The patient had a clear progression disease at 27 months with the presence of T790M gatekeeper mutation. Although treatment change was warranted, the patient was continued on gefitinib for an additional 10 months due to unavailability of osimertinib in China at that time. Unfortunately, this patient developed progressive disease occurred 12 months later with brain, bone and liver metastases and eventually died from multi-organ dysfunction nine months later (15).

All three cases reported by Song et al., Zheng et al. and Zang et al., not only reflect the challenge related to availability of EGFR TKIs but also highlight an even greater challenge—the emergence of resistance to this group of antineoplastics. Despite initial responses to EGFR TKI therapy, most patients will progress due to acquisition of resistant mutations. Undoubtedly, the most common mechanism of acquired resistance to first- and second-generation EGFR TKIs is the appearance of T790M gatekeeper mutation (approximately 50%). The T790M mutation is sensitive to osimertinib, therefore patients who acquire this mutation while on first or second generation TKIs are eligible for second line osimertinib with additional PFS of about 9–13 months (10,16,17). However, most patients will also eventually develop resistance to osimertinib. The most frequent resistance mechanisms for osimertinib are summarized in Table 2 (18-21). In the case reported by Song et al. (13), after the initial 4 cycles of chemotherapy, the patient was started on icotinib on which he acquired the T790M resistance mutation after 9 months of treatment. The patient was appropriately transitioned to osimertinib, however on imaging studies 4 weeks later was found to have progressive disease. Although it was too early to assess response to osimertinib at 4 weeks, NGS of a wedge resection of a metastatic pulmonary lesion showed the presence of L858R, L718Q and EGFR amplification with a copy number of 11.54, a genomic profile associated with resistance to osimertinib. The EGFR T790M mutation was negative in this resection specimen, which is likely due to suppression by Osimertinib and/or tumor heterogeneity. As per the authors, the patient was subjected to a second course of 4 cycles of platinum doublet therapy to ‘clear’ the composition of the tumor after which he was rechallenged with osimertinib with which he enjoyed a PFS of 4.7 months. At this point, another tumor biopsy demonstrated another well-characterized osimertinib-resistant mutation, EGFR C797S, which occurs with a frequency of 0.60%. This case indeed raises multiple issues that are pertinent to EGFR-mutation driven LADC, specifically tumor heterogeneity, development of resistance mechanisms to EGFR TKI, and the importance of repeated genomic testing by tissue or liquid biopsy at every progression. It also highlights the need for effective treatments after progression on osimertinib.

Table 2. Mechanisms of acquired osimertinib resistance (18-21).

On target

EGFR mutations: C797S, L718Q, G724S, C79X, L792X, G769X, S768I, G724S, G796S, V834L exon 20 insertion

EGFR amplification

Off target

MET amplification

HER2 mutation/amplification

PIK3CA mutation/amplification

KRAS mutation/amplification

PTEN mutation

Cell cycle gene alterations: CCND1, CCND2, CDKN2A, CDK6, CCNE1

Small cell transformation

Squamous translocation

EGFR, epidermal growth factor receptor.

Co-existence of LADC driven by two separate genomic drivers is a rare occurrence and this is highlighted by case report authored by Du et al. In this report, the authors describe the case of a 42-year-old woman who presented with two approximately 2cm synchronous pulmonary lesions in each lung. Initial diagnostics included CT guided biopsy of one lesion and was consistent with LADC with EGFR exon 21 L858R point mutation (22). The patient was treated ‘neoadjuvantly’ with gefitinib for 8 weeks. Evaluation of response by imaging studies showed decrease in size of the biopsied lesion but not the lesion on the contralateral lung. The patient subsequently underwent bilateral surgical resection of both lesions 3 months apart. Post-operative pathological result indicated a diagnosis of two stage I synchronous primary tumors. The second lesion had no EGFR mutation but harbored KIF5B-RET fusion. While this case points to the success of EGFR TKIs in evoking a response in EGFR mutant LADC, it also underscores the importance of genomic testing of individual tumors when the clinical picture is suspicious of two primary lesions. Biopsy of both lesions would have led to diagnosis of synchronous early-stage cancers and curative-intent surgery without any need for systemic treatment. Currently, EGFR TKIs are now incorporated into adjuvant therapy for LADC, but they currently have no established role in the neoadjuvant setting for early-stage LADC (23). The case report, however, underscores the importance of genomic testing of tumors that are clinically or morphologically suspicious for separate primaries.

Surgery is a mainstay modality in the diagnosis and management of lung cancer including EGFR mutant cancers. However, as with most invasive procedures, comes with an inherent risk of complications such as infections, air leaks, bleeding, and long term oxygen dependence due to decreased lung capacity. Dai et al. describe the case of a noncancer patient whose lobectomy was complicated by infection and a protracted treatment and recovery course, serving as a cautionary tale of the potential morbidity that can be associated with surgery (24). The case brings to attention the need for adequate pre-operative risk assessment, appropriate patient selection and use of minimally invasive surgical approaches whenever possible. It is worth mentioning that emerging technologies such as AI-based radiology reads, complementary biomarker assays may help distinguish between malignant and benign lesions more accurately. Wang et al. report one such potentially useful application of a novel localization technology to better visualize and localize a sub centimeter ground glass nodule intraoperatively to enable minimally invasive surgical approach (25). In conclusion, EGFR TKIs have revolutionized the management of LADCs and resulted in improved outcomes in these patients. From the initial years of first-generation EGFR TKIs, great strides have been made in understanding their resistance mechanisms and development of next generation drugs to overcome these, improving their efficacy in combination with other drugs and broadening their applicability now to include use in the adjuvant setting. While it is extremely important to continue exploring novel agents and combinations through clinical trials, these series of case reports reviewed in this manuscript highlight unique clinical scenarios that we frequently face in the real world. Publication of cases such as these and strengthening them by the unique tumor-board like commentary by international experts adds great value to existing literature.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.