Third generation EGFR TKI landscape for metastatic EGFR mutant non-small cell lung cancer (NSCLC)

KEYWORDS:

• EGFR mutation
• nizartinib
• non-small cell lung cancer
• osimertinib
• third generation EGFR TKI

1. Introduction

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are now established first-line options for EGFR mutation positive non-small cell lung cancer (NSCLC). While the first (1G) and second generation (2G) EGFR TKIs demonstrated superiority in terms of progression-free survival (PFS) and quality of life (QoL) over platinum-based chemotherapy – no difference in overall survival (OS) was previously observed. Traditionally, this has been attributed to the impact of patients who cross over from chemotherapy to EGFR TKI. However, with emerging long-term data on 2G and 3^rd generation (3G) EGFR TKIs demonstrating statistically and clinically significant improvement in PFS, there remains clinical equipoise on the optimal treatment approach and sequence for each individual patient.

1.1. Clinical development of 3G TKI

The 3G EGFR TKIs were developed to address the common T790M ‘gatekeeper’ mutation present in 50–60% of patients resistant to 1^st generation (1G) TKI. Initially discovered through focused library screens of kinase inhibitor core scaffolds, this resulted in the discovery of a pyrimidine-based irreversible inhibitor – structurally distinct to the quinazoline-based 1G/2G compounds. The strong covalent binding to cysteine 797 circumvented the T790M mutation and resulted in greater selectivity for mutant EGFR compared with wild-type EGFR. These favorable properties resulted in subsequent rapid translation from proof of concept phase I trial [1] to positive registration phase III trials in the 2^nd line setting in patients harboring the T790M mutation and in 1^st line treatment naïve patients [2,3]. Importantly, these studies also demonstrated greater intracranial efficacy with reduced rates of CNS progression [4], a more favorable safety profile with lower frequency of rash and diarrhea, and greater PFS benefit in EGFR exon 19 deletion compared with L858R mutation. With the striking success of osimertinib, several other 3G EGFR TKIs have been in early to late phase development (Table 1).

Table 1. Selected third-generation EGFR tyrosine kinase inhibitors.

Drug	Structure	RP2D	Status of development	IC50 in H1975 cell line with EGFR T790M + L858R (nM)	Off target kinase inhibition	Reference
Osimertinib (AZD9291)		80mg OD	Approved for first-line use in EGFR exon 19 deletion/L858R mutations Approved for post-EGFR TKI T790M mutation	27.5	ACK1, ALK, BLK, BRK, BTK, ERBB2/4 MLK1, MNK2	Yun et al. [5], Cross et al. [29]
Olmutinib (HM61713)		800mg OD	Production halted	67.3	Unknown	Yun et al. [5]
Nazartinib (EGF816)		150mg OD	Phase 2, Phase 3 trial withdrawn	52	ALK, ABL1, BRAF, FGFR3, FLT3, KIT, LRRK2, MET, PIK3CA, RET	Cheng et al. [6], Jia et al. [7]
Lazertinib (YH25448)		To be determined	Phase 1/2	10	AXL, FER, MLK1, MER, RET	Yun et al. [5]
CK-101 (RX518)		To be determined	Phase 1/2 Planned for Phase 3 (2019)	5	Unknown	Johnson et al. [8]
Maverlertinib (PF06747775)		200mg OD	Phase 1/2, development terminated	12	Unknown	Planken et al. [9]
Naquotinib (ASP8273)		300mg OD	Phase 1, development terminated	8–33	Unknown	Cheng et al. [6]

1.2. Not all 3G TKI are alike

Rociletinib (CO-1686) [10] commenced evaluation in clinical trials at a similar time to osimertinib, however, the pivotal phase 3 trials were halted after it failed to receive FDA accelerated approval. There was also controversy regarding the initial reported response rates, and concern over off-target toxicity including hyperglycemia and QTc prolongation [11]. The toxicity profile also included diarrhea, but not rash. Olmutinib (HM61713), approved in Korea, was similarly hampered by toxicity, with fatal cases of Stevens Johnson syndrome [12], and diarrhea, hyperkeratosis, nausea, and rash being the most common side effects overall [13]. Early data for nazartinib (EGF816) was recently reported with the ongoing first-line phase II trial, demonstrating promising efficacy with an objective response rate (ORR) of 64%, although survival data is immature [14]. Toxicity to nizartinib included diarrhea, maculopapular rash, stomatitis, and cough, although overall it exhibited a tolerable safety profile. Avitinib (AC0010), lazertinib (YH25448), and CK-101 are other third-generation EGFR TKIs that have been or are currently in early phase trials, and several phase III studies in the treatment-naïve setting have commenced. Also, important to consider, is off target kinase inhibition.

1.3. Should all patients receive upfront 3^rd generation EGFR TKI?

Preliminary analysis of post-progression endpoints from the phase III FLAURA trial of first-line osimertinib indicates there may be preserved clinical benefit for osimertinib beyond first progression [15]. However despite this, in the context of immature OS data for osimertinib, there remains some debate over the optimal sequencing of therapy. This is underpinned by concerns on the potential impact of selective pressures imposed by 3G TKI, best revealed by emerging understanding of resistance mechanisms. Multiple studies have attempted to characterize resistance to osimertinib, with a range of different mechanisms described to date [16–20]. These include EGFR dependent mechanisms and non-canonical mechanisms such as alternative bypass pathway activation and histological changes. Reported resistance mechanisms to osimertinib in the second or later line setting include EGFR C797S or other acquired EGFR mutations such as L718 and L792. Loss of T790M with concurrent acquisition of oncogenic alterations including PIK3CA, RAS-MAPK pathway mutations, HER2, MET, and FGFR amplifications and novel fusions, also accounts for a significant proportion. A number of patients may also develop small cell histological transformation or lack an identifiable mechanism of resistance. The limited reports of resistance to osimertinib given as first-line therapy, reveal MET amplification and EGFR C797S mutation as possible predominant mechanisms [17]. Similarly, there may be significant heterogeneity in resistance mechanisms to rociletinib [21,22] and nazartinib [23]. Synthesizing this data however is problematic, as these studies are diverse with regards to line of therapy, use of tumor tissue or plasma circulating tumor DNA (ctDNA) and method and extent of genomic sequencing or alteration detection. Whilst there is some overlap with 1G/2G T790M negative mediated mechanisms of resistance, the presence of novel mechanisms such as kinase gene fusions (such as RET and FGFR fusions) and alternate drivers (such as BRAF and KRAS mutations) [24,25], suggest a different resistance landscape and altered tumor biology. Ultimately, comprehensive deep genomic and transcriptomic profiling of patients at baseline and resistance will be critical to wholly appreciate the importance and relevance of these novel findings.

1.4. Optimal sequencing based on individual risk

With expanding therapeutic options, however, including chemotherapy, immunotherapy, and other targeted therapies, and advances in non-invasive tools to detect resistance alterations, one attractive approach would be to adopt a stratified approach based on individual risk of progression, to selecting EGFR TKIs and combinations thereof (Figure 1). EGFR mutant NSCLC has diverse clinical trajectories, with some patients charting an indolent course while a proportion display aggressive behavior with rapid acquisition of resistance. The factors that drive these differences are poorly understood. Potential tumor and patient factors include EGFR co-alterations, for example, MET [26,27] and SNPs around drug binding sites [28]. Off-target kinase inhibition may therefore have increasing importance (Table 1), with osimertinib, for example, having activity against HER2/4, ALK, BLK, and BRK [29]. Additional insights have been gleaned from inferring the evolutionary dynamics from understanding intra-tumor heterogeneity. Multi-region sequencing studies have revealed the unique clonal architecture of EGFR mutant NSCLC, with frequent and early whole genome doubling and low mutation/driver burden, but proportionally higher number of late branch and private mutations [30]. These genomic traits of EGFR mutant NSCLC can dictate the clinical and evolutionary trajectories of individual patients and potentially contribute to fitness of drug-tolerant, ‘persister’ populations.

Figure 1. Therapeutic options in EGFR mutant NSCLC.

1G – 1^st generation, 2G – 2^nd generation, 3G – 3^rd generation, ADC – antibody-drug conjugate, CNS – central nervous system, EGFR – epidermal growth factor receptor, NSCLC – non-small cell lung cancer, TKI – tyrosine kinase inhibitor, WGD – whole genome doubling

1.5. Therapeutic targeting of persistence

The exact intrinsic properties of ‘persister cells’ that provide the substrate for the development of resistance remain to be elucidated. However, activation of bypass signaling, e.g. alternative receptor tyrosine kinases or adaptive signaling is almost certainly a predominant mechanism [31], and this may occur through autocrine, paracrine or systemic increased ligand production [32]. This has significant implications on potential combination therapies with other targeted or immunotherapies, and numerous trials of agents targeting multiple receptor kinases are ongoing. It is also plausible that choice of EGFR TKI may play a role, not just from feasibility of combination with other agents, but due to underlying differences in binding affinity, EGFR mutation selectivity and off-target effects (Table 1). There are several reports of patients that have responded to different third-generation agents [33,34], suggesting there may even be a role for sequencing within this class of drug. Finally, the role of the tumor microenvironment in modulating tumor evolution, is also gaining interest, particularly with respect to immune cell infiltration. Paired biopsies from the AURA1 trial of osimertinib, demonstrated the significant increased immune cell infiltrate (particularly CD8+ cells) associated with therapy [35]. Unfortunately, an early trial of combination osimertinib with durvalumab was suspended due to high rates of interstitial lung disease, much greater than would be expected with either agent alone [36]. Nevertheless, this implies an underlying interaction and relationship between initial response to EGFR TKI and the immune system, which needs to be identified for better trial design of combination strategies.

2. Conclusion and expert summary

Although the current 3G EGFR TKI landscape is dominated by osimertinib, several other 3G TKIs and combinations are in development. Augmenting the natural history of the disease with these more potent and selective therapies need to be evaluated carefully to fully understand the optimal role of third-generation EGFR TKIs. We anticipate that improved patient selection incorporating clinical and molecular characteristics to optimize treatment sequencing and combination approaches will translate to durable improvement in overall survival and quality of life.

Declaration of interest

DSW Tan has received honoraria from Bristol-Myers Squibb, Takeda Pharmaceuticals, Novartis, Roche and Pfizer, consultancy/advisory fees from Novartis, Merck, Loxo Oncology, AstraZeneca, Roche and Pfizer, research funding from Novartis, GlaxoSmithKline and AstraZeneca and travel/accommodation expenses from Pfizer, Boehringer Ingelheim, and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.