Review articles
 

By Dr. Esther Una Cidon
Corresponding Author Dr. Esther Una Cidon
Oncology Department, Royal Bournemouth Hospital, Castle Lane East - United Kingdom BH7 7DW
Submitting Author Dr. Esther Una Cidon
CANCER

Tyrosine Kinases, Epidermal growth factor receptors, Non-small cell lung cancer, Adenocarcinoma, Erlotinib, Resistance

Una Cidon E. EGFR TKIs IN NON-SMALL CELL LUNG CANCER: HEAD AND TAIL OF THE COIN. WebmedCentral CANCER 2021;12(4):WMC005708

This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
No
Submitted on: 16 Apr 2021 06:47:59 PM GMT
Published on: 19 Apr 2021 07:02:05 AM GMT

Abstract


TKIs against the human EGFR have become standard of care for patients with advanced EGFR mutant NSCLC. But despite the initial good results with first generation EGFR TKIs, patients’ cancers will progress after a median duration of response of around 12 months. And some patient will not even show response or only for a short time.

These are due to the development of resistance. Significant research has tried to understand the mechanism behind these two different types of resistance to be able to overcome it with the development of newer drugs. Different generations of TKIs are currently approved to use in routine clinical practice but further investigations need to be carried out to ascertain the best approach to this significant group of patients to be able to extend their cancer natural history with good quality of life.

This article will review the timeline of development of EGFR-TKIs and the mechanism behind the emerging resistance to be able to understand where are we know and where our efforts should be directed.

Introduction


Primary lung cancer is the second most common malignancy and still the most frequent cause of cancer related deaths worldwide, being non-small cell lung cancer (NSCLC) the majority of them (around 80%–90%). [1,2]

The most frequent type of NSCLC is adenocarcinoma, accounting for around 40%. This is the most common type in smokers and non-smokers and both genders regardless their age [3].  

Unfortunately >50% of primary NSCLC present already with stage IV disease which continues to be incurable.

For many years, cytotoxic chemotherapy has been the only systemic treatment available aiming at improving survival by controlling disease related issues [4-6]. 

Four large multicenter randomized clinical trials assessing different regimens of hemotherapy with platinums, came to the conclusion that no regimen was superior to another, obtaining a median overall survival (mOS) of about 8-10 months [7-10]; yet not ideal.

However, when bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, was added to the doublet chemotherapy regimen, better OS was reported (12.3 vs 10.3 months) [11].   

In 2015, the American Society of Clinical Oncology guidelines recommended then a platinum based chemotherapy combination for patients with a performance status (PS) of 0 or 1,  [12] and although cisplatin seemed to be slightly more effective than carboplatin, it produced  more adverse events, therefore it was not advised for patients with a PS of 2 [13].

The addition of bevacizumab to carboplatin plus paclitaxel was recommended as long as no contraindicated.

Pemetrexed, another cytotoxic agent, had gradually become part of the systemic treatment for advanced non-squamous NSCLC based on its demonstrated activity as first-line, maintenance and second or third-line therapy for this group of NSCLC and it has been generally well tolerated [14].

But, despite all these results, chemotherapy based treatment’s benefits had plateaued, and thus more effective drugs were desperately needed.

Finding personalised treatments have become the dream in NSCLC with a double hope. First to improve OS with good control of cancer related events and second, but very important as well, to improve the tolerance profile of the new drugs or regimens by targeting cancer molecular drivers, minimising damage to healthy cells.

This dream became real following the success of imatinib, a BCR-ABL tyrosine kinase inhibitor (TKI) in chronic myeloid leukemia (CML) which was a therapeutic breakthrough.

BCR/ABL is an ideal target because this fusion protein is present in all CML cells but not in healthy cells. Thus, imatinib binds to BCR-ABL kinase domain and switches off the leukemogenesis pathway [15].

This prompted the search for key genetic alterations that stimulate proliferative signals in malignant cells and could be targeted by a treatment [16].

In NSCLC (mainly adenocarcinomas), molecular driver mutations have been found during the past decade and subsequently several specific targeted therapies have been developed.  

This has turned around the landscape of therapies in NSCLC. The presence of molecular driver mutations in epidermal growth factor receptor (EGFR) is, among others, in the eye of the storm of the oncogenesis in NSCLC [17-19].

The fact is that several clinical trials have shown an improvement in progression free survival (PFS) with a first line EGFR TKI in comparison with standard chemotherapy when patients’ tumours show positivity for EGFR mutations [20-25].

However, despite this initial boom of happiness, the reality shows that most patients will acquire drug resistance at some point, and some of them will not even respond at all or only for a very short period of time.

Thus further research is needed to ascertain the underlying causes for such resistances and to create either new agents or different strategies to overcome this issue and extend the treatment benefits for our patients.

This article will review these two aspects of the EGFR-TKIs (heads and tails) in NSCLC patients with metastatic disease.  

EGFR in NSCLC


EGFR belongs to the erbB family which includes several members (erbB1 or EGFR, erbB2 (HER-2), erbB3 and erbB4.

It holds an extracellular ligand binding domain, a transmembrane area and intracellular TK domain.

When a specific ligand attaches to it, EGFR suffers a configurational adjustment and phosphorylation of the intracellular part, leading to the activation of the downstream cascade of events that will eventually impact on cell growth and blockage of apoptosis [26].

DNA mutations as identified by polymerase chain reaction (PCR), can appear in extracellular or intracellular domains of the protein.

In NSCLC, some authors have reported that EGFR is overexpressed or mutated in intracellular areas in around 43-89% [27], while others have found that 25% of NSCLC had mutations in the EGFR TK domain, associated to EGFR overexpression in 75% of cases [28,29].

These activating mutations of EGFR are identified in the first four exons (18 through 21) of the TK domain and classified into three groups: group 1 incorporates the in-frame deletions in exon 19 (44%); group 2 (41%) includes single-nucleotide replacements in exon 21 (arginine is replaced by leucine at codon 858 (L858R) and group 3 (5%) with in-frame duplications or insertions in exon 20.

The first two groups are recognised as “classical mutations”, and are more frequent in females, never smokers, East Asians and adenocarcinomas [30]. In fact, those account for around 90% of all EGFR activating mutations. The presence of these will constitutively activate the signal transduction cascades in different pathways, guiding to cell proliferation and anti-apoptosis.

It is well documented that the presence of these activating mutations is linked to a response to EGFR TKIs, but unfortunately only in 70% of the patients [31,32].

The rest either do not respond or only get a benefit for a short time, generally < 3 months, due to the presence of primary resistance.

This phenomenon creates the first tail of the coin of TKIs development.  

Moreover, [33] patients treated with EGFR-TKIs with good initial response, will eventually show evidence of progressive disease (PD), linked to the appearance of resistance to these drugs, with a mPFS of about 9 to 13 months, being this the second tail in these agents development.

 

First-generation EGFR TKIs – the head of the coin

 

First-generation EGFR TKIs (gefitinib, erlotinib and icotinib) are drugs that will reversibly attach to the ATP-binding site of the EGFR TK domain and block the attachment of ATP to the TK domain, preventing phosphorylation of the EGFR and thus stopping cell growth and causing cell death [34].

Gefitinib and erlotinib, are globally approved for EGFR-mutant NSCLC while icotinib is only approved in China.

These agents have documented higher response rate (RR), PFS and quality of life when compared to standard platinum-based chemotherapy in patients whose tumours show an activating EGFR mutation [20, 21, 23-25, 35-37].

In fact, as mentioned earlier in this review, EGFR activating mutations NSCLC tend to respond well to TKIs, whereas those who carry wild-type (WT) EGFR and/or KRAS mutations will not respond [38-40].

Randomized phase III trials have shown that first-line EGFR TKIs have improved PFS in comparison to chemotherapy in advanced EGFR mutated NSCLC [20-25].

OS was not improved but this is probably related to the high crossover rate after PD was determined [20-25].

These findings led to the approval of these drugs as the standard of care for such patients.

Gefitinib

In initial clinical studies, gefitinib showed only some tumour responses (around 10-19%) in chemotherapy-refractory advanced NSCLC and when combined to chemotherapy, no further benefit was seen [41-44].

This drug received accelerated approval by the U.S. Food and Drug Administration (FDA) in May 2003 as monotherapy for advanced NSCLC after failure of both platinum-based and docetaxel chemotherapies [45].   

This was based on a RR of 15% as reported in two phase II clinical trials: the IRESSA Dose Evaluation in Advanced NSCLC (IDEAL)-1 and 2 [41,42].

However, in June 2005, FDA restricted its use to patients who were already on it showing a benefit or for those included in clinical trials with an Institutional Review Board approval before June 2005, being withdrawn later (April 2012) due to the negative results of three phase III trials (IBREESE, ISEL, and INTEREST) [45-47].

In 2004 the IRESSA NSCLC Trial Assessing Combination Treatment (INTACT-1 and 2) phase III clinical trials assessed the effect of gefitinib in first-line setting combined with chemotherapy [44,48]. Both studies were negative.

Once activating EGFR mutations were evidenced in 2004 [49-51] gefitinib was incorporated again to phase III trials, showing significant benefits. This finally led to its approval in 2015 for first-line of EGFR-mutant patients.

First line gefitinib vs carboplatin/paclitaxel was assessed in Asia [Iressa Pan-Asia Study (IPASS)] in a clinically selected population [35]. Results were superior for gefitinib especially when EGFR mutations were positive [35,52].

Moreover, two phase III Japanese trials (NEJ002 and WJTOG3405) [20,21,53] were carried out in NSCLC EGFR mutated, obtaining similar results.

IMPRESS is another phase 3 trial [54], assessing the benefits in PFS with the continuation of gefitinib/platinum based chemotherapy after PD, in comparison to placebo/chemotherapy. Results showed that the continuation with gefitinib does not prolong PFS, suggesting that chemotherapy would be the standard of care in that situation.

Erlotinib

The second EGFR-TKI first generation is erlotinib. This was initially approved by the FDA in November 2004 for metastatic NSCLC after failure of chemotherapy [55].

Later, the Sequential Tarceva in unresectable NSCLC (SATURN) assessed erlotinib after finishing chemotherapy, as a maintenance treatment. It showed significant improvement in OS from 11.1 months with placebo to 12.3 months with erlotinib, with even further benefit in a subgroup of patients whose tumours had EGFR mutations [56].

Therefore, it was approved in 2010 as a maintenance treatment for unselected NSCLC who had shown a benefit from first-line platinum-based cytotoxic chemotherapy.

Several randomized trials, EURTAC (European Randomized Trial of Tarceva vs Chemotherapy), the OPTIMAL (CTONG0802) and the ENSURE have shown the superiority of erlotinib compared to chemotherapy in terms of RR and PFS for first-line of EGFR-mutant NSCLC patients [23,25,57].

And based on those results, EMA and FDA have approved erlotinib for first-line therapy of EGFR-mutant NSCLC.

Further studies were carried out as the TRIBUTE [58] and the Tarceva Lung Cancer Investigation Trial [59]. These two phase III clinical trials assessed erlotinib or placebo in combination with a platinum-based chemotherapy for the first-line of NSCLC patients unselected for EGFR mutations.

Neither of them showed a survival benefit for the combination with erlotinib and chemotherapy [58,59].

And the TOPICAL phase III clinical trial is a large study to assess whether erlotinib as monotherapy in first-line for unselected advanced stage NSCLC who are not suitable for chemotherapy. Results showed no differences in OS for both groups (3.7 months for erlotinib and 3.6 for placebo), concluding that its administration is not beneficial for unselected patients [60].

As second line treatment, it has been compared to chemotherapy in two randomized trials (TaiLOR, DELTA) again for unselected NSCLC patients. Results showed that chemotherapy significantly extended PFS compared with erlotinib [61,62].

Following these studies, a multicenter randomized phase III trial (WJOG 5108L) was carried out to compare two first generation TKIs, erlotinib vs gefitinib in NSCLC adenocarcinoma, initially regardless of the EGFR mutation status [63] but later amended to include only EGFR mutation-positive patients.

561 patients were recruited and the results showed a PFS of 8.3 and 10.0 months for gefitinib and erlotinib among EGFR mutated NSCLC patients respectively (p = 0.424). Thus, authors did not demonstrate non-inferiority of gefitinib vs erlotinib in terms of PFS. However, when comparing the Kaplan–Meier survival curves for both arms, these two drugs were considered pretty similar.

These results transformed these EGFR TKIs as the treatment of choice for newly diagnosed EGFR-mutant advanced NSCLC.

Unfortunately, not all that glitters is gold and after a median duration of response of around 12 months, all patients will develop tumour resistance, and in >50% of cases, this will be due to the emergence of a specific mutation, the EGFR T790M mutation.

For those cases which show PD on gefitinib or erlotinib, it is vital to understand the mechanisms of resistance to be able to choose the best therapeutic approach. 

Secondary resistance: the tail of the coin

Patients with EGFR mutant NSCLC will eventually show resistance to the EGFR TKIs and it is crucial to understand the underlying mechanisms to be able to develop a new group of agents or combination regimens to overcome this issue. 

Several molecular processes are involved in acquired resistance to the first-generation EGFR-TKIs, but the most important one seems to be the emergence of a secondary EGFR-TK domain mutation in exon 20, known T790M.  

This mutation is due to a single nucleotide change replacing a threonine with methionine which leads to inability of TKIs to bind [64-66]

Around 40% to 50% of NSCLC patients resistant to gefitinib or erlotinib showed positivity for T790M mutations [67].

It has been suggested that T790M causes resistance to EGFR-TKIs probably by increasing the affinity to ATP [68]. In any case, this is not the only mechanism behind this secondary resistance.

Others implicated are the NF-kB activation, which affects mainly rociletinib (a third-generation EGFR-TKI) [69]. A study showed that on H1975 NSCLC cells, with T790M mutation, therefore resistant to gefitinib and erlotinib, are sensitive to rociletinib.

And the induction of resistance to rociletinib led to NF-kB activation replacing oncogenic EGFR signalling. Also, the blockage of this pathway with the proteasome inhibitor bortezomib, made those cells sensitive again to rociletinib. This is a relevant point to explore further as could be [70-72] a promising intervention in patients showing PD after a third-generation EGFR-TKI.

Second generation TKIs: brought to resolve resistance to first generation EGFR-TKIs

As big problems need big solutions, recently EGFR irreversible inhibitors have opened new hopes for NSCLC patients who showed PD after first generation EGFR-TKIs.

These drugs were developed to delay or defeat acquired resistance by showing a wider kinases blockage and by irreversibly attaching to the TK domain.

Second generation TKIs will irreversibly block human EGFR 2 (Her2) and EGFR kinases [73] and presumably, they might as well inhibit T790M EGFR, increasing the efficacy of the drug and reducing the rate of further drug resistance [73].

AFATINIB

Afatinib is an example of this new generation [74] that further delays PD by keeping irreversible attachment to EGFR and HER2 [74].

It has higher affinity for the EGFR-TK domain than the first-generation, causing longer suppression of EGFR signalling [74].

A randomized, open label phase IIb trial (LUX-Lung 7) comparing afatinib vs gefitinib was carried out in 319 patients, in first-line for advanced lung adenocarcinoma EGFR activating mutations positive (exon-19 deletions or the L858R point mutation) [75].

Afatinib showed better PFS (11.0 vs 10.9 months; HR = 0.73, p = 0.017) and TTF (median of 13.7 vs 11.5 months; HR = 0.73, p = 0.0073) but not OS.

LUX-Lung 3 compared afatinib to cisplatin/pemetrexed in first-line advanced lung adenocarcinoma with activating EGFR mutations showing a significantly increased PFS, but not OS [76,77].

Similar results were obtained in the LUX-Lung 6 trial when compared to gemcitabine and cisplatin [25].  

However, when looking at the subgroup of patients with deletions in exon 19 only, OS was significantly increased with afatinib in both studies LUX-Lung 6 and 3 [76,77].  

In second-line afatinib significantly prolonged PFS and OS when compared with erlotinib, regardless of EGFR mutation status (LUX-Lung 8 trial) [78].   

Overall, it seems that afatinib is a relevant option for first-line in patients with advanced NSCLC and activating EGFR mutations [74].  

After the discovery of T790M many new agents targeting this mutation have been  developed. Second-generation EGFR inhibitors (neratinib, afatinib, and dacomitinib) have shown a positive anti-T790M effect in the laboratory, but unfortunately their clinical activity has been poor, with RR of less than 10% among patients resistant to gefitinib or erlotinib [79-81]. Moreover, higher signs of toxicity, mainly skin and digestive, were seen due to WT EGFR inhibition at lower concentrations than those required to inhibit T790M.

LUX-Lung 5 trial was carried out to know the efficacy of continuing with afatinib after PD. This trial compared paclitaxel alone vs in combination with afatinib for patients heavily pre-treated who had also progressed on previous EGFR TKIs (first generation and afatinib). Authors concluded that the combination achieved further benefits in PFS and RR in patients who had acquired resistance to TKIs after initial benefit.

This trial was the first in showing the improvement in efficacy by continuing ErbB targeting treatment after PD vs changing to chemotherapy single agent.

Moreover, this regimen of afatinib combined with paclitaxel warrants further investigation in patients with EGFR T790M mutation-negative who have progressed on a first-generation EGFR-TKI [82].

DACOMITINIB

Dacomitinib is a potent, second-generation EGFR-TKI that irreversibly binds EGFR, as well as the related proteins ErbB2 and ErbB4 [83].

Early-phase clinical trials have reported efficacy in NSCLC [84].

The phase III randomized trial ARCHER 1050, in first-line [85], compared dacomitinib vs gefitinib in patients with sensitizing EGFR mutations advanced NSCLC.

This trial excluded patients with brain metastases as opposed to LUX-Lung 7 (with afatinib).

The results reported a significant benefit in PFS with dacomitinib (14.7 months vs 9.2 months) vs gefitinib (HR = 0.59, p < 0.0001) [85]. OS was also improved with dacomitinib (34.1 months vs 26.8 months; HR = 0.76, p = 0.044) [85].

ARCHER 1028 is a phase III trial comparing dacomitinib vs erlotinib after one or two lines of chemotherapy in unselected patients with NSCLC [86].

To notice that despite randomization, patients included in the dacomitinib arm, had worse  ECOG (PS 2 - 10.1% vs 1.6%), EGFR-mutant (10.1% vs 5.8%), and heavily pre-treated (22.8% vs 16.4%) than patients on the erlotinib arm. The primary endpoint PFS was achieved with a median of 2.86 vs 1.91 months in the dacomitinib and erlotinib respectively (p 0.012). In the analysis of subgroups, dacomitinib showed further benefit if KRAS WT/any EGFR and KRAS/EGFR WT with not statistically significant advantage among EGFR mutations. Although dacomitinib obtained higher RR, OS was not different. Unfortunately, dacomitinib showed a more concerning pattern of side effects than erlotinib and needed a dose reduction more frequently (double than with erlotinib).

ARCHER 1009 is another randomized, multicentre (in Asian and non-Asian countries), double-blind trial, comparing again dacomitinib to erlotinib in advanced NSCLC previously treated with one or two chemotherapy regimens. 878 patients were recruited, 82 patients (9.3%) had an EGFR activating mutation and 136 (15.5%) had a mutated KRAS [87].  

PFS (2.6 months in both arms) or OS (7.9 m in dacomitinib vs 8.4 m in erlotinib) did not show significant differences.

Once again, if EGFR sensitizing mutations were present, longer PFS (11.0 months with dacomitinib and 10.9 with erlotinib) and OS (26.6 months with dacomitinib and not reached with erlotinib) were seen, in comparison to WT-EGFR (PFS 1.9 m for both and OS 6.8 with dacomitinib and 7.6m with erlotinib).

Safety profile favoured erlotinib with less diarrhoea, rash, acneiform dermatitis, paronychia and stomatitis.

All side effects associated to dacomitinib are related to the EGFR blockade. Phase II–III trials have documented rates of dose reduction of 30 to 66% and discontinuation of 6 to 10% [88].  

Some side-effects, such as skin toxicity, improved after adequate management.

In fact, the ARCHER 1042 study that doxycycline reduced the rate of Grade ≥2 skin toxicity in comparison to placebo (23.2% vs 46.6%, P=0.016) and a slight though not significant reduction in Grade ≥2 diarrhoea [89].  

Therefore, randomized studies suggest that second-generation EGFR-TKIs are better than first-generation, at least in terms of PFS [90]. 

Overcoming T790M with second generation TKIs

Previous reports have shown that T790M mutation is the main cause of resistance to gefitinib in NSCLC [91].  Preclinical observations showed afatinib combined with cetuximab (an anti-EGFR monoclonal antibody) overcame T790M resistance [92].  This led to a phase Ib study with 126 heavily treated patients with advanced EGFR-mutant NSCLC resistant to first generation TKIs.

Results showed a RR of 29%, similar regardless of T790M status and PFS of 4.7 months. Unfortunately, the dual EGFR blockade caused higher rates of toxicity, mainly rash, diarrhoea and fatigue, documented in 46% of patients [32].

A randomized phase II/III trial (NCT02438722) of afatinib plus cetuximab vs. afatinib alone is currently open in treatment-naïve patients with advanced EGFR-mutant NSCLC.

Third-Generation EGFR TKIs 

The previous generation of EGFR-TKIs caused some disappointment when looking at the reversal of resistance to gefitinib/erlotinib.

This led to another generation of TKIs to developed, the third. These include osimertinib, EGF816, olmutinib, PF-06747775, YH5448, avitinib and rociletinib.

The common characteristics of this generation are the greater activity in EGFR mutant cells than in WT-EGFR, selective targeting of T790M mutations and irreversible attachment to EGFR-ATP site [94].

The only approved third generation TKI is osimertinib.

All these drugs show only a few toxicities related to the small activity against WT-EGFR.

Osimertinib is an irreversible EGFR-TKI selective for both EGFR mutated and T790M resistance mutations [95]. This was the first approved by FDA and EMA in November 2015 and February 2016, respectively, for metastatic EGFR T790M+ NSCLC, which has shown PD on or after EGFR TKI.

Osimertinib acts as a covalent TKI with potent efficacy against several EGFR mutations (L858R, L858R/T790M, exon 19 deletion, and exon 19 deletion/T790M) and evidenced as well nearly 200 times higher potency against L858R/T790M than WT-EGFR.

The drug is metabolized to two circulating metabolites, AZ5104 and AZ7550.

AZ7550 is similar in potency and selectivity to osimertinib, whereas AZ5104 showed higher potency against exon 19 deletions, T790M mutants and WT-EGFR [95].

A phase I/II dose-escalation study of osimertinib (AURA, NCT01802632) was carried out in patients with locally advanced or metastatic EGFR-mutated NSCLC who had shown PD on first- or second-generation EGFR TKIs.

Yang et al, published the results from the phase II extension trial.

201 patients received osimertinib, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015).

198 patients were evaluable and the results showed a RR of 62%, median duration of response 15.2 months and PFS of 12.3 months.

In terms of toxicities, diarrhoea followed by rash were the most frequent ones, involving around 40% of patients each with less than 1% being grade 3 or above.

The phase II study AURA2 (NCT02094261) showed a similar RR and PFS in patients with  T790M mutation positive [96].

These authors reported as well positive PFS with osimertinib in patients with CNS metastases and a significant CNS response (64%).

Ahn et al presented the results of a pre-planned pooled analysis of two phase II studies, the AZD9291 First Time in Patients Ascending Dose Study (AURA) extension trial (NCT01802632) and the AURA2 trial (NCT02094261). 411 patients were included. Most of them received osimertinib as third line or later [97].

At the data cutoff (date of November 1, 2016), the median treatment exposure was 16.4 months (range, 0?29.7 months) with a RR of 66%, median response duration of 12.3 months and PFS of 9.9 months.

At a later data cutoff (date of May 1, 2018), OS was 26.8 months and the 12?month, 24?month, and 36?month survival rates were 80%, 55%, and 37%, respectively. The most frequent side effects again diarrhoea and rash in about 40% each being grade 3 or above in 1% or less.

These results emphasise once more the relevance of osimertinib in patients with pre-treated, T790M?positive, advanced NSCLC.

But osimertinib has also demonstrated activity in first-line. Soria et al carried out a study to compare osimertinib with standard EGFR-TKIs in NSCLC, EGFR mutation–positive (exon 19 deletion or L858R). This FLAURA trial [97] was a phase III, double blind, that randomised 556 patients to osimertinib or either gefitinib or erlotinib). The primary end point was PFS and reported a significantly longer PFS with osimertinib (18.9 months vs. 10.2 months; P< 0.001). RR was similar in both arms, 80% with osimertinib and 76% with standard EGFR-TKIs (P=0.24). Median duration of response 17.2 months with osimertinib vs 8.5 months with standard EGFR-TKIs. OS data were immature at the interim analysis but at 18months, the survival rate was 83% with osimertinib and 71% with standard EGFR-TKIs  (NS). Toxicity of grade 3 or higher was less frequent with osimertinib (34% vs. 45%). These authors concluded that osimertinib showed superior efficacy to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation–positive advanced NSCLC, with a similar safety profile and lower rates of serious toxicities.

The AURA 3 is an open-label, phase III, randomized, international trial that compared in a 2:1 ratio osimertinib vs pemetrexed plus carboplatin or cisplatin for up to six cycles; maintenance pemetrexed was allowed.

All patients had a T790M-positive advanced NSCLC which had progressed on first-line EGFR-TKI. The primary end point was PFS.

419 patients were recruited. PFS was longer with osimertinib (10.1 months vs. 4.4 months, P< 0.001) and RR favoured as well osimertinib (71% vs 31%; P< 0.001) compared with chemotherapy.  

144 patients had brain metastases and in those cases, the PFS was longer with osimertinib (8.5 months vs. 4.2 months) as well.  

Moreover, toxicity grade 3 or above was lower with osimertinib (23%) than with chemotherapy (47%) [99].

This trial showed a significant benefit of osimertinib among T790Mpositive patients after PD during first-line EGFR-TKI therapy.

Other EGFR-TKI third generation  - 

Rociletinib (CO-1686) 

Rociletinib is a third generation EGFR-TKI that shows irreversible inhibitor of frequently mutated forms of EGFR, including T790M, with minimal effect against wild-type EGFR in preclinical studies [100].

It is a third generation TKI, mutant-selective, covalent inhibitor of both the activating EGFR mutations, (exon 19 deletions and L858R) and the resistance mutation T790M. It lacks activity against exon 20 insertions [101].

TIGER-X (NCT01526928) was a phase I/II study for patients with NSCLC with acquired resistance to first or second generation EGFR TKIs [101].

The phase II part of the trial required the presence of T790M mutation. At the time of the report, 130 patients had been recruited. Among the 46 evaluable patients with centrally confirmed T790M-positive cancers, RR was 59% whereas for 17 patients with T790M negative, RR was 29%. No duration of response was presented. PFS at the time of the analysis was 13.1 months with data on 82% of the patients censored [101].

In November 2015 a pooled analysis of TIGER-X and TIGER-2 (NCT02147990), another phase II trial assessing rociletinib in second line for EGFR T790M+ NSCLC.

325 patients were assessed (dose range, 500–750 mg twice daily) and overall RR was 30.2%. The median duration of response for the two treatment doses was 8.8 and 9.1 months, respectively. The significant difference in RR prompted an updated analysis of cases (intention-to-treat population) included in TIGER-X trial confirming RR of 45% and 17% among T790M+ and T790M− tumours, respectively [102].

These results led to a halt in the enrollment of all ongoing rociletinib studies, including the phase III TIGER-3 trial (NCT02322281) and its clinical development has stopped.

Olmutinib (BI-1482694/HM61713; Olita™) 

Olmutinib is another third generation TKI against mutant EGFR including T790M, not active against WT EGFR [103].

It has been investigated in a phase I/II trial Olmutinib (NCT01588145) assessing Korean NSCLC who failed previous EGFR TKI [104].

In the phase II study of patients with T790M, RR was 56% with DCR of 90%. PFS was 7.0 months. The most frequent side effects were diarrhoea (55%), rash (39%) and nauseas (38%) [104].

The initial plan was to continue with further clinical development of this drug within the ELUXA trials. However, due to a drug safety report of a fatal case of toxic epidermal necrolysis (TEN), its development stopped there [105].

ASP8273

ASP8273 is an irreversible TKI that specifically blocks TK activity of EGFR mutations including T790M, with poor effect against WT EGFR [106]. It might also suppress signalling via ERK and Akt.

It is active in EGFR cell lines resistant to other TKIs such as osimertinib and rociletinib (47).

ASP8273 was evaluated in an open-label phase I/II study (NCT02192697) for safety and efficacy [107].

In a phase I/II trial in Japanese patients with EGFR mutant NSCLC after failure of first line EGFR TKI, RR was 50% for all patients dosed with ≥100 mg with RR of 80% in T790 M positive patients. The most frequent toxicities were diarrhoea (56%), nausea (31%), vomiting (31%) and thrombocytopenia (31%) [106].

In a North American trial with 60 patients with EGFR mutated NSCLC who had failed after EGFR TKI, 90% of patients had T790M mutation. In the latter group, RR was 37.5% with disease control rate of 65%. PFS 6.7 months [108].

A phase III study assessed ASP8273 vs first generation EGFR TKI in NSCL with EGFR activating mutations in the first line setting (SOLAR) [109].

Primary end point was PFS. 530 were randomized 1:1 to receive ASP8273 or erlotinib/gefitinib.

PFS was 9.3 months for ASP8273 and 9.6 months for erlotinib/gefitinib group. (P=0.992).

RR of 33% for ASP8273 vs 47.9% in the erlotinib/gefitinib arm with similar duration of response (9.2 months for ASP8273 vs 9.0 months for erlotinib/gefitinib).

More grade ≥3 adverse events were seen in those receiving ASP8273 (54.7% vs 43.5%).

An independent data monitoring committee carried out an interim safety analysis and adviced against continuing this study due to toxicity and limited efficacy of ASP8273 relative to erlotinib/gefitinib. Authors concluded that this drug in first-line did not show improved PFS or equivalent toxicities versus erlotinib/gefitinib.

Avitinib

This agent will irreversibly inhibit EGFR TKI with activity against EGFR mutations including T790M without effect in WT EGFR. It is structurally different from other TKIs such as as osimertinib [110].

It has been assessed in a phase I/II study for EGFR mutant patients who had progressed on first line EGFR TKI [111] and had acquired T790M mutation.

136 patients were treated in seven dose cohorts (50-350 mg BID). RR (including unconfirmed responses) and disease control rate were 44% and 84% respectively. The cohorts of 150-300 mg BID showed a RR and disease control rate of 51% and 89% respectively.

It was well tolerated with diarrhoea (38%) and rash (24%) mainly grade 1 and 2 [111]. A subgroup of patients with brain metastases, the intracranial PFS of two patients were shorter than extracranial PFS. This finding may be attributed to a low blood-brain-barrier penetration rate of 0.046%-0.146% [112].

Nazartinib (EGF816) 

Nazartinib is another irreversible EGFR mutated inhibitor targeting both EGFR-activating mutations (L858R, Del19) and the resistant T790M mutation, while no active against WT EGFR [113].

NCT02108964 is a phase I/II first-in-human trial of nazartinib in EGFR-mutated locally advanced or metastatic NSCLC [114].  

Patients were assigned to receive once-daily nazartinib with doses ranging from 75 to 350 mg. At the cutoff date of January 29, 2016, 152 patients had been treated in seven cohorts (51). Among them, 147 patients were evaluable for response. The confirmed RR was 46.9%. The estimated median PFS was 9.7 months. Among 69 patients with confirmed responses at the cutoff date, the estimated median duration of response was 9.5 months.

The most frequent side effects were rash (54%), diarrhoea (37%), and pruritus (34%). Curiously, these rashes had a different pattern, location, and histology than those seen with other EGFR TKIs that target WT-EGFR.

This agent is also investigated in association with INC280, a specific MET inhibitor (based on the potential escape pathway for third-generation EGFR TKIs) in an ongoing phase Ib/II study in patients with advanced EGFR mutant NSCLC (NCT02335944), and with nivolumab, an anti- PD-1 monoclonal antibody in a phase II study in EGFR mutant/ T790M+ NSCLC who have progressed on first-line EGFR TKI (NCT02323126). 

Primary resistance to EGFR TKIs


This is a complex event. While acquired resistance has been studied by checking further the tumour samples obtained at PD, it seems more difficult to recognise what factors are behind the primary resistance to TKIs [115]. 

Recently, the development of next generation sequencing (NGS) analyses has granted access to the whole genome and given further insight on the most common driver aberrations.

In fact, the concept of activating EGFR mutations mutually exclusive, has recently changed dramatically with the demonstration of their co-existence with other driver mutations in a high proportion of patient naïve for any treatment [116, 117]. 

A large French Biomarkers molecular database with 17664 lung cancer patients was used to assess the prevalence of multiple molecular alterations in treatment naïve patients, and their impact on prognosis as compared to those cases with one mutation or no mutation at all. Results evidence that almost 1% of cases harboured multiple aberrations (2-3 driver mutations) [118]. 

Authors concluded that a concurrent PIK3CA or KRAS mutations in cases with EGFR mutations, confer lower sensitivity to EGFR TKIs. However, the number of responses appears to be good enough as to continue to use these drugs as first or second line of treatment. The identification of the allelic fraction of each mutation would be relevant to quantify the relative importance of each of them and guide the first-line treatment.

It is generally accepted that after being treated with EGFR-TKIs, NSCLCs may develop resistance by selecting already resistant clones or the tumour changing to a different oncogenic pathway controlling proliferation and survival, even if the TKI-sensitive clones are destroyed.

This reflects once again the cancer heterogeneity and that EGFR mutated adenocarcinoma depends not only on EGFR but also on other concurrent drivers [119]. 

It has been suggested that primary and secondary TKI-resistance may share some genetic mechanisms or it may be that surviving malignant cells are able to quickly adjust to  the targeted treatment [120,121]. Whatever the mechanism is, these resistances are usually noticed within the first 3 months after starting TKIs.

Several genetic alterations conferring resistance can be detected within the same tumour or even in different metastatic deposits within the same patient which complicates this issue even further [119]. 

Drug tolerance could explain as well primary resistance [122]. 

It seems that small groups of malignant cells can escape selective drug activity by switching to a quiet mode with negligible rate of proliferation. In fact, this has been claimed as a mechanism behind the acquired resistance as can provide with a latent group of cancer cells which will eventually develop proper resistance events, leading to cancer progression.

Rare mutations in EGFR, such as the exon 20 insertion, accounts for 5-10% of all EGFR mutations in NSCLC adenocarcinoma and it has been reported in 4% of NSCLC. This is related to TKI resistance [123,124] as well.   

Vanita et al carried out a retrospective study of 580 NSCLC patients. 39.1% had EGFR TKI-sensitizing activating mutations and 3.4% had exon 20 insertion mutations [125].    

Authors concluded that patients with exon 20 insertion showed a poorer OS prognosis in comparison to EGFR- L858R mutation or an exon 19 deletion. The incidence of de novo exon 20 insertions was 3.4%. Different types of exon mutations seem to have different results.

Another way of showing resistance is the activation of other downstream pathways. Some of those mechanisms are involved as well in primary resistance to first-, second- and third-generation EGFR TKIs.

The hepatocyte growth factor (HGF)-cMET pathway, where amplification of cMET will give the ability of evading EGFR-TKI. This has been reported in 3% of TKI-naïve NSCLC patients and in 10%-20% of EGFR-TKI treated [126,127].    

This pathway is important for both the first- and third generation EGFR-TKIs [128-130].    .

KRAS mutations usually appear in codon 12 (G12C/D/S/V) and codon 13 (G13C) and [131]    

KRAS will generally become activated after stimulation of EGFR. This will turn KRAS permanently active regardless EGFR-stimulation and unlikely to respond to EGFR-TKIs [38]     

This is relevant again for first and third generation of EGFR-TKIs [132,133].

Upregulation of the receptor TK Axl or its ligand GAS6 is another mechanism [134].

Axl is involved in epithelial to mesenchymal transition (EMT) and its increased activation can bypass EGFR-inhibition [135].

The insulin growth factor receptor 1 (IGF-1R) induces EMT in NSCLC cells with EGFR exon 19 deletion [136].

The activation of the downstream pathway signalling of IGF-1R will produce EGFR TKI resistance and this is relevant for first [137,138], second [139] and third [140] generation.

However, double inhibition of EGFR and IGF-1R at the same time can overcome this resistance [141,142].

Furthermore, fibroblast growth factor (FGF) family is involved in intrinsic and acquired resistance against EGFR-TKIs. FGFR1 and 2 as well as ligands FGF2 and 9 are overexpressed in NSCLC [143,144].

The activation of FGFR entails more mesenchymal phenotype and activates MEK-ERK and PI3K signalling [145].

Through response to an EGFR inhibitor (erlotinib or gefitinib) [146], FGF ligands become active and this will produce EGFR-TKI resistance [147]. This mechanism has been involved in resistance to afatinib, but not for acquired resistance to osimertinib [148].

The PIK3CA signalling is involved in primary resistance to first- and second-line EGFR TKIs. Through either a mutation or a gain in copy number, will confer poor prognosis. Mutations are present in 1%-10% of EGFR-mutant NSCLC whereas increased copy number in about 40% of NSCLC [149,150].

A meta-analysis assessed the effects of concurrent presence of EGFR and PIK3CA mutations in NSCLC on treatment with TKIs first and second generation. Authors concluded that the concurrency might not preclude a response [151].

BRAF mutations are a rare primary resistance pathway in NSCLC (1.5%-3.5%) and

It consists of a V600E mutation in 50% of the cases [152].

Finding this mutation at the same time as EGFR mutations is very rare (< 1%) in NSCLC but

its activation can bypass EGFR inhibition [153]. It has been seen in patients during treatment with osimertinib [154].

Combinations with BRAF inhibitors could be contemplated in cases of EGFR TKI resistance due to BRAF activation although further studies are needed.

PTEN is a tumour suppressor whose loss of PTEN is present in 5% of EGFR mutant NSCLC and linked to primary resistance against EGFR-TKIs [155].

PTEN is a connector link between EGFR and Akt. When PTEN is lost, the connection is lost as well resulting in resistance to EGFR-TKIs [156].

Overexpression of PTEN in cell lines with low/no PTEN levels resulted in increased sensitivity to erlotinib or gefitinib [157].

Loss of PTEN is involved in primary and acquired resistance. For the latter, around 10% of patients without any other known resistance mechanisms are reported to have PTEN loss [155].

TP53 in NSCLC is mutated in 50% of patients and it has been reported as showing lower PFS in cases of concurrent TP53 exon 8 mutations and exon 19 deletions in EGFR [158].

However, two studies did not find any significant effect, thus the role of TP53 mutations in EGFRTKI resistance is not clear [159,160].

The yes-associated protein (YAP) is a part of the HIPPO-pathway, and seems involved in primary and acquired resistance to EGFR-TKI. The MEK1/2 inhibitor trametinib decreases YAP levels and HIPPO-signalling and in cell lines resistant against erlotinib, gefitinib or osimertinib, YAP is found activated [161,162].

Overexpression of YAP confers resistance to erlotinib [163].

YAP expression increases after EGFR-TKIs and when active, it increases Axl activation and a change to EMT-phenotype of the cells.

Blocking YAP and inhibiting Axl resensitize the cells to EGFR-TKIs [164].

Further mutations involved in resistance  

As is the case with first and second-generation EGFR TKIs, mutations mediating resistance to third-generation EGFR TKIs are emerging [165].

The recurrent acquisition of EGFR C797S mutation in exon 20 is considered the most frequent mechanism of resistance to osimertinib [166,167].

This mutation cancels the link of osimertinib to EGFR and it appears in between 22% to 40% of cases who have progressed on osimertinib [168-170].

It also confers resistance to other third generation TKIs, such as olmutinib [168-171], rociletinib [172] and nazartinib [173].

By-pass mechanisms affecting MET amplification or activation of the MAPK pathway may be involved as well in the development of resistance to third-generation EGFR TKIs [166].

This occurs in less than 3% of patients treated with rociletinib [174].

The C797S mutation was also reported in one case that led to resistance to olmutinib [174].

Recently, the acquired L798I mutation observed with T790M in one patient following rociletinib [174].

And another mutation in the same codon (L798Q) described in one patient at the time of progression under osimertinib [174].

The acquired resistance linked to EGFR T790M mutation may appear by either selection of pre-existing EGFR T790M+ clones or through genetic evolution of EGFR T790M− drug-tolerant cells. This suggests that malignant cells that survive third-generation TKIs may act as a reservoir from which acquired resistance can emerge while on therapy [174].

Additional EGFR-independent mechanisms of resistance have been reported such as NRAS mutations or KRAS that have been connected with secondary resistance to osimertinib,  gefitinib and afatinib [174].

Amplifications in HER2 and MET genes involved in acquired resistance to osimertinib and rociletinib in EGFR T790M+ NSCLC patients [174].

Loss of T790M at the time of progression which could be due to overgrowth of cells showing HER2 amplification, or BRAF V600E or PIK3CA mutations, as recently detected in plasma of patients included in the phase I AURA study [174].

Small-cell lung cancer transformation has been reported in two cases of rociletinib resistance and one osimertinib-resistant; in these cases, the T790M was lost while kept the original EGFR mutation in the small cell transformed cancer [174].

The future: EGFR TKIs under development


Further third generation TKIs are under development such as PF-06747775 whish is a potent irreversible inhibitor of the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790 M/L858R and T790 M/Del), with activity against EGFR T790M and barely effect in WTEGFR [175].

There is a phase I study, with 44 EGFR mutant NSCLC after progression on first line EGFR TKI. Results are still pending.

HS-10296 is another inhibitor under evaluation within the trial NCT02981108, which is under recruitment.

And a fourth generation EGFR TKIs are also under development.

Current EGFR TKIs target the ATP binding site, however, the C797S mutation blocks the attachment of these agents, conferring resistance.

Despite the initial good results with 3rd generation EGFR TKIs, acquired resistance invariably develops. Several mechanisms of resistance that are EGFR-dependent and EGFR-independent have been described. EGFR-dependent mechanisms include the development of EGFR C797S mutation whereas examples of EGFR-independent mechanisms include activation of pathways downstream of EGFR and parallel signalling pathways

Preclinical studies have demonstrated the acquired C797S mutation in cells resistant to 3rd generation TKIs and of interest was the finding that the allelic context in which C797S was acquired may predict responsiveness to subsequent TKI treatments [176].

EAI001 and EAI045 are new drugs that bind allosterically to EGFR away from the usual binding site, with specificity for mutant EGFR over WT-EGFR [176].

EAI001 has activity against L858R/T790 M mutant EGFR, but less active against individual L858R or T790 M mutant EGFR.

EAI045 is active in L858R or T790 M mutations, or both [176].

In cell lines with L858R/T790 M/C797S mutations, EAI045 has reported effect in controlling cell growth when combined with cetuximab, not as a monotherapy.

Further novel EGFR TKIs are under development as well. These agents showed activity cells expressing the triple mutation (T790 M/C797S/L858R) and had more than 300-fold selectivity for double EGFR mutant (T790 M/L858R) over WT-EGFR. Further studies are required to assess clinical efficacy and safety of these new agents.

 

First generation EGFR TKIs after acquired resistance to third generation TKIs


Niederst et al. reported that cell lines with C797S and EGFR activating mutations (C797S/del19) without the T790 M mutation were resistant to third-generation TKIs but kept sensitivity to first generation [177].

This implies that those cases who received a third generation TKIs in first line and develop secondary resistance by C797S but still undetectable for T790 M may respond to first-generation TKIs.

First and third generation EGFR TKI combinations 

The T790M and C797S mutations of EGFR cause resistance to first- and third-generation EGFR TKIs respectively in NSCLC harbouring EGFR activating mutations.

C797S has been identified in cis or in trans with T790M in tumour specimens from patients who showed PD with first- and third-generation EGFR-TKIs.

When the mutations occur in trans (i.e. on separate alleles), cells become resistant to third generation EGFR TKIs but sensitive to a combination of first and third generation EGFR TKIs. However, when the mutations are in cis, no EGFR TKIs alone or in combination are effective [178].

In a patient who developed the triple mutation (T790 M/C797S/del19) in trans after PD on osimertinib, the combination of erlotinib and osimertinib achieved partial response. After showing PD again, C797S in cis to T790 M appeared and the patient did not further respond with EGFR TKIs, requiring chemotherapy for disease control [179].

Overcoming resistance to third generation TKIs with new agents 

The favourable toxicity profiles of the third-generation EGFR TKIs make them particularly attractive for combination, and many trials are currently ongoing.

Navitoclax is a BCL-2 inhibitor which increased the apoptotic response of late-resistant EGFR T790M cells with reduced sensitivity to EGFR blockage. When combined with a third-generation EGFR TKI WZ4002 (in preclinical development) induced more apoptosis compared to WZ4002 alone in vivo and in vitro analyses [180].

This could be a promising strategy for EGFR T790M-positive cancers that have a minimal apoptotic response to EGFR inhibition [180].

When combined to trametinib, another MEK inhibitor, it prevents the appearance of acquired resistance in EGFR-mutant lung cancer models. A phase Ib trial is ongoing to assess the tolerability of the osimertinib/navitoclax in patients with EGFR-mutant NSCLC following resistance to prior EGFR TKIs (NCT02520778).

Conclusion


The identification of EGFR activating mutations in NSCLC and the development of targeted treatment has revolutionised the therapeutic landscape of NSCLC.

Different generations of EGFR-TKIs have been implemented in clinical practice as a step forward to personalised medicine.

However, despite the initial success, hopes were limited by the emergence of resistance.

The identification of the mechanisms behind this resistance will eventually lead us to the development of newer active drugs able to block multiple pathways at the same time to overcome this resistance.

The FLAURA trial has established osimertinib (third generation TKI) as an effective treatment for advanced EGFR mutant NSCLC in the first-line setting.

But further research is mandatory to develop newer generations of EGFR-TKIs and to understand the optimal therapeutic approach to achieve the goal of extending the natural history of the cancer with the lowest rate of side effects as possible.

Patient selection has already improved, which is crucial to decide what would be the best strategy to get durable OS and quality of life.

Several EGFR-TKIs are now available in clinical practice, but the best sequence for administration of these drugs to optimise the blockage of the EGFR signalling has not been determined.

Comprehensive characterization of resistance mechanisms for each EGFR-TKI will serve to a better understanding of how to develop more effective strategies.

References


  1. IARC. Cancer Incidence, Mortality and Prevalence Worldwide GLOBOCAN 2012. http://gco.iarc.fr/.
  2. Jemal A, Bray F, Center MM et al. Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.
  3. Couraud S, Zalcman G, Milleron B, et al. Lung cancer in never smokers--a review. Eur J Cancer 2012;48:1299-311)
  4. Jackman DM, Zhang Y, Dalby C, et al. Cost and Survival Analysis Before and After Implementation of Dana-Farber Clinical Pathways for Patients With Stage IV Non-Small-Cell Lung Cancer. J Oncol Pract. 2017;13:e346–e352.
  5. Putora PM, Ess S, Panje C, et al Prognostic significance of histology after resection of brain metastases and whole brain radiotherapy in non-small cell lung cancer (NSCLC). Clin Exp Metastasis. 2015;32:143–149.
  6. Rasco DW, Yan J, Xie Y, et al. Looking beyond surveillance, epidemiology, and end results: patterns of chemotherapy administration for advanced non-small cell lung cancer in a contemporary, diverse population. J Thorac Oncol. 2010;5:1529–1535.
  7. Kelly K, Crowley J, Bunn PA Jr, et al. randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001;19:3210-8.
  8. Scagliotti GV, De Marinis F, Rinaldi M, et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 2002;20:4285-91.
  9. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-smallcell lung cancer. N Engl J Med 2002;346:92-8.
  10. Fossella F, Pereira JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21:3016-24.
  11. Sandler AGray RPerry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50.
  12. Masters GA, Temin S, Azzoli CG, et al. Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2015;33:3488-515.
  13. Gridelli C, Ardizzoni A, Le Chevalier T, et al. Treatment of advanced non-small-cell lung cancer patients with ECOG performance status 2: results of an European Experts Panel. Ann Oncol 2004;15:419-26.
  14. Tomasini P, Barlesi F, Mascaux C, Greillier L. Pemetrexed for advanced stage nonsquamous non-small cell lung cancer: latest evidence about its extended use and outcomes. Ther Adv Med Oncol 2016, Vol. 8(3) 198–208
  15. Sacha T. Imatinib in chronic myeloid leukemia: an overview. Mediterr J Hematol Infect Dis. 2014;6(1):e2014007. Published 2014 Jan 2.
  16. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-1037
  17. Lindeman NI, Cagle PT, Beasley MB et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 2013; 8: 823–859.
  18. Kerr KM, Bubendorf L, Edelman MJ et al. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol 2014; 25: 1681–1690.
  19.  Lindeman N, Cagle P, Aisner D et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med 2018; 142: 321–346.
  20. Maemondo, M.; Inoue, A.; Kobayashi, K.; et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 2010, 362, 2380–2388. [CrossRef] [PubMed]
  21. Mitsudomi, T.; Morita, S.; Yatabe, Y.; et al  Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol. 2010, 11, 121–128. [CrossRef]
  22. Zhou, C.; Wu, Y.L.; Chen, G.; et al Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011, 12, 735–742.
  23. Rosell, R.; Carcereny, E.; Gervais, R.; et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012, 13, 239–246.
  24. Sequist, L.V.; Yang, J.C.; Yamamoto, N.; et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 2013, 31, 3327–3334.
  25. Wu, Y.L.; Zhou, C.; Hu, C.P.; et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial. Lancet Oncol. 2014, 15, 213–222.
  26. Inamura K, Ninomiya H, Ishikawa Y, et al. Is the epidermal growth factor receptor status in lung cancers reflected in clinicopathologic features? Arch PatholLab Med 2010;134:66-72.
  27. Gupta R, Dastane AM, Forozan F, et al. Evaluation of EGFR abnormalities in patients with pulmonary adenocarcinoma:the need to test neoplasms with more than one method. Mod Pathol 2009;22:128-33.
  28. Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 2006;118:257-62.
  29. Suzuki M, Shigematsu H, Hiroshima K, et al.Epidermal growth factor receptor expression status in lung cancer correlates with its mutation. Hum Pathol 2005;36:1127-34.
  30. Johnson JL, Pillai S, Chellappan SP. Genetic and biochemical alterations in non-small cell lung cancer. Biochem Res Int 2012;2012:940405. 
  31. Jackman DM, Miller VA, Cioffredi LA, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: Results of an online tumor registry of clinical trials. Clin Cancer Res 2009;15:5267-73.
  32. 32.       Lin L, Bivona TG. Mechanisms of resistance to epidermal growth factor receptor inhibitors and novel therapeutic strategies to overcome resistance in NSCLC patients. Chemother Res Pract 2012;2012:817297
  33. Wang, J.; Wang, B.; Chu, H.; Yao, Y. Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations. Onco. Targets Ther. 2016, 9, 3711–3726.
  34. Bartholomew C, Eastlake L, Dunn P, et al. EGFR targeted therapy in lung cancer; an evolving story. Respir Med Case Rep 2017;20:137-40.
  35. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med (2009) 361:947–57. doi:10.1056/NEJMoa0810699 7.
  36. Han J-Y, Park K, Kim S-W, et al. First-SIGNAL: first- line single-agent iressa versus gemcitabine and cisplatin trial in never-smokerswith adenocarcinoma of the lung. J Clin Oncol (2012) 30:1122–8. doi:10.1200/ JCO.2011.36.8456 8.
  37. Inoue A, Kobayashi K, Maemondo M, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung can-cer with sensitive EGFR gene mutations (NEJ002). Ann Oncol (2013) 24:54–9. doi:10.1093/annonc/mds214 9.
  38. Pao W, Wang TY, Riely GJ, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2: e17, 2005.
  39. Jiang J, Greulich H, Janne PA, et al. Epidermal growth factor-independent transformation of Ba/F3 cells with cancer-derived epidermal growth factor receptor mutants induces gefitinib-sensitive cell cycle progression. Cancer Res 65: 8968-8974, 2005.
  40. Metro G, Chiari R, Duranti S, et al: Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype. Lung Cancer 78: 81-86, 2012.
  41. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA2003;290:2149-2158
  42. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003;21:2237-2246
  43. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial -- INTACT 1. J Clin Oncol 2004;22:777-784
  44. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial -- INTACT 2. J Clin Oncol 2004;22:785-794
  45. Kazandjian D, Blumenthal GM, Yuan W, et al. FDA Approval of Gefitinib for the Treatment of Patients with Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer. Clin Cancer Res 2016;22:1307-12.
  46. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527-37.
  47. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008;372:1809-18.
  48. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol 2004;22:777-84.
  49. Sordella R, Bell DW, Haber DA, et al. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 2004;305:1163-7.
  50. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-39.
  51. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500.
  52. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 2005;353:133-44.
  53. Inoue A, Kobayashi K, Maemondo M, et al. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013;24:54-9.
  54. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015; 16:990–8. https://doi.org/10.1016/S1470- 2045(15)00121-7.
  55. Ganjoo KN, Wakelee H. Review of erlotinib in the treatment of advanced non-small cell lung cancer. Biologics. 2007;1(4):335–346.
  56. Cappuzzo FCiuleanu TStelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010 Jun;11(6):521-9.
  57. Wu YL, Zhou C, Liam CK, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 2015;26:1883-9.
  58. Herbst RSPrager DHermann R, et al. TRIBUTE Investigator Group. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005 Sep 1;23(25):5892-9. Epub 2005 Jul 25.
  59. Gatzemeier UPluzanska ASzczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 2007 Apr 20;25(12):1545-52.
  60. Lee SMKhan IUpadhyay S, et al. First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2012 Nov;13(11):1161-70.
  61. Garassino MCMartelli OBroggini M, et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013 Sep;14(10):981-8. doi: 10.1016/S1470-2045(13)70310-3. Epub 2013 Jul 22.
  62. Kawaguchi TAndo MAsami K, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014 Jun 20;32(18):1902-8.
  63. Urata YKatakami NMorita S, et al. Randomized Phase III Study Comparing Gefitinib With Erlotinib in Patients With Previously Treated Advanced Lung Adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016 Sep 20;34(27):3248-57.
  64. Watanabe M, Kawaguchi T, Isa S, et al. Ultra-sensitive detection of the pretreatment EGFR T790M mutation in non-small cell lung cancer patients with an EGFR activating mutation using droplet digital PCR. Clin Cancer Res. 2015;21:3552–60.
  65. Hata A, Katakami N, Yoshioka H, et al. Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: comparison between T790M mutation-positive and mutation-negative populations. Cancer. 2013;119:4325–32.
  66. Denis MG, Vallee A, Theoleyre S. EGFR T790M resistance mutation in non small-cell lung carcinoma. Clin Chim Acta. 2015;444:81–5.
  67. Kuiper JL, Heideman DA, Thunnissen E, et al. Incidence of T790M mutation in (sequential) rebiopsies in EGFRmutated NSCLC-patients. Lung Cancer. 2014;85:19–24.
  68. Morgillo F, Della Corte CM, Fasano M, Ciardiello F. Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO Open. 2016; 1:e000060. https://doi. org/10.1136/esmoopen-2016-000060.
  69. Galvani E, Sun J, Leon LG, et al. NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor. Oncotarget2015;6:42717-32.
  70. Voortman J, Checi?ska A, Giaccone G. The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells. Mol Cancer 2007;6:73.
  71. Voortman J, Pham TV, Knol JC, et al. Prediction of outcome of non-small cell lung cancer patients treated with chemotherapy and bortezomib by time-course MALDI-TOF-MS serum peptide profiling. Proteome Sci 2009;7:34.
  72. Ceresa C, Giovannetti E, Voortman J, et al. Bortezomib induces schedule-dependent modulation of gemcitabine pharmacokinetics and pharmacodynamics in non-small cell lung cancer and blood mononuclear cells. Mol Cancer Ther 2009;8:1026-36.
  73. Takeda M, Nakagawa K. First and second generation EGFR-TKIs are all replaced to osimertinib in chemo naïve EGFR mutation positive NSCLC? Int J Mol Sci 2019;20:146.
  74. Deeks E, Keating G. Afatinib in advanced NSCLC: a profile of its use. Drugs Ther Perspect (2018) 34:89–98.
  75. Park K, Tan E-H, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive nonsmall-cell lung cancer (LUX-Lung 7): a phase 2B, open-label,randomised controlled trial. Lancet Oncol. 2016;17(5):577–89.
  76. Yang JC-H, Wu Y-L, Schuler M, et al. Afatinib versus cisplatin based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015;16(2):141–51.
  77. Kato T, Yoshioka H, Okamoto I, et al. Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non-small cell lung cancer harboring activating EGFR mutations: subgroupanalysis of LUX-Lung 3. Cancer Sci. 2015;106(9):1202–11.
  78. Soria J-C, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16(8):897–907.
  79. Sequist LV, Besse B, Lynch TJ, et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J Clin Oncol (2010) 28:3076–83.
  80. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol (2012) 13:528–38.
  81. Reckamp KL, Giaccone G, Camidge DR, et al. A phase 2 trial of dacomitinib (PF-00299804), an oral, irrevers-ible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib. Cancer (2014) 120:1145–54. doi:10.1002/ cncr.28561
  82. Schuler MYang JCPark K, et al. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial. Ann Oncol. 2016 Mar;27(3):417-23. doi: 10.1093/annonc/mdv597. Epub 2015 Dec 8.
  83. Engelman, J.A.; Zejnullahu, K.; Gale, C.M.; et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 2007, 67, 11924–11932.
  84. Janne, P.A.; Ou, S.H.; Kim, D.W.; et al. Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: A multicentre, open-label, phase 2 trial. Lancet Oncol. 2014, 15, 1433–1441.
  85. Wu, Y.L.; Cheng, Y.; Zhou, X.; et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): A randomised, open-label, phase 3 trial. Lancet Oncol. 2017, 18, 1454–1466.
  86. Ramalingam SS, Blackhall F, Krzakowski M, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2012;30:3337–3344.
  87. Ramalingam SS, Jänne PA, Mok TS, et al. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:1369–1378.
  88. Lavacchi D, Mazzoni F, Giaccone G. Clinical evaluation of dacomitinib for the treatment of metastatic non-small cell lung cancer (NSCLC): current perspectives. Drug Design, Development and Therapy 2019:13)
  89. Lacouture MEKeefe DMSonis S, et al. A phase II study (ARCHER 1042) to evaluate prophylactic treatment of dacomitinib-induced dermatologic and gastrointestinal adverse events in advanced non-small-cell lung cancer.Ann Oncol. 2016 Sep;27(9):1712-8. doi: 10.1093/annonc/mdw227. Epub 2016 Jun 10.
  90. Lau SCMBatra UMok TSKLoong HH. Dacomitinib in the Management of Advanced Non-Small-Cell Lung Cancer. Drugs. 2019 Jun;79(8):823-831. doi: 10.1007/s40265-019-01115-y.
  91. Uchibori K, Inase N, Araki M et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat Commun 2017; 8: 14768.
  92. Regales L, Gong Y, Shen R, et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest (2009) 119:3000–10. doi:10.1172/JCI38746
  93. Janjigian YY, Smit EF, Groen HJM, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor- resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov (2014) 4:1036–45. doi:10.1158/2159-8290.CD-14-0326
  94. Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790Mmutation in advanced non-small cell lung cancer. J Hematol Oncol. 2016;9:34.
  95. Cross DA, Ashton SE, Ghiorghiu S, et al: AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 4:1046-1061, 2014.
  96. Goss G, Tsai C-M, Shepherd F.A, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced NSCLC (AURA2): a multicentre, open-label, single arm, phase 2 study. The Lancet Oncology 2016;17:1643-52.
  97. Myung?Ju Ahn,  Chun?Ming Tsai, Frances A. Shepherd et al.  Osimertinib in patients with T790M mutation?positive, advanced non–small cell lung cancer: Long?term follow?up from a pooled analysis of 2 phase 2 studies.  CAncer Volume125, Issue6March 15, 2019Pages 892-901
  98. Soria J-C, Ohe Y, Vansteenkste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. N Engl J Med 2018; 378:113-125.
  99. Mok T, Wu Y-L, Ahn M-J, et al. Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer. N Engl J Med 2017; 376:629-640.
  100. Jonathan Wade Goldman, Jean-Charles Soria, Heather A. Wakelee, et al. Updated results from TIGER-X, a phase I/II open label study of rociletinib in patients (pts) with advanced, recurrent T790M-positive non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2016 34:15_suppl, 9045-9045
  101. Sequist et al. Rociletinib in EGFR-mutated non–small-cell lung cancer. N Engl J Med 2015;372:1700-1709
  102. Sequist LV, Soria J-C, Camidge DR. Update to rociletinib data with the RECIST confirmed response rate. N Engl J Med (2016) 374:2296–7. doi:10.1056/ NEJMc1602688
  103. Lee K-O, Cha M, Kim M, et al. Discovery of HM61713 as an orally available and mutant EGFR selective inhibitor. Clin Cancer Res (2014) 74(Suppl 19):LB–100. doi:10.1158/1538-7445.AM2014-LB-100 43.
  104. Park K, Lee J-S, Lee KH, et al. Updated safety and efficacy results from phase I/II study of HM61713 in patients (pts) with EGFR mutation positive non-small cell lung cancer (NSCLC) who failed previous EGFR-tyrosine kinase inhibitor (TKI). J Clin Oncol (2015) 33:abstract 8084.
  105. Park K, Lee J-S, Lee KH, et al. BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M+ NSCLC: efficacy and safety at the RP2D. J Clin Oncol. 2016;34:9055.
  106. Goto Y, Nokihara H, Murakami H, et al. ASP8273, a mutant-selective irreversible EGFR inhibitor in patients (pts) with NSCLC harboring EGFR activating mutations: Preliminary results of first-in-human phase I study in Japan. J of Clin Oncol. 2015;33(15_suppl):8014–4.
  107. Konagai S, Sakagami H, Yamamoto H, et al. Abstract 2586: ASP8273 selectively inhibits mutant EGFR signal pathway and induces tumor shrinkage in EGFR mutated tumor models. Cancer Res. 2015;75(15 Supplement):2586
  108. Yu HA, Spira AI, Horn L, et al. Antitumor activity of ASP8273 300 mg in subjects with EGFR mutation-positive non-small cell lung cancer: Interim results from an ongoing phase 1 study. 2016;J of Clinical Oncol, 34(15_suppl):9050–0.
  109. Astellas Announces Decision to Discontinue ASP8273 Treatment Arm and Close Randomization for Clinical Study Protocol 8273-CL-0302 [http://newsroom.astellas.us/2017-05-10-Astellas-Announces-Decision-to-Discontinue-ASP8273-Treatment -and-Close-Randomization-for-Clinical-Study-Protocol-8273-CL-0302].
  110. Xu X, Mao L, Xu W, et al. AC0010, an irreversible EGFR inhibitor selectively targeting mutated EGFRand overcoming T790M-induced resistance in animal models and lung cancer patients. Mol Cancer Ther. 2016;15(11):2586–97
  111. Long Wu Y, Zhou Q, Liu X, et al: MA16.06 Phase I/II Study of AC0010, Mutant-Selective EGFR Inhibitor, in Non-Small Cell Lung Cancer (NSCLC) Patients with EGFR T790M Mutation, vol. 12; 2017.
  112. Wang H, Zhang L, Zheng X, et al. The ability of avitinib to penetrate the blood brain barrier and its control of intra−/extra- cranial disease in patients of non-small cell lung cancer (NSCLC) harboring EGFR T790M mutation. J of Clin Oncol. 2017;35(15_suppl):e20613–3.
  113. Lelais G, Epple R, Marsilje TH, et al. Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methyl isonicotinamide (EGF816), a novel, potent, and WT sparing covalent inhibitor of oncogenic (L858R, ex19del) and resistant (T790M) EGFR mutants for the treatment of EGFR mutant non-small-cell lung cancers. J Med Chem. 2016;59(14):6671–89.
  114. Tan DSW, Yang JCH, Leighl NB: Updated results of a phase 1 study of EGF816, a third-generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC) harboring T790M. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2016(3415(Suppl):abstr9044).
  115. Chevrier, S., Arnould, L., Ghiringhelli, F., et al. Next-generation sequencing analysis of lung and colon carcinomas reveals a variety of genetic alterations. Int J Oncol. 2014; 45: 1167–1174
  116. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014, 511, 543–550. Erratum in Nature 2014, 514, 262.
  117. Jordan, E.J.; Kim, H.R.; Arcila, M.E.; et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for e_cient patient matching to approved and emerging therapies. Cancer Discov. 2017, 7, 596–609.
  118. Guibert, N.; Barlesi, F.; Descourt, R.; et al. Characteristics and outcomes of patients with lung cancer harboring multiple molecular alterations: Results from the IFCT study biomarkers France. J. Thorac. Oncol. 2017, 12, 963–973.
  119. Blakely, C.M.; Watkins, T.B.K.; Wu, W.; et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 2017, 49, 1693–1704.
  120. Morgillo, F.; Della Corte, C.M.; Fasano, M.; Ciardiello, F. Mechanisms of resistance to EGFR-targeted drugs:Lung cancer. ESMO Open 2016, 1, e000060.
  121. Kleczko, E.K.; Heasley, L.E. Mechanisms of rapid cancer cell reprogramming initiated by targeted receptor tyrosine kinase inhibitors and inherent therapeutic vulnerabilities. Mol. Cancer 2018, 17, 60.
  122. Ramirez, M.; Rajaram, S.; Steininger, R.J.; et al. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat. Commun. 2016, 7, 10690.
  123. Robichaux JP, Elamin YY, Tan Z, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med 2018;24:638-46.
  124. Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol. 2012;13(1):e23–e31.
  125. Vanita N, Anuradha C, Vijay M. P, et al. Epidermal growth factor receptor exon 20 mutation in lung cancer: types, incidence, clinical features and impact on treatment. Oncotargets 2017;10:2903-8.
  126. Cappuzzo F, Jänne PA, Skokan M, et al. MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Ann Oncol 2009;20:298-304.
  127. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 2007;104:20932-7.
  128. Shi P, Oh YT, Zhang G, et al. Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment. Cancer Lett 2016;380:494-504.
  129. Ou SI, Agarwal N, Ali SM. High MET amplification level as a resistance mechanism to osimertinib (AZD9291) in a patient that symptomatically responded to crizotinib treatment post-osimertinib progression. Lung Cancer 2016;98:59-61.
  130. Minari R, Bordi P, La Monica S, et al. Concurrent acquired BRAF V600E mutation and MET amplification as resistance mechanism of first-line osimertinib treatment in a patient with EGFR-mutated NSCLC. J Thorac Oncol 2018;13:e89-91.
  131. Roberts PJ, Stinchcombe TE. KRAS mutation: should we test for it, and does it matter. J Clin Oncol 2013;31:1112-21.
  132. Linardou H, Dahabreh IJ, Kanaloupiti D, et al. Assessment of somatic KRAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 2008;9:962-72.
  133. Eberlein CA, Stetson D, Markovets AA, et al. Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res 2015;75:2489-500.
  134. Zhang Z, Lee JC, Lin L, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. NatGenet 2012;44:852-60.
  135. Tian Y, Zhang Z, Miao L, et al.  Anexelekto (AXL) increases resistance to EGFR-TKI and activation of AKT and ERK1/2 in non-small cell lung cancer cells. Oncol Res 2016;24:295-303.
  136. Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, et al. IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations. Sci Rep 2013;3:2560.
  137. Morgillo F, Woo JK, Kim ES, et al. Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib. Cancer Res 2006;66:10100-11.
  138. Morgillo F, Kim WY, Kim ES, et al. Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res 2007;13:2795-803.
  139. Lee Y, Wang Y, James M, et al. Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells. Mol Carcinog 2016;55:991-1001.
  140. Park JH, Choi YJ, Kim SY, et al. Activation of the IGF1R pathway potentially mediates acquired resistance to mutant-selective 3rd-generation EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer. Oncotarget 2016;7:22005-15.
  141. Choi YJ, Rho JK, Jeon BS, et al. Combined inhibition of IGFR enhances the effectsof gefitinib in H1650: a lung cancer cell line with EGFR mutation and primary resistance to EGFR-TK inhibitors. Cancer ChemotherPharmacol 2010;66:381-8.
  142. Hurbin A, Wislez M, Busser B, et al. Insulin-like growth factor-1 receptor inhibition overcomes gefitinib resistance in mucinous lung adenocarcinoma. J Pathol2011;225:8395.
  143. Kono SA, Marshall ME, Ware KE, Heasley LE. The fibroblast growth factor receptor signaling pathway as a mediator of intrinsicresistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer. Drug Resist Updat 2009;12:95-102.
  144. Marek L, Ware KE, Fritzsche A, et al. Fibroblast growth factor ( FGF ) and FGF receptor-mediated autocrine signaling in non – small-cell lung cancer cells. Mol Pharmacol 2009;75:196-207.
  145. Thomson S, Petti F, Sujka-Kwok I, et al. Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy. Clin Exp Metastasis 2008;25:843-54.
  146. Ware KE, Marshall ME, Heasley LR, et al. Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS One2010;5:e14117.
  147. Terai H, Soejima K, Yasuda H, et al. Activation of the FGF2-FGFR1 autocrine pathway: a novel mechanism of acquired resistance to gefitinib in NSCLC. MolCancer Res 2013;11:759-67.
  148. Azuma K, Kawahara A, Sonoda K, et al. FGFR1activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor. Oncotarget2014;5:5908-19.
  149. Ludovini V, Bianconi F, Pistola L, et al. Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors ofresistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. J Thorac Oncol 2011;6:707-15.
  150. VanderLaan PA, Rangachari D, Mockus SM, et al. Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: correlation with clinical outcomes. Lung Cancer 2017;106:17-21.
  151. Martín Martorell P, Huerta M, Compañ Quilis A, et al. Coexistence of EGFR, KRAS, BRAF, and PIK3CA mutations and ALK rearrangement in a comprehensive cohort of 326 consecutive Spanish nonsquamous NSCLC patients. Clin Lung Cancer 2017;18:e395-402.
  152. Leonetti A, Facchinetti F, Rossi G, et al. BRAF in non-small cell lung cancer (NSCLC):pickaxing another brick in the wall. Cancer Treat Rev 2018;66:82-94.
  153. Marchetti A, Felicioni L, Malatesta S, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 2011;29:3574-9.
  154. Ho CC, Liao WY, Lin CA, et al. Acquired BRAF V600E mutation as resistant mechanism after treatment with osimertinib. J Thorac Oncol 2017;12:567-72.
  155. Yamamoto C, Basaki Y, Kawahara A, et al. Loss of PTEN expression by blocking nuclear translocation of EGR1 in gefitinib-resistant lung cancer cells harboring epidermal growth factor receptor-activating mutations. Cancer Res 2010;70:8715-25.
  156. Sos ML, Koker M, Weir BA, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 2009;69:3256-61.
  157. Sos ML, Koker M, Weir BA, et al. PTEN losscontributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 2009;69:3256-61.
  158. Canale M, Petracci E, Delmonte A, et al. Impact of TP53 mutations on outcome in EGFR -mutated patients treated with first-line tyrosine kinase inhibitors. Clin Cancer Res 2017;23:2195-202.
  159. Labbé C, Cabanero M, Korpanty GJ, et al. Prognostic and predictive effects of TP53 co-mutation in patients withEGFR-mutated non-small cell lung cancer (NSCLC). Lung Cancer 2017;111:23-9.
  160. Shepherd FA, Lacas B, Le Teuff G, et al. LACE-Bio Collaborative Group. Pooled analysis of the prognostic and predictive effects of TP53 comutation status combined with KRAS or EGFR mutation in early-stage resected non–small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol 2017;35:2018-27.
  161. You B, Yang YL, Xu Z, et al. Inhibition of ERK1/2 down-regulates the hippo/YAP signaling pathway in human NSCLC cells. Oncotarget 2015;6:4357-68.
  162. McGowan M, Kleinberg L, Halvorsen AR, et al. NSCLC depend upon YAP expression and nuclear localization after acquiring resistance to EGFR inhibitors. Genes Cancer 2017;8:497-504.
  163. Hsu PC, You B, Yang YL, et al. YAP promotes erlotinib resistance in human non-small cell lung cancer cells. Oncotarget 2016;7:51922-33.
  164. Ghiso E, Migliore C, Ciciriello V, et al. YAP-dependent AXLoverexpression mediates resistance to EGFR inhibitors in NSCLC. Neoplasia 2017;19:1012
  165. Ercan D, Choi HG, Yun CH, et al. EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clinical cancer research: an official journal of the American Association for Cancer Research. 2015;21(17):3913–23
  166. Ortiz-Cuaran, S. et al. Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors. Clin. Cancer Res. 22,4837–4847 (2016).
  167. Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560–562 (2015).
  168. Ercan D, Choi HG, Yun CH, Capelletti M, et al. EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clinical cancer research: an official journal of the American Association for Cancer Research. 2015;21(17):3913–3923. doi: 10.1158/1078-0432.CCR-14-2789.
  169. Oxnard GR, Thress K, Paweletz C, et al. ORAL17.07 Mechanisms of Acquired Resistance to AZD9291 in EGFR T790M Positive Lung Cancer. J of Thoracic Oncol 2015(10(9 Suppl.2); ORAL 17.07).
  170. Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21(6):560–562. doi: 10.1038/nm.3854.  
  171. Song HN, Jung KS, Yoo KH, et al. Acquired C797S mutation upon treatment with a T790Mspecificthird-generation EGFR inhibitor (HM61713) in non-small cell lung cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 2016;11(4):e45–7.
  172. Chabon JJ, Simmons AD, Lovejoy AF, et al. Circulating tumour DNAprofiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun. 2016;7:11815.
  173. Tan DS-W, Kim D-W, Leighl NB, et al. Genomic profiling of resistant tumor samples following progression on EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC). J of Clin Oncol. 2017;35(15_suppl):11506–6.
  174. Fassunke J et al Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors. Nature communication 2018; 9:4655
  175. Planken S, Behenna DC, Nair SK, et al. Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolid ine-3-yl)acrylamide (PF-06747775)through structure-based drug design: a high affinity irreversible inhibitor targeting oncogenic EGFR mutants with
  176. Niederst MJ, Hu H, Mulvey HE, et al. The allelic context of the C797S mutationacquired upon treatment with third-generation EGFR inhibitors impactssensitivity to subsequent treatment strategies. Clinical cancer research: anofficial journal of the American Association for Cancer Research. 2015;21(17):3924–33.
  177. Niederst MJ, Hu H, Mulvey HE, et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treat-ment strategies. Clin Cancer Res (2015) 21:3924–33. doi:10.1158/1078-0432. CCR-15-0560
  178. Ballard P, Yates JWT, Yang Z, et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR- mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res (2016) 22:5130–40. doi:10.1158/1078- 0432.CCR-16-0399
  179. Stahel R, Dafni U, Gautschi O, et al. A phase II trial of erlotinib (E) and bevacizumab (B) in patients with advanced non-small-cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations with and without T790M muta-tion. The Spanish Lung Cancer Group (SLCG) and the European Thoracic Oncology Platform (ETOP) BELIEF trial. Eur J Cancer (2015) 51(Suppl 3): S711–12. doi:10.1016/S0959-8049(15)30068-X
  180. Hata AN, Niederst MJ, Archibald HL, et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med (2016) 22:262–9. doi:10.1038/nm.4040 69.

Acknowledgements


To Drs TRG and EEG for their support 

Tables


Table 1 Selected trials of gefitinib in NSCLC

 

Trial

Phase

N

Eligibility criteria

Primary end-points

Conclusion

IDEAL 1

II

210

Gef 250mg/day

vs

Gef 500mg/day

After ≥ 1 chemo  lines, including at least one platinum

RR

safety

18.4% vs 19% NS

>50% DCR both mPFS2.7 vs 2.8m NS

mOS 7.6vs7.9m NS

IDEAL 2

II

250 (2/3 adc)

 

Gef 250mg/day

vs

Gef 500mg/day

PD after two previous chemo lines, including docetaxel and cis or carbo

RR

Reduction in symptoms

12% vs 9%

mOS 6.5vs5.9m

INTACT 1

III

1093

Gef two doses/Gem/Cis

Plac/Gem/Cis

 

First line

OS

No differences in efficacy

INTACT 2

III

1037

Gef/paclit/carbo

Plac/paclit/carbo

First line

OS

No added benefit

INTEREST

III

1433

 

Second line vs Docetaxel

 

non-inferior survival

ISEL

III

1692

 

Second or third line vs placebo

OS whole population

OS in adc

OS favoured Asian and non-smokers

IBREESE

III

Gef vs BSC

Second or third line vs placebo

 

Closed due to feasibility issues

IPASS

III

Retrospective analysis of EGFR pos

1217

Gef vs paclit/carbo

First-line

Asian, non-smokers adc

Retrospective analysis in EGFR mut

OS

RR and PFS benefit over platinum-doublet

NEJ002

III

Gef vs paclit/carbo

First line

EGFR mut

PFS

Better RR and PFS for Gef

WJTOG3405

III

172

Gef vs doce/cis

First line

EGFR mut (either the exon 19 deletion or L858R point mutation)

 

PFS

9.2 vs 6.3m favouring Gef

IMPRESS

III

265

Continuation of Gef/chemo vs

Plac/chemo

EGFR mut with PD after first line Gef

PFS

Gef does not prolong PFS after PD

IFUM

IV

106

First line in caucasian

EGFR mut

RR

70%

 

 

 

Table 2 Selected trials with erlotinib

Trial

Phase

N

Eligibility criteria

Primary end-point

Conclusion

EURTAC

III

174

First line, EGFR mut, european

Erlo vs Cis/doce or Gem

PFS

9.9 vs 5.2

OPTIMAL

III

165

First line, EGFR mut

Erlo vs gem/carbo

PFS

13.1 (erlo) vs 4.6m

ENSURE

III

217

First line, EGFR mut

Erlo vs gem/cis

PFS

11 vs 5.5m

OS NS (26.3 vs 25.5m)

TRIBUTE

III

1059

First line

Erlo/pacli/carbo

Plac/pacli/carbo

OS

Never smokers

OS 22.5 vs 10.1

Overall – OS 10.6 vs 10.5m

Tarceva lung cancer investigation trial

III

1172

First line

Erlo/gem/cis

Plac/gem/cis

OS

43 vs 44.1weeks NS

Never smokers – OS better in erlo

TAILOR

III

222

WT EGFR

Second line

Erlo vs Docetaxel

OS

5.4 vs 8.2m (docetaxel)

Delta

III

301

Second line

EGFR unselected

Erlo vs Docetaxel

PFS

2 vs 3.2m (docetaxel)

In EGFR WT:

1.3 vs 2.9m (docetaxel)

WJOG 5108

III

561

Previously treated unselected

Gef vs erlo

PFS

6.5 vs 7.5m NS

In EGFR pos:

8.3 vs 10m NS

TOPICAL

III

670

Unsuitable for chemo

First line

Unselected

Erlo vs plac

OS

3.7 vs 3.6 (plac) NS

If first-cycle rash - better OS 

 

Table 3 Selected trials with afatinib

Trial

Phase

Line of treatment

 

PFS

OS

LUX-Lung 3

III

First line

Afa vs cis/peme

11.1 vs 6.9

All: 28.2 vs 28.2m

Exon 19 del: 33.3 vs 21.1m

Leu858arg mut : 27.6 vs 40.3m

LUX-Lung 6

III

First line

Afa vs cis/gem

11 vs 5.6m

All: 23.1 vs 23.5m

Exon 19 del : 31.4 vs 18.4m

Leu858arg mut: 19.6 vs 24.3m

 

 

LUX-Lung 7

III

First line

Afa vs gefi

11 vs 10.9

27.9 vs 24.5m

LUX-Lung 5

III

heavily treated PD after ≥1 chemo and after disease controlled ≥12 weeks on erlotinib or gefitinib and later on afatinib monotherapy

Afa + pacli vs pacli

 

5.6 (combo) vs 2.8m

 

RR 32.1 vs 13.2% p+ 0.005

12.2 vs 12.2m NS

 

Table 4 Selected dacomitinib trials

Trial

Phase

N

Eligibility

Other mutations

Efficacy

ARCHER 1001

I

121 (57NSCLC)

Pretreated with TKIs

5 ptes insertion exon 20

DCR 60%

ARCHER 1003

I/II

12 (I)

43 (II)

KRAS WT advanced NSCLC pretreated with at least one chemo line and a first-gen EGFR-TKI

one patient T790M mut

 

1PR on T790M

ARCHER 1017

II

89

First line

 

Never-smokers or former light smokers, with KRAS WT if non-Asian.

 

Later amended to EGFR mut regardless of smoking status.

EGFR exon 19 or 21 – 51%

RR 53.9%

PFS 11.5m

OS 29.5m

ARCHER 1002

II

66

After erlotinib + 1-2 chemo lines

 

EGFR 19 or 21 28.8%

EGFR others 10.1%

T790M 9.01%

ARCHER 1028

II

188

Daco vs erlo

After one or two chemo lines

Unselected patients

EGFR 31.9%

KRAS 32.9%

2.86 vs 1.91m Benefit seen in KRAS WT, any EGFR,

KRAS/EGFR WT

NS if EGFR mut

 

OS 9.53 vs 7.4m NS

ARCHER 1009

III

878

Daco vs erlo

After one or two chemo lines

EGFR exon 19,20,21 – 9.3%

KRAS 15.3%

EGFR others 1%

OVERALL:

PFS 2.6 vs 2.6m

OS 7.9 vs 8.4m (erlo) NS

WT KRAS:

PFS 2.6 vs 2.6m

OS 8.1 vs 8.5 NS

EGFRmut :

PFS 11 vs 10.9m (erlo)

OS 26.6 vs not reached with erlo

WT EGFR:

PFS 1.9 vs 1.9

OS 6.8 vs 7.6m (erlo)

 

ARCHER 1050

III

452

First line

Daco vs gefi

EGFR del exon 19 – 59%

EGFR L858R – 41%

PFS 14.7 vs 9.2 m (gefi) p < 0.001

NCIC CTG BR-26

III

720

Daco vs plac

Up to three chemo lines and a first-generation EGFR-TKI

EGFR 23.3%

KRAS 10.8%

OS 6.83 vs 6.31 m (NS)

NS differences with EGFR or KRAS mut

PFS 2.66 vs 1.38m  p < 0.0001

 

 

Table 5 Selected trials with osimertinib

Trial

Phase

N

End point

Efficacy

Mutations and efficacy

AURA

I/II

252

After progression on EGFR-TKIS

PFS

RR 51%

PFS 8.2

 

T790 M (N= 127)

DCR of 95%

RR of 61%

PFS of 9.6 m

AURA 2

II

201

After progression on EGFR-TKI

All had T790M-positive

RR

70%

PFS 9.9m

EGFRm T790M advanced NSCLC who progress after EGFR-TKI osimertinib provides a high RR, encouraging PFS, and durable response.

Poole analysis of AURA extension and AURA 2

II

411

RR

66%

 

AURA 3

III

419

T790 M mutations

Second line after progression on TKIs

Osi vs peme/cisp

PFS

10.1 vs 4.4m p< 0.001

RR 71 (osi) vs 31% p < 0.001

 

FLAURA

III

556

First line Ex19del/L858R EGFR mutated

Osi vs gefi or erlo

PFS

OS

18.9 vs 10.2m (gefi)

38.6 vs 31.8m

Crossover permitted but T790M should be identified post-PD

 

 

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