Attacking a Moving Target: Understanding Resistance and Managing Progression in EGFR-Positive Lung Cancer Patients Treated With Tyrosine Kinase Inhibitors

Multiple randomized studies have demonstrated improved response rates, progression-free survival, and quality of life for treatment-naive, advanced-stage adenocarcinoma patients harboring sensitizing EGFR mutations when they are treated with tyrosine kinase inhibitor therapy, as compared with chemotherapy. Despite improved outcomes with these agents, the majority of patients will eventually develop resistance and subsequent clinical progression. Recently, there has been a firmer understanding of the molecular mechanisms of the resistance that develops as a consequence of treatment, most notably the identification of a second-site EGFR mutation, T790M. While this understanding can inform subsequent treatment decisions, disease progression can be heterogeneous, and there are several competing therapeutic options. Treatment decisions must consider this clinical heterogeneity, factoring in the pace of disease growth, lung cancer–related symptoms, and the potential presence of T790M mutations. Herein, we review the available literature addressing these competing strategies and attempt to clarify best treatment practices, including the emerging role of T790M-directed therapies.

Introduction

The discovery of relevant genetic alterations in non–small-cell lung cancer (NSCLC) has led to the development of novel targeted therapies and a new treatment paradigm for patients with advanced adenocarcinoma of the lung. The epidermal growth factor receptor (EGFR) plays a key role in cell proliferation and survival, and when mutated activates oncogenic pathways that promote cell survival. The most common activating mutations in the EGFR tyrosine kinase domain are deletions in exon 19 and point mutations in exon 21 (L858R).[1-5] Tumors that harbor EGFR-sensitizing mutations are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs) because of a structural change in the adenosine triphosphate (ATP) binding pocket that causes an increased binding affinity for EGFR TKIs compared with ATP.[6] Multiple randomized studies have demonstrated that, compared with chemotherapy, TKI therapy with gefitinib, erlotinib, or afatinib yielded greater improvements in response rates, progression-free survival (PFS), and quality of life for patients with treatment-naive, advanced-stage adenocarcinoma harboring EGFR-sensitizing mutations.[7-12] In addition, an overall survival (OS) benefit was demonstrated in a preplanned subgroup analysis of patients with exon 19 deletions but not exon 21 L858R mutations of EGFR in two trials comparing afatinib vs platinum doublet chemotherapy.[13] Based on the improved outcomes and quality of life witnessed with these agents, the current standard of care in the treatment of advanced-stage EGFR-mutated NSCLC is single-agent EGFR TKI therapy.

Despite improved outcomes observed in patients treated with these agents, the majority of patients will eventually develop resistance and clinical progression.[7-10,14] Recent studies have deepened our understanding of molecular mechanisms of resistance that develop as a consequence of treatment. While this new knowledge can inform subsequent treatment decisions, treating disease progression in this patient population remains challenging, with several competing therapeutic options available. In this article, we review the available literature addressing these competing strategies and attempt to clarify best treatment practices, including the emerging role of T790M-directed therapies.

Primary Mechanisms of Resistance

Primary resistance, defined as the lack of an objective response to EGFR TKIs, is observed in approximately 20% to 40% of patients with EGFR-mutant NSCLC.[15,16] This estimate may be misleading, however, since many of these patients have a reduction in tumor burden that is too small to be considered an objective response by Response Evaluation Criteria in Solid Tumors (RECIST). The most common mutations associated with primary resistance to EGFR TKIs are exon 20 insertions and de novo T790M point mutations in EGFR. In addition, second oncogenic mutations, alterations in apoptotic pathways, and suboptimal drug exposure may also play a role in primary resistance to TKI therapy.[17-20]

Exon 20 insertion mutations account for approximately 2% to 4% of all EGFR mutations.[18,19,21] Unlike the sensitizing mutations, however, EGFR exon 20 insertion mutations do not alter the ATP binding pocket, leaving EGFR TKIs largely ineffective.[19] A retrospective analysis of 1,882 patients with stage IV lung adenocarcinoma demonstrated that the median time to progression following treatment with erlotinib was 2.5 months for the subset of patients with the exon 20 insertion, compared with 12.2 months for the subset of patients with an EGFR-sensitizing mutation (P < .01).[19] Given the observed clinical outcomes with TKI therapy for exon 20 patients, standard chemotherapy should be considered first-line therapy for these patients.

The T790M mutation is characterized by the amino acid substitution of methionine for threonine at position 790, leading to decreased binding through steric hindrance and increased binding affinity with ATP at the expense of TKIs. While T790M mutations most commonly develop as a resistance mechanism after TKI treatment, rare cases of de novo T790M mutations have been reported. De novo T790M mutation rates vary by the method used for detection and have been identified in 1% to 8% of all NSCLC patients with activating EGFR mutations evaluated by direct sequencing.[22] Most studies evaluating the outcomes for patients with de novo T790M mutations treated with TKI therapy have suggested that the presence of de novo T790M mutations predict lack of sensitivity to TKI therapy.[23-25]

Signaling through alternate oncogenic kinases, most notably phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and mesenchymal-epithelial transition (MET), have also been identified as causes of primary resistance.[26,27] Mutations of PIK3CA occur alongside activating EGFR mutations in up to 4% of patients with lung cancer and confer resistance to TKI therapy in preclinical models.[16,26] MET protein expression and phosphorylation also were reported to be associated with primary resistance and shorter time to progression in a small cohort of EGFR mutation–positive patients (n = 10) with NSCLC treated with EGFR TKIs.[28] In addition, hepatocyte growth factor, the ligand for the receptor tyrosine kinase, was recently found to be overexpressed in 30% of EGFR mutation–positive patients with advanced-stage lung cancer and intrinsic resistance to EGFR-directed therapy.[27] Despite these and similar preclinical and clinical observations, the presence of these alterations in treatment-naive patients should not guide routine treatment decisions.

The apoptotic pathway activated by EGFR inhibition may also affect the initial response to treatment with EGFR TKIs. Activity of the BCL-2 interacting mediator of cell death (BIM) is necessary for EGFR TKI–induced apoptosis. In a retrospective analysis of patients treated on the EURTAC trial, low expression of BIM was associated with a lower response rate and shorter PFS in patients treated with erlotinib but not chemotherapy.[29] Preclinical studies suggest that restoring BIM function with histone deacetylase inhibitors may overcome TKI resistance in patients whose tumors express low levels of BIM.[30,31]

Pharmacokinetic failure resulting in inadequate drug exposure may manifest as primary EGFR TKI resistance.[32] Subtherapeutic levels of EGFR TKIs may result from several mechanisms. Concurrent administration of agents that induce the expression of cytochrome P450 3A4 or P-glycoprotein, which increases the metabolism of first-generation TKIs (erlotinib and gefitinib) and second-generation (afatinib) TKIs, respectively, can result in subtherapeutic drug levels. Furthermore, current smokers have increased clearance of erlotinib, likely due to the induction of cytochrome P450 1A2 and cytochrome P450 1A1.[33] Finally, drugs that increase the gastric pH can reduce absorption of erlotinib and gefitinib, and have been shown to lower the serum levels of these drugs.[34-36]

Secondary Resistance

Criteria for acquired resistance to EGFR TKIs were proposed by Jackman and colleagues in 2010 (Table 1).[37] Patients with secondary resistance generally fall into three distinct clinical groups: those with central nervous system (CNS) progressive disease, those with oligoprogressive disease, and those with systemic progressive disease.[38] Acquired resistance can be due to acquisition of secondary EGFR mutations that prevent the treatment drug from accessing the ATP binding pocket, reactivation of survival signaling pathways, and histologic or phenotypic transformation.

EGFR T790M mutations

The most common secondary resistance mechanism is the EGFR T790M mutation in exon 20; as described previously, this mutation occurs when the “gatekeeper” threonine residue is substituted for a methionine at position 790. The methionine side chain not only causes steric hindrance, interfering with the ability of first-generation TKIs to bind to the ATP-kinase pocket (Figure 1), but also restores ATP as a preferred substrate compared with EGFR.[39,40] The T790M mutation has been reported in up to 60% of patients with advanced NSCLC who have progressed on an EGFR TKI.[41-46] Some investigators have postulated that T790M mutations exist at low levels within a heterogeneous tumor cell population, and selection pressures created by treatment with EGFR TKIs provide a survival advantage for these mutants.[47] While T790M mutations of EGFR are generally associated with a more indolent tumor biology, patients with this mutation can also have rapid clinical and radiographic progression.

Reactivation of survival signaling pathways

Acquired resistance to TKI therapy can also occur through secondary mutations that bypass EGFR inhibition to reactivate proliferation and survival pathways. These alterations can occur in parallel oncogenes that share common downstream effectors with EGFR or in the downstream effectors themselves. MET amplification is the most common example, and has been identified in 5% to 22% of EGFR TKI–resistant tumors.[41,48] In vitro, MET amplification mediates resistance through activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling downstream of EGFR; limited clinical experience suggests that concurrent MET inhibition may overcome EGFR TKI resistance.[49] Similarly, amplification of HER2 been identified in 13% of tumors that progressed on EGFR TKIs and may represent an alternative bypass pathway.[41,50] Moreover, mutations in the downstream effector PI3K have been identified in up to 5% of tumors with acquired resistance to EGFR TKIs and can induce TKI resistance in vitro.[17,41] A variety of other mechanisms of EGFR TKI resistance are summarized in Figure 2.

Histologic transformation

Histologic transformations from NSCLC tumors to small-cell lung cancer (SCLC) and epithelial-to-mesenchymal transition (EMT) represent additional mechanisms of acquired resistance to TKI therapy. Transformation to SCLC has been observed in 3% to 14% of biopsies of tumors that have progressed after treat ment with EGFR TKIs, and can occur simultaneously with other resistance mutations.[17,41] The mechanism by which SCLC transformation occurs and leads to TKI resistance is not clear, but EGFR mutations have been detected in tumors with mixed adenocarcinoma and small-cell histology, suggesting that treatment may select for a TKI-resistant small-cell population that is present at diagnosis.[51] The molecular mechanisms leading to EMT are now better understood: they involve induction of transforming growth factor β by EGFR inhibition, which activates the SMAD pathway and promotes drug resistance, tumor cell invasion, and metastasis.[52,53] Evidence of EMT was reported in 5% of patients who had progressed on treatment with EGFR TKIs.[17]

Treatment of Patients With TKI-Resistant Disease: Current Guidelines and Controversies

Although various mechanisms of resistance inevitably lead to progression of EGFR-positive lung cancer treated with TKIs, not all forms of progression are the same. Treatment decisions must consider this clinical heterogeneity, factoring in the pace of disease growth, lung cancer–related symptoms, and the potential presence of T790M mutations. Prior to the introduction of second- and third-generation TKIs (discussed later in this article), two of the most relevant clinical questions were whether TKIs should be continued in the setting of overall disease progression and how to manage oligometastatic progression. Fortunately, several studies have helped to define the optimal treatment options for these clinical scenarios, and will be discussed.

Continuation of EGFR TKI therapy in the setting of overall disease progression

Until recently, a common clinical practice was to continue TKI therapy beyond progressive disease by RECIST for EGFR mutation–positive patients who had experienced initial clinical benefit. This strategy is based on the scientific premise that progressive lesions represent clonal heterogeneity that includes TKI-sensitive tumor cells. This has also been supported by the clinical observation that patients who are removed from TKI therapy can experience a disease flare, defined as hospitalization and/or death occurring during a washout period often required for a clinical trial.[15,54] Two studies evaluating small numbers of patients have reported the incidence of disease flare to be 8.8% and 23%, respectively.[54,55] The true incidence of this phenomenon, however, has not been evaluated in larger studies including patients who receive immediate treatment with second-line agents.

Several studies have evaluated the role of continuing TKI therapy beyond overall disease progression. ASPIRATION was an open-label, single-arm, phase II study that evaluated continuation of erlotinib (at 150 mg/day) beyond progression by RECIST in patients with advanced-stage EGFR-positive lung cancer.[56] Among the 176 patients who experienced disease progression, 93 continued to receive erlotinib therapy and 73 discontinued treatment. Decisions regarding continuation were made at the discretion of the treating physician. The median PFS for those who continued treatment was 13.0 months (95% CI, 11.5–14.8 months), with an addition of 3.7 months between the first disease progression and discontinuation of drug at second progression.[56] Post hoc analysis suggested that OS was longer in patients who continued to receive erlotinib (33.6 months [95% CI, 27.3–34.2 months]) compared with those who did not (22.5 months [95% CI, 20.1–27.0 months]).

While the continuation strategy did allow patients to remain on treatment longer and potentially delayed salvage therapy, this study was not randomized, and results could have been confounded by selection bias on the part of physicians when considering which patients should continue treatment with erlotinib.[56] Similarly, a retrospective study evaluated 123 EGFR-positive patients treated with first-line TKI therapy and compared ou comes between patients who continued TKI therapy beyond RECIST-defined progression (n = 50) vs those who did not (n = 73). While there was no difference in median PFS (10.5 vs 9.5 months; P = .4), there was a nonsignificant trend in OS favoring the continuation group (33.0 vs 21.2 months; P = .054).[57]

Finally, Nishie et al retrospectively evaluated 64 patients with advanced-stage EGFR-positive disease treated with an EGFR TKI as either first- or second-line therapy and demonstrated a survival advantage in the 39 patients who continued to receive a TKI (without added chemotherapy) compared with the 25 patients who switched to chemotherapy (OS, 32 vs 23 months; P = .005).[58] These studies suggest that continuation of TKI therapy beyond disease progression by RECIST may confer therapeutic value and improve outcomes.

Despite these results, a larger phase III study did not confirm the benefit of TKI continuation beyond progression according to RECIST. IMPRESS was a placebo-controlled phase III study evaluating chemotherapy (cisplatin at 75 mg/m² and pemetrexed at 500 mg/m²) and gefitinib (250 mg/day) vs the same chemotherapy regimen plus placebo for patients with advanced-stage EGFR-positive lung cancer (n = 265) who experienced disease progression on single-agent treatment with gefitinib.[59] There were no differences between the two groups in response rates (31% vs 34%) or PFS (5.4 months in both groups; hazard ratio [HR], 0.86; P = .273). In addition, OS was longer for the placebo group (17.2 vs 14.8 months; HR, 1.62; P = .029), suggesting a potential detrimental effect from continuing TKI therapy beyond progression.[59] A subgroup analysis evaluating outcomes by T790M mutational status demonstrated a PFS advantage in T790M-negative patients (n = 105) who received continuation gefitinib vs placebo (6.7 vs 5.4 months; HR, 0.67; P = .07), but not in T790M-positive patients (n = 142; PFS, 4.6 vs 5.3 months; HR, 0.97; P = .88).[59] These results suggest that there may be a role in continuing TKI therapy beyond disease progression for T790M-negative patients; however, the observed benefit was modest, and larger studies would be needed to confirm these findings.

Management of oligometastatic progression

Oligometastatic progression is defined by a small number of new metastases in just a few organ sites. This clinical scenario poses challenges for patients with advanced NSCLC who develop resistance to TKI therapy. While there have been no prospective trials addressing treatment options for EGFR-positive patients with oligometastatic progression, several retrospective studies have demonstrated that management of extracranial oligometastatic sites with local measures (radiation and surgery) followed by continuing TKI therapy can maintain disease control and delay the need to change the plan of therapy.[60,61] Oligoprogression may also appear in the form of CNS metastases only, in the setting of otherwise stable extracranial disease. This may be due to suboptimal blood-brain barrier penetration by TKI therapy or metastasis of resistant clones to the brain. A retrospective study of 17 patients who developed CNS metastases after initial clinical benefit from TKI therapy demonstrated that continuing EGFR-targeted TKIs following either whole-brain radiation therapy or stereotactic radiotherapy appears to be a feasible option.[62] Specifically, median PFS, extracranial PFS, and median OS were 80 days, 171 days, and 403 days, respectively. These retrospective studies suggest that oligometastatic progression represents a distinct clinical scenario in which aggressive management of progressing sites followed by continuation of TKI therapy may be considered.

Second-generation TKIs (afatinib and dacomitinib)

Afatinib and dacomitinib are second-generation TKIs developed and clinically evaluated in the settings of both EGFR TKI–naive and –refractory lung cancer. Despite the theoretical advantages of these agents, including irreversible binding of the EGFR/HER1 domain, pan-HER inhibition, and in vitro activity against the T790M cell lines, afatinib and dacomitinib have not demonstrated significant clinical benefit in patients whose disease has progressed during treatment with either erlotinib or gefitinib.

The LUX-Lung 1 study evaluated afatinib at 50 mg/day vs placebo in patients (n = 390) unenriched for EGFR mutations who experienced disease progression while on one or two lines of chemotherapy as well as treatment with a first-generation TKI. While there were modest improvements in response rate (7% vs < 1%; P = .0071) and PFS (3.3 vs 1.1 months; HR, 0.38; P < .0001), there was no difference in OS between the two groups (10.8 vs 12.0 months; HR, 1.08; P = .74).[63] A total of 133 patients who met the Jackman criteria of resistance and were treated with afatinib demonstrated a median PFS of 4.5 months; this result is similar to outcomes demonstrated with platinum chemotherapy in this setting.

Similar results were demonstrated in the LUX-Lung 4 trial, a Japanese single-arm, phase II study that evaluated afatinib at 50 mg/day in patients with advanced-stage adenocarcinoma (n = 62) who had received up to two lines of chemotherapy and at least 12 weeks of a first-generation TKI. The response rate and PFS for patients meeting the Jackman criteria for acquired resistance were 6% and 4.4 months, respectively, suggesting limited clinical activity in this setting.[64] Dacomitinib has also been evaluated in patients whose disease progressed during treatment with first-generation TKIs.

A phase III study randomized patients (n = 720) unenriched for EGFR mutations who had received up to three lines of chemotherapy and a first-generation TKI to either dacomitinib or placebo. This trial demonstrated no meaningful improvement in survival (OS, 6.8 vs 6.31 months, respectively; HR, 1.00; P = .50),[65] suggesting a limited role for dacomitinib in this setting.

Combination approaches (afatinib + cetuximab)

The combination of afatinib and cetuximab has been explored in patients who have developed resistance to first-generation TKI therapy. A phase Ib trial recently evaluated dual EGFR blockade with afatinib (at 40 mg orally daily) plus cetuximab (at 500 mg/m² intravenously every 2 weeks) in 126 heavily pretreated patients with advanced EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib. While the combination demonstrated modest efficacy both in patients with and without T790M mutations, with response rates of 32% and 25%, respectively, the strategy was associated with significant toxicities; 20% of patients had grade 3/4 skin reactions, including rash, and 6% had grade 3 or higher diarrhea.[66] While this combination strategy is actively being pursued in clinical trials, its future role remains unclear, given the better tolerability and efficacy of third-generation TKIs.

Identifying Mechanisms of Resistance: The Role of Liquid Biopsies

The National Comprehensive Cancer Network recommends rebiopsying patients who experience disease progression on first-line EGFR TKI therapy to evaluate mechanism of resistance, including the identification of potential actionable mutations such as T790M.[67] Despite this, roughly three-quarters of clinicians do not follow this recommendation.[46] Although traditional biopsy methods are useful, they can be cumbersome; invasive; and may not accurately identify relevant molecular alterations, due to both suboptimal tissue acquisition and tumor heterogeneity.[68,69] More recently, technological advances have led to the development of blood-based diagnostics or “liquid biopsies,” which allow for identification and genomic interrogation of cell-free DNA (cfDNA) present in plasma. Multiple studies have demonstrated that cfDNA is increased in lung cancer patients compared with healthy controls, and its concentration further increases in advanced disease.[70,71]

Advances in digital genomic technologies, including digital polymerase chain reaction; the amplification-refractory mutation system; beads, emulsions, amplifications, and magnetics; tagged-amplicon deep sequencing; and next-generation sequencing have the capability to detect very low levels of cfDNA in plasma or serum and can accurately identify relevant genetic alterations, including T790M, in advanced-stage lung cancer. The ability of these platforms to serve as a reliable molecular proxy of disease has the potential to aid in therapeutic decision making, including for questions regarding the use of third-generation TKIs.[72-77]

Third-Generation TKIs

A better understanding of the mechanisms of resistance that emerge during TKI therapy has led to the development of novel third-generation TKIs. These drugs have demonstrated efficacy against both activating EGFR (exon 19 and 21) mutations as well as T790M, sparing cells with wild-type EGFR. In addition to osimertinib, which has recently been approved by the US Food and Drug Administration (FDA), other third-generation agents are currently being evaluated in phase I, II, and III trials (Table 2).

Osimertinib

Osimertinib is an oral irreversible EGFR TKI that has broad activity against both sensitizing mutations and EGFR T790M mutations, with little inhibition of tumors with wild-type EGFR.[78] Recently, a phase I/II trial evaluated osimertinib at escalating doses (from 20 mg/day to 240 mg/day) in 253 patients with advanced-stage lung cancer and known EGFR-sensitizing mutations who had prior clinical benefit as defined by the Jackman criteria.[79] Among the 138 patients with EGFR T790M mutations confirmed by central testing, the objective response rate (ORR) was 61% (95% CI, 52%–70%), and the disease control rate (DCR) was 95% (95% CI, 90%–98%). Median PFS was 9.6 months (95% CI, 8.3 months–not reached; 30% maturity). The most common adverse reactions (all grades) that occurred in > 20% of patients treated with osimertinib were diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%). Importantly, grade 3/4 diarrhea and rash occurred in just 1% and 0% of patients, respectively, at the 80-mg dose. Based on the efficacy results and favorable toxicity, osimertinib was approved by the FDA for EGFR-positive patients with advanced-stage lung cancer who have received prior TKI therapy and who have developed a secondary point mutation in T790M. Several other clinical trials are underway to assess the safety, tolerability, and efficacy of this agent (Table 2).

Rociletinib

Similar to osimertinib, rociletinib is an oral irreversible TKI that targets the common EGFR-sensitizing mutations L858R and Del19, as well as the gatekeeper mutation T790M. In the interim analysis for a phase I/II dose-finding study, a total of 130 patients who had disease progression after previous treatment with an EGFR TKI were given rociletinib at different doses (500 to 1,000 mg bid).[80] While the phase I cohort was not limited by T790M mutation status, the phase II group was restricted to patients with a confirmed T790M mutation.

At the time of publication, patients with T790M-positive tumors (n = 46) had an unconfirmed ORR of 59%, a DCR of 93%, and PFS of 13.1 months (95% CI, 5.4–13.1 months). Hyperglycemia was the most common dose-limiting adverse event, and grade 3 events occurred in 22% of patients who received therapeutic doses of rociletinib. Despite the original outcomes reported, a recent update from the pooled TIGER-X/TIGER-2 analysis, which included 325 patients with EGFR T790M mutation–positive lung cancer treated with rociletinib, demonstrated an ORR of only 32% (95% CI, 25%–40%).[81] In April 2016, the FDA’s Oncology Drug Advisory Committee denied rociletinib accelerated approval in lung cancer.[82] June 28 is the current action date for a final approval decision.

Additional considerations for treatment with osimertinib and rociletinib

Osimertinib and rociletinib appear to have differing clinical activity, based on the recent update from the TIGER-X/TIGER-2 analysis. In addition, their tolerability profiles are distinct. Dose reductions or interruptions with osimertinib therapy were associated with electrocardiogram QTc prolongation and neutropenia,[83] whereas rociletinib was associated with dose-limiting grade 3 hyperglycemia in 22% of patients.[80]

There is also emerging interest in the activity of these drugs in patients confirmed to be T790M-negative; while the reasons for this clinical observation are not completely understood, possible explanations include tissue heterogeneity, false-negative results, a re-treatment effect, and active metabolites inhibiting alternate signaling pathways. For osimertinib, the 62 patients in the T790M-negative cohort had an ORR of 21%, a DCR of 61%, and a median PFS of 2.8 months.[79] The 17 patients with T790M-negative status treated with rociletinib had an unconfirmed ORR of 29%, a DCR of 59%, and a median PFS of 5.6 months.[80]

Finally, recent data highlight different mechanisms of resistance that may develop upon disease progression during treatment with osimertinib or rociletinib. Several case reports have identified a tertiary EGFR mutation, C797S,[81] in patients who develop resistance to osimertinib, while MET amplification may be a more common mechanism of resistance to rociletinib.[84,85] Further study is needed to delineate the true differences in resistance mechanisms between these two drugs.

HM61713

HM61713 is also an oral agent designed to target the EGFR T790M mutation while sparing cells with wild-type EGFR. A recently reported phase I/II study evaluated HM61713 in 173 patients with advanced-stage EGFR-mutation positive lung cancer in whom prior TKI therapy had failed. The maximum tolerated dose was 800 mg once daily. Treatment-related adverse events occurred in 87.3% of 165 evaluable patients; these consisted mainly of diarrhea, rash, skin exfoliation, nausea, pruritus, decreased appetite, and dry skin. The ORR and DCR in the 34 patients with centrally confirmed T790M tumors were 58.8% and 97.2%, respectively. Ongoing trials are evaluating this agent as monotherapy or in combination with other agents.[85]

Conclusions

The recent discovery of relevant actionable mutations, coupled with the development of targeted therapies, has reshaped our approach in the management of patients with NSCLC. Despite the impressive response rates and improved outcomes with EGFR-directed therapies, resistance is inevitable, with disease progression generally occurring within 12 months. However, progression on TKI therapy involves several different clinical scenarios, all of which warrant special consideration (Figure 3). To optimize treatment options, it is critical to identify the type of progression, the symptoms presented, and the mechanism of resistance. For patients who experience oligometastatic progression, aggressive management with surgery and/or radiation to progressing lesions with continuation of TKI therapy may offer disease control and delay changes of therapy that may be associated with added toxicity. For patients who develop symptomatic progression without an identifiable T790M mutation, chemotherapy remains a cornerstone of treatment, consistently yielding response rates of 25% to 30%. Based on reported phase III studies, TKIs should be discontinued once chemotherapy commences. A number of questions remain regarding the management of patients who experience asymptomatic progression in this setting. Options include continuing TKI therapy, switching to chemotherapy, or administration of third-generation TKIs for patients harboring EGFR T790M mutations. Finally, impressive outcomes (ORR and PFS) witnessed with T790M-directed therapies underscore the importance of the identification of mechanisms of resistance.

The advent of new diagnostic platforms, including plasma genotyping (using cfDNA), will help facilitate the selection of appropriate treatments for this molecularly susceptible cohort. Given that many of these platforms reported high specificities for several different relevant mutations, evaluation of plasma may be considered as the initial first step in assessment of T790M status, although repeat biopsies remain the most accepted clinical practice. Molecular detection technologies, coupled with strategic drug design, will facilitate identification of new targets in the quest to provide optimal and tailored therapy to patients with advanced NSCLC harboring EGFR mutations.

Financial Disclosure:Dr. Levy has served as a consultant for AstraZeneca, Boehringer Ingelheim, Celgene, Eli Lilly, Genentech, and Pfizer; and he serves on the speakers bureau of Genentech. Dr. K. Becker has served as a consultant to AstraZeneca and Genentech; and he serves on the speakers bureaus of Astellas, Bristol-Myers Squibb, and Genentech. Drs. D. Becker and Rao have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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