Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor

INTRODUCTION — Treatment of patients with lung cancer depends upon the cell type (non-small cell lung cancer [NSCLC] versus small cell lung cancer), molecular characteristics, tumor stage, and an assessment of the patient's overall medical condition.

Patients with stage I, II, or III NSCLC are generally treated with curative intent using surgery or radiation therapy (RT), sometimes combined with concurrent or adjuvant systemic therapy (table 1). By contrast, palliative systemic therapy is appropriate for patients who have stage IV disease at presentation. Palliative systemic therapy is also used for patients who have relapsed with advanced disease following prior definitive treatment.

An improved understanding of the molecular pathways that drive malignancy in NSCLC has led to the development of agents that target specific molecular pathways in malignant cells. Therapy can then be individualized based upon the specific abnormality, if any, present in a given patient.

The use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of patients with advanced NSCLC that contains a somatic mutation in EGFR will be reviewed here.

Other relevant topics include:

●(See "Overview of the initial treatment of advanced non-small cell lung cancer".)

●(See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

●(See "Brain metastases in non-small cell lung cancer", section on 'EGFR mutations'.)

●(See "Initial management of advanced non-small cell lung cancer lacking a driver mutation".)

●(See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

RATIONALE

Molecular pathogenesis — Tumor growth and progression depend upon the activity of cell surface membrane receptors that control intracellular signal transduction pathways regulating cell proliferation, apoptosis, angiogenesis, adhesion, and motility.

These cell surface receptors include the EGFR (also called HER1 or erbB-1) tyrosine kinases (TKs). EGFR exists as a monomer on the cell surface, and it must dimerize to activate the TK. While the TK activity of EGFR is tightly controlled in normal cells, the genes encoding these receptors may have escaped from their usual intracellular inhibitory mechanisms in malignant cells (figure 1).

EGFR mutation as a predictor of responsiveness — Advanced NSCLCs that contain characteristic mutations in EGFR, exon 19 deletions or exon 21 L858R mutations, are highly sensitive to EGFR TK inhibitors (TKIs). Analysis for the presence or absence of a driver mutation in EGFR is the standard approach to decide whether or not to use an EGFR TKI for the initial treatment of a patient with advanced NSCLC. Multiple reliable techniques are available to assay for EGFR mutations, and these are feasible on formalin fixed tissue [1]. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

Mutations in the EGFR tyrosine kinase are observed in approximately 15 percent of NSCLC adenocarcinoma in the United States and occur more frequently in women and nonsmokers. In Asian populations, the incidence of EGFR mutations is substantially higher.

In the PIONEER study, tumor was analyzed from 1482 patients with adenocarcinoma in seven Asian regions (China, Hong Kong, India, Philippines, Taiwan, Thailand, Vietnam) [2]. The incidence of EGFR mutations ranged from 22 to 62 percent. Although EGFR mutations were more common in nonsmokers, the incidence still was 37 percent in regular smokers. The frequency of such mutations was higher in women than in men, but the difference was not significant after considering the frequency of smoking.

If systemic treatment is required before the results of genotype testing are available, systemic chemotherapy is indicated [3]. If an EGFR mutation is identified after initiation of chemotherapy, we suggest continuing chemotherapy for four cycles as long as therapy is tolerated and there is no evidence of disease progression. When the results of genotype testing become available, the treatment plan should be reassessed. There are no clinical trials that directly address the optimal approach when a driver mutation is identified after chemotherapy has been initiated.

Avoidance of EGFR overexpression as a predictor of responsiveness — Unlike activating mutations in EGFR, amplification of EGFR does not predict improved outcomes with EGFR inhibitors. Furthermore, EGFR overexpression by immunohistochemistry is not sufficiently predictive of activity of EGFR TKIs to be an appropriate surrogate for the presence of an activating EGFR mutation.

In the IPASS trial, high EGFR gene copy number was associated with improved progression-free survival (PFS) with gefitinib over chemotherapy only if there was a coexisting EGFR mutation (hazard ratio [HR] 0.48; 95% CI, 0.34-0.67) [4]. However, if high EGFR gene copy number was not accompanied with an EGFR mutation, PFS outcomes were worse with gefitinib compared with chemotherapy (HR 3.85, 95% CI 2.09-7.09).

Clinical predictors of responsiveness — Initial studies identified several clinical parameters that were associated with a high response rate to EGFR TKIs and a relatively favorable prognosis. These include adenocarcinoma histology, women, nonsmokers, and Asian ethnicity. Subsequent studies showed that these clinical parameters are surrogates for the presence of specific activating mutations in the tyrosine kinase domain of the EGFR (exon 19 deletions, L858R point mutation in exon 21). However, clinical parameters should not replace actual mutational testing since clinical profiling is not highly accurate [1].

EFFICACY OF SINGLE-AGENT EGFR TKIS

Preferred: Osimertinib, with or without chemotherapy — We suggest osimertinib, with or without chemotherapy, as the initial strategy for advanced NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations. (See 'Alternatives' below and 'Immune-related toxicities with EGFR TKI after immunotherapy' below.)

Osimertinib is approved by the US Food and Drug Administration (FDA) for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations [5], and has shown benefit over older EGFR tyrosine kinase inhibitors. Osimertinib has been associated with QTc prolongation as well as decreases in left ventricular ejection fraction, which are reversible with discontinuation of the drug [6]. Subsequent data have shown progression-free survival (PFS) benefits with the addition of chemotherapy to osimertinib at the expense of added toxicity, but survival benefits are unknown. Although we have not incorporated this strategy into our clinical practice pending longer term data, we recognize that it is an acceptable strategy.

Data regarding these strategies are below:

●Single-agent osimertinib – In the phase III FLAURA trial, 556 patients with treatment-naïve, EGFR-mutated advanced NSCLC were randomly assigned to osimertinib versus standard of care (SOC) EGFR TKI (gefitinib or erlotinib) [7]. Neurologically stable patients with central nervous system metastases were permitted in this study. Osimertinib demonstrated improvement in PFS (18.9 versus 10.2 months; hazard ratio [HR] 0.46, 95% CI 0.37-0.57) and duration of response (17.2 versus 8.5 months) relative to SOC. The PFS benefit was consistent across subgroups, including either patients with or without brain metastases. In reporting of overall survival (OS) results at 58 percent maturity, osimertinib improved OS relative to SOC (38.6 versus 31.8 months; HR 0.80, 95% CI 0.64-0.997) [8]. Response rates for osimertinib and SOC were 80 and 76 percent, respectively. Grade 3 or higher toxicities were lower for osimertinib versus SOC (34 versus 45 percent).

●Osimertinib with chemotherapy – In a randomized open-label trial including 557 patients with advanced EGFR-mutated NSCLC, the addition of platinum-pemetrexed chemotherapy to osimertinib improved PFS, as assessed by blinded, independent central review (29.4 versus 19.9 months; HR 0.62, 95% CI 0.48-0.80) [9]. Patients assigned to osimertinib plus chemotherapy received four cycles of investigator's choice of platinum agent plus pemetrexed, with pemetrexed continuing as maintenance therapy, along with osimertinib. Although OS results are immature, at 24 months the OS rate with osimertinib-chemotherapy was 79 versus 73 percent with osimertinib alone (HR 0.90, 95% CI 0.65-1.24). Adverse events of grade 3 or higher were reported in 64 percent in the osimertinib-chemotherapy group and in 27 percent in the osimertinib group.

Potential approaches to patients with resistance to osimertinib are discussed below. (See 'Resistance to osimertinib-based therapy' below.)

Alternatives — Data comparing gefitinib, erlotinib, and afatinib with chemotherapy and each other are discussed in the sections below. However, data suggest improved outcomes with osimertinib, which is discussed above. (See 'Preferred: Osimertinib, with or without chemotherapy' above.)

Erlotinib — Erlotinib has been compared with chemotherapy in several randomized trials in patients with EGFR-mutated lung cancer, summarized below, all of which demonstrated a benefit in progression free survival with erlotinib, but not in OS. This likely reflects the effect that post-trial treatments have on OS, especially given that cross-over to TKI upon progression on chemotherapy was permitted.

Trials of erlotinib versus chemotherapy are discussed here. One study assessed erlotinib versus gefitinib and is discussed below. (See 'Gefitinib' below.)

●OPTIMAL trial – 154 patients were randomly assigned to erlotinib or gemcitabine plus carboplatin [10]. Treatment with erlotinib improved PFS compared with chemotherapy (13.1 versus 4.6 months, HR 0.16, 95% CI 0.10-0.26). Similarly, the objective response rate was improved with erlotinib (83 versus 36 percent). OS in patients receiving erlotinib versus chemotherapy was not significantly different (22.8 versus 27.2 months, HR 1.19, 95% CI 0.83-1.71) [11].

●EURTAC trial – 174 patients were randomly assigned to erlotinib or a platinum-based chemotherapy doublet [12]. PFS was increased with erlotinib compared with chemotherapy (9.7 versus 5.2 months, HR 0.37, 95% CI 0.25-0.54). There was no difference in OS in the erlotinib versus chemotherapy groups (19.3 versus 19.5 months, HR 1.04, 95% CI 0.65-1.68).

●ENSURE trial – Two-hundred seventy-five patients were randomized to erlotinib or gemcitabine and cisplatin [13]. Patients treated with erlotinib experienced an improved PFS compared with chemotherapy (11.0 versus 5.5 months, HR 0.34, 95% CI 0.22-0.51). Median OS was similar in the two groups (26.3 versus 25.5 months, HR 0.91, 95% CI 0.63-1.31).

For patients receiving erlotinib, we avoid concomitant use of proton pump inhibitors, given observational evidence of decreased efficacy of erlotinib [14]. Further details regarding drug interactions are found in the drug interactions program.

Gefitinib — While gefitinib previously was approved outside the United States for patients with EGFR driver mutations, it was subsequently approved by the FDA for patients whose tumor contains an EGFR exon 19 deletion or the exon 21 (L858R) substitution mutation [15]. It is an appropriate option in this setting.

Gefitinib was compared with cytotoxic chemotherapy as the initial therapy in three randomized trials in patients with advanced NSCLC whose tumors contained activating EGFR mutations. The most extensive data come from the IPASS trial, in which 1217 patients were randomly assigned to gefitinib or carboplatin plus paclitaxel [4,16]. Patients were included based upon clinical criteria consistent with responsiveness to gefitinib; all were Asian, had adenocarcinoma and were either never smokers or former light smokers. For the entire cohort, PFS was significantly better with gefitinib compared with chemotherapy (12-month progression-free rate 25 versus 7 percent, HR for progression 0.74). The difference in OS was not statistically significant (median 18.8 versus 17.4 months, HR for death 0.90, 95% CI 0.79-1.02) [4].

Results depended upon the EGFR mutation status. EGFR mutations were present in 60 percent of the 437 evaluable patients; among these, 96 percent had either an exon 19 deletion or the exon 21 L858R mutation.

●For patients whose tumors contained an EGFR mutation, PFS was significantly prolonged with gefitinib compared with carboplatin plus paclitaxel (median 9.5 versus 6.3 months, HR for progression 0.48) [16]. OS was not increased (median 22 months in both groups, HR 1.00) [4].

●For those without an EGFR mutation, PFS was significantly shorter with gefitinib (median 1.5 versus 6.5 months, HR 2.85 for progression, 95% CI 2.05-3.95) [16]. The difference in OS was not statistically significant (median 11.2 versus 12.7 months, HR for death 1.18).

Two additional phase III trials were conducted exclusively in patients with EGFR mutations (the West Japan Oncology Group 172 trial [17,18] and the North-East Japan Study Group 002 trial [19,20]). The overall results and magnitude of the benefit were essentially the same as in the IPASS trial.

Afatinib — Afatinib is as an irreversible EGFR TKI, which has been shown to have clinical activity in multiple clinical trials [21-25].

Afatinib was compared with chemotherapy as the initial therapy for advanced NSCLC in two phase III trials in patients whose tumors contain activating mutations. The efficacy of afatinib in this setting is illustrated by the results of the phase III Lux-Lung 3 trial, in which 345 previously untreated patients were randomly assigned to treatment with afatinib or cisplatin plus pemetrexed [23,24]. The primary endpoint of the trial was PFS based upon independent review.

At a median follow-up of 16 months, key results included the following:

●PFS was significantly increased with afatinib compared with chemotherapy (median 11.1 months versus 6.9 months, 12-month progression-free rate 51 versus 21 percent, HR for progression 0.58, 95% CI 0.43-0.78).

●The objective response rate was significantly increased with afatinib (56 versus 23 percent). Time to symptom progression and quality of life were also significantly improved with afatinib.

●The most frequent side effects included diarrhea, rash, stomatitis, paronychia, and dry skin (95, 89, 72, 57, and 29 percent of cases, respectively), and were consistent with those seen with other EGFR TKIs. (See 'EGFR TKI toxicity' below.)

A second phase III trial was conducted in 364 Asian patients (Lux-Lung 6), in which afatinib was compared with gemcitabine plus cisplatin [26]. Similar results were observed with afatinib resulting in an increased PFS (11.0 versus 5.6 months) and improved response rate (67 versus 23 percent).

In a combined analysis of these two trials (n = 709), the median OS was not significantly increased for patients assigned to afatinib compared with chemotherapy (median 25.8 versus 24.5 months, HR for death 0.91, 95% CI 0.75-1.11) [27]. When the combined trial data were analyzed based upon the specific mutation present, a statistically significant benefit was observed in OS and PFS in patients with exon 19 deletion. There was a significant benefit in progression-free, but not OS for those with the L858R mutation.

Afatinib in NSCLC with uncommon EGFR mutations is discussed below. (See 'EGFR S768I, L861Q, and G719X mutations' below.)

Comparisons of gefitinib, erlotinib, and afatinib — Available data suggest that erlotinib, gefitinib, and afatinib all have efficacy in EGFR-mutant lung cancer and are generally well tolerated. Some data suggest that afatinib may yield the strongest disease outcomes but may also cause the most side effects [28,29]. Some evidence suggests gefitinib may be the best tolerated of the agents, though this has not been consistently observed. Osimertinib is preferred in the front-line setting, however. (See 'Preferred: Osimertinib, with or without chemotherapy' above.)

Brain metastases — Surgery and/or radiation therapy may be indicated for patients with brain metastases from NSCLC. In selected patients with brain metastases whose tumor possesses an activating mutation of the EGFR tyrosine kinase, treatment with an EGFR TKI may possess clinically useful activity against the brain lesion. Efficacy of osimertinib against brain metastases is discussed above. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases" and "Overview of the treatment of brain metastases" and "Brain metastases in non-small cell lung cancer", section on 'EGFR mutations' and 'Preferred: Osimertinib, with or without chemotherapy' above.)

Duration of therapy — Treatment with an EGFR TKI is generally continued until there is disease progression. However, some patients have rapid disease progression when therapy with an EGFR TKI is discontinued after a prolonged course of treatment. This has led some groups to continue the EGFR TKI in patients with progressive disease who had an initial response to treatment [30-32]. However, when chemotherapy is initiated, treatment with EGFR TKI generally should be discontinued.

The IMPRESS trial in 265 NSCLC patients whose tumor contained an activating mutation in EGFR compared chemotherapy plus gefitinib versus chemotherapy alone after disease progression on first-line gefitinib [33,34]. This trial found that continuing gefitinib in conjunction with chemotherapy did not prolong PFS compared with chemotherapy alone and was associated with a shorter OS compared with placebo.

RESISTANCE TO EGFR TKIS

Approach — The use of EGFR tyrosine kinase inhibitors (TKIs) should be integrated with other treatment strategies to prolong survival and maintain quality of life for as long as possible. For patients with an EGFR mutation who progress on an EGFR TKI and are found to have a substitution of methionine for threonine at position 790 (T790M) mutation, we treat with osimertinib. (See 'Osimertinib' below.)

Methods of assessing for T790M are discussed elsewhere. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Molecular testing'.)

For patients who do not have a T790M mutation, or for those who progress on osimertinib, combination chemotherapy, with or without the addition of immunotherapy, is usually the next treatment option when progressive disease develops. (See 'Resistance to osimertinib-based therapy' below.)

Chemotherapy with platinum-etoposide is recommended for patients with evidence of small cell transformation, after standard EGFR TKI therapy [35].

Mechanisms — Almost all patients who initially respond to an EGFR TKI subsequently develop disease progression. The causes of acquired resistance are not fully understood, but include secondary mutations in EGFR (eg, T790M) [36-39], amplification of MET [40-45], and histologic transformation to small cell lung cancers [46,47].

Tumors with neuroendocrine transformation may be sensitive to small cell lung cancer chemotherapy regimens [46,48]. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Initial treatment'.)

Resistance to gefitinib, erlotinib, or afatinib

Osimertinib — Osimertinib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in patients with NSCLC harboring a T790M mutation whose disease progressed on other EGFR-inhibiting therapy, based on results of a phase I/II study suggesting a response rate of 61 percent and median progression-free survival (PFS) of 10 months in this setting [49]. In the subsequent phase III trial of 419 patients with T790M-positive NSCLC who had progressed on first-line EGFR TKI, osimertinib demonstrated improved PFS (10.1 versus 4.4 months; hazard ratio [HR] for progression or death 0.30, 95% CI 0.23-0.41) and objective response rate (71 versus 31 percent; odds ratio [OR] for objective response 5.4, 95% CI 3.47-9.48) compared with a pemetrexed- and platinum-based chemotherapy combination [50]. At longer follow-up of over 20 months, the median overall survival (OS) was 27 versus 23 months for osimertinib versus platinum-pemetrexed, respectively (HR 0.87, 95% CI 0.67-1.12) [51]. Although the difference was not statistically significant, crossover may have affected these results. Grade 3 or higher toxicities were lower with osimertinib than chemotherapy (23 versus 47 percent).

Among the 144 patients with central nervous system (CNS) disease, the median duration of PFS was longer with osimertinib than with chemotherapy (8.5 versus 4.2 months; HR 0.32, 95% CI 0.21-0.49). Preliminary results demonstrated higher CNS response rates with osimertinib among those with measurable disease (40 versus 17 percent; OR 3.24, 95% CI 1.33-8.81) and longer CNS PFS among those with either measurable or nonmeasurable disease (11.7 versus 5.6 months; HR 0.32, 95% CI 0.15-0.69) [52].

Additional randomized clinical trials are ongoing to determine the role of other agents in patients with an activating mutation. For example, agents such as rociletinib and HM61713 also demonstrate activity against EGFR-mutant tumors with the T790M resistance mutation, though these are not approved by the FDA [53-55].

The irreversible EGFR TKI afatinib may also have some activity in patients with acquired resistance to gefitinib or erlotinib [21]. Results of a phase III trial in patients who had progressed after both chemotherapy and an EGFR TKI (either erlotinib or gefitinib) found that afatinib increased PFS but did not improve OS [21]. (See 'Afatinib' above.)

Resistance to osimertinib-based therapy — There are no targeted agents that are FDA approved for those who have progressed on osimertinib (either in the adjuvant or metastatic setting).

Consistent with expert guidelines, we typically biopsy a site of progressive disease to determine if another targetable mutation is present [35].

●If an actionable driver mutation is identified, we treat with the appropriate targeted agent. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

●If no alternative actionable driver mutation is identified, our approach to those with progression on osimertinib is to offer treatment with a platinum-based chemotherapy regimen, similar to those without an EGFR mutation who are chemotherapy naϊve.

•For those with small cell transformation, a platinum-etoposide regimen is typically used [35], with or without an immune checkpoint inhibitor.

•For those without small cell transformation, the combination of bevacizumab plus platinum-based chemotherapy could be considered an alternative option [35].

•The addition of the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab to bevacizumab and platinum-based doublet chemotherapy has been shown to improve PFS, with a trend toward improved OS, in nonsquamous NSCLC, including among those with activating driver mutations. However, in this subset, trial results are conflicting.

In the IMpower 150 trial, the addition of atezolizumab to the combination of bevacizumab, carboplatin, and paclitaxel improved PFS among 800 patients with advanced NSCLC [56]. The benefit was also seen in the subset of 111 patients with EGFR mutations or anaplastic lymphoma kinase (ALK) translocations, all of whom had progressed on a prior targeted agent (median PFS, 9.7 versus 6.1 months; HR 0.59, 95% CI 0.37-0.94; median OS, not estimable versus 17. 5 months; HR 0.54, 95% CI 0.29-1.03) [57]. In the overall study population, serious adverse events occurred in 25 percent of those who also received atezolizumab versus 19 percent of those receiving standard therapy only. Further details of this study are described elsewhere. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'In nonsquamous cancers'.)

In contrast to IMpower 150, the addition of atezolizumab to initial chemotherapy (nabpaclitaxel and carboplatin) did not improve PFS (HR 0.75, 95% CI 0.36-1.54) or OS (HR 0.98, 95% CI 0.41-2.31) in the subset of 44 patients with EGFR- or ALK-positive NSCLC in IMpower 130 [58]. We await full reporting and follow-up of these trials for clarification on the role of immunotherapy for those with activating driver mutations, upon progression on available targeted agents.

●For those with no other actionable driver mutation who have progressed on both platinum-based chemotherapy and osimertinib (either sequentially or in combination), options include enrollment in a clinical trial, palliative care only, or single-agent chemotherapy. (See "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation".)

Studies are evaluating mechanisms of resistance to osimertinib. For example, in one study of patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to an early-generation EGFR TKI, loss of T790M at the time of progression on osimertinib was identified as a resistance mechanism [59].

UNCOMMON EGFR MUTATIONS

EGFR exon 20 insertion mutations

For treatment-naïve disease — Amivantamab is a bispecific EGFR and MET receptor antibody that has shown progression-free survival (PFS) improvements when combined with front-line chemotherapy for patients with EGFR exon 20 insertion mutations. We suggest its use with chemotherapy in this setting, if available, while recognizing that it does not yet have regulatory approval for this indication, and availability may therefore be restricted. If amivantamab is unavailable for front-line use, we treat patients with EGFR exon 20 insertion mutations with platinum-based chemotherapy alone, reserving targeted therapy for next line treatment. (See 'For those treated with initial chemotherapy' below.)

In a randomized trial in 308 patients with advanced NSCLC with EGFR exon 20 insertions who had not received previous systemic therapy, those assigned to amivantamab plus chemotherapy experienced a longer PFS relative to those assigned to chemotherapy alone (11.4 versus 6.7 months; HR 0.40, 95% CI 0.30-0.53) [60]. At 18 months, PFS rates were also improved with the addition of amivantamab to chemotherapy, 31 percent versus 3 percent, respectively. At median follow-up of approximately 15 months, response rates were 73 versus 47 percent, respectively (rate ratio 1.50, 95% CI 1.32-1.68). In the interim overall survival analysis (with 33 percent maturity), the HR for death for amivantamab–chemotherapy versus chemotherapy alone was 0.67 (95% CI 0.42-1.09). Grade ≥3 adverse effects occurred in 75 percent in the amivantamab-chemotherapy group and 54 percent with chemotherapy alone. The most common adverse events in the amivantamab-chemotherapy group were reversible hematologic effects.

For those treated with initial chemotherapy — For patients with EGFR exon 20 insertion-mutated NSCLC that have progressed on chemotherapy (either with or without immunotherapy), we suggest amivantamab as a later-line option.

●Amivantamab – Amivantamab is approved by the US Food and Drug Administration (FDA) for patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy [61].

In a phase I study, among 81 patients with advanced NSCLC with EGFR exon 20 insertions that had experienced progression on platinum-based chemotherapy, the overall response rate with amivantamab was 40 percent, the clinical benefit rate (stable disease for at least 11 weeks or response to treatment) was 74 percent, and the median duration of response was 11.1 months [62]. Median progression-free survival was 8.3 months, and the median overall survival was 23 months.

The most frequent adverse events (AEs) were rash (86 percent), infusion-related reaction (IRR; 66 percent), and paronychia (45 percent). Additional EGFR-related AEs were stomatitis (21 percent), pruritus (17 percent), and diarrhea (12 percent). Grade ≥3 AEs were reported in 35 percent of patients; 16 percent were related to treatment, with rash (4 percent) and IRR (3 percent) being the most common.

●Others – Mobocertinib is an oral tyrosine kinase inhibitor that was previously approved by the FDA for patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations progressive on or after platinum-based chemotherapy, but the manufacturer is removing it from the market because of lack of efficacy in the confirmatory trial. Other agents, including zipalertinib [63] are under investigation.

EGFR S768I, L861Q, and G719X mutations — Afatinib is also approved for the first-line treatment of patients with NSCLC whose tumors contain EGFR mutations S768I, L861Q, and G719X, as well as those that harbor the more common activating genetic alterations (exon 19 deletions or exon 21 L858R). However, afatinib is not the ideal treatment for all uncommon EGFR mutations [64]. In a pooled posthoc analysis of three trials in which afatinib was compared with platinum-based chemotherapy as initial treatment for those with EGFR mutations, clinical benefit was lower in patients with de novo Thr790Met and exon 20 insertion mutations compared with those with EGFR S768I, L861Q, or G719X mutations [64,65].

Osimertinib has also demonstrated favorable activity in patients with uncommon EGFR mutations. In an observational study of 37 patients with metastatic or recurrent NSCLC harboring EGFR mutations other than the exon 19 deletion, L858R and T790M mutations, or the exon 20 insertion, the objective response rate was 50 percent [66]. Approximately 60 percent of patients received osimertinib as first-line therapy. Although, for those with advanced NSCLC associated with uncommon EGFR mutations, we typically offer afatinib, given the FDA approval for this indication, osimertinib is a reasonable alternative.

COMBINATION REGIMENS — EGFR tyrosine kinase inhibitors (TKIs) have been studied in combination both with bevacizumab and ramucirumab, antibodies targeting vascular endothelial growth factor (VEGF), and with chemotherapy.

Such combinations, however, are less favored options, compared with osimertinib in the front-line setting. (See 'Preferred: Osimertinib, with or without chemotherapy' above.)

EGFR TKI TOXICITY — Important toxicities associated with inhibition of the EGFR pathway include a characteristic rash, diarrhea, and uncommonly interstitial pneumonitis.

Rash — All agents targeting the EGFR pathway, including both small molecule tyrosine kinase inhibitors (TKIs) as well as monoclonal antibodies that bind EGFR, are associated with dermatologic toxicity (predominantly dry skin and an acneiform rash, although more severe reactions have been reported). This is thought to be due to high levels of EGFR expression in the basal layer of the epidermis. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

Gastrointestinal toxicity — Diarrhea is common in patients receiving small-molecule EGFR TKIs. It has been reported in a majority of patients (especially with afatinib), but it is only occasionally severe and typically can be easily managed by the use of loperamide. Rarely, episodes of gastrointestinal perforation, some of which were fatal, have also been reported in patients receiving erlotinib. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Small molecule EGFR inhibitors' and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'EGFR inhibitors'.)

Pulmonary toxicity — Potentially fatal lung toxicity has been reported with erlotinib, gefitinib, and dacomitinib. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Anti-EGFR agents'.)

Hepatic toxicity — Hepatic failure and hepatorenal syndrome, potentially resulting in death, have been reported in patients treated with erlotinib. Patients with hepatic impairment should be closely monitored during treatment with erlotinib, and extra caution should be used in those with an elevated serum bilirubin. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents", section on 'Erlotinib and gefitinib'.)

Ocular toxicity — All EGFR inhibitors have been associated with dysregulated hair cycles, which may lead to trichomegaly or trichiasis, with eyelashes directed at the cornea. Poor healing of the outermost epithelial layer of the cornea is reported with all EGFR inhibitors, leading to dry eyes, and persistent corneal epithelial defects and erosions as well as corneal thinning that may predispose to corneal perforation. Erlotinib can cause conjunctivitis, eyelid changes such as entropion and ectropion, and rarely, anterior uveitis. Clinical trials with gefitinib have reported mostly dry eye, blepharitis, conjunctivitis, and visual disturbances such as hemianopia, blurred vision, and photophobia. (See "Ocular side effects of systemically administered chemotherapy", section on 'Epidermal growth factor receptor (EGFR) inhibitor'.)

Immune-related toxicities with EGFR TKI after immunotherapy — Although osimertinib is our suggested front-line option for EGFR-mutated, advanced NSCLC, some patients may have already been exposed to immunotherapy, for example, as part of treatment for unresectable stage III disease (durvalumab), or because their EGFR status was unknown at the time of diagnosis. For such patients, we suggest delaying osimertinib for at least three months following completion of immunotherapy in order to avoid excess in toxicities associated with EGFR tyrosine kinase inhibitors (TKIs) following immunotherapy. Chemotherapy during this interval may be appropriate for some. Alternatively, for patients who require immediate treatment and are poor candidates for chemotherapy, proceeding directly with an EGFR inhibitor may be preferred, after a clear discussion of the potential risks and benefits. In such instances, we often opt for erlotinib rather than osimertinib, recognizing that although the increased toxicities with EGFR inhibition after immunotherapy may be a class effect, observational data suggest that the association may be stronger for osimertinib than for other EGFR inhibitors.

In an observational study including 41 patients treated first with programmed cell death ligand 1 (PD-L1) blockade and then with osimertinib, 15 percent experienced a severe immune-related adverse event [67]. These toxicities were most common among those who initiated osimertinib within three months of prior immunotherapy (5 of 21 patients, 24 percent) versus those who initiated it within 3 to 12 months (1 of 8 patients, 13 percent) or after 12 months (0 of 12 patients, 0 percent). By contrast, no severe immune-related adverse events (AEs) were observed among the 29 patients who received osimertinib and then immunotherapy.

While in this study, the association appeared to be specific to osimertinib (with no severe immune-related AEs noted among the 27 patients treated first with immunotherapy and then with either afatinib or erlotinib), severe pneumonitis with erlotinib following pembrolizumab has been reported elsewhere [68].

CHEMOTHERAPY

Those initially treated with chemotherapy in whom a mutation is subsequently identified — Most patients with advanced NSCLC whose tumors contain a driver mutation are initially treated with the appropriate targeted agent (eg, erlotinib, gefitinib, crizotinib). For patients with advanced NSCLC who were initially treated with chemotherapy but in whom a driver mutation has subsequently been identified, continuation of therapy is indicated with an appropriate targeted agent after the initial cycles of chemotherapy are complete. However, if an immune checkpoint inhibitor was used as part of initial management, the risk of immune-mediated pneumonitis rises with subsequent use of osimertinib (and possibly other EGFR tyrosine kinase inhibitors [TKIs]). This risk and management are discussed elsewhere. (See 'Immune-related toxicities with EGFR TKI after immunotherapy' above.)

There are no randomized trials directly addressing the situation in which patients are found to have an EGFR mutation or other driver mutation after the initiation of chemotherapy. However, analysis of outcomes based upon mutation status in a subset of patients in the SATURN trial provides evidence that maintenance therapy with erlotinib after chemotherapy substantially improves progression-free survival (PFS) in these patients [69,70]. In the SATURN trial, previously untreated patients with advanced NSCLC were treated with four cycles of platinum-based doublet chemotherapy. Patients with an objective response or stable disease were then randomly assigned to treatment with erlotinib or placebo. EGFR mutation status was not determined prior to inclusion in the clinical trial.

Subsequently, tumor samples were analyzed for an EGFR mutation in 437 of the randomized patients [69]. EGFR mutations were detected in 49 cases (11 percent), while 388 were wildtype (89 percent). For patients with an EGFR mutation, PFS was significantly increased in those receiving maintenance erlotinib compared with placebo (median, 45 versus 13 weeks; hazard ratio for progression 0.10, 95% CI 0.04-0.25). Differences in overall survival were not statistically significant for patients with an EGFR mutation, but 67 percent of patients given a placebo subsequently received an EGFR TKI as second-line therapy.

Those with progression on an EGFR inhibitor — For some patients who develop resistance to an EGFR inhibitor, chemotherapy may be indicated. The approach is discussed above. (See 'Resistance to EGFR TKIs' above.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Non-small cell lung cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Non-small cell lung cancer treatment; stage IV cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Rationale for EGFR inhibitors – The presence of a characteristic mutation in the epidermal growth factor receptor (EGFR) defines a subset of patients with non-small cell lung cancer (NSCLC) who are likely to have a favorable response to EGFR tyrosine kinase inhibitors (TKIs). (See 'Rationale' above.)

●Assessment for driver mutations – Whenever possible, therapy of patients with advanced NSCLC should be individualized based upon the molecular and histologic features of the tumor. If feasible prior to treatment, patients should have tumor tissue assessed for the presence of a somatic mutation in the EGFR as well as for other driver mutations. (See 'EGFR mutation as a predictor of responsiveness' above and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

●Efficacy of single-agent EGFR tyrosine kinase inhibitors (TKIs) for common activating EGFR mutations – For patients with previously untreated metastatic NSCLC and an exon 19 deletion or exon 21 L858R activating mutation of the EGFR, we recommend monotherapy with an EGFR TKI rather than chemotherapy (Grade 1B). In randomized trials, this approach significantly prolongs progression-free survival (PFS), although the impact on overall survival (OS) remains uncertain. (See 'Efficacy of single-agent EGFR TKIs' above.)

•For most patients with advanced EGFR-mutant NSCLC, we suggest osimertinib as the front-line treatment rather than other TKIs (Grade 2B). Data have shown PFS benefits with the addition of chemotherapy to osimertinib at the expense of added toxicity, but survival benefits are unknown. Although we have not incorporated this strategy into our clinical practice pending longer term data, we recognize that it is an acceptable strategy. (See 'Alternatives' above and 'Preferred: Osimertinib, with or without chemotherapy' above.)

•Use of an EGFR inhibitor in combination with standard platinum-based chemotherapy regimens is not a standard option for patients with NSCLC that contains an EGFR mutation, given increased toxicity and the fact that trials were conducted prior to routine use of osimertinib. Results with the combination of first-generation EGFR inhibitors and chemotherapy in the frontline setting are provocative, however, and deserving of further study. (See 'Combination regimens' above.)

•Patients with previously untreated metastatic NSCLC but without an activating mutation of the EGFR should be treated with either chemotherapy or other targeted agents, depending upon the molecular characteristics of their tumor. (See 'EGFR mutation as a predictor of responsiveness' above and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

●Patients with progression on EGFR inhibitors – For patients with an EGFR mutation who progress on a first- or second-generation EGFR TKI and are found to have a substitution of methionine for threonine at position 790 (T790M) mutation, we treat with osimertinib. For those who do not have a T790M mutation, or for those who progress on osimertinib, subsequent management usually consists of cytotoxic chemotherapy and immunotherapy, in the same way as for other chemotherapy-naïve patients. The addition of the anti-programmed cell death ligand 1 (PD-L1) antibody atezolizumab to bevacizumab and platinum-based doublet chemotherapy has been shown to improve outcomes in nonsquamous NSCLC, including among those with activating driver mutations, and is an off-label option in such patients upon progression on osimertinib. (See "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation" and "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'In nonsquamous cancers'.)

•Continuing an EGFR TKI beyond progression and during subsequent treatment with chemotherapy is not recommended and is associated with shortened OS.

●Uncommon EGFR mutations – For patients with EGFR exon 20 insertion-mutated NSCLC, we suggest the addition of amivantamab to front-line chemotherapy (Grade 2B), if available. If amivantamab is not available for front-line use, we use either amivantamab as a single agent after progression on platinum-based chemotherapy.

For those with advanced NSCLC and EGFR S768I, L861Q, or G719X mutations, we suggest initial treatment with afatinib (Grade 2C), although osimertinib is a reasonable alternative.