Version October 2024
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, 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 systemic therapy for advanced non-small cell lung cancer lacking a driver mutation".)
EPIDEMIOLOGY — Mutations in the EGFR tyrosine kinase are observed in approximately 15 percent of NSCLC adenocarcinoma in the United States and occur more frequently in females and nonsmokers. In Asian populations, the incidence of EGFR mutations is substantially higher.
In the PIONEER study, tumors were analyzed from 1482 patients with adenocarcinoma in seven Asian regions (China, Hong Kong, India, Philippines, Taiwan, Thailand, Vietnam) [1]. 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 females than in males, but the difference was not significant after considering the frequency of smoking.
IDENTIFICATION OF MUTATIONS AND RATIONALE FOR TARGETED THERAPY — All patients with advanced NSCLC should have their tumor assessed for the presence of driver mutations. Molecular testing of NSCLC is discussed elsewhere. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Molecular testing'.)
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).
Advanced NSCLCs that contain characteristic mutations in EGFR, exon 19 deletions or exon 21 L858R mutations, are highly sensitive to EGFR TK inhibitors (TKIs).
For example, in the IPASS trial, among patients with an EGFR mutation, progression-free survival (PFS) was longer with gefitinib compared with carboplatin plus paclitaxel (median 9.5 versus 6.3 months, hazard ratio [HR] for progression 0.48); but among those lacking an EGFR mutation, PFS was shorter with gefitinib than with chemotherapy (median 1.5 versus 6.5 months, HR 2.85 for progression) [2]. Furthermore, EGFR overexpression by immunohistochemistry was shown to be an inappropriate biomarker, PFS outcomes were worse with gefitinib compared with chemotherapy for those with high EGFR copy number (HR 3.85, 95% CI 2.09-7.09), unless an activating mutation was also present [3]. Further results of the IPASS trial are discussed below. (See 'Earlier generation TKIs as alternatives' below.)
INITIAL THERAPY FOR COMMON MUTATIONS
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 (algorithm 1). (See 'Earlier generation TKIs as 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 [4], and has shown benefit over older EGFR tyrosine kinase inhibitors (TKI). It is approved as a single agent or in combination with pemetrexed and platinum-based chemotherapy. Osimertinib has been associated with QTc prolongation as well as decreases in left ventricular ejection fraction, which are reversible with discontinuation of the drug [5]. 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) [6]. 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) [7]. Approximately a quarter of the patients in the SOC arm received an EGFR TKI (including osimertinib) as next-line therapy. 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).
In a separate trial, initial treatment with osimertinib was compared with gefitinib followed by osimertinib upon progression (either molecular progression with detection of plasma T790M resistance mutation, or radiologic progression) [8]. Both groups experienced comparable overall survival (HR 1.01), but osimertinib was associated with a lower risk of brain progression compared with the sequential approach (HR 0.54, 90% CI 0.34-0.86).
●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 'Progressive disease' below.)
Earlier generation TKIs as alternatives — Data suggest improved outcomes with osimertinib over older agents such as gefitinib and erlotinib, which are discussed above. (See 'Initial therapy for common mutations' above.)
However, if osimertinib is unavailable, other EGFR inhibitors are available and have shown benefit over chemotherapy. Representative data are below.
●Erlotinib — Erlotinib has been compared with chemotherapy in several randomized trials in patients with EGFR-mutated lung cancer, all of which demonstrated a benefit in PFS with erlotinib, but not in OS. This likely reflects the effect that post-trial treatments have on OS, especially given that cross-over to tyrosine kinase inhibitors (TKI) upon progression on chemotherapy was permitted.
As an example, in the ENSURE trial, 275 patients were randomized to erlotinib or gemcitabine and cisplatin [10]. 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). Other trials have shown similar results [11,12].
●Gefitinib — Gefitinib is approved by the FDA for patients whose tumor contains an EGFR exon 19 deletion or the exon 21 L858R substitution mutation [13].
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 [2,3]. 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) [2]. OS was not increased (median 22 months in both groups, HR 1.00) [3].
Two additional phase III trials were conducted exclusively in patients with EGFR mutations (the West Japan Oncology Group 172 trial [14,15] and the North-East Japan Study Group 002 trial [16,17]). 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 [18-22].
Afatinib was compared with chemotherapy as the initial therapy for advanced NSCLC in two phase III trials in patients whose tumors contain activating mutations. In a combined analysis of two randomized trials including 709 patients with advanced NSCLC and activating EGFR mutations, OS was similar for patients assigned to afatinib versus chemotherapy in the overall group and in patients with L858R mutations [23]; however, afatinib improved OS in patients with exon 19 deletions (HR 0.54 in one trial [20,21], and 0.64 in the other [24]). There were PFS benefits in both trials, irrespective of whether patients had tumors with L858R or exon 19 deletions.
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 [25,26]. Some evidence suggests gefitinib may be the best tolerated of the agents, though this has not been consistently observed. Osimertinib is preferred in the frontline setting, however. (See 'Initial therapy for common mutations' above.)
DURATION OF THERAPY — We discontinue treatment with an EGFR tyrosine kinase inhibitor (TKI) at the point of disease progression. However, alternatively, some groups continue the EGFR TKI in patients with progressive disease who had an initial response to treatment [27-29], given the possibility of rapid disease progression.
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 [30,31]. 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.
PROGRESSIVE DISEASE
Rebiopsy — Consistent with expert guidelines, we typically biopsy a site of progressive disease to determine if another targetable mutation is present [32]. Our subsequent approach is described below (algorithm 1).
Subsequent-line therapy
Actionable driver present — If another actionable driver mutation is identified, we treat with the appropriate targeted agent. For example, MET amplification has been reported as a resistance mechanism for patients experiencing progression on osimertinib [33]. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)
Although most patients will have received prior osimertinib, some patients may have been treated with an earlier generation tyrosine kinase inhibitor TKI. For patients with an EGFR mutation who progress on a first or second generation EGFR TKI (erlotinib, gefitinib, or afatinib) and are found to have a substitution of methionine for threonine at position 790 (T790M) mutation [34-37], we treat with osimertinib. (See 'Preferred: Osimertinib, with or without chemotherapy' above.)
In a randomized trial of 419 patients with T790M-positive NSCLC who had progressed on first-line EGFR TKI, osimertinib demonstrated improved progression-free survival (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 [38]. 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) [39]. 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).
The irreversible EGFR TKI afatinib may also have some activity in patients with acquired resistance to gefitinib or erlotinib [18]. 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 [18].
No other actionable driver present — If no alternative actionable driver mutation is identified, our approach depends on whether histologic transformation was present.
Histologic transformation — Our approach depends on the type of histologic transformation.
●For those with small cell transformation, we suggest a platinum-etoposide regimen [32], and incorporate an immune checkpoint inhibitor, as for de novo small cell lung cancer. Response rates to platinum-etoposide have been reported to be on the order of 50 percent in a retrospective review including 46 patients with small cell lung cancer transformation, although the median PFS was low (3.4 months) [40]. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Preferred option: Immunotherapy plus platinum-etoposide'.)
●For patients with squamous cell transformation [41], we suggest a platinum-based doublet, and incorporate a checkpoint inhibitor as for de novo squamous cell carcinoma, although data are limited [42]. We extrapolate from data in the initial treatment setting for patients without EGFR mutations. (See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation", section on 'Preference for platinum-based regimens'.)
No histologic transformation — For those without histologic transformation, we suggest the combination of amivantamab plus platinum-based chemotherapy [32]. Platinum-based doublet chemotherapy with bevacizumab, with or without the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab, is an acceptable alternative.
In a randomized trial, among patients with EGFR-mutated NSCLC progressive on osimertinib, PFS was significantly longer for amivantamab chemotherapy versus chemotherapy alone, based on blinded central review (median of 6.3 versus 4.2 months; HR 0.48, 95% CI 0.36-0.64) [43]. The combination of amivantamab and the third generation EGFR inhibitor lazertinib also improved median PFS relative to chemotherapy (8.3 versus 4.2 months, respectively; HR 0.44, 95% CI 0.35-0.56). Objective response rates were 64 percent for amivantamab-chemotherapy, 63 percent for amivantamab-lazertinib-chemotherapy, and 36 percent for chemotherapy alone. At the first interim OS analysis, the HRs for death were 0.77 (95% CI 0.49-1.21) for amivantamab chemotherapy versus chemotherapy and 0.96 (95% CI 0.67- 1.35) for amivantamab-lazertinib chemotherapy versus chemotherapy, although these improvements were not statistically significant. Grade ≥3 adverse events, mainly hematologic, were reported by 72 percent of patients treated with amivantamab chemotherapy, 92 percent with amivantamab-lazertinib chemotherapy, and 48 percent with chemotherapy. Lazertinib does not have regulatory approval in this setting.
As an alternative to amivantamab and chemotherapy, the addition of immune checkpoint inhibitors to platinum-based doublet chemotherapy (with or without bevacizumab) are options, but has shown conflicting results among those with activating driver mutations.
●In an open label randomized trial in 228 patients with either activating EGFR or ALK genetic alterations who had experienced progression on a targeted agent, the addition of atezolizumab and bevacizumab to carboplatin and paclitaxel (ABCP) improved objective response rate (70 versus 42 percent) and median PFS (8.5 versus 5.6 months) compared with platinum-paclitaxel (PC) [44]. Greater benefits were observed with increasing PD-L1 expression (HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1, ≥10, and ≥50 percent, respectively). Overall survival was similar between ABCP and PC arm (20.6 versus 20.3 months; HR 1.0). Approximately 90 percent of patients in this trial had cancers with EGFR activating mutations. Grade ≥3 treatment related adverse events were 35 percent in the ABCP arm and 15 percent in the PC arm.
●Benefits were also seen in the Impower 150 trial, in which the addition of atezolizumab to the combination of bevacizumab, carboplatin, and paclitaxel improved PFS in the overall trial population, and 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; median OS, not estimable versus 17.5 months; HR 0.54) [45].
●In contrast to the data above, the addition of atezolizumab to initial chemotherapy (nabpaclitaxel and carboplatin) did not show improved PFS or OS in the subset of 44 patients with EGFR- or ALK-positive NSCLC in Impower 130 [46]. Moreover, in a separate trial, the addition of nivolumab to doublet-based chemotherapy failed to improve PFS among patients with EGFR-mutated metastatic NSCLC previously treated with EGFR TKIs [47].
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 targeted agents.
Later-line therapy — For those with no other actionable driver mutation who have progressed on both platinum-based chemotherapy and a next generation TKI, 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".)
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 "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation", section on 'Small molecule EGFR inhibitors' and "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation", section on 'EGFR inhibitors'.)
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 "Hepatotoxicity of molecularly targeted agents for cancer therapy", section on 'Erlotinib and gefitinib'.)
Pulmonary toxicity — Potentially fatal lung toxicity has been reported with erlotinib, gefitinib, and dacomitinib. (See "Pulmonary toxicity of molecularly targeted agents for cancer therapy", section on 'Anti-EGFR agents'.)
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'.)
SPECIAL CONSIDERATIONS
Management of uncommon EGFR mutations — Our approach to advanced NSCLC with uncommon EGFR mutations is discussed below (algorithm 1).
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 frontline chemotherapy for patients with EGFR exon 20 insertion mutations. We suggest its use with chemotherapy in this setting. If amivantamab is unavailable for frontline 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; hazard ratio [HR] 0.40, 95% CI 0.30-0.53) [48]. 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 (AEs) 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 [49].
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 [50]. Median PFS was 8.3 months, and the median OS was 23 months.
The most frequent 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.
●Other options – Mobocertinib is an oral TKI 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, although it may be available from the manufacturer for compassionate use in patients already receiving the drug. Other agents, including zipalertinib [51] are under investigation.
EGFR S768I, L861Q, and G719X mutations — For patients with NSCLC whose tumors contain EGFR mutations S768I, L861Q, and G719X, we suggest afatinib, but consider osimertinib an acceptable option as well. However, afatinib is not the ideal treatment for all uncommon EGFR mutations [52]. 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 [52,53].
Osimertinib has also demonstrated favorable activity in patients with uncommon EGFR mutations [54,55]. 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 [55]. 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.
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 tyrosine kinase inhibitor (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 'Initial therapy for common mutations' above.)
Immune-related toxicities with EGFR TKI after immunotherapy — Although osimertinib is our suggested frontline 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 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 blockade and then with osimertinib, 15 percent experienced a severe immune-related adverse event (AE) [56]. 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 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 [57].
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 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 [58,59]. 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 [58]. 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.
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 5th to 6th 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 10th to 12th 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 – Patients should have tumor tissue assessed for the presence of a somatic mutation in the epidermal growth factor receptor (EGFR) as well as for other driver mutations. The presence of a characteristic mutation in the 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 'Identification of mutations and rationale for targeted therapy' above.)
●Initial treatment – 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 (algorithm 1) (Grade 1B). In randomized trials, this approach significantly prolongs progression-free survival, although the impact on overall survival remains uncertain.
•For patients with advanced NSCLC with EGFR exon 19 deletions or exon 21 L858R, we suggest osimertinib as the frontline 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 'Earlier generation TKIs as alternatives' above and 'Initial therapy for common mutations' above.)
●Progressive disease – Consistent with expert guidelines, we typically biopsy a site of progressive disease to determine if another targetable mutation is present.
•If an actionable driver mutation is identified (eg, MET amplification), we treat with the appropriate targeted agent. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)
•For those with small cell transformation, we suggest a platinum-etoposide regimen with an immune checkpoint inhibitor (Grade 2C). (See 'Histologic transformation' above.)
•For those without histologic transformation, we suggest the addition of amivantamab to platinum-based chemotherapy (Grade 2B). (See 'No histologic transformation' above.)
●EGFR toxicities – Important toxicities associated with inhibition of the EGFR pathway include a characteristic rash, diarrhea, and uncommonly interstitial pneumonitis. (See 'EGFR TKI toxicity' above.)
●Special considerations – The approach to those with uncommon EGFR mutations is as follows:
•For patients with EGFR exon 20 insertion-mutated NSCLC, we suggest the addition of amivantamab to frontline chemotherapy (Grade 2B). Platinum-based chemotherapy alone is an acceptable alternative. (See 'EGFR exon 20 insertion mutations' above.)
•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. (See 'EGFR S768I, L861Q, and G719X mutations' above.)
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