Introduction
Lung cancer continues to be the most frequent cancer globally with 2.1 million new lung cancer cases and 1.8 million deaths, accounting for about 18.4% of all cancer-related deaths.[1] Per GLOBOCAN 2018, the number of new lung cancer cases reported in India was 67,695. Non–small-cell lung cancer (NSCLC) accounts for 85% of all cases of lung cancer.[2] The 5-year survival rate of patients with Stage IV NSCLC is <5%. Epidermal growth factor receptor (EGFR) is the most established driver mutation in NSCLC.[3] Targeted therapies with EGFR-based tyrosine kinase inhibitors (TKIs) have become standard of care treatment options to modulate these molecular pathways and improve patient outcomes. However, tumors eventually develop resistance leading to disease progression; thus, overcoming the resistance is always a priority. With the emergence of recent evidence, third-generation EGFR-TKI therapy (osimertinib) is now recommended as the front-line therapy for patients with advanced EGFR-mutated (EGFRm) NSCLC. Nevertheless, there is a dilemma in clinical practice for deciding the preferential EGFR-TKI therapy with manageable toxicity, improved quality of life, and better survival prospects in patients. This review discusses the rationale and data that support the ideal sequencing of EGFR-TKIs in Stage IV NSCLC patients to maximize clinical benefits.
Driver mutations and targeted therapies in NSCLC
NSCLC being a heterogeneous disease is marked with a high rate of somatic mutations in the tumor suppressor protein 53 (TP53), EGFR, and Kirsten rat sarcoma viral oncogene homolog (KRAS) genes with an incidence of approximately 52%, 17%, and 25%; respectively.[456] The incidence of EGFR mutations is the highest in women, nonsmokers, and patients with adenocarcinoma.[7] About 90% of EGFR mutations are at Exon 19 and L858R point mutation at Exon 21. Approximately 10% to 20% of Caucasian patients with NSCLC and up to 50% of Asian patients exhibit sensitizing EGFR mutations.[8] The incidence of EGFR mutations in Indian patients is 25% to 35%, which is higher than the Western population and closer to the Asian data.[9] Without a driver mutation, the first-line treatment for Stage IV NSCLC is guided by programmed death Ligand 1 (PD-L1) expression and histologic type. Immunotherapy or chemoimmunotherapy is recommended based on PD-L1 expression.[101112] TKIs have become the standard first-line treatment for patients with EGFRm NSCLC.
First- and second-generation TKIs
Several large controlled and randomized trials have shown improved progression-free survival (PFS), favorable toxicity profiles, and better quality of life with gefitinib or erlotinib compared with platinum-based combination chemotherapy as the first-line treatment for Stage IIIB or IV NSCLC. The Iressa Pan-ASia Study (IPASS),[13] First-Line Single-Agent Iressa Versus Gemcitabine and Cisplatin Trial in Never-Smokers With Adenocarcinoma of the Lung (FIRST-SIGNAL),[14] and West Japan Oncology Group (WJTOG) 3405[15] trials proved the efficacy and safety of gefitinib, where the PFS was significantly higher than chemotherapy (8.0–9.5 months vs. 6.3 months with chemotherapy). The pivotal trials with erlotinib (OPTIMAL[16] and EURTAC [EURopean TArceva vs. Chemotherapy][17]) demonstrated PFS >9 months. However, there was no clear benefit in terms of overall survival (OS) with first-generation EGFR-TKIs when compared with chemotherapy. Second-generation EGFRTKIs (afatinib and dacomitinib) were developed to overcome the low OS with first-generation TKIs. Second-generation EGFR-TKIs irreversibly bind to EGFR and have higher potency for inhibiting several members of the human epidermal receptor (HER) family.[18] Afatinib showed significant improvement in PFS (>11 months) compared with platinum-based chemotherapy (5.6N6.9 months) in EGFRm NSCLC patients in two randomized trials (LUX-Lung 3 and LUX-Lung 6).[1819] Dacomitinib and afatinib significantly prolonged PFS when compared with gefitinib in Phase IIB LUX-Lung 7 trial[20] (afatinib vs. gefitinib 11.0 months vs. 10.9 months; P = 0·017) and Phase III ARCHER 1050 trial (dacomitinib vs. gefitinib 14.7 months vs. 9.2 months; P < 0·0001).[21] However, potent inhibition of EGFR wild-type translates clinically to higher incidences of skin and gastrointestinal tract toxicities, which limits the use of second-generation TKIs.
Disease progression in first- and second-generation TKIs
Despite TKIs becoming a standard of care option of EGFRm NSCLC, disease progression is eventually observed post-TKI therapy. Secondary or acquired resistance develops after 9 to 12 months of therapy with first- or second-line TKIs.[22] The most common acquired resistance is the T790M substitution mutation at Exon 20 (Gatekeeper mutation), reported in 50% to 60% of patients with disease progression after initial response to first-line TKIs.[232425] Rarely, the T790M mutation may also occur in patients who have not previously received any EGFR-TKI therapy.[26] Figure 1 highlights the mechanisms responsible for acquired resistance to first- and second-generation EGFR-TKIs.[2425]
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Figure 1: Mechanism of acquired resistance to EGFR-TKIs. EGFR = epidermal growth factor receptor; EMT = epithelial mesenchymal transition; KRAS = ki-ras2 Kirsten rat sarcoma viral oncogene homolog; PI3K = phosphoinositide 3-kinase; SCLC = small-cell lung cancer; TKI = tyrosine kinase inhibitor. Figure recreated from Camidge et al.[24] and Westover et al.[25].
Additionally, brain metastasis is another common form of disease progression in EGFRm NSCLC patients with an incidence of 23% to 32% at initial diagnosis and 15% to 20% higher on disease progression.[27] The prevalence of EGFR mutations in NSCLC brain metastasis among Asian populations ranges from 39% to 63% and among North American and European populations ranges from 2% to 40%.[2829] Approximately, 30% of patients with NSCLC develop brain metastasis after TKI therapy, thereby reducing its effectiveness.[30] Lower blood–brain barrier penetration and poor bioavailability of first- and second-generation EGFR-TKIs contribute further to the emergence of resistance and thus restricts their efficacy in patients with brain metastases.
Third-Generation TKIs
Novel third-generation EGFR-TKIs such as osimertinib, rociletinib, olmutinib, naquotinib, and nazartinib were developed targeting emerging resistance especially T790M, which accounts for a majority of acquired TKI resistance.[31] They have a low affinity to the wild-type EGFR, which results in decreased toxicity, as observed with first- and second-generation EGFR-TKIs. Except for osimertinib, all other third-generation EGFR-TKIs are currently in the clinical trial phase, or their development has been halted because of toxicity.[32]
Osimertinib, an irreversible EGFR-TKI, targets the cysteine-797 residue in the EGFRs ATP-binding site and binds to this site with a covalent bond. Preclinical and clinical studies have demonstrated its effectiveness on EGFR sensitizing mutations and T790M mutation.[33]
Clinical program of osimertinib
The AURA extension phase and AURA2 evaluated osimertinib as a second-line treatment in patients with locally advanced/metastatic NSCLC with EGFR- and T790M mutation-positive tumors. The objective response rate (ORR), PFS, and OS in the pooled analysis of AURA extension phase and AURA2 studies were reported as 66% (95% confidence interval [CI]: 61%–70%), 9.9 months (95% CI: 9.5–12.3 months), and 26.8 months (95% CI: 24.2–29.1 months), respectively.[34] The AURA3 study reported a significantly longer median PFS (10.1 vs. 4.4 months; hazard ratio [HR], 0.30; 95% CI: 0.23–0.41; P < 0.001) and better ORR (71% vs. 31%, odds ratio 5.39; 95% CI: 3.47–8.48; P < 0.001) with osimertinib compared with chemotherapy.[35] In patients with central nervous system (CNS) metastases, the PFS was longer (8.5 months vs. 4.2 months, respectively; HR = 0.32; 95% CI: 0.21–0.49) with osimertinib treatment. Based on this evidence, osimertinib received the European Medicines Agency and Food and Drug Administration (FDA) approval for Stage IV EGFR mutant NSCLC with acquired T790M resistance mutation in 2015.[36] Recently, data on OS in the AURA3 study have been published. The OS was longer with osimertinib compared with chemotherapy (26.8 months vs. 22.5 months; HR 0.87; 95% CI: 0.67–1.12; P = 0.277).[37]
Osimertinib as a first-line therapy
The efficacy of osimertinib as the first-line agent was initially evaluated in the treatment-naïve cohort of the AURA3 study.[38] With once-daily dosing of osimertinib 80 mg, the reported ORR was 67%, the disease control rate was 93%, and the median duration of response was 19.3 months. The Phase 3 FLAURA trial evaluated osimertinib versus comparator EGFR-TKI (erlotinib or gefitinib) as first-line therapy in treatment-naïve patients with previously untreated EGFR mutation-positive (Ex19del or L858R) advanced NSCLC.[39] Osimertinib resulted in significantly longer PFS (18.9 months vs. 10.2 months, respectively; HR = 0.46; 95% CI: 0.37–0.57; P < 0.001) and higher median duration of response (17.2 months vs. 8.5 months, respectively) compared with comparator EGFR-TKI. Prespecified subgroup analyses for PFS favored osimertinib over comparator EGFR-TKI therapy across all subgroups. There was no evidence of acquired EGFR T790M mutation in postprogression plasma samples.[38] The recently published matured data from the FLAURA study showed a statistically significant and clinically meaningful improvement in OS with osimertinib.[40] A 20% reduction in the risk of death was reported in the osimertinib arm compared with comparator EGFR-TKIs (38.6 months; 95% CI: 34.5–41.8 months vs. 31.8 months; 95% CI: 26.6–36.0 months; HR: 0.80; 95% CI: 0.64–1.00; P = 0.046). The OS results for osimertinib and comparator EGFR-TKI at 12, 24, and 36 months were as follows: Month 12, 89% versus 83%; Month 24, 74% versus 59%; and Month 36, 54% versus 44%. The largest numerical between-group differences in the HRs for OS were observed between Asian and non-Asian patients.
Osimertinib demonstrated a favorable tolerability profile as the first-line therapy in patients with advanced NSCLC in the FLAURA trial.[39] The rates of discontinuation due to adverse events (AEs) and Grade ≥3 AEs were relatively lower with osimertinib (13% and 34%, respectively) than with gefitinib/erlotinib (18% and 45%, respectively). The most common Grade 3 AEs occurring in the osimertinib arm were decreased appetite (2%), diarrhea (2%), and rash or acne (1%). In April 2018, osimertinib received approval as the first-line treatment for EGFRm NSCLC by both the FDA and the European Union.[41] Table 1 shows the efficacy of osimertinib in the AURA and FLAURA clinical trials.[35373839424344]
Table 1: Efficacy outcomes of osimertinib against standard TKIs and chemotherapy in NSCLC in clinical trials
Place of osimertinib therapy in CNS metastasis
The CNS penetration ability of osimertinib is better than that of gefitinib, rociletinib, and afatinib.[45] The AURA3 study evaluated osimertinib in 116 (28%) patients in CNS full analysis set and 46 patients in CNS evaluable for the response set. For patients with baseline CNS disease, the median PFS was longer with osimertinib (11.7 months vs. 5.6 months; HR, 0.32, P = 0.004) compared with chemotherapy. The CNS response rate was higher with osimertinib compared with the chemotherapy group (70% vs. 31%; odds ratio, 5.13; 95% CI: 1.44–20.64; P = 0.015). The median CNS duration of response was 8.9 months with osimertinib compared with 5.7 months with chemotherapy.[4647] In the FLAURA study, a higher proportion of patients in the osimertinib (n = 61) than in the control group (n = 67) achieved a CNS objective response (66% vs. 43%; odds ratio = 2.5; 95% CI: 1.2–5.2; P = 0.011), whereas the incidence of CNS progression was lower (20% vs. 39%) as was the rate of CNS progression due to new lesions (12% vs. 30%).[48] CNS PFS was also longer with osimertinib than with standard EGFR-TKIs (median CNS PFS was not reached with osimertinib and was 13.9 months with standard EGFR-TKI therapy; HR, 0.48; 95% CI: 0.26–0.86; P = 0.014). In the subset of patients without CNS lesions at baseline, there was a lower number of new CNS lesions in the osimertinib arm than in the EGFR-TKI comparator arm (3.1% vs. 7.0%, respectively). In a post hoc competing risk analysis of this study, after adjusting for the non-CNS progression and death to estimate, the osimertinib-treated patients had a 5% probability of experiencing a CNS event at 6 months and an 8% probability at 12 months compared with 18% and 24%, respectively, in patients with EGFR standard of care (gefitinib or erlotinib).[49] The FLAURA study has demonstrated that the clinically and statistically significant PFS and intracranial efficacy benefit of osimertinib are compounded by an extended median OS, with 20% reduction in risk of death.[40]
Clinical practice guideline recommendations
The National Comprehensive Cancer Network (NCCN) 2019 guidelines revised the status of osimertinib to a first-line treatment option for EGFRm NSCLC patients making osimertinib at par with other first- and second-generation TKIs in the management of patients with EGFRm NSCLC.[50]
The 2019 European Society for Medical Oncology (ESMO) Clinical Practice Guidelines on Metastatic NSCLC suggest recommendations for the management of advanced/metastatic NSCLC, with an update on the use of targeted therapies for patients with tumors with specific gene mutations [Table 2].[51]
Table 2: Recommendations for management of EGFR-mutated NSCLC per ESMO 2018 guidelines[51]
Optimal sequencing of tyrosine kinase inhibitors: A dilemma
In patients with EGFRm NSCLC, the sequencing of EGFR-TKIs has changed over the past decade. The NCCN and ESMO guidelines do not provide a clear consensus on which is the most preferred EGFR-TKI for the first-line management of NSCLC. Most patients with EGFRm NSCLC show an initial pronounced response to TKI treatment; however, they acquire a resistance to the targeted therapy approximately 9 to 12 months after treatment initiation.[22] Table 3 demonstrates improved PFS benefit with all EGFR-TKI treatment compared with standard chemotherapy; osimertinib as the first-line treatment has shown maximum benefit.[52]
Table 3: Median PFS in clinical trials on EGFR-TKIs[52]
Because EGFRm tumors are highly dependent on EGFR signaling, optimization of the sequence of administration of the currently available EGFR-TKIs – erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib – is necessary. Some clinical studies have compared the first-, second-, and third-generation TKIs for PFS and OS benefits [Figure 2].[2021394053] Data from these clinical studies clearly show the superiority of osimertinib in a first-line setting for EGFRm NSCLC. The FLAURA study is particularly important for providing evidence regarding optimal sequencing.[40] The study had a provision for patients to crossover to osimertinib open-label treatment from gefitinib or erlotinib arm after disease progression. About 31% (85 of 277) patients from the comparator arm entered the second-line treatment with osimertinib; this is in line with the real-world data, where 30% to 70% patients do not receive second-line treatment because of bad performance status, disease progression, or death.[545556] This group receiving osimertinib treatment represented 47% (85 of 180 patients) of those who opted for any second-line therapy. It is postulated that increased OS of 31.8 months in the gefitinib or erlotinib arm was seen because of crossover to the osimertinib group; earlier studies of first- and second-generation TKIs have reported a median OS to range between approximately 18 and 28 months.[1757585960] Patients receiving osimertinib as first-line and those who continued to receive osimertinib (48%, 133 of 279) had significantly longer OS of about 38.6 months.[40] Hence, the claim that third-generation TKIs are ideal to be administered first in untreated (TKI-naïve) patients and as a subsequent second-line therapy in previously treated patients is substantiated by the data from Phase 3 studies.
Figure 2: Head-to-head comparison of EGFR-TKIs. EGFR = epidermal growth factor receptor; TKI = tyrosine kinase receptors. Figure recreated from Park et al.,[20] Wu et al.,[21] Soria et al.,[39] Ramalingam et al.,[40] and Urata et al.[53]
Clinical decision making for optimum sequencing is critical for two important reasons: (1) Patients may not opt for, or may die before the start of, second-line therapy and (2) the patients who will eventually develop the T790M mutation cannot be predicted.[6162] In an Indian study on EGFR-positive NSCLC patients, approximately 23% of patients did not undergo a repeat biopsy. The most common reasons for not undergoing repeat biopsy were patient refusal, technical difficulties, and poor performance status at the time of rebiopsy.[62] Similar results were observed in several other studies.[6364] In a recent study on gefitinib in Indian patients, gefitinib plus pemetrexed–carboplatin combination was compared with gefitinib alone as first-line therapy in advanced EGFRm NSCLC patients.[65] Although the PFS was significantly higher in the gefitinib plus chemotherapy arm (18 months) versus gefitinib-alone arm (8 months), approximately 58% of patients in the combination arm and 77% of patients in the gefitinib only arm discontinued the therapy. These studies justify the importance of ideal sequencing, as a high majority of patients receiving the first-line therapy may not receive the second-line therapy because of several factors.
Furthermore, the sequencing of therapy options in EGFRm NSCLC is a dynamic equation. The dynamics will depend on several factors such as expected efficacy, CNS activity, tolerability, and options available after progression. When treated with a first- or second-generation EGFR-TKI as the first-line therapy, it is difficult to predict patients who will develop T790M at progression and thus benefit from osimertinib as the second-line therapy.[66] Identification of T790M mutation at disease progression is possible through a circulating tumor DNA (ctDNA) testing or a repeat tissue biopsy.[67] ctDNA testing for T790M mutation has limited sensitivity and requires reflex tissue testing for confirming a negative test because of the heterogeneity of tumor mass. Repeat tissue biopsy may not be feasible always. Additionally, progression in about 40% of patients after first- and second-generation EGFR-TKI treatment may be due to mechanisms other than T790M mutation for which there is no approved therapy.[6268] Lack of efficacy in CNS metastasis is another concern when patients are treated with first- and second-generation EGFR-TKIs in a first-line setting. Currently, only osimertinib has shown to provide PFS benefit in patients with CNS metastasis compared with gefitinib or erlotinib. Osimertinib has a longer time to disease progression when used in first line compared with other first- and second-generation TKIs with manageable toxicity profile.[3940] In a recent network meta-analysis, the efficacy and safety of five EGFR-TKIs (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) were evaluated.[69] Osimertinib was associated with improved PFS, OS, and ORR compared with all other EGFR-TKIs along with a favorable toxicity profile. This makes osimertinib a preferred choice for first-line treatment irrespective of T790M mutation status or CNS metastasis.
The past, current, and future practices and the dilemma for sequencing of TKIs are depicted in Figure 3.
Figure 3: Sequencing of EGFR-TKIs in NSCLC. CHT = chemotherapy; EGFR = epidermal growth factor receptor; IMT = immunotherapy; m = months; mPFS = median progression-free survival; NSCLC = non–small-cell lung cancer; PD = disease progression; TKI = tyrosine kinase inhibitors
Resistance to third-generation TKIs
Although osimertinib has demonstrated clinical benefits in both second- and first-line settings, resistance will eventually develop. The major mechanism of resistance to osimertinib (AURA3 and FLAURA trials) was MET amplification (19% and 15%), EGFR C797S mutation (15% and 7%), and other mutations such as HER2 amp, PIK3CA, and RAS mutations (2%–7% for all three mutations). Other forms of EGFR mutations that confer resistance to osimertinib include L718Q, S768I, G724S, and C797X.[70] Amplification of EGFR ex19del and wild-type EGFR and loss of EGFR T790M were observed in osimertinib-resistant patients. EGFR-independent mutations include HER2 and MET amplification and increased dependence on RAS signaling.[7172] Several strategies are being tested to overcome the problem of resistance to osimertinib.
Future perspective
In addition to developing fourth-generation EGFR-TKIs, combination strategies can be an effective way of delaying the development of resistance.[7374] According to a recent study, gefitinib is a possible second-line option to C797S/activating mutation emerging after first-line osimertinib treatment failure.[75] A meta-analysis of efficacy endpoints demonstrated better ORR, OS, and PFS when radiotherapy was combined with EGFR-TKIs in patients with CNS metastases. The Asian subgroup with EGFR mutation adenocarcinoma showed a better prognosis with this treatment regimen.[76] Another area of development is the use of immune checkpoint inhibitors (ICIs) after the failure of EGFR-TKIs. A landmark study IMpower150 evaluating efficacy combination of ICI (atezolizumab), antivascular endothelial growth factor (VEGF; bevacizumab), and chemotherapy (carboplatin plus paclitaxel) resulted in increased OS in patients with EGFR mutations. This regimen reduced the risk of death by 46% versus bevacizumab plus chemotherapy. The median PFS was 9.7 months and 6.1 months for atezolizumab plus bevacizumab plus chemotherapy and bevacizumab plus chemotherapy, respectively (HR, 0.59; 95% CI: 0.37–0.94).[77] Another strategy includes a combination of TKIs with chemotherapy drugs or bevacizumab. In the north east Japan (NEJ) 009 study, combination of gefitinib and chemotherapy significantly prolonged the PFS and also had an impact on long-term survival of patients.[78] In the JO25567 study, a combination of erlotinib plus bevacizumab resulted in increased PFS (16.0 months) compared with erlotinib alone (9.7 months HR, 0.54; 95% CI: 0.36–0.79; P = 0.0015).[79]
Conclusion
Ideal sequence strategy should consider factors such as efficacy endpoints, safety data, CNS disease, unpredictable T790M in second line after first- and second-generation TKI and patient preference. The current third-generation EGFR-TKI therapy landscape is dominated by osimertinib with benefits of broader coverage of mutations, including T790M, significant OS benefit, better CNS penetration with PFS gain, and a manageable tolerability profile. The optimal sequencing of EGFR-TKIs and combination approaches can be challenging. First-line chemotherapy alone is inferior to any EGFR-TKI and should not be recommended unless to bridge the treatment gap, where significant delay in reporting of molecular testing results is expected. Combination treatment options with TKI and chemotherapy can be considered keeping the toxicity profile consideration in select patients and patient preference on chemotherapy maintenance. Currently, there is no biomarker to predict which patient will develop T790M mutation after first- or second-generation TKI; hence, reserving osimertinib for the second line would not be a fair strategy from the patient's perspective because many of them do not survive to receive the second line and also considering the lower PFS benefit in the first line from first- or second-generation TKIs. However, the available evidence from the FLAURA trial has provided substantial evidence, including an OS benefit, regarding the clinical benefits of first-line treatment with osimertinib in TKI-naïve patients. Ongoing research for the comprehensive characterization of resistance mechanisms for each EGFR-TKI will contribute to the continued development of more effective strategies.
Financial support and sponsorship
AstraZeneca Pharma India Ltd
Conflicts of interest
Mangesh S. Kamle is an employee of AstraZeneca Pharma India Ltd.
Acknowledgments
The authors would like to thank AstraZeneca Pharma India Ltd. for the development of this manuscript in collaboration with Ms. Prajakta Nachane, M. Pharm. from Covance Scientific Services & Solutions Pvt. Ltd. in accordance with the GPP3 guidelines (http://www.ismpp.org/gpp3).
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