Best Initial Treatment Strategies for EGFR-Mutant Lung Cancer

Abstract

EGFR activating mutations were described in lung cancer over a decade ago, and in that time, targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have become the treatment of choice as first-line therapy. Targeted therapy improves responses and progression-free survival when compared with chemotherapy in these patients with advanced disease. Despite improvements in outcomes, resistance develops and the majority of patients expe- rience tumor progression and are not cured. The intro- duction of third-generation EGFR TKIs that effectively block activating mutations and the T790M resistance mutation while sparing wild-type EGFR has led to improved outcomes following the development of resis- tance. The future of EGFR therapy will explore the use of these agents and combinations to potentially delay or eliminate resistance to increase efficacy and ultimately survival. This review will focus on current therapies used in the first-line setting for advanced EGFR mutation positive non—small cell lung cancer (NSCLC) followed by emerging data that may lead to a transition in the choice for initial therapy in these patients.

Introduction

Lung cancer is the leading cause of cancer related mortality worldwide in both men and women.¹ Patients with advanced epidermal growth factor receptor (EGFR) mutated non—small- cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, and afatinib, show improved progression-free survival (PFS) compared with standard chemo- therapy as first-line therapy.^2-5 Unfortunately, patients develop resistance through multiple routes, including acquired EGFR mutations such as T790M.⁶ In order to combat this resistance, second- and third-generation EGFR TKIs have been developed. In order to prevent or delay the development of resistance, multiple strategies have been investigated, such as the combina- tion of high-dose pulses with low-dose continuous EGFR TKI therapy or co-targeting bypass signaling pathways as in the com- bined inhibition of both EGFR and MET.⁷ The development of third-generation TKIs has improved patient outcomes; however, therapeutic resistance still occurs. As the options for therapy increase, the available data should be considered in choosing a frontline treatment.

Current Options for First-Line Therapy

EGFR TKIs have been established as frontline therapy for patients with metastatic EGFR mutant lung. Differentiating between these treatment options requires an evaluation of the studies that have been performed.

The IPASS trial led the field, and was a randomized, phase 3 trial that compared gefitinib to carboplatin and paclitaxel in 1217 previously untreated never or light ex-smokers with advanced NSCLC, but did not require EGFR mutation. The pri- mary endpoint was PFS, and at 12 months, the PFS was 24.9% with gefitinib and 6.7% with carboplatin/paclitaxel. In the sub- group of patients with an EGFR mutation, PFS was significantly longer among those who received gefitinib.² Importantly, those without EGFR mutation had improved PFS with chemotherapy, highlighting the importance of molecularly testing for activating EGFR mutations.

A randomized, phase 3 trial compared gefitinib versus carboplatin/paclitaxel in previously untreated patients with EGFR-mutated metastatic NSCLC.⁸ Analysis of the first 200 patients revealed that PFS was significantly longer in patients in the gefitinib group resulting in early termination. The gefitinib group had a median PFS of 10.8 versus 5.4 months in the chemotherapy group and a higher response rate of 73.7% versus 30.7%.

A third study comparing gefitinib and cisplatin plus docetaxel had similar results.⁹ This randomized, phase 3 study involved 177 previously untreated patients diagnosed with stage IIIB/IV NSCLC or postoperative recurrence with EGFR mutations and evaluated PFS as the primary endpoint. The gefitinib group had significantly longer median PFS compared with the cisplatin plus docetaxel group (9.2 versus 6.3 months).

A randomized, phase 3 trial compared erlotinib with carbo- platin/gemcitabine in 165 patients with stage IIIB/IV NSCLC and EGFR mutations.5 The analysis of PFS included 82 patients in the erlotinib group and 72 in the chemotherapy group. Median PFS was significantly longer in the patients treated with erlotinib than those treated with chemotherapy (13.1 versus 4.6 months).

The EURTAC trial compared erlotinib versus platinum-based chemotherapy for first-line treatment of patients with advanced NSCLC with EGFR mutations in a randomized, phase 3 trial.¹⁰ In that study, 86 patients received erlotinib and 87 received standard chemotherapy. The preplanned interim analysis showed the study met its primary endpoint and enrollment was stopped. The median PFS in the erlotinib group was 9.7 months com- pared with 5.2 months in the chemotherapy group.

The LUX-Lung 3 study was a randomized, phase 3 trial that compared afatinib to pemetrexed/cisplatin in previously

untreated EGFR-positive stage IIIB/IV NSCLC patients.³ The study enrolled 345 patients who were randomly assigned in a 2:1 ratio and stratified by EGFR mutation (exon 19 deletion, L858R, or other). The median PFS was 11.1 months for the afatinib group and 6.9 months for the chemotherapy group. Median PFS among patients with exon 19 deletions and L858R deletions was 13.6 months for afatinib and 6.9 months for chemotherapy. The LUX-Lung 6 trial randomized 364 patients with previ- ously untreated EGFR mutation positive stage IIIB/IV NSCLC to receive either afatinib (242 patients) or gemcitabine-cisplatin (122 patients) a 2:1 ratio and stratified patients by EGFR muta- tion (exon 19 deletion, L858R, or other).4 Median PFS in the afatinib group was 11.0 months and 5.6 months in the gemcit- abine-cisplatin group.

A pooled analysis of LUX-Lung 33 and LUX-Lung 64 in- cluded 631 of the 709 patients randomized and evaluated overall survival (OS) in patients with exon 19 (n = 355) and exon 21 mutations (n = 276).¹¹ OS was significantly longer in the del19-positive tumors in the afatinib group than in the chemotherapy group (31.7 versus 20.7 months). There were no significant differences by treatment group for patients with EGFR L858R-positive tumors. This study showed that OS was improved for patients with del19 EGFR mutations in the afati- nib group.11

The LUX-Lung 7 trial was a randomized phase 2B trial that compared first-line treatment with either afatinib or gefitinib in patients with EGFR-mutated stage IIIB/IV NSCLC.¹² In the study, 160 patients received afatinib and 159 patients received gefitinib until disease progression. PFS was 11.0 months with afatinib and 10.9 months with gefitinib and median time

to treatment failure was 13.7 months with afatinib and 11.5 months with gefitinib, and the results were statistically signifi- cant. Furthermore, survival was increased with afatinib at 27.9 versus 24.5 months, but the result was not significant.¹³

The current frontline options with afatinib, erlotinib, and ge- fitinib offer improved outcomes over standard chemotherapy in EGFR-mutant NSCLC patients. Toxicities are manageable and most commonly include rash, and skin toxicity, and diarrhea.^2-5 Despite the benefit to patients, progression invariably occurs so we must consider novel strategies that might increase survival.=

Emerging Frontline Options

Enhancing outcomes for patients may require combination therapy or new generation inhibitors that can prevent or over- come resistance mechanisms. The strategies with early results include combination erlotinib and bevacizumab, afatinib and cetuximab, and osimertinib as first-line therapy for EGFR-mu- tant NSCLC, and other agents and combinations are under investigation.

A randomized, phase 2 study in 154 patients with stage IIIB/ IV or recurrent non-squamous NSCLC with EGFR mutations and no previous therapy for advanced disease compared erlo- tinib alone versus erlotinib plus bevacizumab.¹⁴ The median PFS was 16.0 months in the erlotinib plus bevacizumab group and 9.7 months in the erlotinib alone group. Additional studies are ongoing to confirm these results and assess toxicities.

Osimertinib, a third-generation EGFR TKI, is approved as treatment for patients with EGFR TKI resistance due to emergence of the T790M mutation, and demonstrated over 50% objective response rate (ORR).¹⁵ With the hypothesis that early treatment with osimertinib can prevent the emergence of T790M as a mechanism of resistance and improve PFS, cohorts were studied using osimertinib as first-line therapy. Sixty pa- tients from 2 phase 1 expansion cohorts of the original AURA trial received either 80 mg per day (n = 30) or 160 mg per day (30 patients) of osimertinib as first-line therapy. The ORR was 77%. Median PFS was 19.3 months for the 160 mg dose, and has not yet been reached for the 80 mg dose.¹⁶ This early data are promising, and a phase 3 trial (FLAURA) is evaluating the efficacy of osimertinib in treatment-naïve EGFR mutation posi- tive NSCLC patients (NCT02296125).

Afatinib plus cetuximab demonstrated clinical activity in EGFR-mutated lung cancers with acquired resistance compared with gefitinib or erlotinib, both with and without T790M mutations in a phase 1b study.¹⁷ This combination is now being studied as a frontline therapy for EGFR-mutant NSCLC (NCT02438722).

Central nervous system (CNS) metastases, including leptome- ningeal carcinomatosis, are a challenge in patients with EGFR mutation positive lung cancer. Progression within the brain often occurs in the absence of systemic tumor growth due to inadequate drug concentration in the CNS. Pulse dose erlotinib has been shown to be tolerated while increasing penetration into the brain.^18,19 A phase 1 study evaluated twice weekly pulse dose erlotinib at 1200-mg days 1 and 2 followed by 50 mg on days 3 to 7 in treatment-naïve NSCLC patients with EGFR mutations.²⁰ The study demonstrated similar survival and responses seen in phase 3 trials, but of the 34 patients enrolled, none had progression in an untreated metastasis or developed new CNS metastases while on study. Additional trials evaluat- ing activity of next-generation EGFR inhibitors in patients with CNS metastases are planned.

Future Directions

The use of EGFR TKIs is effective, but patients develop resis- tance, most commonly due to T790M. Molecular analysis of cir- culating tumor cells or cell-free DNA may provide a strategy for monitoring changes in tumor genotypes and the development of drug resistant mutations during treatment. One study found that the T790M was detectable in pretreatment tumor biopsies and circulating tumor cells during treatment and that T790M mutations were associated with reduced PFS (7.7 versus 16.5 months), and an increase in the number of cells with T790M mutations correlated with disease progression.²¹

A number trials investigating EGFR TKIs in the frontline setting are ongoing and the results are forthcoming. These trials will help clarify the optimal use of TKIs in EGFR mutation positive NSCLC, and future studies will address the question of proper sequencing of therapy to provide the best outcomes for patients. The timing of third-generation EGFR inhibitors, such as earlier use of osimertinib will likely lead to new mechanisms of resistance, the emergence of the C797S EGFR mutation is one example.²² Additional studies to understand these mecha- nisms and therapies to overcome resistance will be needed.

Author affiliations: Emily A. Barber is with the University of California, Irvine, and Karen L. Reckamp is with the City of Hope Comprehensive Cancer Center.

Author disclosures: Karen Reckamp discloses that she has provided consultant services to Amgen, Ariad, Astellas, Nektar, and received research support (to institution) from Ariad, Bris- tol Myers Squibb, Boehringer Ingelheim, Clovis, Eisai, Novartis, Pfizer, Xcovery, Adaptimmune, Medimmune, Stemcentrx.

Address correspondence to: Karen L. Reckamp, MD, City of Hope City of Hope Comprehensive Cancer Center, 1500 E. Du- arte Road, Bldg 51, Duarte, CA 91010. phone: (626) 256-4673,

fax: (626) 301-8233; e-mail: [email protected].

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016.
2. CA Cancer J Clin. 2016;66(1):7-30. doi: 10.3322/caac.21332.Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carbo- platin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957. doi: 10.1056/NEJMoa0810699.
3. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastat- ic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327-3334. doi: 10.1200/JCO.2012.44.2806.
4. Wu YL, Zhou C, Hu CP, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX- Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(2):213-222. doi: 10.1016/S1470-2045(13)70604-1.
5. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemother- apy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742. doi: 10.1016/S1470- 2045(11)70184-X.
6. Yu HA, Riely GJ, Lovly CM. Therapeutic strategies utilized in the setting of acquired resistance to EGFR tyrosine ki- nase inhibitors. Clin Cancer Res. 2014;20(23):5898-5907. doi: 10.1158/1078-0432.CCR-13-2437.
7. Lovly CM, Shaw AT. Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies. Clin Cancer Res. 2014;20(9):2249-2256. doi: 10.1158/1078-0432. CCR-13-1610.
8. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380-2388. doi: 10.1056/ NEJMoa0909530.
9. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121-128. doi: 10.1016/S1470- 2045(09)70364-X.
10. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246. doi: 10.1016/ S1470-2045(11)70393-X.
11. Yang JC, Wu YL, Schuler M, et al. Afatinib versus cispla- tin-based chemotherapy for EGFR mutation-positive lung ade- nocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16(2):141-151. doi: 10.1016/S1470-2045(14)71173-8.
12. Park K, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-la- bel, randomised controlled trial. Lancet Oncol. 2016;17(5):577- 589. doi: 10.1016/S1470-2045(16)30033-X.
13. Paz-Ares L, Tan EH, Zhang L, et al. Afatinib (A) vs gefitinib (G) in patients (pts) with EGFR mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC): overall survival (OS) data from the phase IIb trial LUX-Lung 7 (LL7). ESMO 2016 abstract LBA43.
14. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevaci- zumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236-1244. doi: 10.1016/S1470-2045(14)70381-X.
15. Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689-1699. doi: 10.1056/NEJMoa1411817.
16. Ramalingam S, Yang JC, Lee C, et al. Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two phase I expansion cohorts. ELCC 2016; Abstract LBA1_PR 2016.
17. Janjigian YY, Smit EF, Groen HJ, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mu- tant lung cancer with and without T790M mutations. Cancer Discov. 2014;4(9):1036-1045. doi: 10.1158/2159-8290.CD-14-0326.
18. Clarke JL, Pao W, Wu N, Miller VA, Lassman AB. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol. 2010;99(2):283-286. doi: 10.1007/s11060-010-0128-6.
19. Grommes C, Oxnard GR, Kris MG, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 2011;13(12):1364-1369. doi: 10.1093/ neuonc/nor121.
20. Yu HA, Sima C, Feldman D, Liu LL, Vaitheesvaran B, Cross J, Rudin CM, Kris MG, Pao W, Michor F, Riely GJ. Phase 1 study of twice weekly pulse dose and daily low dose erlotinib as initial treat- ment for patients with EGFR-mutant lung cancers. Ann Oncol 2016; epub Ocober 25, 2016.
21. Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359(4):366-377. doi: 10.1056/NEJMoa0800668.
22. Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21(6):560-562. doi: 10.1038/nm.3854.