Afatinib for <em>EGFR</em> Mutation-Positive, Advanced Non-Small Cell Lung Cancer

November 11, 2013
Hongbin Chen, MD, PhD

The Journal of Targeted Therapies in Cancer, October 2013, Volume 2, Issue 5

Activating EGFR mutations are associated with response to TKIs. Afatinib (Gilotrif) is an oral, irreversible ErbB family TKI that targets EGFR, HER2, and ErbB4. Afatinib is being formally evaluated in the LUX-Lung clinical trial program for NSCLC.

Hongbin Chen, MD, PhD

Department of Medicine, Roswell Park Cancer Institute,

Buffalo, NY; hongbin.chen

@roswellpark.org

Abstract

ActivatingEGFRmutations are associated with response to tyrosine kinase inhibitors (TKIs). Afatinib (Gilotrif) is an oral, irreversible ErbB family TKI that targets EGFR, HER2, and ErbB4. Afatinib is being formally evaluated in the LUX-Lung clinical trial program for non-small cell lung cancer (NSCLC). The results of the improvement in progression-free survival in the first-line treatment setting of patients with metastatic NSCLC whose tumors haveEGFRexon 19 deletions or exon 21 (L858R) substitution mutations led to the approval of afatinib along with a companion diagnostic test. This article will review pivotal clinical trial data, with a brief discussion of other EGFR TKIs.

On July 12, 2013, the FDA approved afatinib (Gilotrif) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.1The companion diagnostic test, the therascreen EGFR RGQ PCR Kit (QIAGEN), detects whether the NSCLC tumor cells harbor EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

Afatinib is an oral, irreversible, selective ErbB family tyrosine kinase inhibitor (TKI) that targets ErbB1/EGFR, ErbB2/HER2, and ErbB4/HER4.

EGFR Mutations and TKIs in NSCLC

This article will provide an overview ofEGFRmutations in NSCLC and targeted therapy with TKIs. This will be followed by a review of the clinical studies of afatinib, especially the pivotal trial that led to its approval inEGFRmutation-positive NSCLC. Finally, the approval of afatinib will be put into perspective with a discussion of erlotinib, another recently approved TKI in the same treatment setting.Somatic mutations in the tyrosine kinase domain of theEGFRgene in lung cancer were identified nearly a decade ago.2-4The most commonEGFRmutations found in patients with NSCLC are deletion of exon 19 (E19del [LREAdeletion]), which occurs in 45% of patients withEGFRmutations, and a substitution mutation in exon 21 (substitution of arginine for leucine at position 858 [L858R]), which accounts for about 40% ofEGFRmutations. These so-called driver mutations, which occur in genes that encode signaling proteins crucial for cellular proliferation and survival, and thus drive tumor formation and also maintenance through mutant oncogenes,5are found in approximately 10% of Caucasian patients and up to 50% of Asian patients with NSCLC.6

These drug-sensitive mutations have been targeted by EGFR TKIs in the treatment of advanced NSCLC (Figure).7Several large phase III trials have shown that patients withEGFRmutation-positive advanced NSCLC benefit from EGFR TKIs such as gefitinib or erlotinib compared with standard firstline combination chemotherapy (Table 1).8-10The Iressa Pan-Asia Study (IPASS) randomized 1217 previously untreated East Asian patients to gefitinib or chemotherapy with carboplatin and paclitaxel.11There was a significant improvement in progression- free survival (PFS) among 261 patients with EGFR-mutant disease who received gefitinib (hazard ratio [HR] = 0.48; 95% CI, 0.36-0.64;P< .001).

In the OPTIMAL trial in a Chinese patient population, erlotinib demonstrated significant improvement in PFS as compared with carboplatin/gemcitabine in the first-line treatment ofEGFRmutation- positive advanced NSCLC.12However, overall survival (OS) was not significantly different in these trials, likely due to the high crossover rate to the TKIs from the chemotherapy group.13-16

Figure. EGFR Signaling Cascade and Therapeutic Targets

Both ErbB1/EGFR and ErbB2/HER2 have an extracellular domain, a transmembrane domain, and an intracellular kinase domain that initiate the signaling pathways. EGFR and HER2 are targets in non-small cell lung cancer. Monoclonal antibodies such as cetuximab target the extracellular domains of EGFR, and tyrosine kinase inhibitors (TKIs) target the intracellular kinase domains. Erlotinib and gefitinib are first-generation EGFR TKIs, which bind reversibly to the kinase domain and effectively inhibit EGFR. Afatinib and dacomitinib are secondgeneration irreversible pan-HER inhibitors.

P, phosphorylation.

Afatinib, an Irreversible TKI

Erlotinib and gefitinib are first-generation EGFR TKIs. They bind reversibly to the kinase domain and effectively inhibit both wild-type and mutatedEGFR.17Eventually, nearly all patients withEGFR-mutated NSCLC develop resistance to reversible EGFR TKIs after a median of 12 to 14 months.18The most common acquired secondary resistance mutation is theT790Mmissense mutation in exon 20 (a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid, in this case leading to substitution of methionine for threonine at position 790 in the kinase domain). This accounts for 50% to 60% of patients with disease progression while taking a first-generation EGFR TKI.19Treatment options are limited in patients who develop resistance to EGFR TKIs, and usually include cytotoxic chemotherapy or clinical trials.Afatinib, formerly known as BIBW2992, is an aniline- quinazoline derivative that covalently binds directly to the ATP-binding site in the kinase domains of both EGFR and HER2. Preclinical data indicated that the irreversible binding of afatinib potently suppresses the kinase activity of wild-type and activatedEGFRandHER2mutants, including erlotinibresistant isoforms; suppresses transformation in isogenic cell-based assays; inhibits survival of cancer cell lines; and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib.20In particular, afatinib was effective in both xenograft models driven byEGFR L858R/T790MorHER2overexpression, and in a murine lung cancer model driven byEGFR L858R/ T790Mdouble-mutant, suggesting its potential use in overcoming acquired resistance associated with first-generation EGFR TKIs. Combining afatinib and a mammalian target of rapamycin (mTOR) inhibitor induced apoptosis,21 while dual targeting with afatinib and cetuximab induced dramatic shrinkage of erlotinib-resistant tumors harboring theT790Mmutation,22because together they efficiently depleted both phosphorylated and total EGFR.

Peak plasma concentrations of afatinib were reached 3 to 4 hours after administration and declined with a half-life of 30 to 40 hours, suggesting that it was suitable for once-daily dosing.23There was reduced drug absorption with food intake, suggesting that afatinib is best administered under fasting conditions.24Phase I trials determined the recommended phase II dosage of afatinib at 50 mg orally daily. Some phase II and III trials began a starting dosage of 40 mg instead of 50 mg, as it was deemed to provide a more favorable therapeutic index.25

Clinical Trials of Afatinib inEGFRMutation- Positive NSCLC

Afatinib is the first of the second-generation EGFR TKIs that received approval for clinical use. With longer and more complete blockade of EGFR signaling than the first-generation reversible TKIs, irreversible TKIs are currently under active investigation. Dacomitinib (PF-00299804) is an irreversible pan-HER TKI of HER1, HER2, and HER4 with preclinical activity in gefitinib-resistant tumor cells and in xenograft models expressingEGFR T790MorHER2mutations.26,27In a randomized phase II trial in 188 patients who had failed one or two lines of chemotherapy, dacomitinib demonstrated significantly improved PFS versus erlotinib, with more frequent but manageable toxicity.28The efficacy of afatinib in NSCLC is being formally evaluated in the LUX-Lung clinical trial program, which has progressed from LUX-Lung 1 through 8 (Table 2).29LUX-Lung 1,30,314,23,32and 5 (ongoing) trials investigated afatinib as a second- or third-line treatment in patients who have acquired resistance to gefitinib and/or erlotinib following platinumbased chemotherapy; therefore,EGFRmutation was not required for study participation. Although no benefit in OS was observed, PFS and objective response rates (ORRs) were promising. Interaction between treatment andEGFRmutation status was not statistically significant, possibly because of the small sample sizes.30The ongoing phase III LUX-Lung 8 trial is comparing afatinib with erlotinib as a second- or third-line treatment after platinum-containing regimen in squamous cell NSCLC.

TABLE 1. Results of Phase III Trials of EGFR TKIs in the First-Line Treatment ofEGFRMutation-Positive Advanced NSCLC

Phase III Trials

Treatment Groups

Number of Patients

RR (%)

PFS* (months)

OS (months)

WJTOG34058,15

Gefitinib vs cisplatin/docetaxel

172

62 vs 32

9.2 vs 6.3

36 vs 39

NEJ00210,14

Gefitinib vs carboplatin/ paclitaxel

228

74 vs 31

10.8 vs 5.4

27.7 vs 26.6

EURTAC9

Erlotinib vs platinum/docetaxel or gemcitabine

173

65 vs 16

10.4 vs 5.2

22.9 vs 19.5

IPASS11,13

Gefitinib vs carboplatin/ paclitaxel

261

71 vs 47

9.5 vs 6.3

21.6 vs 21.9

OPTIMAL12,16

Erlotinib vs carboplatin/ gemcitabine

154

83 vs 36

13.1 vs 4.6

22.7 vs 28.9

LUX-Lung 334,35

Afatinib vs cisplatin/pemetrexed

345

56 vs 23

11.1 vs 6.9 (13.6 vs 6.9 in common mutations)

NYR

LUX-Lung 636,37

Aafatinib vs cisplatin/gemcitabine

364

67 vs 23

11.0 vs 5.6

NYR

* PFS was the primary endpoint and was statistically significant across all of the studies listed. EGFR, epidermal growth factor receptor; EURTAC, European Tarceva versus Chemotherapy; IPASS, Iressa Pan-Asia Study; NEJ, North East Japan (Gefitinib Study Group); NSCLC, non-small cell lung cancer; NYR, not yet reached; OPTIMAL, Open Label, Multicenter Phase III Study of Tarceva versus Cisplatin plus Gemcitabine as First-Line Treatment in Stage IIIB/IV Advanced/Metastatic Non—Small-cell Lung Cancer Patients with EGFR Activating Mutations in Exon 19 or 21; OS, overall survival; PFS, progression-free survival; RR, response rate; TKI, tyrosine kinase inhibitor; WJTOG, West Japan Thoracic Oncology Group.

LUX-Lung 2, 3, 6, and 7 trials evaluated afatinib in the first-line treatment setting ofEGFRmutation-positive advanced NSCLC.33The LUX-Lung 2 trial was a phase II open-label, single-arm study in 129 patients with stage IIIb/IV adenocarcinoma of the lung with confirmedEGFRmutations.25Most patients were Asian, women, had good performance status, and were never-smokers. Sixty-one patients received afatinib as first-line treatment, and 68 received afatinib after one line of chemotherapy. Two afatinib starting dosages were tested to establish whether tolerability could be improved with retention of antitumor activity: 99 with a starting dosage of 50 mg and 30 with a starting dosage of 40 mg. The primary endpoint was ORR, which was 61%, with two complete responses (CR). Importantly, the ORR was 69% among 106 patients with the two common activatingEGFRmutations (exon 19 deletion or exon 21 L858R), but was only 39% among 23 patients with less-common mutations. Similar ORRs were observed with the two different starting dosages. However, of the two most common adverse events (AEs), diarrhea and rash or acne, grade 3 events were more common in patients receiving a 50-mg starting dosage (22% for diarrhea and 28% for rash or acne) than they were in those receiving a 40-mg starting dosage (7% for both diarrhea and rash or acne). Median PFS for all patients was 10.1 months (95% CI, 8.12-13.80) and OS was 24.8 months (95% CI, 21.98-38.74), both of which were slightly better in patients with the two commonEGFRmutations.

The FDA approval of afatinib was based on the demonstration of improved PFS in the multicenter, international, open-label, randomized (2:1) LUXLung 3 trial.34This landmark phase III trial enrolled 345 patients with metastatic NSCLC whose tumors tested positive forEGFRmutations. Median laboratory turnaround time forEGFRmutation analysis was 5 days (range, 1 to 15 days). Patients were randomized to receive afatinib 40 mg orally once daily (n = 230) or pemetrexed/cisplatin (n = 115). Randomization was stratified according toEGFRmutation status (exon 19 deletion vs exon 21 L858R vs “other”) and race (Asian vs non-Asian). Treatment arms were balanced in terms of patient demographics and clinical characteristics. Of 345 patients enrolled, 65% were female, median age was 61 years, 26% were Caucasian, and 72% were Asian. The majority of patients had a tumor sample with anEGFRmutation categorized as either exon 19 deletion (49%) or exon 21 (L858R) substitution mutations (40%), while the remaining 11% had other mutations.

TABLE 2. LUX-Lung Clinical Trials Investigating Afatinib in Treatment of Advanced NSCLC

Study

Phase

Treatment

Line of Therapy

EGFRMutation Requirement

Number of Patients

Primary Endpoint

Results (months)

LUX-Lung 130,31

IIb/II

Afatinib (50 mg/day) vs placebo (2:1)

2nd or 3rd line after 1-2 lines of platinum-doublet chemotherapy and at least 12 weeks of erlotinib or gefitinib

Not required

585

OS

10.8 vs 12.0

LUX-Lung 225

II

Afatinib (50 mg/day or 40 mg/day)

1st or 2nd line (after 1 line of chemotherapy only)

Positive required

129

ORR

61% (69% in common mutations)

LUX-Lung 334,35

III

Afatinib (40 mg/ day) vs cisplatin/ pemetrexed (2:1)

1st line

Positive required

345

PFS

11.1 vs 6.9 (13.6 vs 6.9 in common mutations)

LUX-Lung 423,32

I/II

Afatinib (50 mg/day)

2nd or 3rd line after 1-2 lines of platinum-doublet chemotherapy and at least 12 weeks of erlotinib or gefitinib

Not required

62

ORR

8.2%

LUX-Lung 5

III

Afatinib monotherapy followed by either afatinib + weekly paclitaxel vs investigator’s choice of chemotherapy

2nd line after 1 line of platinum-doublet chemotherapy and at least 12 weeks of erlotinib or gefitinib

Not required

1021

PFS

Ongoing

LUX-Lung 636,37

III

Aafatinib (40 mg/day) vs cisplatin/ gemcitabine (2:1)

1st line

Positive required

364

PFS

11.0 vs 5.6

LUX-Lung 7

IIb

Aafatinib vs gefitinib

1st line

Positive required

316

PFS

Ongoing

LUX-Lung 8

III

Aafatinib vs erlotinib

2nd line (after 1 line of chemotherapy only)

Not required (squamous cell histology)

800

PFS

Ongoing

EGFR, epidermal growth factor receptor; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

The primary endpoint was PFS as assessed by an independent review committee (IRC). A statistically significant prolongation of PFS determined by the IRC was demonstrated for patients assigned to the afatinib treatment arm (HR = 0.58; 95% CI, 0.43- 0.78;P<.001). The median PFS was 11.1 months in the afatinib arm and 6.9 months in the chemotherapy arm. ORR was 56% and 23% in the afatinib and chemotherapy arms, respectively. In patients whose tumors had common exon 19 deletions or exon 21 (L858R) substitution mutations, the outcomes were even more striking: median PFS was 13.6 months in the afatinib arm and 6.9 months in the chemotherapy arm. Median OS has not yet been reached for any group. A high degree of post-progression crossover to EGFR TKIs among patients receiving chemotherapy (65%) and to chemotherapy among those receiving afatinib (62%) was noted. Patient reported- outcomes (PROs) showed significantly better health-related quality of life (HRQOL) measures and control of cancer-related cough, dyspnea, and pain with afatinib.35

The most frequent (≥20% incidence) AEs from afatinib were diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, and pruritus. Serious AEs were reported in 29% of patients treated with afatinib. The most frequent serious AEs were diarrhea (6.6%), vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Drug-related AEs led to discontinuation in 8% (afatinib; 1% due to diarrhea) and 12% of patients (pemetrexed/cisplatin). Fatality in afatinib-treated patients included pulmonary toxicity/interstitial lung disease-like reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).

Afatinib vs Erlotinib

Most recently, the results of the phase III LUXLung 6 trial, which compared afatinib with chemotherapy with cisplatin and gemcitabine, were reported and consistent with the LUX-Lung 3 trial.36Following central testing forEGFRmutations (using the therascreen EGFR RGQ PCR kit), 364 Asian patients (stage IIIB/IV, PS 0-1, chemotherapy-naïve) were randomized 2:1 to daily afatinib 40 mg or standard cisplatin/gemcitabine up to 6 cycles. The primary endpoint was PFS by central independent review. Baseline characteristics were balanced in both arms: female (64% vs 68%), nonsmoker (74.8% vs 81.1%), exon 19 deletion (51.2% vs 50.8%), L858R (38% vs 37.7%) in the afatinib and chemotherapy arms, respectively. PFS was significantly prolonged with afatinib compared with chemotherapy (median PFS, 11.0 vs 5.6 months; HR = 0.28; P <.0001); this finding was consistent across all subgroups. Objective response (66.9% vs 23.0%; P <.0001) and disease control (92.6% vs 76.2%; P <.0001) rates were significantly higher with afatinib. Based on 43% of events, OS was 22.1 months for afatinib versus 22.2 months for gemcitabine/cisplatin (HR = 0.95; P =.7593). Drug-related AEs of ≥ grade 3 were reported in 36.0% (afatinib) and 60.2% (chemotherapy) of patients, the most common of which were rash/ acne (14.6%), diarrhea (5.4%), and stomatitis/mucositis (5.4%) with afatinib, and neutropenia (17.7%), vomiting (15.9%) and leukopenia (13.3%) with chemotherapy. Related AEs led to discontinuation in 5.9% (afatinib) and 39.8% (chemotherapy) of patients, suggesting a more favorable safety profile with afatinib. Similarly, PROs also showed significantly better HRQOL measures and control of cancer- related dyspnea, cough, and pain with afatinib.37 As the largest prospective trial inEGFRmutation-positive advanced NSCLC, LUX-Lung 6 provides further evidence of superiority of afatinib over standard chemotherapy in this setting.Afatinib is the second TKI that was approved by the FDA for the identical indication within a period of two months. On May 14, 2013, the FDA approved erlotinib (Tarceva) for the first-line treatment of patients with metastatic NSCLC whose tumors haveEGFRexon 19 deletions or exon 21 (L858R) substitution mutations.38This indication was approved concurrently with the cobas EGFR Mutation Test, a companion diagnostic test for patient selection. The approval was based on the results of the randomized, multicenter, open-label EURTAC trial comparing erlotinib (n = 86) to platinum-based doublet chemotherapy (n = 88) in a European population.9 Eligible patients were randomly allocated (1:1) to receive erlotinib, 150 mg/day orally, or platinumbased doublet chemotherapy. The primary endpoint was investigator-assessed PFS, and secondary endpoints included OS and ORR. The median age of patients was 65 years, and the majority were female (72%), Caucasian (99%), and never-smokers (69%), and had adenocarcinoma histology (93%).

The median PFS was 10.4 months in the erlotinib arm and 5.2 months in the chemotherapy arm (HR = 0.34; 95% CI, 0.23-0.49;P< .001). The median OS was 22.9 months in the erlotinib arm and 19.5 months in the chemotherapy arm (HR = 0.93; 95% CI, 0.64-1.35;P=.6482). The ORR was 65% in the erlotinib arm and 16% in the chemotherapy arm. The majority of patients in the chemotherapy arm (82%) subsequently received an EGFR TKI following disease progression. Analysis of PFS in theEGFRmutation-positive patients was consistent with the primary analysis. The most frequent (≥ 30%) AEs of any grade in the erlotinib arm were rash, diarrhea,

asthenia, cough, dyspnea, and decreased appetite. The most frequent (≥ 5%) grade 3/4 AEs in the erlotinib arm were rash and diarrhea.

The outcomes of the two pivotal trials, LUX-Lung 3 for afatinib and EURTAC for erlotinib, seem comparable despite the difference in the ethnicity of the patient populations (one mostly Asian and the other non-Asian). The chemotherapy regimen used in the control group of LUX-Lung 3 was more state-of-theart in this patient population,39even though no continuation maintenance therapy of pemetrexed was given, as is standard therapy nowadays.40The side effects seem generally milder in the EURTAC trial with erlotinib than with afatinib in LUX-Lung 3. The ongoing randomized, open-label, phase IIb LUX-Lung 7 trial, conducted outside of the United States, directly compares afatinib with gefitinib head-tohead as first-line treatment of patients withEGFRmutation-positive advanced adenocarcinoma of the lung, and results are awaited with interest.

Clinical Pearls

  • Afatinib is an oral, irreversible ErbB family TKI that targets EGFR, HER2, and ErbB4.
  • Afatinib improves PFS compared with cisplatin and pemetrexed for the first-line treatment of patients withEGFRmutation-positive metastatic NSCLC.
  • The recommended dosage for afatinib is 40 mg orally once daily at least 1 hour before or 2 hours after a meal.
  • Afatinib and erlotinib have both been recently approved by the FDA for the same indication. Although side effects seem milder with erlotinib therapy, afatinib is an alternative for patients who cannot tolerate erlotinib.

Conclusions

Afatinib monotherapy has not been shown to be very effective in the second- or third-line treatment in patients who have acquired resistance to gefitinib and/or erlotinib, as illustrated in the LUX-Lung 130and 432trials. Dual-targeting EGFR blockade has been proposed to overcome such resistance (Figure).41Adding cetuximab, an EGFR monoclonal antibody, to erlotinib revealed no significant activity in patients whose NSCLC developed resistance to erlotinib.42Based on the promising preclinical data,22a phase Ib/II study combined afatinib and cetuximab in patients with NSCLC with acquired resistance to erlotinib or gefitinib.43Preliminary results in 22 patients who received the predefined maximum dosage (afatinib 40 mg oral daily plus cetuximab 500 mg/m2 intravenously every 2 weeks) reported that this combination was well tolerated with encouraging clinical activity: disease control in all patients and 36% confirmed partial response (PR), including 29% confirmed PRs inT790M-positive NSCLC.ActivatingEGFRmutations are associated with response to TKIs. As an irreversible ErbB family TKI, afatinib has demonstrated activity in preclinical experiments. Afatinib is being formally evaluated in the LUX-Lung clinical trial program for NSCLC. The results of the improvement in PFS in the firstline treatment setting ofEGFRmutation-positive advanced NSCLC led to the approval of afatinib along with a companion diagnostic test. Afatinib should be taken at least 1 hour before or 2 hours after a meal. The recommended dosage and schedule for afatinib is 40 mg orally once daily until disease progression or no longer tolerated by the patient.

Afatinib is the second EGFR TKI approved for this use in the United States. The clinical selection of TKIs likely will depend on the familiarity and comfort level as well as cost concerns of the prescribing oncologists. Although side effects seem milder in erlotinib therapy, afatinib now becomes an alternative option for patients who cannot tolerate erlotinib. It should be pointed out that, as with erlotinib, the efficacy of afatinib has not been established in patients whose tumors have otherEGFRmutations. In addition, afatinib as a single agent is not very effective againstT790Mmutations.

Future efforts should be directed toward establishing afatinib use in other, less-commonEGFRmutation-positive NSCLC, as well as testing its efficacy in overcoming acquired resistant mutations by combining with other targeted agents (such as in ongoing trials with cetuximab or an mTOR inhibitor). Still unresolved questions are the use of afatinib in combination with chemotherapy (ongoing LUX-Lung 5 trial) and in the switch maintenance treatment setting, and continuation of afatinib after disease resistance/progression. Afatinib in the adjuvant setting in early-stage NSCLC withEGFRmutation is also being explored.

Author Disclosure

Dr. Chen has no conflicts of interest to report.

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