Targeting Epidermal Growth Factor Receptor in the Management of Lung Cancer Tony S.K. Mok, Kirsty Lee, and Linda Leung The epidermal growth factor receptor (EGFR) mutation is a potent oncogenic driver that accounts for carcinogenesis and tumor growth of pulmonary adenocarcinoma. Targeting EGFR with tyrosine kinase inhibitors (TKIs) is highly effective in terms of tumor response rate, progression-free survival (PFS), and quality of life. Multiple randomized studies have confirmed the superiority of EGFR TKIs over platinum-based chemotherapy and established EGFR TKIs as standard first-line therapy for patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). However, almost all patients will develop resistance to EGFR TKIs and post progression therapy may include a combination of local therapy, systemic chemotherapy, and second-generation EGFR TKIs. Semin Oncol 41:101-109 & 2014 Elsevier Inc. All rights reserved.

T

he epidermal growth factor receptor (EGFR) has been a focus of research for over four decades before the eventual discovery of its activating mutation in 2004.1,2 This discovery is now the foundation for personalized therapy for management of advanced stage non-small cell lung cancer (NSCLC). It is standard practice to analyze a NSCLC tumor for the presence or absence of an activating EGFR mutation, and direct therapy according to mutation status. EGFR mutation-positive lung cancer is now recognized as a distinguished disease entity that is dissimilar to EGFR wild-type lung cancer or lung cancer defined by another oncogenic driver. Being a separate disease entity since 2004, questions remain as to the optimal management of EGFR mutation-positive NSCLC patients and if the standard approach to the management of lung cancer is applicable to this unique patient population. For example, it is common knowledge that chemotherapy should be stopped whenever there is clinical or radiological evidence of disease progression. But for patients with an EGFR mutation, EGFR tyrosine

State Key Laboratory of Southern China, The Chinese University of Hong Kong, Sir YK Pau Cancer Center, Prince of Wales Hospital, Hong Kong, China. Conflicts of interest: T.S.K.M.–Consultancy and Honorarium: Astrazeneca, Eli Lilly, Pfizer, Merck Serono, GSK, Roche, Beigene, AVEO. The other authors have nothing to disclose. Address correspondence to Tony S.K. Mok, MD, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China. E-mail: [email protected] 0093-7754/ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2013.12.010

kinase inhibitors (TKIs) are frequently given beyond disease progression. We are in the process of learning and discovering the best way to manage this specific disease. The objectives of this review are to summarize the existing knowledge on targeted therapies approved for the treatment on EGFR mutation NSCLC, to examine the optimal sequence of therapy, to explore the potential combination of chemotherapy and EGFR TKIs, to discuss the management of TKI resistance, and to project on future developments in the field.

EGFR AS A TARGET FOR BIOLOGIC THERAPY EGFR is an important growth signal receptor that controls cell proliferation and survival. The discovery of epidermal growth factor by Stanley Cohen in 1964 led to a Nobel prize,3 but its receptor was not isolated until almost two decades later when Mendelsohn and colleagues first proposed EGFR as a potential anti-cancer target.4 Based on this concept, monoclonal antibodies (Mabs) targeting EGFR and TKIs targeting the intracellular domain were developed. Cetuximab (Erbitux; Merck Serono, Geneva, Switzerland) is an IgG1 Mab that binds to the extracellular ligand-binding domain of EGFR inhibiting EGFR signaling. It is approved as a standard firstline therapy in combination with chemotherapy for patients with KRAS wild-type metastatic colorectal cancer and in combination with radiotherapy for patients with head and neck cancer. A number of randomized studies were conducted assessing combination chemotherapy plus cetuximab compared to

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102

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Table 1. 4 Combination of Chemotherapy Plus Cetuximab Versus Chemotherapy in Patients With Advanced-Stage NSCLC Authors

No. of Patients 5

Butts et al Rosell et al6 Lynch et al7 Pirker et al8

Tumor Response Rate(%)

131 86 676 1,125

28 35 26 36

v 18 v 28 vs17 v 29

chemotherapy alone in patients with advanced-stage NSCLC (Table 1). The randomized phase II studies demonstrated a modest but statistically insignificant difference in overall survival (OS) favoring combination therapy, which was confirmed in the phase III study.5–8 However, the small benefit was not recognized by approval agencies and the drug has not been approved for use in lung cancer patients. Further data have demonstrated that while EGFR is a potential target in NSCLC, not all patients with expression of EGFR will benefit from anti-EGFR therapy with cetuximab. Gefitinib was one of the first EGFR TKIs designed to target the intracellular domain of EGFR. Initial clinical development was met with excitement as there were selective patients with dramatic tumor response. However, phase II studies in unselected patients reported tumor response rates (RRs) of 18.4%–19% in the Japanese population and 9%–12% in the western population.9,10 The low response rate is explained by the low incidence of EGFR mutations in unselected patient populations but this was not evident until Lynch and colleagues and Paez and colleagues independently discovered EGFR mutations in almost all responders to gefitinib.1,2 Their discovery showed that the true target of EGFR TKIs, such as gefitinib, is the EGFR with either a deletion in exon 19 or point mutation in exon 21. Multiple phase II studies were performed to investigate the efficacy of EGFR TKIs as second-/third-line therapy for biomarker-selected populations.11–14 Tumor response rates were consistently above 60% irrespective of patients’ age, gender, and ethnicity. Clinical observations have confirmed that the real target is the mutated EGFR receptor and not the wild-type receptor.

EFFICACY OF EGFR TKIs IN PATIENTS HARBORING EGFR MUTATIONS Early investigations of the clinical efficacy of EGFR TKIs focused on patients with specific clinical features including Asian ethnicity, female gender, never/light smoker, and adenocarcinoma. Only retrospectively was it confirmed that these patient

Median PFS (mo)

Median OS (mo)

v v v v

12 v 9 8.3 v 7.3 9.7 v 8.4 11.3 v 10.1

5.1 5.0 4.4 4.8

4.2 4.6 4.2 4.8

subgroups were associated with a higher incidence of activating EGFR mutations.15,16 IPASS (Iressa PanASia Study) was the first randomized phase III study that confirmed the role of EGFR TKIs as first-line therapy in patients with EGFR mutations.17 Patients were accrued according to clinical features for enrichment of a study population with activating EGFR mutations and tumor samples were analyzed retrospectively for the presence or absence of the mutation. This study confirmed the EGFR mutation to be a potent predictive biomarker for response to EGFR TKIs. Tumor RR to gefitinib in patients with EGFR mutations was 71.2%, which was significantly higher than the RR to chemotherapy (P o.001). The primary endpoint of progression-free survival (PFS) was prolonged in the gefitinib treatment group (hazard ratio [HR] 0.48, P o.0001). The interactiontest of the HR between the EGFR mutation-positive and -negative subgroup was statistically significant, thus confirming the EGFR mutation as the predictive biomarker. The majority of patients treated with firstline chemotherapy were crossed over to gefitinib at time of progression, thus accounting for the lack of OS benefit. A Korean study with a similar design reported comparable results but was limited by the small sample size of patients with known EGFR mutation status.18 Subsequent studies enrolled only patients with EGFR mutations and randomized patients to either an EGFR TKI or chemotherapy. A total of four studies conducted in biomarker-selected patient populations with activating EGFR mutations have confirmed the superiority of EGFR TKIs over standard platinum-based doublet chemotherapy (Table 2).19–22 The significantly higher RR and magnitude of prolongation of PFS were persistent across these randomized studies, thus establishing the unequivocal evidence of EGFR TKIs as standard treatment for patients with EGFR mutations.

FIRST- VERSUS SECOND-/THIRD-LINE TREATMENT WITH EGFR TKIs Irrespective of the extensive data on the use of first line EGFR TKIs, many argue that second-line

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Table 2. Treatment Outcome in Patients With EGFR Mutation to EGFR TKI or Chemotherapy Authors Mok et al17 Han et al18 Maemondo et al19 Mitsudomi et al20 Zhou et al21 Rosell et al22 Sequist et al54 Wu et al55

Study IPASS FIRST-SIGNAL NEJ02 WJTOG 3405 OPTIMAL EURTAC LUX Lung 3 LUX Lung 6

No. of Patients Tumor Response Rate* (%) Median PFS* (mon) 261 42 114 86 154 175 345 364

71.2 v 47.3 84.6 v 37.5 73.7 v 30.7 62.1 v 32.2 83.0 v 36.0 54.5 v 10.5 56 v 23 66.9 v 23

9.8 v 6.4 8.4 v 6.7 10.8 v 5.4 9.2 v 6.3 13.1 v 4.6 9.4 v 5.2 11.1 v 6.9 11.0 v 5.6

⁎

EGFR TKI v chemotherapy. Abbreviations: EGFR TKI, epidermal growth factor receptor tyrosine kinase inhibitor; PFS, progression-free survival; IPASS, Iress PanAsia Study; FIRST-SIGNAL, First-line Single Agent Iressa versus Gemcitabine and Cisplatin Trial in Never-smokers with Adenocarcinoma of the Lung; WJTOG, West Japan Thoracic Oncology Group; NEJ, North East Japan; OPTIMAL, Randomised Phase III Study Comparing First-line Erlotinib versus Carboplatin Plus Gemcitabine in Chinese Advanced Non-small-cell Lung Cancer Patients with EGFR Activating Mutations; EURTAC, Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer; LUX-Lung 3, Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations; LUX-Lung 6, a randomized, open label, phase III study of afatinib versus gemcitabine/cisplatin as first-line treatment for Asian patients with EGFR mutation-positive advanced adenocarcinoma of the lung.

therapy with an EGFR TKI is equally efficacious. The main reason is because none of these randomized studies reported an improvement in OS. The majority of patients in the chemotherapy arm crossed over to an EGFR TKI at the time of disease progression, and derived an equal benefit. However, prospective data on first- and second-line EGFR TKIs in patients with EGFR mutation are limited to single-arm phase II studies. The largest is the Spanish Lung Cancer Study Group report on 113 chemotherapy-naı¨ve and 104 chemotherapy-refractory patients. Tumor RR was 73.5% in the chemotherapy-naı¨ve group and 67.4% in the chemotherapy-refractory group.11 PFS was similar between the two groups (14 v 13 months). Other data supporting the use of secondline EGFR TKIs comes from subgroup analysis of large randomized studies. Both ISEL (Iressa Survival Evaluation in Lung Cancer) and BR-21 (National Cancer Institute of Canada bronchogenic carcinoma study no. 21) were conducted in unselected patient populations after progression on one or two lines of therapy and randomized patients to either an EGFR TKI or best supportive care (BSC).23,24 Only 26 patients with known EGFR mutations from ISEL received gefitinib and the RR was 37.5%, while the 40 patients from BR-21 treated with erlotinib attained a RR of 27%. In another study that compared gefitinib with docetaxel, the response rate in a small subgroup of patients with EGFR mutations was 41% versus 21% for chemotherapy-treated patients.25 A small prospective single-arm study from Japan evaluated the efficacy of first- and second-line EGFR TKIs and reported RRs of 77.8% in chemotherapynaı¨ve and 50% in chemotherapy-refractory patients.26 The reason for the slightly lower RR with

second-line EGFR TKIs in selective studies is not clear. The other important consideration when treating patients with a first-line EGFR TKI is to ensure that patients with EGFR mutations receive the TKI in a timely fashion. According to the single-arm study by the Spanish Lung Cancer Group,11 a total of 296 patients with EGFR mutations were eligible to receive erlotinib; however, 79 patients never did, including 18 patients who died before initiation of treatment. Thus, although first- and second-line therapies with an EGFR TKI have similar efficacy, patients with EGFR mutations may miss the opportunity to receive this effective therapy if they deteriorate rapidly on first-line chemotherapy.27

COMBINATION THERAPY WITH CHEMOTHERAPY AND EGFR TKIs The benefit of combining chemotherapy with EGFR TKIs continues to be an area of active debate. Prior to the discovery of the EGFR mutation, four randomized studies compared combination platinum-based chemotherapy with an EGFR TKI to chemotherapy alone. None of these studies demonstrated any benefit for combination therapy compared to chemotherapy alone in unselected patient populations.28–31 In the absence of a detailed biomarker analysis from these four studies, it is unclear if the lack of benefit is related to enrollment of a large proportion of patients with EGFR wild-type tumors who would derive minimal benefit from an EGFR TKI. Preclinical studies thus sought to explore the possibility of a negative interaction between

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EGFR TKIs and chemotherapy when given concurrently. A study of NSCLC cell lines found that gefitinib caused apoptosis in cell lines with the EGFR activating mutation L858R but only induced G1 cell cycle arrest in EGFR wild-type cell lines.32 Investigators hypothesized that by causing accumulation of tumor cells in the G1 phase, the EGFR TKI may have protected these cells from chemotherapy that specifically targets the S or G2/M phase of the cell cycle. Preclinical studies in NSCLC cell lines supported the rationale for pharmacodynamic separation by demonstrating that concurrent administration of erlotinib and M-phase–specific taxanes abrogated the apoptotic effect of chemotherapy.33 Pretreatment with erlotinib followed by a taxane also resulted in lower levels and a sustained shorter duration of apoptosis when compared to the sequence of taxane followed by erlotinib.33,34 A similarly designed study supported with the importance of scheduling by demonstrating that both concurrent administration of S-phase–specific pemetrexed and erlotinib, and the sequence of erlotinib followed by pemetrexed resulted in inferior cytotoxic effects when compared to treatment with pemetrexed followed by erlotinib.35 A retrospective analysis of the TRIBUTE trial (Tarceva responses in conjunction with paclitaxel and carboplatin) also supported the preclinical data by showing that patients with EGFR wild-type tumors who received combination erlotinib and chemotherapy had higher rates of progressive disease and inferior survival when compared to those patients who received chemotherapy alone, as well as those patients with EGFR-mutant tumors who received either combination therapy or chemotherapy alone.36 Based on this data, an Asian group initiated the FASTACT (First-line Asian Sequential Tarceva And Chemotherapy Trial) studies investigating the role of intercalated chemotherapy with erlotinib. FASTACT is a multicenter randomized placebo-control phase II study comparing intercalated combination of chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8) and erlotinib (days 15–28) with chemotherapy alone in an unselected population with advanced-stage NSCLC.37 The significant improvement in PFS (HR 0.57; log-rank P ¼ .018) provided the foundation for FASTACT 2,38 a phase III trial with the same study design (N ¼ 451). Approximately 85% of patients in the placebo group received second-line erlotinib on progression, which assured the EGFR mutationpositive subgroup had adequate exposure to EGFR TKI. The median PFS was 7.6 versus 6.0 months (HR 0.57; 95% confidence interval [CI], 0.47–0.69; P ≤ .0001) favoring the combination arm, and median OS was 18.3 versus 15.2 months (HR 0.79; 95% CI, 0.64–0.99; P ¼ .042). Biomarker analysis was available in 241 patients, and 97 (40%) had EGFR

T.S.K. Mok, K. Lee, and L. Leung

mutations. Subgroup analysis confirmed that the survival benefit for intercalated combination was confined to patients with activating EGFR mutations but not in patients with EGFR wild-type tumors. The magnitude of improvement in the EGFR mutation subgroup was remarkable with over 10 months improvement in median PFS and OS. Other studies also support the concept of an intercalated combination of chemotherapy and EGFR TKIs.39 A European study (NVALT-10) compared intercalated combination of docetaxel/ pemetrexed and erlotinib (days 2–16) with erlotinib alone as second-line therapy. An OS benefit was observed only in patients with adenocarcinoma (HR 0.67, P ¼ .02). Another phase II study in Asian never-smokers with stage IV non-squamous NSCLC showed that the intercalated combination of pemetrexed and erlotinib was superior to single-agent pemetrexed (HR 0.58, P ¼ .005).40 Both studies suggest that the intercalated combination may benefit the EGFR mutation-positive population. However, the role of intercalated combination therapy needs to be confirmed in a future phase III study comparing combination therapy to an EGFR TKI in patients with activating EGFR mutations.

MANAGEMENT OF ACQUIRED RESISTANCE TO EGFR TKIs Development of resistance to EGFR TKIs is basically a universal event. Only a small portion (o10%) of patients with EGFR mutations has primary resistance to EGFR TKIs, but almost all patients inevitably develop resistance after an effective period on an EGFR TKI. The best-known mechanisms of resistance include (1) acquired gatekeeper mutations (eg, T790M, L747S, D761Y, and T854A); (2) activation of by-pass tracks (eg, C-MET amplification, PIK3CA overexpression); and (3) histologic transformation (eg, small cell lung cancer transformation, epithelial to mesenchymal transition). The EGFR exon 20 T790M mutation is the most common mechanism (50%–63%) of acquired resistance to an EGFR TKI and overlapping of mechanisms are rare.41–43 Re-biopsy of the resistant tumor remains controversial, although this may provide better understanding of the mechanism of resistance. The only clinical application for re-biopsy is histological transformation to small cell lung cancer that warrants switching systemic chemotherapy.44 At this time routine re-biopsy should be confined to clinical investigation. The clinical definition of acquire resistance is being evaluated. According to Jackman’s criteria, RECIST (Response Evaluation Criteria In Solid Tumors) is adopted as the main objective definition

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of progression.45 However, the occurrence of a small new lesion or minimal increase in tumor size does not always warrant a change of therapy. One potential risk of premature termination of an EGFR TKI is disease flare resulting in rapid clinical deterioration.46 Thus, it is acceptable to continue the EGFR TKI beyond RECIST progression provided that patients with small-volume disease are asymptomatic and their tumors are progressing slowly.47–49 It is reasonable to classify TKI resistance into two categories including oligo-progression and systemic progression. The official definition for oligoprogression has not been coined, but generally it is accepted as the progression in fewer than three or four sites of disease. Local therapies, including radiotherapy, local ablation, and surgery, are feasible options for limited sites of progression while the EGFR TKI is continued. However, only retrospective studies are available to support this clinical action. Yu and colleagues offered local radical therapy to 18 patients who progressed on an EGFR TKI and reported a median time to systemic therapy of 22 months and a median OS of 41 months.50 Another retrospective study of 65 patients with oligoprogression (defined as four or fewer sites of progression) while on either an EGFR TKI or ALK (anaplastic lymphoma kinase) inhibitor showed that local therapy might allow continuation of the TKI for more than 6 additional months.51 In the absence of data from prospective comparative studies, local therapy for oligo-progression cannot be recognized as standard therapy but rather an option for selective patients. Platinum-based doublet chemotherapy is the standard therapy for systemic progression if a patient is chemotherapy-naı¨ve and radiotherapy is the standard therapy for a patient with CNS progression only. Questions remain if patients should continue with the EGFR TKI in conjunction with the standard therapy in order to avoid the “flare-up” phenomenon.46 A retrospective study showed improvement in tumor response rate (41% v 18%) but no significant differences in PFS or OS in patients who had exposure to both chemotherapy and an EGFR TKI after the development of TKI resistance.52 More specifically, patients who received a platinumbased doublet and erlotinib had tumor RRs of 63% compared to 23% in patients treated with doublet chemotherapy alone. A small prospective single arm study from Japan reported a RR of 26% and median PFS of 7 months in patients treated with pemetrexed in combination with erlotinib or gefitinib after the development of acquired TKI resistance.53 An ongoing prospective randomized phase III study is comparing the combination of pemetrexed/carboplatin and gefitinib with chemotherapy alone in EGFR mutation-positive patients who progressed

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on gefitinib. The IMPRESS (IRESSA Treatment Beyond Progression in Addition to Chemotherapy Versus Chemotherapy Alone) study is ongoing and has attained 70% enrollment to date. Another United States–based randomized phase II study with a similar design is ongoing.

SECOND-GENERATION EGFR TKIs Second-generation EGFR TKIs are commonly referred to as “irreversible TKIs,” implying an irreversible inhibition on EGFR tyrosine kinases. Both afatinib and dacomitinib are capable of forming covalent bonds with the adenosine triphosphate (ATP) binding site of the enzyme, thus inducing permanent inhibition to the site. Another important property of afatinib is its inhibitory effect on human epidermal growth factor receptor 2 (HER2), while dacomitinib is a pan-HER TKI that inhibits HER 2 and HER4. These properties may inhibit tumors with EGFR exon 20 T790M mutations, implicating a potential role in deferral or treatment of acquired resistance to first generation TKIs. Afatinib is now approved as a first-line treatment option for patients with EGFR mutations. Sequist and colleagues compared first-line afatinib with pemetrexed/cisplatin in the LUX-Lung 3 study and demonstrated an improvement in tumor response rate, PFS, and quality of life.54 Median PFS was 11.1 months for afatinib-treated patients and 13.6 months for patients with exon 19 or 21 mutations. Similar findings were demonstrated in the LUX-Lung 6 study from China and Asia.55 However, afatinib-related grade 3 toxicities such as rash, diarrhea, and mucositis were less common in the LUX-Lung 6 study irrespective of similar dosage of afatinib. The difference in toxicities was attributed to early intervention, which would be an important message for doctors who plan to use this drug. With three EGFR TKIs available as first-line therapy, it is only natural to ask which one is better. The ongoing LUX-LUNG 7 study is a randomized phase IIb study comparing afatinib with gefitinib as first-line therapy for patients with either EGFR exon 19 or 21 mutation. Patient accrual is completed and results are pending. The efficacy of afatinib was also evaluated in patients who had failed to respond to firstgeneration EGFR TKIs. A prospective randomized study (LUX-Lung 1) compared afatinib with placebo in patients who had progressed on gefitinib or erlotinib.56 Tumor response rate was 6% and the median PFS was 3.3 months compared to 1.1 months in the placebo arm. However, the primary endpoint of OS was similar between the two arms and LUXLung 1 was considered a negative study. One reason is that the survival in the control arm was much longer than expected as a significant portion of

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patients from the placebo arm were rechallenged with EGFR TKIs. The other reason is that achievable plasma concentrations of clinically tolerable doses of afatinib are below the inhibitory concentrations for cell lines with EGFR exon 20 mutations.57 To maximize the inhibitory effect on the exon 20 T790M mutation, a proposal on the combination of extraand intracellular blockage of EGFR with cetuximab plus afatinib was investigated in a single-arm phase Ib/II study. Janjigian and colleagues reported tumor response rate of 30% and similar efficacy was observed in patients with or without the T790M mutation.58 The Eastern Cooperative Oncology Group and the Southwest Oncology Group are planning a study of this combination. Dacomitinib is the other second-generation EGFR TKI under development. Investigation of this drug took two directions. Dacomitinib was compared in a randomized phase II study to erlotinib as second-line therapy in an unselected population.59 The median PFS times for dacomitinib and erlotinib were 2.86 months and 1.91 months, respectively (HR 0.66). A retrospective analysis of EGFR mutation status found that dacomitinib achieved a higher tumor RR than erlotinib in patients with EGFR exon 19 and 21 mutations. The phase III randomized study (ARCHER 1009) with a similar study design is completed and results are pending. The other direction focuses on patients with known EGFR mutations. A single-arm phase II study reported a tumor RR of 76.5% and a median PFS of 18.2 months in 45 patients who received dacomitinib as first-line therapy.60 these data are the foundation for the direct head-to-head randomized phase III study (ARCHER 1050) comparing dacomitinib with gefitinib in a mutation-positive population.61 Accrual for this study started in June 2013.

CONCLUSION AND FUTURE DIRECTIONS EGFR TKIs are standard therapy for patients with activating EGFR mutations. Multiple international guidelines have recommended routine EGFR mutation analysis for all patients with adenocarcinoma of the lung and that an EGFR TKI be offered as first-line therapy. Resistance to an EGFR TKI is a universal phenomenon and we continue to gain knowledge on mechanisms and management of acquired resistance. Local therapy is indicated for patients with oligo-progression while the EGFR TKI may continue. A platinum-based doublet is the standard treatment for systemic progression. The role of an EGFR TKI beyond progression is being investigated in a phase III study. New approaches, including secondgeneration EGFR TKIs and an intercalated combination of chemotherapy and an EGFR TKI, may further improve overall treatment outcomes. In addition,

T.S.K. Mok, K. Lee, and L. Leung

EGFR TKIs are being combined with other targeted drugs such as MET inhibitors, HSP 90 inhibitors, and immunomodulatory drugs. The objective is to maximize the duration of disease control and/or conquer resistance. Advanced-stage EGFR mutation-positive lung cancer may not be a curable disease, but it is perceivable to convert it into a chronic illness in the future.

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