Abstract
Purpose
This FAEISS study was designed to confirm the superior efficacy of reactive topical corticosteroid strategies employing serially ranking-DOWN from very strong steroid levels for the treatment of facial acneiform rash induced by epidermal growth factor receptor (EGFR) inhibitors (EGFRIs), in comparison with strategies employing serially ranking-UP from weak steroid levels. This article reports the primary results of the non-small cell lung cancer (NSCLC) part of the trial.
Methods
Patients with EGFR-mutated advanced NSCLC treated with erlotinib or afatinib were enrolled in the first registration. All patients received preemptive therapy with oral minocycline and heparinoid moisturizer from the initiation of an EGFR inhibitor. Enrolled patients who developed facial acneiform rash within 2 weeks were randomized at second registration to either a ranking-UP (WEAK) group or a ranking-DOWN group. The primary endpoint was incidence of grade ≥ 2 facial acneiform rash over 8 weeks.
Results
Fifty-one patients were enrolled at the first registration and received EGFRIs (n = 30 for afatinib, n = 21 for erlotinib). However, 35 patients did not develop facial acneiform rash within 2 weeks; one patient discontinued preemptive treatment. Fifteen patients (29.4%) were enrolled in the second registration; nine were assigned to the WEAK group and six to the DOWN group. There was no significant difference in the incidence of grade ≥ 2 facial acneiform rash between the WEAK group (one patient, twice) and the DOWN group (one patient, twice; p = 0.8417). No patients developed severe facial acneiform rash within 10 weeks.
Conclusion
In NSCLC patients who received EGFRIs, preemptive therapy of oral minocycline and heparinoid moisturizer reduced facial acneiform rash incidence.
Trial registration
UMIN000024113
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Introduction
Epidermal growth factor receptor (EGFR) inhibition is an established and effective treatment option for patients with non-small cell lung cancer (NSCLC) [1,2,3,4], colorectal cancer (CRC) [5, 6], and squamous cell carcinoma of the head and neck (SCCHN) [7]. Many EGFR inhibitors are approved for clinical use, including monoclonal antibodies (such as cetuximab, necitumumab, and panitumumab) and tyrosine kinase inhibitors (TKIs) (such as gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib). Although EGFR inhibitors improve patient survival, they are also associated with skin toxicity, including acneiform rash, xerosis, paronychia, and pruritus, and hair, eyelash, and mucosal changes [8,9,10].
The incidence of facial acneiform rash of all grades has been estimated to be 60–90% from previous clinical trials [11, 12]. Although these adverse reactions are rarely serious or life-threatening, skin toxicity can significantly affect quality of life (QOL), causing both physical discomfort and psychological distress, which can affect compliance, thus affecting the efficacy of treatment with EGFR inhibitors [13,14,15,16]. Therefore, proper management of these toxicities is essential. Lacouture et al. reported that preemptive treatment, including skin moisturizers, sunscreen, topical steroid, and doxycycline, could reduce the severity of EGFR inhibitor-associated skin toxicities in patients with metastatic CRC [17]. Since the application site for these topical steroids is mainly on the face, there is concern over the side effects of steroids due to long-term use [18]. Therefore, few physicians currently recommend long-term, prophylactic topical steroid treatment on the face. Since EGFR-TKIs induce less skin toxicity than EGFR antibodies, patients with NSCLC harboring EGFR mutations are generally treated only with preventative moisturizers, and with reactive oral minocycline and topical steroids only at the onset of the rash.
This FAEISS study (NCCH1512) was designed to confirm the superior efficacy of reactive topical corticosteroid strategies employing serially ranking-DOWN from very strong topical steroids (compared with strategies employing serially ranking-UP from weak topical steroids) for facial acneiform rash induced by EGFR inhibitors in metastatic NSCLC and CRC. Here, we report the primary results of the NSCLC part of a randomized controlled trial evaluating reactive topical corticosteroid strategies in patients with NSCLC and CRC.
Patients and methods
Participants
FAEISS was a randomized, open-label, multicenter, phase III study implemented in ten centers across Japan. Eligible patients were EGFR-mutant NSCLC patients who were to be treated with erlotinib or afatinib, and wild-type KRAS and NRAS patients with metastatic CRC who were to be treated with cetuximab or panitumumab. This paper describes the results obtained for patients with NSCLC. The other key eligibility criteria were age 20 to 79 years; Eastern Cooperative Oncology Group performance status (PS) 0 to 1; and adequate organ function.
Study design and treatment schedule
The anticancer treatment was initiated with an investigator-choice EGFR-TKI (erlotinib or afatinib) at the recommended dose. All patients received 2 weeks of prophylactic treatment with minocycline (orally, 100 or 200 mg, per day) and heparinoid moisturizer at initiation of EGFR-TKI therapy. The dose of minocycline was an investigator’s choice. If facial acneiform rash was observed during the first 2 weeks, treatment of the rash with weak class topical corticosteroids was initiated. Patients who developed facial acneiform rash during the first 2 weeks were enrolled into the second registration.
Patients enrolled into the second registration were randomized to either the WEAK group (ranking-up) or the DOWN group (ranking-down) of reactive topical corticosteroid. The randomization procedure was accomplished using a minimization method balancing institution, type of EGFR inhibitor, and sex, in addition to adjustment factors. The “control treatment” (WEAK group) was defined as a reactive treatment that started with weak topical corticosteroids. In the control treatment group, if symptoms became worse, the reactive treatment was switched to stronger class corticosteroids. On the other hand, in the DOWN group, after the onset of facial acneiform rash, twice daily reactive treatment with very strong topical corticosteroids was started, and the strength of the steroid was gradually decreased every 2 weeks (to strong, then medium, then weak strengths). The types of topical steroids were as follows for each class. Prednisolone is a weak class and hydrocortisone butyrate is a medium class. A strong class is betamethasone valerate/gentamicin sulfate, or dexamethasone propionate. A “very strong” class is diflucortolone valerate, difluprednate, or betamethasone butyrate propionate. All patients continued prophylactic treatment with oral minocycline and heparinoid moisturizer after the second registration (Fig. 1). The evaluations for facial acneiform rash were performed five times beginning from 2 weeks after the first registration (and finishing at 10 weeks). Treatment after closing accrual of NSCLC patients was performed at the discretion of the investigators.
Photographic images of each patient’s face were taken at the participating site. All photos were collected centrally and subsequently reviewed by three dermatologists blinded to treatment status (central review). The reviewers assessed the severity of facial acneiform rash using an adapted grading system developed by Socpe et al. [19]. The adaptive grading system comprised grade 0–grade 3, representing none, mild, moderate, and severe rash.
Outcomes
The primary endpoint was a direct comparison of the incidence of grade 2 (moderate) or higher facial acneiform rash in the WEAK and DOWN groups during the 10-week skin treatment period (by central review). Key secondary endpoints included the proportion of grade 2 or higher facial acneiform rash, the proportion of grade 3 (severe) or higher facial acneiform rash, the proportion of switching EGFR therapies due to facial acneiform rash, the proportion of continuing EGFR therapy at the end of protocol treatment, the proportion of grade 1 (mild) or higher facial acneiform rash at the end of protocol treatment, the incidence of adverse events on the face, and the proportion of stable QOL scores.
Statistical considerations
The main clinical hypothesis of this study was that reactive treatment of facial acneiform rash during administration of EGFR inhibitors is more effective when starting with very strong topical corticosteroids than when starting with weak topical corticosteroids. The primary endpoint, the incidence of grade 2 or higher facial acneiform rash in each group, is assumed to be significantly lower in the DOWN group than in the WEAK group. Moreover, a key secondary endpoint, the incidence of adverse events on the face, is clearly assumed not to exceed in the WEAK group compared with that in the DOWN group. If these two endpoints are met, we may conclude that reactive treatment starting with very strong topical corticosteroids is more effective against facial acneiform rash.
A superiority trial design was applied to detect whether the incidence of grade 2 or higher facial acneiform rash in the DOWN group was less than that in the WEAK group. To provide the Wilcoxon rank sum test with 80% power at a 5% significance level (one-sided), 94 subjects over both groups (47 subjects per group) were required. Assuming facial acneiform rash (grade 1 or higher) occurs in 85% of all enrolled patients at the first registration, and that all affected patients progress to the second registration, 118 patients were required for the first registration. The planned sample size was set to be 120 patients. However, NSCLC patient accrual was closed in the middle of the accrual period since most NSCLC patients enrolled at the first registration did not develop facial acneiform rash within 2 weeks after initiation of EGFR-TKI treatment (and thus did not enroll in the second registration). Due to the non-confirmatory nature of the analysis for the NSCLC part of the trial, a two-sided p value is provided for the primary endpoint in this study. This trial is registered in UMIN-CTR (www.umin.ac.jp/ctr/) with identification number UMIN000024113.
Results
From November 2016 to August 2018, 51 patients with NSCLC harboring EGFR mutations were enrolled for the NSCLC part of the trial in the first registration. All 51 patients received afatinib (n = 30) or erlotinib (n = 21) treatment. Thirty-four patients were female and 17 were male, and the median age was 66 years (range: 39–79). Thirty-five patients (68.6%) did not develop a facial acneiform rash within 2 weeks, while one patient discontinued preemptive treatment with minocycline due to hepatotoxicity. Therefore, only 15 patients (27.4%) were enrolled in the second registration; nine patients were assigned to the WEAK group and six patients to the DOWN group (Fig. 2). The baseline characteristics of these patients are listed in Table 1. NSCLC patient accrual was subsequently closed because patients proceeding to the second registration were fewer than assumed. Thus, the planned number of patients required for the primary analysis could not be obtained.
There was no significant difference in the incidence of grade ≥ 2 facial acneiform rash between the WEAK group (one patient, twice) and the DOWN group (one patient, twice) (Wilcoxon’s rank sum test, two-sided: p = 0.8417) (Fig. 3). The proportion of grade ≥ 2 facial acneiform rash observed in the WEAK and DOWN groups were 11.1% (1/9) and 16.7% (1/6), respectively. No patients developed severe (grade ≥ 3) facial acneiform rash. Therefore, no patient in either group switched EGFR therapies due to facial acneiform rash. The proportion of patients continuing EGFR therapy at the end of protocol treatment was 66.7% (6/9) in the WEAK group and 50% (3/6) in the DOWN group. At the end of protocol treatment, the proportion of mild (grade ≥ 1) facial acneiform rash was 55.6% (5/9) in the WEAK group and 50% (3/6) in the DOWN group. Most patients immediately improved with topical corticosteroids, regardless of steroid strength.
Skin adverse events after the second registration (n = 15) included non-facial acneiform rash (n = 14); pruritus (n = 8); paronychia (n = 5); and dry skin (n = 3). Major non-skin adverse events included diarrhea (grade 3, n = 2); an increase in alanine aminotransferase (grade 2, n = 2), stomatitis (grade 3, n = 1), and pneumonitis (grade 1, n = 1).
Discussion
In the present study, we were unable to confirm the superior efficacy of topical corticosteroids that started at very strong levels for facial acneiform rash when NSCLC patients were treated with EGFR-TKIs. This was because preemptive therapy with oral minocycline and heparinoid moisturizers resulted in an unexpectedly low rate of facial acneiform rash (expected 85% vs. actual 27.4%). However, even though it is not a prespecified hypothesis and this study was not powered for it, low incidence of developing facial acneiform rash is considered to be an evidence that preemptive therapy with oral minocycline and heparinoid moisturizer in NSCLC patients receiving EGFR-TKIs can reduce the incidence and severity of facial acneiform rash. After initiating prophylactic treatment at the start of treatment with EGFR-TKIs, the incidence of facial acneiform rash was decreased, and any subsequent appearance of facial acneiform rash could immediately be treated with reactive topical corticosteroids (regardless of the strength of the steroid).
Presently, five EGFR-TKIs (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) are approved by the US Food and Drug Administration (FDA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) for the first-line treatment of patients with metastatic NSCLC harboring EGFR mutations. The safety and tolerability profiles of first- and second-generation EGFR-TKIs (gefitinib, erlotinib, afatinib, and dacomitinib) are well characterized. Treatment with these inhibitors is associated with skin toxicities such as acneiform rash, pruritus, xerosis, and paronychia. The dermatologic adverse events associated with osimertinib appear to be milder than those of first- and second-generation agents [20, 21]. The incidence of skin rash was 66–71% with gefitinib, 73–99% with erlotinib, 81–100% with afatinib, and 34–58% with osimertinib [11, 21]. In the present study, erlotinib and afatinib treatment regimens (which show higher skin toxicity) were investigated in order to better analyze the effects of topical steroids on the treatment of EGFR-TKI-induced acneiform rash.
Takeda et al. previously reported a pooled analysis of the incidence of acneiform rash (grade ≥ 3) during treatment with EGFR-TKIs (afatinib, 15% vs. erlotinib, 8.8%) [22]. According to the same study, the most common adverse events leading to withdrawal from EGFR-TKI treatment were related to skin toxicity [22]. In the Japanese post marketing surveillance study of erlotinib-treated patients with NSCLC (POLARSTAR study, n = 3488), median time to onset of rash was 8 days (range 1–494) [23].
Previous data concerning the use of topical steroids to treat acneiform rash induced by EGFR inhibitors are limited, and no standard treatment has been established. Published protocols concerning the use of topical steroids can be roughly divided into prophylactic treatments (beginning at the start of EGFR inhibitor administration) and reactive treatments (beginning after the onset of rash). Randomized trials of prophylactic treatments and reactive treatments were conducted for patients with metastatic CRC in the USA (STEPP) [17] and Japan (J-STEPP) [24]. In the STEPP study, Lacouture et al. reported that preemptive skin treatment might reduce the incidence of grade 2 or higher skin toxicities (compared with reactive treatment). These preemptive treatments included the use of skin moisturizers, sunscreen, topical steroids (1% hydrocortisone cream: weak class), and doxycycline [17]. In the J-STEPP study, preemptive skin treatment could reduce the severity of skin toxicities during panitumumab treatment in an Asian population with mCRC [24].
However, since the start time of antibiotic treatment (doxycycline/minocycline) in these trials was also different between the reactive and preemptive treatment groups, it was unclear if prophylactic use of topical steroids was itself beneficial. Moreover, since the application site for topical steroids is mainly on the face, the skin on the face may become thin following long-term use, and steroid acne may be induced. This is potentially an issue during longer term prophylactic administration of topical steroids. Indeed, the use of prophylactic topical steroids is rarely recommended by physicians.
Therefore, in the present study, unlike in the STEPP and J-STEPP trials, prophylactic treatment was initiated by administering oral minocycline and moisturizer at the start of EGFR inhibitors. While preemptive therapy for CRC patients is a standard treatment in Japan, this is not usually the case for NSCLC patients. Although prophylactical sunscreen was used in the STEPP and J-STEPP studies, prophylactical sunscreen was not used in the present study. This was because Japanese individuals normally require less UV protection than individuals of lighter-skinned races.
Five classes of topical steroid are marketed in Japan based on their anti-inflammatory potency: weak (e.g., prednisolone, 0.5%); medium (e.g., hydrocortisone butyrate); strong (e.g., betamethasone valerate); very strong (e.g., diflucortolone valerate); and strongest (e.g., clobetasol propionate). Kiyohara et al. recommended that strong or very strong topical corticosteroids be used for Japanese patients in the event of acneiform rash; in severe cases (grade 2/3), the strongest class of topical corticosteroids should be applied twice daily. Once symptoms have improved, the patient should be switched to a medium-class steroid. If symptoms become worse, the patient should be switched to stronger class steroids [25].
To date, most physicians do not provide prophylactic treatment for EGFR mutation-positive NSCLC patients at the start of EGFR-TKI treatment. Due to concerns about side effects such as interstitial pneumonia and hepatotoxicity caused by minocycline, they do not use in combination with an EGFR-TKI. However, there was no increase in side effects from minocycline in this study and it is worth considering preventive treatment with minocycline and moisturizers in patients with NSCLC. Regarding the amount of minocycline, rash occurred in 10 of 39 patients (26%) at 100 mg and 4 of 10 patients (40%) at 200 mg, and they were enrolled in the second registration (Table 1). This suggests that at least 200 mg minocycline is not always more effective than 100 mg. It is hoped that future studies will be conducted to select patients at risk for treatment, rather than administering it to all patients. Melosky et al. report that prophylactic minocycline and reactive treatment are both acceptable options for the treatment of erlotinib-induced rash in the second- or third-line setting of metastatic NSCLC (Pan Canadian Rash Trial) [26].
In the present study, although 51 patients with NSCLC were enrolled in the first registration, only 15 (27.4%) were enrolled in the second registration. Moreover, most patients showed immediate improvement following reactive treatment with topical corticosteroids, regardless of steroid strength. No patients developed severe facial acneiform rash (grade 3 or higher) within 10 weeks. In conclusion, in NSCLC patients who received EGFR-TKIs, preemptive therapy of oral minocycline and heparinoid moisturizer were effective in preventing facial acneiform rash.
Data availability
All data generated or analyzed during this study are included in this published article.
References
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957
Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31:3327–3334
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Munoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L, Spanish Lung Cancer Group in collaboration with Groupe Francais de P-C, Associazione Italiana Oncologia T (2012) 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 13:239–246
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T, North-East Japan Study G (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380–2388
Peeters M, Oliner KS, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, Andre T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, He P, Yu H, Koukakis R, Terwey JH, Jung AS, Sidhu R, Patterson SD (2015) Analysis of KRAS/NRAS mutations in a phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clin Cancer Res 21:5469–5479
Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS (2015) Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol 26:13–21
Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11:21–28
Lacouture ME (2006) Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6:803–812
Perez-Soler R, Saltz L (2005) Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol 23:5235–5246
Segaert S, Van Cutsem E (2005) Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 16:1425–1433
Kozuki T (2016) Skin problems and EGFR-tyrosine kinase inhibitor. Jpn J Clin Oncol 46:291–298
Lacouture ME, Maitland ML, Segaert S, Setser A, Baran R, Fox LP, Epstein JB, Barasch A, Einhorn L, Wagner L, West DP, Rapoport BL, Kris MG, Basch E, Eaby B, Kurtin S, Olsen EA, Chen A, Dancey JE, Trotti A (2010) A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group. Support Care Cancer 18:509–522
Joshi SS, Ortiz S, Witherspoon JN, Rademaker A, West DP, Anderson R, Rosenbaum SE, Lacouture ME (2010) Effects of epidermal growth factor receptor inhibitor-induced dermatologic toxicities on quality of life. Cancer 116:3916–3923
Rosen AC, Case EC, Dusza SW, Balagula Y, Gordon J, West DP, Lacouture ME (2013) Impact of dermatologic adverse events on quality of life in 283 cancer patients: a questionnaire study in a dermatology referral clinic. Am J Clin Dermatol 14:327–333
Tischer B, Huber R, Kraemer M, Lacouture ME (2017) Dermatologic events from EGFR inhibitors: the issue of the missing patient voice. Support Care Cancer 25:651–660
Tischer B, Bilang M, Kraemer M, Ronga P, Lacouture ME (2018) A survey of patient and physician acceptance of skin toxicities from anti-epidermal growth factor receptor therapies. Support Care Cancer 26:1169–1179
Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Iannotti N, Xu F, Yassine M (2010) Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 28:1351–1357
Hajar T, Leshem YA, Hanifin JM, Nedorost ST, Lio PA, Paller AS, Block J, Simpson EL (2015) A systematic review of topical corticosteroid withdrawal (“steroid addiction”) in patients with atopic dermatitis and other dermatoses. J Am Acad Dermatol 72:541–549 e542
Scope A, Lieb JA, Dusza SW, Phelan DL, Myskowski PL, Saltz L, Halpern AC (2009) A prospective randomized trial of topical pimecrolimus for cetuximab-associated acnelike eruption. J Am Acad Dermatol 61:614–620
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS, Investigators F (2017) Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer N Engl J Med
Chu CY, Choi J, Eaby-Sandy B, Langer CJ, Lacouture ME (2018) Osimertinib: a novel dermatologic adverse event profile in patients with lung cancer. Oncologist 23:891–899
Takeda M, Okamoto I, Nakagawa K (2015) Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer 88:74–79
Nakagawa K, Kudoh S, Ohe Y, Johkoh T, Ando M, Yamazaki N, Seki A, Takemoto S, Fukuoka M (2012) Postmarketing surveillance study of erlotinib in Japanese patients with non-small-cell lung cancer (NSCLC): an interim analysis of 3488 patients (POLARSTAR). J Thorac Oncol 7:1296–1303
Kobayashi Y, Komatsu Y, Yuki S, Fukushima H, Sasaki T, Iwanaga I, Uebayashi M, Okuda H, Kusumi T, Miyagishima T, Sogabe S, Tateyama M, Hatanaka K, Tsuji Y, Nakamura M, Konno J, Yamamoto F, Onodera M, Iwai K, Sakata Y, Abe R, Oba K, Sakamoto N (2015) Randomized controlled trial on the skin toxicity of panitumumab in Japanese patients with metastatic colorectal cancer: HGCSG1001 study. J-STEPP Future Oncol 11:617–627
Kiyohara Y, Yamazaki N, Kishi A (2013) Erlotinib-related skin toxicities: treatment strategies in patients with metastatic non-small cell lung cancer. J Am Acad Dermatol 69:463–472
Melosky B, Anderson H, Burkes RL, Chu Q, Hao D, Ho V, Ho C, Lam W, Lee CW, Leighl NB, Murray N, Sun S, Winston R, Laskin JJ (2016) Pan Canadian Rash Trial: a randomized phase III trial evaluating the impact of a prophylactic skin treatment regimen on epidermal growth factor receptor-tyrosine kinase inhibitor-induced skin toxicities in patients with metastatic lung cancer. J Clin Oncol 34:810–815
Acknowledgments
The authors are grateful to their patients and the staff of all participating institutions. The authors would like to acknowledge Mr. Tomoaki Yamada, Ms. Keiko Ohata, and Ms. Kaoru Koike for their assistance in data analysis.
Funding
This study was supported by Japan Agency for Medical Research and Development (AMED) under Grant Number JP17ck0106326.
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Study conceptualization and design: Katsuko Kikuchi, Yoshio Kiyohara, Naoya Yamazaki, Tetsuya Hamaguchi, Keiko Nozawa, Taro Shibata, and Haruhiko Fukuda. Formal analysis and investigation: Taro Shibata and Haruhiko Fukuda. Funding acquisition: Keiko Nozawa. Material preparation and data collection: Kazumi Nishino, Yutaka Fujiwara, Yuichiro Ohe, Ryota Saito, Eisaku Miyauchi, Tetsu Kobayashi, Yasuo Nakai, and Toshiaki Takahashi. The first draft of the manuscript was written by Kazumi Nishino. All authors contributed comments and helped revise previous versions of the manuscript. All authors read and approved the final manuscript.
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K. Nishino reports personal fees from AstraZeneca, Chugai pharmaceutical, Eli Lilly Japan, Roche Diagnostics, Novartis, Pfizer, and Ono Pharmaceutical, and grants and personal fees from Nippon Boehringer Ingelheim, Y. Fujiwara reports grants and personal fees from Astra Zeneca, Bristol-Myers Squibb, Chugai Pharma, Daiichi Sankyo, MSD, and Novartis; grants from Abbvie, Eisai, Eli Lilly, Incyte, and Merck Serono; and personal fees from Ono Pharmaceutical. Y. Ohe reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, Kyorin, Nippon Kayaku, Novartis, ONO Pharmaceutical, Pfizer, Taiho, and Takeda; personal fees from Boehringer Ingelheim, Celtrion, Amgen, and Janssen; and grants from Ignyta and Kissei. E. Miyauchi reports grants and personal fees from Chugai pharmaceutical and Boehringer Ingelheim. T. Kobayashi reports personal fees from AstraZeneca, Chugai pharmaceutical, Nippon Boehringer Ingelheim, Eli Lilly Japan, Pfizer, and Ono Pharmaceutical. Y. Nakai reports personal fees from ONO Pharmaceutical, Novartis, and Jiho Inc. T. Takahashi reports grants and personal fees from AstraZeneca, Chugai pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical, MSD, Pfizer Japan, and Boehringer Ingelheim Japan, and personal fees from Roche Diagnostics. T. Hamaguchi reports personal fees from Takeda Pharmaceutical Co., Ltd. N. Yamazaki reports grants and personal fees from Ono Pharmaceutical, Novartis Pharma K.K., Bristol-Myers Squibb, and Merck Sharp & Dohme; personal fees from Takeda Pharmaceutical and Chugai Pharmaceutical; and grants from Sysmex. Y. Kiyohara reports grants from MSD, Bristol-Myers Squibb, and Takara Bio, and personal fees from Ono Pharmaceutical. All other authors declare that they have no conflicts of interest.
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This study was conducted according to the Declaration of Helsinki and was approved by the ethics review board of each participating institution. Research ethics boards at all participating institutions approved the study protocol.
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Nishino, K., Fujiwara, Y., Ohe, Y. et al. Results of the non-small cell lung cancer part of a phase III, open-label, randomized trial evaluating topical corticosteroid therapy for facial acneiform dermatitis induced by EGFR inhibitors: stepwise rank down from potent corticosteroid (FAEISS study, NCCH-1512). Support Care Cancer 29, 2327–2334 (2021). https://doi.org/10.1007/s00520-020-05765-7
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DOI: https://doi.org/10.1007/s00520-020-05765-7