Management of cutaneous toxicities under amivantamab (anti MET and anti EGFR bispecific antibody) in patients with metastatic non-small cell lung cancer harboring EGFR Exon20ins: towards a proactive, multidisciplinary approach
在患有 EGFR Exon20 插入突變的轉移性非小細胞肺癌患者中，管理 amivantamab（抗 MET 和抗 EGFR 雙特異性抗體）引起的皮膚毒性：走向積極、多學科的處理方式

1.1. Lung cancer epidemiology and metastatic EGFR adenocarcinoma
1.1. 肺癌流行病學與轉移性 EGFR 腺癌

Lung cancer is one of the most frequent types of cancer and is the most common cause of death from cancer [1]. The five-year survival rate ranges from 4.2 % to 55 % with a median rate of 20 % depending on the stage at diagnosis and the presence or not of an activating oncogenic alteration [2], [3]. Non-small Cell Lung Cancer (NSCLC) accounts for 85–90 % of lung cancers [4], adenocarcinoma representing the main histology [5]. Among patients with adenocarcinoma, a mutation in the EGFR gene is found in 10–15 % of them [6]. Common EGFR primary driver mutations, such as exon 19 deletions and exon 21 L858R point mutations, account for approximately 85 % of EGFR mutations and are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs) [7], [8], [9], [10]. Although the majority of these patients initially respond to TKIs, they acquire resistance, preventing a durable response. Following third-generation TKI treatment, resistance occurs in ∼ 30 % of cases through tertiary mutation at the C797S position and these tumors may also develop resistance through the activation of the cMet pathway [11], [12], [13]. Novel anti-EGFR therapies are under development in this context. The EGFR exon 20 insertion mutation (Exon20ins) is found in 9–12 % of EGFR mutations and is considered to confer primary resistance to EGFR TKIs. Patients with NSCLC harboring Exon20ins were not offered EGFR TKIs until today [14], [15].
肺癌是最常見的癌症之一，也是導致癌症死亡的最主要原因之一。根據診斷時的癌症分期和是否存在活化致癌基因變異，五年存活率範圍從 4.2％到 55％不等，中位數為 20％。非小細胞肺癌（NSCLC）佔肺癌的 85-90％，腺癌是主要的組織學類型。在腺癌患者中，約有 10-15％的人發現 EGFR 基因突變。常見的 EGFR 主要驅動突變，如外顯子 19 缺失和外顯子 21 L858R 點突變，佔 EGFR 突變的約 85％，對 EGFR 酪氨酸激酶抑制劑（TKIs）非常敏感。儘管大多數患者最初對 TKIs 有反應，但他們會產生耐藥性，阻礙持久反應。在接受第三代 TKI 治療後，約 30％的病例會通過 C797S 位置的三級突變產生耐藥性，這些腫瘤也可能通過激活 cMet 途徑來產生耐藥性。在這種情況下，新型抗 EGFR 療法正在開發中。 EGFR 外顯子 20 插入突變（Exon20ins）在 EGFR 突變中佔 9-12％，被認為對 EGFR TKI 產生原發性抗藥性。患有 NSCLC 且帶有 Exon20ins 的患者直到今天仍未被提供 EGFR TKI 治療。

1.2. Amivantamab in the CHRYSALIS trial and expected toxicities
1.2. Amivantamab 在 CHRYSALIS 試驗中及預期毒性

Amivantamab is a fully human IgG1-based bispecific antibody directed against the EGF and cMet receptors. It shows activity against tumors with either the primary activating or the T790M second-site resistance EGFR mutations. In the phase 1 CHRYSALIS trial (NCT02609776) the patients included were harboring an EGFR mutation (both sensitive primary mutations as well as marketed TKI-resistant mutation such as Exon20 insertion). EGFR TKIs are known to have various side effects and especially cutaneous side effects: rash or acneiform eruption (60 % to 80 % of patients), paronychia (35 %), and dry sky (35 %), but also no-dermatological side effects such as diarrhea (60 %) [16]. Adverse events with amivantamab in the CHRYSALIS study included rash (78 % any grade, 3 % grade ≥ 3), infusion-related reaction (65 % any grade, 2 % grade ≥ 3) and paronychia (40 %), followed by stomatitis (19 %), pruritis (19 %) and diarrhea (11 %) [17]. Posology was an intravenous administration of full dose every 2 weeks according to the weight (starting dose was 1400 mg if body weight ≥ 80Kg, and 1050 mg if body weight <80Kg). The infusion related reaction will not be treated in this paper, as common guidelines already exists.
Amivantamab 是一種完全人源的 IgG1 型雙特異性抗體，針對 EGF 和 cMet 受體。它對具有原始活化或 T790M 第二位抗藥性 EGFR 突變的腫瘤表現出活性。在第 1 期 CHRYSALIS 試驗（NCT02609776）中，參與的患者患有 EGFR 突變（包括敏感的原始突變以及市售 TKI 耐藥突變，如 Exon20 插入）。EGFR TKI 已知具有各種副作用，尤其是皮膚副作用：皮疹或痤瘡樣爆發（60％至 80％的患者）、甲溝炎（35％）和乾燥的皮膚（35％），還有非皮膚副作用，如腹瀉（60％）[16]。在 CHRYSALIS 研究中，amivantamab 的不良事件包括皮疹（78％任何等級，3％≥ 3 級）、輸注相關反應（65％任何等級，2％≥ 3 級）和甲溝炎（40％），其次是口腔炎（19％）、瘙癢（19％）和腹瀉（11％）[17]。用法是根據體重每 2 週靜脈注射全劑量（如果體重≥80 公斤，起始劑量為 1400 毫克，如果體重<80 公斤，則為 1050 毫克）。 本文不會討論輸液相關的反應，因為已經有常見的指引存在。

1.3. Cellular and molecular mechanisms of skin toxicity caused by EGFR inhibitors and MET inhibitors
1.3. 由 EGFR 抑制劑和 MET 抑制劑引起的皮膚毒性的細胞和分子機制

Skin is the first line of defense against the invasion of external pathogens. The skin contains accessory organs such as nails, subcutaneous glands, sweat glands, hair follicles, cutaneous nerve and subcutaneous blood vessels. The EGFR gene is known to be widely expressed in skin keratinocytes, dendritic cells, connective tissue cells and skin accessory organs [18], [19], [20], [21]. Normal activation of EGFR signaling promotes wound healing, it also inhibits inflammation and stimulate capillary constriction [22]. The use of anti-EGFR consequently leads to skin toxicity by the destruction of the physical barrier that the skin represents, damages hair follicles, and hosts immune activation [23]. The damage of hair follicles leads to folliculitis also known as acneiform rash and papulopustular exanthema. In addition, EGFR plays an essential role during hair growth cycle [24]. Hair can become brittle, thin and curly under anti EGFR [25], [26]. MET tyrosine kinase inhibitors may also lead to cutaneous toxic effects with hand-foot skin reaction, hair depigmentation, and skin xerosis [27].
皮膚是對外來病原體入侵的第一道防線。皮膚包含輔助器官，如指甲、皮下腺、汗腺、毛囊、皮膚神經和皮下血管。已知 EGFR 基因在皮膚角質細胞、樹突細胞、結締組織細胞和皮膚輔助器官中廣泛表達。EGFR 信號的正常激活促進傷口癒合，同時抑制炎症並刺激毛細血管收縮。使用抗 EGFR 會導致皮膚毒性，破壞皮膚代表的物理屏障，損害毛囊並引發免疫激活。毛囊損傷導致毛囊炎，也稱為痤瘡樣皮疹和丘疹膿疹性皮疹。此外，EGFR 在頭髮生長周期中扮演重要角色。在抗 EGFR 治療下，頭髮可能變得脆弱、細小且捲曲。MET 酪氨酸激酶抑制劑也可能導致皮膚毒性反應，如手足皮膚反應、頭髮脫色和皮膚乾燥。

1.4. Objective 1.4. 目標

The objective of the present work is to propose recommendations for the management of skin toxicities under amivantamab, and to establish guidelines that can be used for the patient who will receive this treatment in the future. Amivantamab is now part of routine practice through its approval in patients with EGFR exon 20 insertion NSCLC.
本研究的目標是提出在使用阿米瓦坦單抗時管理皮膚毒性的建議，並建立可供未來接受此治療的患者使用的指南。阿米瓦坦單抗現已成為常規實踐的一部分，通過其在 EGFR 外显子 20 插入型非小細胞肺癌患者中的批准。

1.5. Methods 1.5. 方法

Our institute participated in the CHRYSALIS trial. Starting from November 1st 2020, all cutaneous adverse events were notified and classified according to the CTCAE 6.0 classification, for patients included in the phase 1 CHRYSALIS trial from November 1st 2019 until November 1st 2020. We established a more detailed description of the lesions of the skin and the hairs according the CTCAE6.0 classification [28] in Table 1. The patients were treated and followed for their skin toxicities until the cut-off date December 31st 2021.
我們的機構參與了 CHRYSALIS 試驗。從 2020 年 11 月 1 日開始，所有皮膚不良事件均按照 CTCAE 6.0 分類進行通報和分類，適用於 2019 年 11 月 1 日至 2020 年 11 月 1 日參與第 1 期 CHRYSALIS 試驗的患者。我們根據表 1 中的 CTCAE6.0 分類[28]對皮膚和毛髮的病變進行了更詳細的描述。患者的皮膚毒性反應將持續治療和追蹤至 2021 年 12 月 31 日截止日期。

Table 1. Skin toxicities of amivantamab according to the CTCAE 6.0 classification.
表 1. 根據 CTCAE 6.0 分類，amivantamab 的皮膚毒性。

Legend: BSA = Body Surface Area; ADL = Activity of Daily Life; IV = intravenous.
傳奇：BSA = 皮膚表面積；ADL = 日常生活活動；IV = 靜脈內。

Skin evaluation was systematic at each treatment administration (once every-two weeks) during the medical visit. A consultation with a podiatrist, member of the Research and Wound Care Unit, was organized the same day of the medical visit. Facing the need for regularly dermatological evaluation, we implemented when needed (persistent grade 2 or grade ≥ 3 toxicity) specific visits with a dermatologist. A QoL questionnaire (DLQI) was used and given to each patient every-four visits (every-two months). Visit with psychologist was suggested to patients when the skin toxicities seemed to impair patient’s quality of life (DLQI ≥ 11), according to our routine care at our Institute.
皮膚評估在每次治療過程中（每兩週一次）在就醫時進行。與足病醫師、研究和傷口護理單位成員的諮詢安排在同一天進行。面對需要定期皮膚學評估的情況，我們在需要時（持續 2 級或 2 級以上的毒性）與皮膚科醫師進行特定的就診。每四次就診（每兩個月一次）給予每位患者一份生活品質問卷（DLQI）。當皮膚毒性似乎影響患者的生活品質（DLQI ≥ 11）時，根據我們在醫院的常規護理，建議患者與心理學家進行會診。

All patients gave their consent to accept photos of cutaneous adverse events and analysis of their evolution in this paper.
所有病患均同意接受皮膚不良事件的照片以及其演變分析在本文中。

2.1. Patients included in the trial
2.1. 參與試驗的病患

Seven patients started amivantamab as monotherapy at our institute from from November 1st 2019 until November 1st 2020. The median age at initiation of treatment was 64 years old [51–81], 5 women (71 %) and 2 men (29 %). All patients had white phototype. The median delay under treatment was 22 months [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24]; and 5 patients were still receiving amivantamab at the cut of date of December 1st 2021.
本院自 2019 年 11 月 1 日至 2020 年 11 月 1 日，有七位患者開始接受 amivantamab 單獨治療。治療開始時的中位年齡為 64 歲[51-81]，其中 5 位為女性（71％），2 位為男性（29％）。所有患者均為白種人。治療延遲的中位數為 22 個月[8]，[9]，[10]，[11]，[12]，[13]，[14]，[15]，[16]，[17]，[18]，[19]，[20]，[21]，[22]，[23]，[24]；截至 2021 年 12 月 1 日，仍有 5 位患者在接受 amivantamab 治療。

2.2. Description of dermatological toxicities of amivantamab
2.2. Amivantamab 皮膚毒性描述

During the first 140 days of treatment, acneiform rash (83 %, n = 6/7) and hirsutism/hypertrichosis (100 %, n = 4/4) were reaching their highest grade (respectively grade 3 and grade 1), whereas paronychia could reach its highest grade of treatment until the 300th day of treatment (100 %, n = 7/7). Skin fissures reached their highest grade (grade 2) at 196 days of treatment (100 %, n = 4/4). In average after 300 days of treatment, skin toxicities remained stable at their level of grade, and it appeared difficult to reduce the grade of these affections after. Among the three patients with an initial dose of amivantamab of 1400 mg, two of them presented grade 3 acneiform rash in less than 100 days after treatment initiation. We noticed hirsutism and hypertrichosis before 140 days of treatment in 3 women and 1 men, Fig. 1. Fig. 2.
在治療的前 140 天內，痤瘡樣皮疹（83％，n = 6/7）和多毛/過度生長（100％，n = 4/4）達到最高等級（分別為 3 級和 1 級），而甲溝炎可能在治療的第 300 天達到最高等級（100％，n = 7/7）。皮膚裂縫在治療的第 196 天達到最高等級（2 級）（100％，n = 4/4）。在治療 300 天後，皮膚毒性保持在其等級水平，並且似乎很難降低這些病症的等級。在初始安維坦單抗劑量為 1400 毫克的三名患者中，有兩名在治療開始後不到 100 天出現 3 級痤瘡樣皮疹。我們注意到在治療的前 140 天內，有 3 名女性和 1 名男性出現多毛和過度生長。Fig. 1. Fig. 2.

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Fig. 1. Evolution of the grade of dermatological toxicities in the 7 patients treated with amivantamab from the initiation of treatment until December 31st 2021.
圖 1. 自治療開始至 2021 年 12 月 31 日，7 名接受 amivantamab 治療的患者皮膚毒性等級的演變。

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Fig. 2. Grade of the two main toxicities encountered under amivantamab in our cohort of seven patients. A. Grade 1 paronychia. B. Grade 2 paronychia. C. Grade 3 paronychia. D. Grade 1 acneiform rash. E. Grade 2 acneiform rash. F. Grade 3 acneiform rash 3 with lesions in the scalp.
圖 2. 在我們七位患者中使用 amivantamab 時遇到的兩種主要毒性等級。A. 一級甲溝炎。B. 二級甲溝炎。C. 三級甲溝炎。D. 一級痤瘡樣皮疹。E. 二級痤瘡樣皮疹。F. 三級痤瘡樣皮疹，頭皮有病變。

2.3. Management of cutaneous adverse events
2.3. 皮膚不良反應的管理

Acneiform rash usually starts on the face, the chest and the top of the back. The scalp can also be affected. To prevent acneiform rash, we implemented a local prevention with moisturizing and prophylactic antibiotics like Tetracycline (DOXYCYCLINE°) 50 mg twice a day at amivantamab initiation. In case of grade 1 toxicity: the management is similar to the one described above in the prevention part. There is no specific other treatment but emphasizing on moisturizing the skin and the scalp with soothing shampoos. In case of grade 2 toxicity, topic corticosteroids are recommended, as well as an increased dose of tetracycline (100 mg twice a day), and if needed amivantamab can be temporary suspended for one injection to give time for healing. In case of grade 3 toxicity, we recommend to continue the measures implemented in grade 2, to suspend amivantamab until grade ≤ 2 and to consider a reduction dose of amivantamab. Hospitalization in dermatology can be an option to consider in case of persistent grade 3 toxicity.
粉刺樣皮疹通常從臉部、胸部和背部頂部開始。頭皮也可能受影響。為了預防粉刺樣皮疹，我們在 amivantamab 開始時實施局部預防措施，包括使用保濕和預防性抗生素，如四環素（DOXYCYCLINE°）50 毫克，每天兩次。如果出現 1 級毒性反應：管理方法與預防部分所述相似。沒有特定的其他治療方法，但強調使用舒緩洗髮水保濕皮膚和頭皮。如果出現 2 級毒性反應，建議使用局部皮質類固醇，並增加四環素的劑量（每天 100 毫克兩次），如有需要，可以暫時停用 amivantamab 一次注射以給予時間恢復。如果出現 3 級毒性反應，建議繼續實施 2 級措施，暫停 amivantamab 直到毒性≤2 級，並考慮減少 amivantamab 的劑量。在持續出現 3 級毒性反應的情況下，可以考慮轉診至皮膚科住院。

Paronychia corresponds to skin budding along the nails. To prevent nails fragility we recommend an alimentation enriched in biotin, to administer nail polishes with filmogel, and to prefer comfortable and large shoes. The local prevention of paronychia is based on moisturizing of hands and feet, and especially of the cuticle around the nail. In toxicities grade 2, we implemented local anesthesia before any care and protection with bandage to avoid frictions. We also added a mechanical debridement, and topic corticosteroids application once a day for minimum 7 days. Antibiotherapy should not be systematic, and only if medically indicated. We suggest cryotherapy if the treatments described before are not efficient enough. Cryotherapy consists of applying an extremely precise flow of nitrous oxide on the lesion. The Freezpen° was used with a temperature of −89 °C (−128°F), without any pain described by patients during the intervention. Several successive applications were realized (2 to 3). Good clinical practice suggest that a typical freeze may last from 5 to 10 s for a small flat wart. After the first freezing cycle, the tissue should be allowed to thaw for about 30 s, followed by a second freezing. In case of a persistent grade 2 paronychia after optimal local care we suggest to consider a temporary suspension of amivantamab. In case of paronychia grade 3, we continue the measures implemented in grade 2, we can suspend amivantamab until grade ≤ 2, and consider a reduction dose of amivantamab. Two patients benefit from cryotherapy which resulted in a reduction to grade 1 paronychia, Fig. 3. If paronychia grade 3 are persistent, phenolization can be an option with very satisfying results. Phenolization is a mini invasive surgical intervention made by dermatologists under local anesthesia. It consists on a resection of the lateral part of the nail where the paronychia is, associated with destruction of the corresponding part of the matrix. This destruction is realized with an application of phenol acid to definitely stop the growth of the nail again (Fig. 4).
甲溝炎是指指甲周圍皮膚的發炎。為了預防指甲脆弱，我們建議飲食中富含生物素，使用含膜凝膠的指甲油，並選擇舒適寬大的鞋子。局部預防甲溝炎的方法是保持手腳的滋潤，特別是指甲周圍的角質。在毒性等級 2 的情況下，我們在進行任何護理之前實施局部麻醉，並使用繃帶保護以避免摩擦。我們還進行機械去除死組織，並每天至少應用一次局部皮質類固醇。抗生素治療不應該是固定的，只有在醫療指示下才應使用。如果前述治療不夠有效，我們建議使用冷凍療法。冷凍療法是將一種極其精確的氧化亞氮流應用在病灶上。我們使用了 Freezpen°，溫度為-89°C（-128°F），在手術過程中患者沒有描述任何疼痛。我們進行了多次連續的應用（2 到 3 次）。良好的臨床實踐建議，對於小平坦疣，典型的冷凍時間可能持續 5 到 10 秒。 第一次冷凍循環後，組織應該允許解凍約 30 秒，然後進行第二次冷凍。如果在最佳局部護理後持續出現 2 級甲溝炎，建議考慮暫時停用阿米瓦坦單抗。對於 3 級甲溝炎，我們會繼續實施 2 級措施，可以暫停阿米瓦坦單抗直到≤2 級，並考慮減少阿米瓦坦單抗的劑量。兩名患者受益於冷凍療法，導致甲溝炎降至 1 級，見圖 3。如果 3 級甲溝炎持續存在，酚化可能是一個選擇，並且效果非常滿意。酚化是一種由皮膚科醫生在局部麻醉下進行的微創手術干預。它包括切除甲溝炎部位的側部，並銷毀相應的基質部分。這種銷毀是通過應用酚酸來永久停止指甲再生的生長來實現的（見圖 4）。

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Fig. 3. Paronychia treated by cryotherapy. A. Grade 3 paronychia before the treatment. B. Application of the nitrous oxide on the lesion. C. At the end of the intervention.
圖 3. 使用冷凍療法治療的甲溝炎。A. 治療前的 3 級甲溝炎。B. 將氮氧化物應用於病灶上。C. 干預結束時。

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Fig. 4. Paronychia treated by phenolization. A. Grade 3 paronychia. B. One month after phenolyzation.
圖 4. 用酚化療法治療的甲溝炎。A. 三級甲溝炎。B. 酚化療法後一個月。

Skin fissures or cracks are often related to cutaneous xerosis. To prevent skin fissures we focused on avoiding skin potential aggressions (household products, cold-ice, micro-traumatisms), with moisturizing of hands and feet. In case of skin fissures grade 1, we did an intensification in moisturizing with an overnight application and occlusion: cling film for lesions on feet and disposable gloves for lesions on hands. Bandage could be used to avoid frictions and infection.
皮膚裂縫常與皮膚乾燥有關。為了預防皮膚裂縫，我們專注於避免皮膚受到潛在侵害（家用產品、冷冰、微創傷），並保持手部和腳部的保濕。對於一級皮膚裂縫，我們會加強保濕，並在夜間塗抹並遮蔽：腳部損傷使用保鮮膜，手部損傷使用一次性手套。也可使用繃帶以避免摩擦和感染。

2.4. Dose modification and temporary suspension of amivantamab for cutaneous toxicities
2.4. 修正阿米瓦坦抹的劑量並暫時停用以處理皮膚毒性。

Considering the patients who started amivantamab at the dose of 1400 mg (n = 3), all of them had two successive dose reductions (dose after first dose reduction = 1050 mg, and dose after second dose reduction = 700 mg); whereas from patients who started amivantamab at the dose of 1050 mg (n = 4) only half of them had one dose reduction (dose after first dose reduction = 700 mg).
考慮到以 1400 毫克劑量開始使用阿米瓦替尼的患者（n = 3），所有這些患者都經歷了兩次連續的劑量減少（第一次減少後劑量 = 1050 毫克，第二次減少後劑量 = 700 毫克）；而從以 1050 毫克劑量開始使用阿米瓦替尼的患者（n = 4）中，只有一半的患者經歷了一次劑量減少（第一次減少後劑量 = 700 毫克）。

In the subgroup of patients with a starting dose at 1400 mg, the median delay before the 1st dose reduction was 84 days [35–98]. Whereas in the subgroup of patients with a starting dose at 1050 mg, the median delay before the first dose reduction was 222 days [140–304]. Paronychia and acneiform rash were the two most common reasons for dose reduction.
在起始劑量為 1400 毫克的患者亞組中，第一次減量前的中位數延遲時間為 84 天[35-98]。而在起始劑量為 1050 毫克的患者亞組中，第一次減量前的中位數延遲時間為 222 天[140-304]。甲溝炎和痤瘡樣皮疹是減量的兩個最常見原因。

Three patients had a treatment suspension at a median delay of 98 days for acneiform rash (66 %) and paronychia (33 %). All of them started with the 1400 mg dose.
三位患者因為痤瘡樣皮疹（66％）和甲溝炎（33％）在中位數延遲 98 天後暫停治療。他們全部是從 1400 毫克的劑量開始的。

2.5. Quality of life/psychological impact on dermatological AEs
2.5. 生活品質/皮膚科不良反應對心理的影響

The DLQI questionnaires reported 3 patients from 7 (43 %) who experienced an important impact from their skin toxicities on their daily life (DLQI score ≥ 11). The range was 0–15. Cutaneous adverse events can have psychological impact on patients: especially hirsutism in women which modifies their external cutaneous aspect of the face; or high-grade acneiform rash. We encourage consultation with psychologist in those patients, and all of them accepted and beneficiated from psychological support.
DLQI 問卷報告中有 3 位患者（佔 7 人的 43％）表示皮膚毒性對他們的日常生活產生了重要影響（DLQI 分數≥11）。分數範圍為 0-15。皮膚不良反應可能對患者產生心理影響：特別是女性的多毛症會改變她們臉部的外部皮膚外觀；或高度痤瘡樣皮疹。我們鼓勵這些患者諮詢心理學家，所有患者都接受並從心理支持中受益。