Neratinib maleate

表皮生长因子受体（EGFR）基因激活突变的发现，彻底改变了非小细胞肺癌（NSCLC）的治疗格局，推动了靶向酪氨酸激酶抑制剂（TKIs）的研发[1]。与传统治疗相比，这类疗法能显著提高患者生存率，并减少不良反应[1]。 近年来的研究进展，极大地重塑了 EGFR 突变型NSCLC的治疗模式：TKIs 已被纳入早期和局部晚期疾病的治疗体系，Ⅲ 期临床试验也在转移性疾病中探索了联合治疗策略。尽管这些强化治疗方案能改善无进展生存期（PFS），但同时也增加了毒性反应风险和治疗成本，因此精准筛选患者（基于基因检测与基因变异特征）以最大化治疗获益至关重要[1]。 生物标志物（如共突变、循环肿瘤 DNA）的最新研究数据，为优化治疗决策提供了新方向；此外，对 EGFR TKIs 耐药机制（基于耐药相关基因变异）的深入理解，也进一步拓宽了治疗选择[1]。 EGFR 基因变异类型及生物学特征 不同 EGFR 基因变异的结构影响与信号通路激活模式不同，直接决定治疗敏感性与预后，主要分为以下四类： 1 经典样突变（classical-like mutations）[1] 核心类型：19 号外显子缺失（ex19del）、21 号外显子 L858R 点突变、21 号外显子 L861Q 点突变，占所有 EGFR 突变的 80%-85%； 变异特征：突变位点均远离 EGFR 激酶结构域的 ATP 结合口袋（药物作用位点），不改变口袋构象，不影响 EGFR TKIs 与口袋的结合； 生物学效应：ex19del/L858R：通过缩短 α 螺旋 N 端侧前导环，限制 α 螺旋运动，使其维持 “向内” 的活性构象；L861Q：突变位于 α 螺旋邻近区域，结构影响与 ex19del/L858R 相似，均导致 EGFR 无需配体即可持续激活，依赖 MAPK/PI3K-AKT 通路驱动肿瘤生长； 治疗敏感性：对一、二、三代 EGFR TKIs 均敏感，其中三代 TKI（奥希替尼）疗效最优 ——FLAURA 试验中，ex19del/L858R 患者接受奥希替尼治疗的中位 OS 达 38.6 个月；L861Q 患者接受奥希替尼治疗的 ORR 约 60%-70%，中位 PFS 12-14 个月。 2 P 环和 αC 螺旋压缩突变（PACC 突变）[1] 核心类型：18 号外显子 G719X 点突变（G719A/G719C/G719S）、20 号外显子 S768I 点突变，占所有 EGFR 突变的 5%-10%，属于 “少见激活突变”； 变异特征：突变位点直接影响 EGFR 蛋白的 P 环（磷酸盐结合环）与 αC 螺旋之间的空间结构，导致该区域压缩变形，间接改变 ATP 结合口袋的构象（但不阻断口袋）； 生物学效应：构象改变使一代 / 三代 EGFR TKIs 与口袋的结合亲和力下降，但二代 TKI（阿法替尼）因不可逆结合模式，仍可有效抑制突变型 EGFR 活性；临床前模型显示，阿法替尼对 PACC 突变的抑制活性（IC50 0.3-0.8nM）显著高于一代 TKI 吉非替尼（IC50 5-12nM）和三代 TKI 奥希替尼（IC50 2.5-4.0nM）； 治疗敏感性：优先对二代 TKI 敏感，LUX-Lung 试验显示，阿法替尼治疗 PACC 突变患者的 ORR 为 71.0%，中位 PFS 10.7 个月；对三代 TKI 敏感性较弱，回顾性数据显示奥希替尼治疗 PACC 突变患者的 ORR 约 45%，中位 PFS 8-9 个月。 3 T790M 样突变（T790M-like mutations）[1] 核心类型：分为 “原发性 T790M 突变” 和 “获得性 T790M 突变”，前者罕见（发生率 <1%），后者是一代 / 二代 EGFR TKI 耐药的最主要机制（发生率 >50%）； 变异特征：突变位于 EGFR 激酶结构域的 “守门人” 残基（20 号外显子 Thr790→Met790），Met 残基的侧链体积大于 Thr，不直接阻断 ATP 结合口袋，但增强 EGFR 与 ATP 的结合亲和力（约为野生型的 10 倍）； 生物学效应：一、二代 TKI（吉非替尼、阿法替尼）与 ATP 竞争结合口袋时，因 ATP 亲和力显著升高而失效；三代 TKI（奥希替尼）因可与口袋底部的 Cys797 残基共价结合，且对 T790M 突变型 EGFR 的亲和力（IC50=1.6nM）远高于野生型（IC50=48nM），可绕过 ATP 竞争机制发挥作用； 治疗敏感性：对一、二代 TKI 耐药，对三代 TKI 高度敏感 ——AURA3 试验中，获得性 T790M 突变患者接受奥希替尼治疗的 ORR 71%，中位 PFS 10.1 个月，中位 OS 26.8 个月；原发性 T790M 突变患者（多合并 ex19del/L858R）对奥希替尼的疗效与获得性突变患者一致。 EGFR tyrosine kinase domain mutations 4 20 号外显子插入突变（ex20ins）[1,2,3] 核心类型：90% 为 α 螺旋后环区（767-775 位氨基酸）的 3-21bp 框内插入 / 重复（如 D770_N771insNPG、V769_D770insASV），10% 为 α 螺旋 C 端（762-766 位氨基酸）插入（如 A763_Y764insFQEA），占所有 EGFR 突变的 4%-10%； 变异特征：插入片段通过 “推动”α 螺旋使其维持 “向内” 的活性构象，同时导致 α 螺旋和 P 环向 ATP 结合口袋移位，产生强烈空间位阻；晶体结构显示，该类突变不降低 EGFR 与 ATP 的亲和力，但显著阻碍一、二、三代 TKIs 进入口袋； 生物学效应：EGFR 持续激活且对常规 TKIs 产生原发性耐药，仅特殊亚型（如 A763_Y764insFQEA，插入位于 α 螺旋内部，构象接近经典样突变）对一代 TKI 敏感； 治疗敏感性：对一、二、三代 TKIs 耐药（缓解率 3%-8%，PFS <3 个月），仅对新型选择性抑制剂（波齐替尼、莫博赛替尼、埃万妥单抗）有效 —— 如莫博赛替尼治疗铂类后进展患者的 ORR 28%，中位 PFS 7.3 个月。 EGFR Exon 20 insertion mutations in NSCLC. 伴随变异（共突变与胚系突变）[1] 1 共突变（非独立突变类型，与上述四类突变共存） 最常见类型：TP53 突变（发生率 40%-50%）、PIK3CA 突变（5%-10%）、RB1 缺失（3%-5%）； 临床影响：TP53 突变：促进基因组不稳定性，增加 MET 扩增、小细胞转化等耐药机制的发生率，使 EGFR TKI 治疗的中位 PFS 从 16.5-19.0 个月缩短至 9.5-12.0 个月；PIK3CA 突变：激活 PI3K-AKT 通路旁路，削弱 EGFR TKI 对下游信号的抑制效果，中位 OS 从 38.6 个月缩短至 24.5 个月； 应对策略：TP53 突变患者优先选择 “EGFR TKI + 化疗” 联合方案（如 FLAURA2 试验中联合化疗的 PFS HR=0.52）；PIK3CA 突变患者可尝试 “EGFR TKI + PI3K 抑制剂”（如阿培利司，ORR 35%-40%）。 2 胚系突变（罕见，多为 T790M 样突变的特殊形式） 核心类型：EGFR T790M 胚系变异（最常见）、G724S、R776H、V769M 等，发生率 <1%； 人群特征：多为女性、欧洲裔、无吸烟史，常表现为双侧多发磨玻璃肺结节（惰性生长）；95% 患者会同时存在体细胞 EGFR 激活突变（ex19del/L858R，即 “二次打击”）； 临床意义：携带 T790M 胚系突变人群 60 岁前患肺癌风险 >50%，需从 40 岁开始每年进行低剂量 CT 筛查；治疗方案与体细胞 “激活突变 + T790M 突变” 一致，优先使用奥希替尼。 EGFR 突变型 NSCLC 的基因检测：方法与临床推荐应用 基因检测是 EGFR 突变型 NSCLC 精准治疗的前提，可明确变异类型、指导治疗选择、监测耐药机制，主要包括组织检测与液体活检两类技术[1,3]。 1 主要检测方法对比 2 临床推荐应用场景 2.1 初诊患者：明确变异类型以指导一线治疗 所有疑似 EGFR 突变型 NSCLC 患者，优先通过 NGS 检测组织样本（若组织可获取），明确是否为 ex19del/L858R（常见突变）、ex20ins 或其他少见突变[1,3]； 组织样本不足时，采用血浆 ctDNA-NGS 补充检测，尤其需确认是否存在 ex20ins（避免 PCR 漏检）[1,3]； 检测范围需包含 EGFR 18-21 号外显子，同时推荐检测 TP53、PIK3CA 等共突变（预测疗效与耐药风险）[1]。 2.2 辅助治疗：疗效预测与复发监测 术后 IB-IIIA 期 EGFR 常见突变患者，通过 ctDNA 检测基线突变状态：ctDNA 阳性患者从辅助奥希替尼中获益更显著（DFS HR=0.18），ctDNA 阴性患者获益较弱（HR=0.45）[1]； 辅助 TKI 治疗期间，每 2-3 个月进行一次 ctDNA 检测：ctDNA 持续阴性提示低复发风险（5 年无复发生存率 92%），ctDNA 转阳提示复发风险增加 8 倍[1]。 EGFR TKI 治疗进展后，优先进行组织活检 + NGS 检测；若组织不可获取，采用血浆 ctDNA-NGS 补充[1]； 检测内容需覆盖：EGFR 继发突变（T790M、C797S、G724S）、靶点外变异（MET 扩增、HER2 扩增、RET/ALK 融合）、共突变及组织学转化相关标志物[1]； 若 ctDNA 检测到明确耐药变异（如 T790M、MET 扩增），即使影像学未进展，也应考虑提前调整治疗方案；若 ctDNA 阴性但影像学进展（如寡进展），需再次组织活检确认机制[1]。 EGFR TKI药物作用机理 1 一代 EGFR TKI 代表药物：吉非替尼（gefitinib）、厄洛替尼（erlotinib）、埃克替尼（icotinib）[1]。 作用机制：可逆性 EGFR 酪氨酸激酶抑制剂，与 ATP 竞争结合 EGFR 激酶域的 ATP 结合口袋[1]；对野生型 EGFR 激酶域有一定活性，部分不良反应与此相关。[1] 治疗敏感性：对经典样突变（ex19del、L858R）敏感[1]；对 PACC 突变（G719X、S768I）敏感性低（IC50 5-12nM）[1]；对 T790M 样突变耐药[1]；对 ex20ins 突变（除 A763_Y764insFQEA 外）耐药，缓解率 3%-8%，中位 PFS<3 个月。[2] 关键临床数据： （1）IPASS 试验：吉非替尼治疗经典 EGFR 突变患者 ORR 72.1%，显著优于化疗（1.1%），PFS 显著延长。[1,2]（2）EURTAC 试验：厄洛替尼治疗经典突变患者 ORR 64%，中位 PFS 9.7 个月，优于化疗（18% ORR、5.2 个月 PFS）。[2]（3）CTONG1104 试验（辅助治疗）：吉非替尼辅助治疗 II-IIIA 期经典突变患者，中位 DFS 30.8 个月，优于化疗（19.8 个月），但长期随访无 OS 获益。[1] （4）CONVINCE 试验：埃克替尼一线治疗经典突变患者，疗效不劣于化疗。[1] 2 二代 EGFR TKI 代表药物：阿法替尼（afatinib）、达可替尼（dacomitinib）、来那替尼（neratinib）[1,2]。 作用机制：不可逆性抑制剂，与 EGFR 激酶域的 Cys797 残基共价结合[1]；同时抑制 EGFR、HER2、HER4 激酶域[1,2]。 治疗敏感性：对经典样突变（ex19del、L858R）敏感[1]；对 PACC 突变（G719X、S768I）敏感性高（阿法替尼 IC50 0.3-0.8nM），为该类突变首选[1]；对 T790M 样突变耐药[1]；对 ex20ins 突变疗效有限，阿法替尼治疗 ORR 8.7%，中位 PFS 2.7 个月[2]；达可替尼仅对含 770 位甘氨酸插入的 ex20ins 突变（如 D770delinsGY）有部分响应[2]。 关键临床数据： （1）LUX-Lung 系列试验：阿法替尼治疗经典突变患者 PFS 优于一代 TKI；治疗 PACC 突变患者 ORR 71.0%，中位 PFS 10.7 个月[1,2]。 （2）ARCHER 1050 试验：达可替尼治疗经典突变患者中位 PFS 14.7 个月，优于吉非替尼（9.2 个月），获 FDA 批准用于转移性经典突变 NSCLC[2]。 （3）来那替尼 phase II 试验：治疗经典突变患者 ORR 仅 3%，无肺癌相关获批适应症[2]。 3  三代 EGFR TKI 代表药物：奥希替尼（osimertinib）、拉泽替尼（lazertinib）、阿美替尼（aumolertinib）、伏美替尼（furmonertinib）、贝福替尼（befotertinib）。[1,3] 作用机制：不可逆性抑制剂，共价结合 EGFR 激酶域的 Cys797 残基[1]；对突变型 EGFR（尤其是 T790M 突变）亲和力高，对野生型 EGFR 抑制较弱[1]；具有较强的血脑屏障穿透性，对 CNS 转移有效。[1] 治疗敏感性：对经典样突变（ex19del、L858R）高度敏感[1]；对 T790M 样突变（原发性 / 获得性）高度敏感[1]；对 PACC 突变敏感性较弱，回顾性数据 ORR 约 45%，中位 PFS 8-9 个月[1]；对 ex20ins 突变（除特殊亚型外）耐药，部分药物（奥希替尼）在临床前模型显示弱活性，相关临床试验（NCT03414814）仍在进行。[2] 关键临床数据： （1）FLAURA 试验：奥希替尼一线治疗经典突变患者，中位 PFS 18.9 个月、OS 38.6 个月，均优于一代 TKI。[1] （2）AURA3 试验：奥希替尼治疗获得性 T790M 突变患者，ORR 71%，中位 PFS 10.1 个月，OS 26.8 个月。[1]（3）LASER301 试验：拉泽替尼一线治疗经典突变患者，PFS 获益与奥希替尼相当。[1]（4）中国研究（阿美替尼、伏美替尼、贝福替尼）：一线治疗经典突变患者，中位 PFS 均优于一代 TKI。[1]（5）LAURA 试验：奥希替尼用于不可切除 III 期经典突变患者放化疗后巩固治疗，中位 PFS 39.1 个月，显著优于安慰剂。[1] 不同 EGFR 基因变异对应的治疗方案 1  早期（I-III 期）EGFR 突变型 NSCLC 的治疗 1.1 常见突变（ex19del/L858R）：辅助治疗与巩固治疗 （1）辅助治疗[1] 术后辅助奥希替尼：推荐用于 IB-IIIA 期患者（无论是否接受辅助化疗），3 年治疗时长可显著改善 DFS（中位未达到 vs. 27.5 个月，HR=0.20），II-IIIA 期患者 5 年 OS 绝对获益 12%（85% vs. 73%）； 一代 TKI 辅助治疗：吉非替尼等仅短期改善 DFS（CTONG1104 试验 30.8 个月 vs. 19.8 个月），长期随访无 OS 获益，不推荐作为首选。 （2）不可切除 III 期：放化疗后巩固治疗 同步放化疗后，采用奥希替尼巩固治疗（直至疾病进展 / 毒性不可耐受），中位 PFS 39.1 个月（vs. 安慰剂 5.6 个月，HR=0.16），且显著降低 CNS 复发风险（HR=0.17）； 不推荐度伐利尤单抗（PACIFIC 试验中 EGFR 突变亚组无 DFS 获益）。 1.2 少见突变（非 ex20ins）：辅助治疗现状[1] 目前缺乏前瞻性试验数据（ADAURA、NeoADAURA 等试验排除少见突变患者）； 回顾性数据提示：PACC 突变患者可尝试辅助阿法替尼（基于其对 PACC 突变的抑制活性），经典样突变（如 L861Q）可参考常见突变方案使用奥希替尼，但需谨慎。 1.3  ex20ins：早期治疗现状 无前瞻性试验数据，回顾性研究显示：辅助化疗（顺铂 + 长春瑞滨）疗效有限，中位 DFS 4.2-5.8 个月；常规 EGFR TKI（如奥希替尼）辅助治疗无效[2,3]； 推荐参加针对性临床试验（如 NCT05609267，评估新型 ex20ins 抑制剂辅助治疗疗效）[3]。 2  转移性（IV 期）EGFR 突变型 NSCLC 的一线治疗 2.1 常见突变（ex19del/L858R）：单药与联合方案 （1）单药 TKI[1] 三代 TKI 优先：奥希替尼为标准方案，中位 PFS 18.9 个月、OS 38.6 个月（均优于一代 TKI）；拉泽替尼（LASER301 试验）、阿美替尼 / 伏美替尼（中国研究）疗效与奥希替尼相当； 一代 / 二代 TKI：吉非替尼、阿法替尼等仅用于无法获取三代 TKI 场景，中位 PFS 10-14 个月。 （2）联合方案（高风险人群优选）[1] 奥希替尼 + 化疗：FLAURA2 试验显示，联合卡铂 + 培美曲塞（4 周期，后续培美曲塞维持）中位 PFS 25.5 个月（vs. 奥希替尼单药 16.7 个月，HR=0.62），基线脑转移患者获益更显著（中位 PFS 24.9 个月 vs. 13.8 个月）； 埃万妥单抗 + 拉泽替尼：MARIPOSA 试验显示，中位 PFS 23.7 个月（vs. 奥希替尼 16.6 个月，HR=0.70），OS 显著获益（未达到 vs. 36.7 个月，HR=0.75），高风险亚组（CNS 转移、TP53 共突变）获益更优； 不推荐方案：奥希替尼联合贝伐珠单抗 / 雷莫芦单抗（无 III 期获益证据，且毒性增加）。 2.2 少见突变（非 ex20ins）：以阿法替尼为基础 PACC 突变（G719X、S768I）：优先选择阿法替尼（LUX-Lung 试验 ORR 71.0%，中位 PFS 10.7 个月）；ACHILLES 试验显示阿法替尼优于化疗（PFS 10.6 个月 vs. 5.7 个月，HR=0.422）[1]； 经典样突变（L861Q）：可选择奥希替尼（基于其 CNS 穿透性优势），或阿法替尼[1]； 联合方案探索：埃万妥单抗 + 拉泽替尼（CHRYSALIS-2 试验 ORR 55%，中位 PFS 19.5 个月），适合单药 TKI 疗效不佳患者[3]。 2.3  ex20ins：新型抑制剂为核心[3] 一线治疗推荐： 体能状态良好（ECOG PS 0-1）患者，优先参加新型抑制剂临床试验（如波齐替尼联合化疗）[2,3]；无临床试验时，选择 “铂类 + 培美曲塞” 或舒沃替尼 / 莫博赛替尼（基于患者耐受性）；不推荐一、二、三代 TKI 单药或 ICIs 联合方案[2]。 3 转移性患者的巩固性局部治疗（寡转移灶）[1] 一线 EGFR TKI 治疗有效且仅存在 ≤5 个转移灶的患者，对残留病灶进行立体定向放疗，可改善 PFS 与 OS： SINDAS 试验：TKI + 放疗中位 PFS 20.2 个月（vs. TKI 单药 12.5 个月，HR=0.22），OS 25.5 个月（vs. 17.6 个月，HR=0.44）；胸部放疗联合埃克替尼：中位 PFS 17.1 个月（vs. 10.6 个月，HR=0.57），OS 34.4 个月（vs. 26.2 个月，HR=0.62）；注意事项：胸部放疗期间需暂时停用奥希替尼（避免严重肺炎），但停药时间不宜过长（23% 的患者停药后 8 天内疾病反跳）。 EGFR TKI 治疗耐药相关基因变异与耐药后治疗 耐药机制分为 “靶点内变异” “靶点外变异” 及 “非基因组机制”，需根据基因检测结果选择对应方案[1,2,3]。 Key clinical data from trials in the first-line metastatic setting of EGFR-mutant NSCLC. 1 靶点内耐药变异及治疗 2  靶点外耐药变异及治疗 3  非基因组耐药机制的处理 （1）组织学转化（小细胞癌 / 鳞癌转化）[1] 发生率 10%-15%，常见于三代 TKI 耐药后，需通过组织活检确认； 治疗方案：参照小细胞肺癌 / 鳞癌标准方案，如 “依托泊苷 + 铂类”（小细胞转化）、“紫杉醇 + 铂类”（鳞癌转化）； 注意事项：转化后患者预后差，中位 OS 仅 6-9 个月，推荐联合 EGFR TKI 维持 EGFR 抑制。 （2）药物耐受持续细胞（DTPs）[1] 机制：表观遗传修饰导致细胞周期停滞，耐受 TKI 毒性； 处理策略：探索 “TKI + 表观遗传药物”（如 HDAC 抑制剂），目前处于临床前阶段，暂无推荐方案。 4  无明确耐药机制的进展后治疗（非选择性策略） 化疗：铂类 + 培美曲塞为标准方案，中位 PFS 4-5 个月，OS 14-15 个月[1]； 埃万妥单抗 + 化疗：MARIPOSA-2 试验显示，中位 PFS 6.3 个月（vs. 化疗 4.2 个月，HR=0.48），CNS PFS 12.5 个月（vs. 8.3 个月，HR=0.55），适合无明确靶点患者[1,3]； 不推荐方案：ICIs 联合化疗（CheckMate 722、KEYNOTE-789 试验均为阴性），仅在无其他选择时谨慎使用[1]。 This figure illustrates key resistance mechanisms to third-generation TKIs in EGFR-mutant NSCLC. 特殊人群的治疗考量（基于基因变异背景） 1 CNS 转移患者（EGFR 突变型 NSCLC 发生率 40%-60%） 治疗核心：选择血脑屏障穿透性强的药物，优先基于 EGFR 变异类型选择[1]： 常见突变：奥希替尼（CNS ORR 54%-70%，中位 CNS PFS 8.5-16.5 个月）；埃万妥单抗 + 拉泽替尼（CNS PFS HR=0.52）[1,3]； ex20ins：舒沃替尼（临床前脑穿透性良好）、埃万妥单抗（部分脑膜转移患者脑脊液肿瘤细胞清除）[3]； 局部治疗时机：有症状 CNS 转移灶优先放疗（立体定向放疗为主），无症状灶优先三代 TKI 治疗，进展后再放疗[1]。 2 老年患者（≥70 岁） 常见突变：辅助奥希替尼安全性可控（3 级及以上不良反应发生率 23%）；转移性患者优先奥希替尼（中位 OS 29.3 个月，3 级毒性 28%），身体弱患者可减量至 40mg/d[1]； ex20ins：选择耐受性好的药物（如舒沃替尼，腹泻发生率低），避免波齐替尼（高皮肤毒性）[3]。 生物标志物指导的个性化治疗策略 Clinical and molecular poor prognostic factors 1  疗效预测生物标志物 （1）循环肿瘤 DNA（ctDNA） 辅助治疗：术后基线 ctDNA 阳性患者辅助奥希替尼 DFS 获益更显著（HR=0.18），ctDNA 持续阴性者 5 年无复发生存率 92%[1]； 转移性治疗：治疗 2 周期后 ctDNA 清除者中位 PFS 28.3 个月（vs. 11.2 个月，HR=0.31）；“埃万妥单抗 + 拉泽替尼” 治疗后 ctDNA 清除率 68%（vs. 奥希替尼 42%），清除者 OS 更长[1,3]。 （2）共突变状态 TP53 突变：携带患者 TKI 治疗中位 PFS 缩短（9.5-12.0 个月 vs. 16.5-19.0 个月），联合化疗获益更优（FLAURA2 试验 HR=0.52）[1]； PIK3CA 突变：携带患者中位 OS 缩短（24.5 个月 vs. 38.6 个月），联合 PI3K 抑制剂试验中 ORR 35%-40%[1]。 2  耐药监测与动态治疗调整 监测频率：EGFR TKI 治疗期间每 2-3 个月进行 ctDNA 检测[1]； 调整策略：ctDNA 检测到耐药突变（如 T790M、MET 扩增），即使影像学未进展也需提前调整；ctDNA 阴性但影像学进展，需组织活检确认机制[1]； 早期干预：提前换用奥希替尼（T790M 突变）中位 PFS 11.2 个月（vs. 进展后 6.8 个月）；提前联合 MET 抑制剂 ORR 58%（vs. 进展后 42%）[1]。 未来研究方向与挑战 1 新型治疗药物研发： （1）四代 EGFR TKIs BLU-945：对 ex19del/L858R/C797S 三重突变 IC50=0.5nM，单药 ORR 45%-50%，联合奥希替尼 ORR 60%-65%[1]； BBT-176：对四重突变（ex19del/L858R/T790M/C797S）活性，单药 ORR 35%-40%[1]。 （2）抗体 - 药物偶联物（ADCs） Telisotuzumab vedotin（c-MET 靶向）：奥希替尼进展后 ORR 58%，联合奥希替尼 ORR 65%[1,3]； Datopotamab deruxtecan（TROP2 靶向）：TKI 进展后 ORR 35%-40%，适合无明确靶点患者[1,3]。 2  挑战与未解决的问题 （1）罕见耐药机制的应对 20%-30% 患者耐药机制不明（如未知旁路激活），需单细胞测序、空间转录组解析，开发多靶点抑制剂；这类患者中位 OS 仅 9-12 个月，治疗选择有限[1]。 （2）免疫治疗在 EGFR 突变型 NSCLC 中的定位 仅高 TMB（≥10 mut/Mb）、PD-L1 高表达（≥50%）患者可能获益，临床试验（如 NCT05262403）探索奥希替尼联合 PD-L1 抑制剂；需联合免疫调节剂逆转免疫抑制微环境[1]。 结论 EGFR 突变型非小细胞肺癌的治疗已进入精准医疗时代，从早期辅助治疗到晚期一线治疗，EGFR TKIs（尤其是三代 TKI 奥希替尼）及联合治疗方案（如 “奥希替尼联合化疗”“埃万妥单抗 + 拉泽替尼”）显著改善了患者生存。生物标志物（如 ctDNA、共突变）的应用，为疗效预测、耐药监测和动态治疗调整提供了重要工具；针对罕见耐药机制的新型药物（如四代 EGFR TKIs、MET 靶向 ADC）和优化的联合治疗策略（如 “埃万妥单抗 + 化疗”），进一步拓宽了治疗选择。 对于不同 EGFR 变异亚型，需实施分层治疗：常见突变（ex19del/L858R）以三代 TKI 单药或联合化疗为核心，高风险人群优先选择双靶向联合方案；少见突变（PACC 型）以阿法替尼为基础，联合方案可作为单药疗效不佳的补充；ex20ins 亚型需依赖新型抑制剂（如埃万妥单抗、舒沃替尼），一线联合化疗展现出更优潜力。 同时，临床实践中仍需关注特殊人群的治疗优化：CNS 转移患者优先选择血脑屏障穿透性强的药物（如奥希替尼、舒沃替尼），老年患者需平衡疗效与毒性（如低剂量奥希替尼），妊娠哺乳期患者需结合孕周和肿瘤进展制定个体化方案。 未来，随着单细胞测序、空间转录组等技术的应用，罕见耐药机制的解析将更深入；新型药物（如四代 TKIs、多靶点 ADC）的研发和精准降阶治疗策略（如基于 ctDNA 的辅助治疗时长调整）的验证，将进一步推动 EGFR 突变型 NSCLC 患者的长期生存改善。但同时也需解决检测可及性（降低 ctDNA NGS 成本、缩短周转时间）、免疫治疗定位不明确等挑战，通过多学科协作和临床研究转化，最终实现全周期的个体化治疗。 参考文献 1.Maxime Borgeaud, et al. Personalized care for patients with EGFR-mutant nonsmall cell lung cancer: Navigating early to advanced disease management. CA Cancer J Clin. 2025;75:387–409. 2.Donghyun Seo and Jun Hyeok Lim. Targeted Therapies for EGFR Exon 20 Insertion Mutation in Non-Small-Cell Lung Cancer. Cancer. Int. J. Mol. Sci. 2024, 25, 5917. 3.Simon Vyse and Paul H. Huang. Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduction and Targeted Therapy (2019) 4:5. 关于伯科 伯科生物是一家专注于DNA/RNA合成技术的生命科学上游企业，致力于面向基因组学与合成生物学的新技术开发与应用转化，为构建精准诊疗和临床转化体系提供工具平台。依托自研自造的DNA/RNA合成平台，为医疗健康、生物制药等领域提供底层技术支持，公司产品线涵盖NGS测序、长读长测序、PCR平台检测、CRISPR基因编辑、以及RNA干扰等领域。现已在国内搭建了全流程国产化的高通量核酸合成与应用技术转化中心，建立了GMP厂房和ISO9001、ISO13485质量体系。 伯科生物的各种型号的多功能Oligo合成仪已完成自研自造，深度优化的硬件和软件系统可满足从科学试验、分子检测、药物研发等不同的合成需求。不同类型的Oligo合成仪可进行pmol~mmol的oligo合成，开展不同类别、规格、长度和修饰的高品质DNA和RNA Oligo合成，满足不同领域的应用需求。 未来，依托合成生物学的底层技术工具平台，伯科生物将向基因治疗、核酸药物、DNA存储、DNA材料学、分子育种等领域积极拓展，为实现“精益求精创新，为人类美好生活”的企业使命而努力。

Raising 2025 NERLYNX® revenue and net income estimates LOS ANGELES--(BUSINESS WIRE)-- Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, announced financial results for the third quarter ended September 30, 2025. Unless otherwise stated, all comparisons are for the third quarter of 2025 compared to the third quarter of 2024. Product revenue, net consists entirely of sales revenue from NERLYNX®, Puma’s first commercial product. Product revenue, net in the third quarter of 2025 was $51.9 million, compared to $56.1 million in the third quarter of 2024. Product revenue, net in the first nine months of 2025 was $144.2 million, compared to $140.8 million in the first nine months of 2024. Based on accounting principles generally accepted in the United States (GAAP), Puma reported net income of $8.8 million, or $0.18 per basic share and $0.17 per diluted share, for the third quarter of 2025, compared to net income of $20.3 million, or $0.41 per basic and diluted share, for the third quarter of 2024. Net income for the first nine months of 2025 was $17.7 million, or $0.35 per basic and diluted share, compared to net income of $11.0 million, or $0.23 per basic share and $0.22 per diluted share, for the first nine months of 2024. Non-GAAP adjusted net income was $10.5 million, or $0.21 per basic and diluted share, for the third quarter of 2025, compared to non-GAAP adjusted net income of $22.4 million, or $0.46 per basic share and $0.45 per diluted share, for the third quarter of 2024. Non-GAAP adjusted net income for the first nine months of 2025 was $23.0 million, or $0.46 per basic and diluted share, compared to non-GAAP adjusted net income of $17.5 million, or $0.36 per basic and diluted share, for the first nine months of 2024. Non-GAAP adjusted net income excludes stock-based compensation expenses. For a reconciliation of GAAP net income to non-GAAP adjusted net income and GAAP net income per share to non-GAAP adjusted net income per share, please see the financial tables at the end of this news release. Net cash provided by operating activities for the third quarter of 2025 was $9.7 million, compared to $11.0 million in the third quarter of 2024. Net cash provided by operating activities for the first nine months of 2025 was $27.4 million, compared to net cash provided by operating activities of $23.3 million in the first nine months of 2024. At September 30, 2025, Puma had cash, cash equivalents and marketable securities of $94.4 million, compared to cash, cash equivalents and marketable securities of $101.0 million at December 31, 2024. “We are very happy to report the continuation of our positive earnings trend, which is driven by increased demand for NERLYNX®,” said Alan H. Auerbach, Chairman, Chief Executive Officer, and President of Puma. “According to our current projections, 2025 will mark the first year-over-year demand increase for NERLYNX in the United States since 2018 and we are very pleased with our commercial execution, which contributed to this. We are also pleased with our continued clinical progress in the advancement of alisertib for patients facing chemotherapy-naïve HER2-negative, hormone receptor-positive metastatic breast cancer in ALISCATM-Breast1 and for patients with extensive-stage small cell lung cancer in ALISCATM-Lung1, where there continues to be a need for new treatment.” Mr. Auerbach added, “We anticipate the following key milestones over the next 12 months: (i) presentation of interim data from ALISCA™-Breast1, a Phase II trial of alisertib in combination with endocrine treatment in patients with chemotherapy-naïve HER2-negative, hormone receptor-positive metastatic breast cancer (H1 2026) and (ii) presentation of additional interim data from the ALI-4201/ALISCA™-Lung1, a Phase II clinical trial of alisertib monotherapy for the treatment of patients with extensive stage small cell lung cancer (H1 2026).” Revenue Total revenue consists of product revenue, net from sales of NERLYNX®, Puma’s first commercial product, and royalty revenue. For the third quarter of 2025, total revenue was $54.5 million, of which $51.9 million was product revenue, net and $2.6 million was royalty revenue. This compares to total revenue of $80.5 million for the third quarter of 2024, of which $56.1 million was product revenue, net and $24.4 million was royalty revenue. This decrease in product revenue, net, compared to the three months ended September 30, 2024, was attributable to a decrease in product supply revenue to our international licensees (reduction in China sales), and higher Gross to Net reduction, partially offset by an increase in U.S. sales resulting from an 8% increase in bottles of NERLYNX sold in the U.S. market and an increase in net selling price. For the first nine months of 2025, total revenue was $152.9 million, of which $144.2 million was product revenue, net and $8.7 million was royalty revenue. This compares to total revenue of $171.4 million for the first nine months of 2024, of which $140.8 million was product revenue, net and $30.6 million was royalty revenue. Operating Costs and Expenses Total operating costs and expenses were $44.9 million for the third quarter of 2025, compared to $58.4 million for the third quarter of 2024. Operating costs and expenses in the first nine months of 2025 were $132.7 million, compared to $153.8 million in the first nine months of 2024. Cost of Sales Cost of sales was $12.2 million for the third quarter of 2025, compared to $29.1 million for the third quarter of 2024. Cost of sales was $35.0 million for the first nine months of 2025, compared to $50.5 million for the first nine months of 2024. The year-to-date decrease was primarily due to timing of sales made into China by our sub-licensee and the related cost of products shipped and royalty expense. Selling, General and Administrative Expenses Selling, general and administrative (SG&A) expenses were $16.8 million for the third quarter of 2025, unchanged from the third quarter of 2024. SG&A expenses for the first nine months of 2025 were $52.5 million, compared to $63.5 million for the first nine months of 2024. The $11.0 million year-over-year decrease in SG&A expenses resulted primarily from legal fees associated with the AstraZeneca litigation in 2024. Research and Development Expenses Research and development (R&D) expenses were $15.9 million for the third quarter of 2025, compared to $12.5 million for the third quarter of 2024. R&D expenses for the first nine months of 2025 were $45.2 million, compared to $39.8 million for the first nine months of 2024. The $5.4 million year-over-year increase in R&D expenses resulted primarily from increased alisertib study activity. Total Other Expenses Total other expenses were $0.4 million for the third quarter of 2025, compared to $1.5 million for the third quarter of 2024. Total other expenses were $1.5 million for the first nine months of 2025, compared to $5.7 million for the first nine months of 2024. The $4.2 million decrease for the first nine months of 2025 was primarily due to a lower debt balance as we continue to pay down our principal. Fourth Quarter and Full Year 2025 Financial Outlook Fourth Quarter 2025 Full Year 2025 (prior) Full Year 2025 (updated) Net Product Revenue $54–$56 million $192–$198 million $198–$200 million Royalty Revenue $13–$14 million $20–$24 million $22–$23 million License Revenue $0 million $0 million $0 million Total Revenue $67--$70 million $212--$222 million $220--$223 million Net Income/(Loss)* $9–$11 million $23–$28 million $27–$29 million Gross to Net Adjustment 24%–25% 21.5%–22% 23%–23.5% *The outlook above does not include any potential adjustments for tax valuation allowance. Conference Call Puma Biotechnology will host a conference call to report its third quarter 2025 financial results and provide an update on Puma’s business and outlook at 1:30 p.m. PT/4:30 p.m. ET on Thursday, November 6, 2025. The call may be accessed by dialing (877) 709-8150 (domestic) or (201) 689-8354 (international). Please dial in at least 10 minutes in advance and inform the operator that you would like to join the “Puma Biotechnology Conference Call.” A live webcast of the conference call and presentation slides may be accessed on the Investors section of the Puma Biotechnology website at https://www.pumabiotechnology.com. A replay of the call will be available shortly after completion of the call and will be archived on Puma’s website for 90 days. About Puma Biotechnology Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. Puma in-licensed the global development and commercialization rights to PB272 (neratinib, oral) in 2011. Neratinib, oral was approved by the U.S. Food and Drug Administration in 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX® (neratinib) tablets. In February 2020, NERLYNX was also approved by the FDA in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. NERLYNX was granted marketing authorization by the European Commission in 2018 for the extended adjuvant treatment of adult patients with early stage hormone receptor-positive HER2-overexpressed/amplified breast cancer and who are less than one year from completion of prior adjuvant trastuzumab-based therapy. NERLYNX® is a registered trademark of Puma Biotechnology, Inc. In September 2022, Puma entered into an exclusive license agreement for the development and commercialization of the anti-cancer drug alisertib, a selective, small molecule, orally administered inhibitor of aurora kinase A. Initially, Puma intends to focus the development of alisertib on the treatment of small cell lung cancer and breast cancer. In February 2024, Puma initiated ALISCA™-Lung1, a Phase II clinical trial of alisertib monotherapy for the treatment of patients with extensive-stage small cell lung cancer. In November 2024, Puma initiated ALISCA™-Breast1, a Phase II clinical trial of alisertib in combination with endocrine therapy for the treatment of patients with HER2-negative, HR-positive metastatic breast cancer. To help ensure patients have access to NERLYNX, Puma has implemented the Puma Patient Lynx support program to assist patients and healthcare providers with reimbursement support and referrals to resources that can help with financial assistance. More information on the Puma Patient Lynx program can be found at https://www.NERLYNX.com or by calling 1-855-816-5421. Further information about Puma Biotechnology may be found at https://www.pumabiotechnology.com. INDICATIONS NERLYNX® (neratinib) tablets, for oral use, is a kinase inhibitor indicated: As a single agent, for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy. In combination with capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer, who have received two or more prior anti-HER2 based regimens in the metastatic setting. Important Safety Information Regarding NERLYNX® (neratinib) U.S. Indication CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS: Diarrhea: Manage diarrhea through either NERLYNX dose escalation or loperamide prophylaxis. If diarrhea occurs despite recommended prophylaxis, treat with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction. Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities. Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ADVERSE REACTIONS: The most common adverse reactions (reported in ≥ 5% of patients) were as follows: NERLYNX as a single agent: Diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increased, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, and urinary tract infection. NERLYNX in combination with capecitabine: Diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms. To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) or FDA at 1-800-332-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS: Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors. Separate NERLYNX by at least 2 hours before or 10 hours after H2-receptor antagonists. Or separate NERLYNX by at least 3 hours after antacids. Strong CYP3A4 inhibitors: Avoid concomitant use. P-gp and moderate CYP3A4 dual inhibitors: Avoid concomitant use. Strong or moderate CYP3A4 inducers: Avoid concomitant use. Certain P-gp substrates: Monitor for adverse reactions of P-gp substrates for which minimal concentration change may lead to serious adverse reactions when used concomitantly with NERLYNX. USE IN SPECIFIC POPULATIONS: Lactation: Advise women not to breastfeed. Please see Full Prescribing Information for additional safety information. Forward-Looking Statements This press release contains forward-looking statements, including statements regarding Puma’s anticipated milestones and estimates of future financial results for the fourth quarter and full year 2025. All forward-looking statements involve risks and uncertainties that could cause Puma’s actual results to differ materially from the anticipated results and expectations expressed in these forward-looking statements. These statements are based on current expectations, forecasts and assumptions, and actual outcomes and results could differ materially from these statements due to a number of factors, which include, but are not limited to, any adverse impact on Puma’s business or the global economy and financial markets, any changes in Puma’s product candidates’ regulatory approvals, results from Puma’s clinical trials, any litigation involving Puma, any changes to Puma’s in-licensed intellectual property and the risk factors disclosed in the periodic and current reports filed by Puma with the Securities and Exchange Commission from time to time, including Puma’s Annual Report on Form 10-K for the year ended December 31, 2024 and subsequent filings. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Puma assumes no obligation to update these forward-looking statements, except as required by law. (Financial Tables Follow) PUMA BIOTECHNOLOGY, INC. AND SUBSIDIARY CONSOLIDATED STATEMENTS OF OPERATIONS (in millions except share and per share data) Three Months Ended Nine Months Ended September 30, September 30, 2025 2024 2025 2024 (Unaudited) (Unaudited) (Unaudited) (Unaudited) Revenues: Product revenue, net $ 51.9 $ 56.1 $ 144.2 $ 140.8 Royalty revenue 2.6 24.4 8.7 30.6 Total revenue 54.5 80.5 152.9 171.4 Operating costs and expenses: Cost of sales 12.2 29.1 35.0 50.5 Selling, general and administrative 16.8 16.8 52.5 63.5 Research and development 15.9 12.5 45.2 39.8 Total operating costs and expenses 44.9 58.4 132.7 153.8 Income from operations 9.6 22.1 20.2 17.6 Other income (expenses): Interest income 1.0 1.3 3.1 3.5 Interest expense (1.5 ) (3.1 ) (5.5 ) (9.8 ) Other income 0.1 0.3 0.9 0.6 Total other expenses, net (0.4 ) (1.5 ) (1.5 ) (5.7 ) Net income before income taxes 9.2 20.6 18.7 11.9 Income tax expense (0.4 ) (0.3 ) (1.0 ) (0.9 ) Net income $ 8.8 $ 20.3 $ 17.7 $ 11.0 Net income per share of common stock—basic $ 0.18 $ 0.41 $ 0.35 $ 0.23 Net income per share of common stock—diluted $ 0.17 $ 0.41 $ 0.35 $ 0.22 Weighted-average shares of common stock outstanding—basic 50,339,456 49,008,464 49,881,181 48,498,579 Weighted-average shares of common stock outstanding—diluted 50,929,893 49,173,361 50,334,553 49,025,103 PUMA BIOTECHNOLOGY, INC. AND SUBSIDIARY LIQUIDITY AND CAPITAL RESOURCES (in millions) September 30, December 31, 2025 2024 (Unaudited) Cash and cash equivalents $ 53.5 $ 69.2 Marketable securities 40.9 31.7 Working capital 60.9 51.5 Current portion of long-term debt 33.7 45.3 Long-term debt — 21.7 Stockholders’ equity 115.3 92.1 Nine Months Ended Nine Months Ended September 30, 2025 September 30, 2024 (Unaudited) (Unaudited) Cash provided by (used in): Operating activities $ 27.4 $ 23.3 Investing activities (9.2 ) (18.1 ) Financing activities (33.9 ) (22.5 ) Net decrease in cash, cash equivalents and restricted cash $ (15.7 ) $ (17.3 ) Use of Non-GAAP Measures In addition to operating results as calculated in accordance with GAAP, Puma uses certain non-GAAP financial measures when planning, monitoring, and evaluating operational performance. The following table presents Puma’s net income and net income per share calculated in accordance with GAAP and as adjusted to remove the impact of stock-based compensation expense. For the three months and nine months ended September 30, 2025, stock-based compensation represented approximately 5.1% and 5.5% of operating expenses, respectively, and 7.0% and 6.3% for the same periods in 2024, in each case excluding cost of sales and acquired in-process research and development. Puma’s management believes that these non-GAAP financial measures are useful to enhance understanding of Puma’s financial performance, are more indicative of its operational performance, and facilitate a better comparison among fiscal periods. These non-GAAP financial measures are not, and should not be viewed as, substitutes for GAAP reporting measures. PUMA BIOTECHNOLOGY, INC. AND SUBSIDIARY Reconciliation of GAAP Net Income to Non-GAAP Adjusted Net Income and GAAP Net Income Per Share to Non-GAAP Adjusted Net Income Per Share (in millions except share and per share data) (Unaudited) Three Months Ended September 30, 2025 2024 GAAP net income $ 8.8 $ 20.3 Adjustments: Stock-based compensation - Selling, general and administrative(1) 1.1 1.5 Research and development(2) 0.6 0.6 Non-GAAP adjusted net income $ 10.5 $ 22.4 GAAP net income per share—basic $ 0.18 $ 0.41 Adjustment to net income (as detailed above) 0.03 0.05 Non-GAAP adjusted basic net income per share $ 0.21 (3) $ 0.46 (4) GAAP net income per share—diluted $ 0.17 $ 0.41 Adjustment to net income (as detailed above) 0.04 0.04 Non-GAAP adjusted diluted net income per share $ 0.21 (5) $ 0.45 (6) Nine Months Ended September 30, 2025 2024 GAAP net income $ 17.7 $ 11.0 Adjustments: Stock-based compensation - Selling, general and administrative (1) 3.3 4.3 Research and development (2) 2.0 2.2 Non-GAAP adjusted net income $ 23.0 $ 17.5 GAAP net income per share—basic $ 0.35 $ 0.23 Adjustment to net income (as detailed above) 0.11 0.13 Non-GAAP adjusted basic net income per share $ 0.46 (3) $ 0.36 (4) GAAP net income per share—diluted $ 0.35 $ 0.22 Adjustment to net income (as detailed above) 0.11 0.14 Non-GAAP adjusted diluted net income per share $ 0.46 (5) $ 0.36 (6) (1) To reflect a non-cash charge to operating expense for selling, general, and administrative stock-based compensation. (2) To reflect a non-cash charge to operating expense for research and development stock-based compensation. (3) Non-GAAP adjusted basic net income per share was calculated based on 50,339,456 and 49,881,181 weighted-average shares of common stock outstanding for the three and nine months ended September 30, 2025, respectively. (4) Non-GAAP adjusted basic net income per share was calculated based on 49,008,464 and 48,498,579 weighted-average shares of common stock outstanding for the three and nine months ended September 30, 2024, respectively. (5) Non-GAAP adjusted diluted net income per share was calculated based on 50,929,893 and 50,334,553 weighted-average shares of common stock outstanding for the three and nine months ended September 30, 2025, respectively. (6) Non-GAAP adjusted diluted net income per share was calculated based on 49,173,361 and 49,025,103 weighted-average shares of common stock outstanding for the three and nine months ended September 30, 2024, respectively. Alan H. Auerbach or Mariann Ohanesian, Puma Biotechnology, Inc., +1 424 248 6500 info@pumabiotechnology.com ir@pumabiotechnology.com David Schull or Olipriya Das, Russo Partners, +1 212 845 4200 david.schull@russopartnersllc.com olipriya.das@russopartnersllc.com