背景：Mirvetuximab-soravtansine（MIRV）是一種由 FRa 結合抗體、可切割連接體和 maytansinoid DM4（一種有效的微管蛋白靶向劑）組成的靶向抗腫瘤藥物結合物（ADC）。作為 1b 期 FORWARD II 試驗（NCT02606305）的一部分，在 FRa 陽性（中/高表達≥50%/≥75%的細胞具有 PS2+染色強度），鉑敏感不明的卵巢癌使用非鉑類的雙藥方案是合適的。鉑敏感不敏的定義為鉑耐藥（PROC）（最後一次鉑劑量後 6 個月內複發）或鉑敏感（PSOC）對最後一次鉑治療有反應且在 6 個月內沒有進展）。

Background: Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. As part of the Phase 1b FORWARD II trial (NCT02606305), the combination of MIRV with bevacizumab (BEV) was evaluated in pts with FRα-positive (medium/high expression; ≥50%/ ≥75% of cells with PS2+ staining intensity), platinum agnostic ovarian cancer, defined as pts with either platinum resistant (PROC) (recurrence within 6 months after last platinum dose) or platinum sensitive (PSOC)responded to the last platinum therapy and did not progress within 6 months) for whom a non-platinum based doublet would be appropriate.

方法：患者接受 MIRV (6mg/Kg；調整後的理想體重）和 BEV（15mg/Kg）在 21 天周期的第 1 天。療效評價由研究者根據 RECIST 1.1 進行評估，不良事件（AE）由研究者根據 CTCAE 4.03 版進行評估。

Methods: Pts received MIRV (6 mg/kg; adjusted ideal body weight) and BEV (15 mg/kg) on Day 1 of a 21-day cycle. Responses were assessed by investigator according to RECIST 1.1 and adverse events (AEs) evaluated by CTCAE v4.03.

結果：共有 60 例患者接受了聯合治療，中位年齡為 60 歲，中位為 2 次係統化療（範圍 1-4），中位隨訪時間 17.5 月。該隊列包括 32 名患者（53%）患有 PROC 疾病，28 名患者（47%）患有 PSOC 疾病。在60名患者中，有 28 名患者出現客觀反應，總體反應率（ORR）為 47%（95%CI，34，60），中位緩解期（mDOR）為 9.7 個月（95%CI 中位無進展生存期（mPFS）為 8.3 個月（95%CI 5.6，10.6）。在 FRa 高表達的患者（n=33），確診的 ORR 為 64%（95%CI 45，80），mDOR 為 11.8 個月（95%CI 6.7，13.7），mPFS 為 10.6 個月（95%CI8.3，13.3）；FRa 高表達患者的 PROC 和 PSOC 亞群的療效結果如下表所示。最常見的治療相關不良事件（所有級別，級別 3+）為腹瀉（68%，2%）視力模糊（63%，2%）、疲勞（58%，7%）和惡心（57%，0%）。最常見的治療相關的 3 級和 4 級不良事件分別為中性粒細胞減少和高血壓（12%、3%和 13%、0%）；所有其他 3 級以上的事件發生在≤10%的患者中。

Results: In total, 60 pts received the combination, with a median age of 60 years, a median of 2 prior lines of systemic therapy (range 1-4) and a median follow-up of 17.5 months. The cohort included 32 pts (53%) with PROC disease and 28 (47%) with PSOC disease. Objective responses were seen in 28 of 60 pts for a confirmed overall response rate (ORR) of 47% (95% CI, 34, 60), median duration of response (mDOR) of 9.7 months (95% CI 6.7, 12.9), and median progression free survival (mPFS) of 8.3 months (95% CI 5.6, 10.6). In pts with high FRα expression (n=33), the confirmed ORR was 64% (95% CI 45, 80), mDOR of 11.8 months (95% CI 6.7, 13.7), and mPFS of 10.6 months (95% CI 8.3, 13.3); efficacy results in PROC and PSOC subsets of pts with high FRα expression are shown in the table below. The most common treatment related AEs (all grade, grade 3+) were diarrhea (68%, 2%), blurred vision (63%, 2%), fatigue (58%, 7%), and nausea (57%, 0%). The most common treatment related grade 3 and 4 AEs were neutropenia and hypertension, (12%, 3% and 13%, 0%, respectively); all other grade 3+ events occurred in ≤ 10% of pts.

Efficacy Results.
	All pts	High FRα	PROC High FRα	PSOC High FRα
N	60	33	17	16
Confirmed ORR (95% CI)	47% (34, 60)	64% (45, 80)	59% (33, 82)	69% (41, 89)
mDOR months (95% CI)	9.7 (6.7, 12.9)	11.8 (6.7, 13.7)	9.4 (4.0, NR)	12.9 (6.5, 15.7)
mPFS months (95% CI)	8.3 (5.6, 10.6)	10.6 (8.3, 13.3)	10.1 (5.6, 12.9)	13.3 (8.3, 18.3)

結論：MIRV 與 BEV 聯合應用具有顯著的抗腫瘤活性和持久的療效高 FRa 複發卵巢癌的耐受性良好。這些結果建立在先前報道的 PROC 患者 MIRV/BEV 的數據基礎上（Gyn Oncology O'Malley，et al 2020），表明 MIRV 有可能成為高 FRa 患者 BEV 的首選伴侶複發性卵巢癌與鉑敏感性無關。

Conclusions: The combination of MIRV with BEV demonstrates impressive anti-tumor activity with durable responses and favorable tolerability in high FRα recurrent ovarian cancer. These results build on data previously reported for MIRV/BEV in PROC patients (Gyn Oncology O’Malley, et al 2020), suggesting that MIRV has the potential to be a preferred partner for BEV in patients with high FRα recurrent ovarian cancer regardless of platinum sensitivity.