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Clinical Trial
. 2025 Mar 17;31(6):993-1001.
doi: 10.1158/1078-0432.CCR-24-3128.

Randomized Phase II Study of Bevacizumab with Weekly Anetumab Ravtansine or Weekly Paclitaxel in Platinum-Resistant/Refractory High-Grade Ovarian Cancer (NCI Trial)

Husam A Alqaisi  1   2 , David E Cohn  3 , Jing-Yi Chern  4 , Linda R Duska  5 , Andrea Jewell  6 , Bradley R Corr  7 , Ira Seth Winer  8 , Eugenia Girda  9 , Marta A Crispens  10 , Neesha C Dhani  2 , Ainhoa Madariaga  2   11 , Robert C Grant  2 , Matthew Malaguti  2 , Crystal Lee  2 , Valerie Bowering  2 , Horace Wong  2 , Andrew Poothullil  2 , Vanessa Speers  2 , Lisa Wang  12 , Philippe L Bedard  2 , John C Brady  13 , Andrew B Nixon  13 , Li Chen  14   15   16 , Claire O'Connor  14   15   16 , William Zamboni  14   15   16 , Tawyna McKee  17 , Jeffrey A Moscow  17 , Amit M Oza  2 , Stephanie Lheureux  2
Affiliations
Clinical Trial

Randomized Phase II Study of Bevacizumab with Weekly Anetumab Ravtansine or Weekly Paclitaxel in Platinum-Resistant/Refractory High-Grade Ovarian Cancer (NCI Trial)

Husam A Alqaisi et al. Clin Cancer Res. .

Abstract

Purpose: Mesothelin (MSLN) is highly expressed in high-grade serous/endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody-drug conjugate directed at the MSLN antigen with a tubulin polymerization inhibitor. We assessed the safety, activity, and pharmacokinetics of the combination AR/bevacizumab (Bev; ARB) versus weekly paclitaxel/Bev (PB) in patients with platinum-resistant/refractory HGOC (prrHGOC).

Patients and methods: Following a run-in phase I study to assess ARB safety, patients with prrHGOC with centrally confirmed MSLN-positive expression were randomized to ARB or PB (weekly paclitaxel 80 mg/m2 with Bev 10 mg/kg biweekly). Patients were stratified by platinum resistance/refractory and prior Bev. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall response rate, safety, and blood-based angiome biomarker assessment. A futility analysis was planned after 35 PFS events.

Results: The combination of Bev (10 mg/kg) biweekly with AR (2.2 mg/kg) weekly was well tolerated. About phase II results, MSLN positivity was 88%, and 57 patients were randomized (28 ARB and 29 PB). Forty-two percentage of patients received prior Bev, and 23% were platinum-refractory. At futility analysis, the median PFS was 5.3 and 12.7 months for ARB and PB, respectively [P = 0.03; HR = 2.02 (1.06-3.86)]. The overall response rate was 21% with ARB and 65% with PB. The most common treatment-related grade ≥3 adverse events were anemia (18%) with ARB and neutropenia (24%) with PB. Higher baseline levels of circulating IL6 were associated with worse PFS, and its levels decreased with PB treatment.

Conclusions: Our study stopped at interim analysis highlighting the benefit of PB in prrHGOC as the standard of care.

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Conflict of interest statement

J.-Y. Chern reports other support from AstraZeneca, American Society of Health-System Pharmacists, Equinox Group, The Dedham Group, Association of Cancer Care Centers, IDEOlogy Health, Cardinal Health, Reckner Health, and Techspert outside the submitted work. L.R. Duska reports grants from sponsored trials; other support from Inovio, Agenus, and Merck advisory board; and personal fees from Daiichi Sankyo outside the submitted work. B.R. Corr reports other support from ImmunoGen, Clovis, GSK, ImmunoGen/AbbVie, Merck, Eisai, and Gilead outside the submitted work. M.A. Crispens reports grants from the NCI during the conduct of the study. A. Madariaga reports personal fees from AstraZeneca, AbbVie, GSK, PharmaMar, Pharma&, and MSD during the conduct of the study. R.C. Grant reports personal fees from AstraZeneca; nonfinancial support from Tempus; and personal fees from Eisai, Incyte, Knight Therapeutics, Guardant Health, and Ipsen outside the submitted work. P.L. Bedard reports grants from AstraZeneca, Amgen, Bristol Myers Squibb, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Medicenna, LegoChem, Roche/Genentech, Pfizer, Merck, Zymeworks, Novartis, Gilead, Lilly, Takeda, and Bicara outside the submitted work and uncompensated advisory for Janssen, Repare, Roche, Lilly, Seagen/Pfizer, and Zymeworks. A.B. Nixon reports grants from Genentech, Genmab, MedImmune/AstraZeneca, and Seagen/Pfizer and personal fees from LeapTherapuetics, Sanofi, and Promega outside the submitted work. W. Zamboni reports grants from NCI during the conduct of the study. A.M. Oza reports other support from AstraZeneca, personal fees and other support from GSK, and other support from Pharma&, PharmaMar, and Merck Sharp & Dohme outside the submitted work. S. Lheureux reports grants and personal fees from GSK, AstraZeneca, Roche, Seagen, Repare, Schrodinger, Eisai, and Merck, as well as personal fees from Gilead, Abbvie, and Zai Lab outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Phase II PFS Kaplan–Meier curve for all phase II population.
Figure 2.
Figure 2.
Objective response: (A) radiologic response and (B) CA 125 response.
Figure 3.
Figure 3.
Phase II PFS Kaplan–Meier curve for prior Bev (subgroup).
Figure 4.
Figure 4.
Phase II PFS Kaplan–Meier curve for prior PARP inhibitor (subgroup).
Figure 5.
Figure 5.
Relationship between TBW and ADC AUC, DM4 AUC, and the ratio of DMA AUC to ADC. Relationship between TBW (kg) and AR AUC0–inf (A), DM4 AUC0–168 hours (B), and the ratio of DM4 to AR AUC0–168 hours (C). The green dots represent patients with TBW <80 kg. The red dots represent patients with TBW ≥80 kg. The blue solid line represents the linear regression for all patients. The green solid line represents the linear regression for patients with TBW <80 kg. The green dashed line represents the extrapolated line from patients with TBW <80 kg to higher TBW. The red solid line represents the linear regression for patients with TBW ≥80 kg. In all patients, there is a positive association between patients’ TBW and AR AUC0–inf (P = 0.012) and DM4 AUC0–168 hoursP < 80 kg (0.008 ± 0.002), but not statistically different (P = 0.132) (D). Individual patients, mean, and SD are represented by the open circles, solid circles, and line interval, respectively.
See this image and copyright information in PMC

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