Phase 2 Study of M6620 (VX-970) in Combination With Gemcitabine Versus Gemcitabine Alone in Subjects With Platinum-Resistant Recurrent Ovarian or Primary Peritoneal Fallopian Tube Cancer

Platinum resistant ovarian cancer

70; median 2 prior therapies (1-8)

Recurrence

Open-Label, Randomized

PFS, OS, evaluated per RECIST

Exploratory: PFI, Replication Stress (RS) High/Low

Ber+Gem (n=36) vs Gem (n=34):

PFS: 5.7 vs 3.7 months, HR: 0.57 (0.33-0.98, p=0.044)
OS: 13.7 vs 9.9 months, HR: 0.79 (0.52-1.2, p=0.18)

Exploratory analysis; PFI, RS High, RS Low:
Ber+Gem vs Gem:
PFI ≤ 3 months (n=26): PFS: 6.9 vs 2.3 months, HR : 0.29, p = 0.0087; OS: HR: 0.48 (0.22-1.01, p=0.04)
3 months < PFI < 6 months (n=44): PFS: 4.7 vs 3.8 months, HR:  1.04, p = 0.46
RS Low - w/o alteration in CCNE1, RB1, CDKN2A, KRAS, NF1, MYC, MYCL1 or ERBB2
6.9 vs 2.5 months, HR: 0.34 (0.13-0.86)
RS High - w/ alteration in CCNE1, RB1, CDKN2A, KRAS, NF1, MYC, MYCL1 or ERBB2
HR: 1.11 (0.47-2.62)
ATM-/low (n=24): OS: HR: 0.50 (0.23 to 1.08, p=0.06)

RS High vs RS High Low:
Gem: 11.3 vs 2.5 months, HR: 0.38 (0.17-0.86)
Gem+Ber: 4.7 vs 6.9 months, HR: 1.34 (0.52-3.48)

Ber+Gem vs Gem:
Serious AE: overall (26 vs 28%)
Grade 3-4 AE: neutropenia (47 vs 39%), thrombocytopenia (24 vs 6%), anemia (11 vs 15%)

Addition of berzosertib to gemcitabine increases PFS without additional toxicity, the benefit was observed mainly in patients with platinum-free interval less than 3 months

Konstatinopoulos PA et al. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol (2020) 21(7):957-968

https://pubmed.ncbi.nlm.nih.gov/32553118/

Konstatinopoulos PA et al. A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer. Nat Commun (2021) 12(1):5574
https://pubmed.ncbi.nlm.nih.gov/34552099/

Konstantinopoulos P et al. Randomized Phase II Study of Gemcitabine With or Without ATR Inhibitor Berzosertib in Platinum-Resistant Ovarian Cancer: Final Overall Survival and Biomarker Analyses. JCO Precis Oncol (2024) 8:e2300635
https://pubmed.ncbi.nlm.nih.gov/38635934/