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

Trial ID # NCT02595892
Phase II
Drug Class DNA Damage Repair Pathway Inhibitors: ATR
Drug Name Berzosertib
Alternate Drug Names ATR kinase inhibitor VX-970, VE-822, M6620, VX-970
Drugs in Trial Berzosertib, Gemcitabine
Eligible Participant

Platinum resistant ovarian cancer

Patients Enrolled

70; median 2 prior therapies (1-8)

Therapy Setting

Recurrence

Study Design

Open-Label, Randomized

Endpoints

PFS, evaluated per RECIST

Biomarkers

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

Efficacy

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)

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
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)

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)

Clinically Significant Adverse Events

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%)

Conclusion

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

Reference

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/

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