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|Ref Type||Journal Article|
|Authors||Oza AM, Estevez-Diz M, Grischke EM, Hall M, Marmé F, Provencher D, Uyar D, Weberpals JI, Wenham RM, Laing N, Tracy M, Freshwater T, Lee MA, Liu J, Qiu J, Rose S, Rubin EH, Moore K|
|Title||A Biomarker-enriched, Randomized Phase II Trial of Adavosertib (AZD1775) Plus Paclitaxel and Carboplatin for Women with Platinum-sensitive TP53-mutant Ovarian Cancer.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2020 Jul 01|
|Abstract Text||Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes TP53-mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in TP53-mutated ovarian cancer.Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with TP53-mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m2), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib.A total of 121 patients were randomized to adavosertib (A+C; n = 59) and placebo (P+C; n = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9-9.9) vs. 7.3 months (5.6-8.2); HR 0.63 (95% CI, 0.38-1.06); two-sided P = 0.080], meeting the predefined significance threshold (P < 0.2). Clinical benefit was observed following A+C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%).Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Adavosertib||MK-1775|AZD1775|AZ1775||WEE1 Inhibitor 5||Adavosertib (MK-1775) is a small molecule inhibitor of the tyrosine kinase WEE1 with potential antineoplastic sensitizing activity (PMID: 22084170, PMID: 32611648).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|TP53 inact mut||ovarian cancer||sensitive||Adavosertib + Carboplatin + Paclitaxel||Phase I||Actionable||In a Phase I trial, treatment with Adavosertib (MK-1775) plus Paraplatin (carboplatin) and Taxol (paclitaxel) resulted in an improved progression-free survival by enhanced RECIST of 7.9 mo vs. 7.3 mo with placebo plus chemotherapy, and complete response in 11/9% (7/59) vs. 8.9% (5/62), partial response in 62.7% (37/59) vs. 61.3% (38/62), and stable disease in 5.1% (3/59) vs. 4.8% (3/62) of patients with platinum-sensitive ovarian cancer harboring an inactivating TP53 mutation (PMID: 32611648; NCT01357161)||32611648|