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A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170)
Edward Maldonado1, W Kimryn Rathmell2, Geoffrey I Shapiro3
1University of California, San Francisco, San Francisco, California.
Abstract:
We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response.
Significance:
WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.
Insights
Adavosertib, a WEE1 inhibitor, showed limited efficacy in treating solid tumors with SETD2 mutations, including clear cell renal cell carcinoma. While some patients experienced stable disease, no objective responses were observed, suggesting combination therapies may be needed.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The WEE1 kinase is a target for cancer therapy, particularly in tumors with specific genetic alterations.
- SETD2 mutations lead to loss of H3K36me3, a mark associated with DNA repair and transcription, potentially creating a synthetic lethal vulnerability.
- Adavosertib is an oral WEE1 inhibitor investigated for its anti-cancer effects.
Purpose of the Study:
- To evaluate the efficacy of adavosertib monotherapy in patients with solid tumors and clear cell renal cell carcinoma (ccRCC) harboring pathogenic SETD2 mutations.
- To assess the correlation between SETD2 mutation status, loss of H3K36me3, and clinical response to adavosertib.
- To determine the safety and tolerability of adavosertib in this patient population.
Main Methods:
- A Phase II, parallel cohort, Simon two-stage study (NCT03284385) of adavosertib (300 mg orally daily) in patients with solid tumors or ccRCC with SETD2 mutations.
- Primary endpoint was objective response rate (ORR).
- Correlative analysis included immunohistochemistry (IHC) for H3K36me3 loss in archival tumor tissue.
Main Results:
- Eighteen patients were enrolled (9 per cohort). Median age was 60 years. Median treatment duration was 1.28 months.
- No objective responses were observed in either cohort; accrual was halted.
- Minor tumor regressions (22%) and stable disease (56%) were observed in evaluable patients, with some achieving prolonged stable disease (>4 months).
- Common adverse events included nausea, anemia, diarrhea, and neutropenia. 50% experienced Grade ≥3 adverse events.
- Loss of H3K36me3 was confirmed in 75% of evaluable archival tumor samples.
Conclusions:
- Adavosertib monotherapy demonstrated limited clinical activity in SETD2-altered solid tumors and ccRCC, failing to achieve objective responses.
- Despite preclinical rationale, adavosertib did not translate into robust tumor regression, although a subset of patients benefited from prolonged stable disease.
- Future strategies may require combination approaches to enhance anti-tumor efficacy in this setting.
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