Combination olaparib and durvalumab for patients with recurrent IDH-mutated gliomas.
Bibliographic record
Abstract
e14026 Background: Isocitrate dehydrogenase (IDH) mutations are frequently observed in low grade gliomas and secondary glioblastoma. Mutant IDH enzymes aberrantly convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG). Accumulation of 2HG inhibits αKG-dependent dioxygenases, many of which are involved in epigenetic regulation. This can lead to cellular dedifferentiation and tumor formation. IDH-mutated cancer cells exhibit defective homologous recombination repair, providing the rationale for investigating poly (adenosine 5’-diphophate-ribose) polymerase (PARP) inhibitors in these tumors. Blockade of programmed cell death ligand 1 (PD‐L1) re‐sensitizes PARP inhibitor treated cancer cells to T‐cell killing. We report the preliminary results of the glioma arm of a clinical trial of a PARP inhibitor, olaparib plus PD-L1 inhibitor, durvalumab, for IDH-mutated solid cancer. Methods: This is a single arm phase II basket study (NCT03991832). Patients with IDH-mutated solid tumors are divided into three cohorts; A: glioma; B: cholangiocarcinoma; C: all other solid tumors. Major eligibility criteria include IDH mutation by immunohistochemistry or sequencing, progressive disease with maximum two prior systemic therapies, Eastern Cooperative Oncology Group performance status (ECOG) 0 –1 and adequate organ function. Patients were excluded if they had received prior PARP inhibitors or anti-PD-1/PD-L1 antibodies. Patients were treated with olaparib 300 mg orally twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Each cycle was 4 weeks. Tumor response was evaluated by MRI after every 2 cycles of study treatments using response evaluation criteria in solid tumors (RECIST). Results: As of Jan 2021, 9 patients were enrolled in Arm A, 7 men and 2 women. The median age was 42 years. Eight patients had IDH1 mutations and 1 had an IDH2 mutation. There were two patients with 1p/19q codeletion. Two patients had grade 2 tumors, four had grade 3, and three had grade 4 tumors. Median time since tumor diagnosis was 7 years. Objective response was seen in 1 patient with an IDH-mutated glioblastoma who remains on study treatments after 8 cycles. Six patients (67%) had tumor progression after two cycles. Two patients had stable disease as per RECIST but had clinical deterioration and did not continue the combined treatment. Common treatment emergent adverse events were all grade 1: fatigue (8 patients), nausea (6), abdominal pain (3), anemia (3), thrombocytopenia (3), and diarrhea (2). Median progression free survival was 2.5 months (range 1.9–8 months). Updated analysis and correlative studies will be presented at the meeting. Conclusions: Combination treatment with olaparib and durvalumab for patients with IDH-mutated glioma is well tolerated but appears to lack adequate antitumor activity. Clinical trial information: NCT03991832.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".