- An emerging strategy for treating relapsed small-cell lung cancer (SCLC) is to combine a DNA-damaging agent with an inhibitor of DNA-damage repair, such as veliparib or olaparib
- This single-arm, open-label phase 1/2 trial of olaparib plus temozolomide (OT) showed a strong signal of efficacy in 48 evaluable patients, with a confirmed overall response rate of 42% and median progression-free survival of 4.2 months
- In a study of 32 patient-derived xenografts (PDX) from 22 patients (four from the phase 1/2 trial), the responses of the PDX models to OT matched their corresponding patients, and models from patients with relapsed SCLC were more resistant to therapy
- The PDX models also showed that four inflammatory-response genes (CEACAM1, TNFSF10, OAS1, TGIF1) were markers of OT sensitivity and and may prove useful for identifying which SCLC patients will respond to treatment with DNA-damaging regimens
Small-cell lung cancer (SCLC) is one of the most aggressive and lethal malignancies, but initially it's highly sensitive to DNA damage. An emerging treatment strategy is to combine a DNA-damaging agent with an inhibitor of DNA-damage repair, such as veliparib or olaparib.
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Massachusetts General Hospital Cancer Center's Nicholas Dyson, PhD, geneticist in the Center for Cancer Research and the James and Shirley Curvey MGH Research Scholar, Anna F. Farago, MD, oncologist, and Benjamin J. Drapkin, MD, PhD, oncologist, report in Cancer Discovery that olaparib plus temozolomide (OT) has substantial antitumor activity in patients with relapsed SCLC.
Between October 2015 and April 2018, the team conducted a phase 1/2 trial of OT. 13 patients participated in the dose-escalation phase and 37 received the dose selected in phase 1.
The most common study-wide treatment-related adverse events were thrombocytopenia, anemia and neutropenia, most grade 1/2. One grade 3 case of pneumonitis resolved with steroids. Two deaths during phase 2 were considered possibly treatment-related: one due to pneumonia and the other to neutropenic sepsis.
Among 48 patients evaluable for response, over median follow-up of 7.1 months:
- Confirmed overall response rate, the prespecified primary outcome measure—42%
- Median duration of response—4.3 months
- Median progression-free survival—4.2 months
- Median overall survival—8.5 months
The team collected tumor cells from 22 SCLC patients: four from the trial, including four patients treated on the OT trial. The tumors had a range of genomic features and sensitivity to first-line etoposide/platinum. When the cells were injected into severely immunodeficient mice, the range of responses was similar to those in the trial.
Using these models the researchers also determined that four inflammatory-response genes (CEACAM1, TNFSF10, OAS1, TGIF1) predicted response to OT as well as other chemotherapies. These genes may prove useful for identifying SCLC patients who will respond to treatment with DNA-damaging regimens.
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