medwireNews: A phase I/II trial has shown promising efficacy and tolerability for the combination of the PARP inhibitor olaparib with temozolomide in patients with previously treated small-cell lung cancer (SCLC).
The results show “substantial clinical activity” for the combination, say Anna Farago (Massachusetts General Hospital Cancer Center, Boston, USA) and co-researchers, who describe olaparib plus temozolomide as “a promising new therapeutic strategy for this highly recalcitrant malignancy.”
The results, published in Cancer Discovery, show that the 48 evaluable patients treated with this regimen had an overall response rate (ORR) of 41.7% and median duration of response of 4.3 months. And with a median follow-up of 7.1 months, the median progression-free survival (PFS) and overall survival (OS) durations were 4.2 and 8.5 months, respectively.
While noting that “cross-study comparisons are difficult to interpret,” the ORR and median PFS described here “are numerically superior to several recent second- and third-line SCLC studies,” the researchers say.
Trial participants received the combination on days 1–7 of every 21-day cycle at a dose of 100 or 200 mg twice daily for olaparib and 50, 75, or 100 mg/m2 once a day for temozolomide, with olaparib 200 mg plus temozolomide 75 mg/m2 chosen as the recommended phase II dose.
The efficacy findings for the 39 evaluable patients treated at the recommended phase II dose were similar to those of the overall cohort, with an ORR of 41.0%, and respective median PFS and OS times of 4.2 and 6.7 months.
The most common treatment-related adverse events were thrombocytopenia, anemia and neutropenia (occurring in 68%, 68%, and 54% of patients, respectively), with most events being of grade 1 or 2. Two grade 5 events that were felt to be possibly related to the study drugs also occurred: one case of pneumonia and one of neutropenic sepsis.
Dose reductions were required by 44% of patients treated at the recommended phase II dose, and by 64% of those who received at least three cycles of the combination therapy at the recommended dose.
Farago and colleagues explain that patients with SCLC who are initially sensitive to standard first-line chemotherapy generally experience relapse and develop broad cross-resistance to second-line agents. They therefore used patient-derived xenograft models to pinpoint biomarkers that might indicate tumor sensitivity to olaparib plus temozolomide, finding that aggregate expression of the inflammatory response genes CEACAM1, TNFSF10, TGIF1, and OAS1 was able to “strongly distinguish” models that were sensitive or resistant to both the current combination and to standard first-line chemotherapy with etoposide and a platinum agent.
“The performance of these interferon response genes as classifiers […] further supports the inflammatory response signature as a marker of sensitivity to [olaparib plus temozolomide], and likely other DNA damaging regimens, in SCLC,” say Farago et al.
Together with previous results, the team concludes that “these data support the further development of strategies that combine induction of DNA damage with PARP inhibition.”
By Catherine Booth
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Cancer Discov 2019; doi:10.1158/2159-8290.CD-19-0582