Talazoparib + low-dose temozolomide seems promising in ES-SCLC

Talazoparib exhibits cytotoxic effects by inhibiting poly ADP-ribose polymerase (PARP) proteins 1 and 2 in addition to ‘trapping’ PARP on DNA; temozolomide has demonstrated increased antitumor response when combined with a PARP inhibitor in small-cell lung cancer (SCLC) models [1]. It was hypothesised that combining PARP inhibition with temozolomide as second-line therapy for extensive-stage (ES)-SCLC may improve disease-related outcomes.

This hypothesis is currently being assessed in a phase 2, open-label, single-arm study of the safety and efficacy of talazoparib plus temozolomide in patients with ES-SCLC. The primary endpoint is objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Secondary endpoints include progression-free survival (PFS), overall survival (OS), duration of response, and time to response. Exploratory endpoints include biomarker studies such as DNA damage response gene analysis and patient reported outcomes (PROs). Eligible patients had relapsed (progressed within 6 months) or refractory (progressed during or within 4 weeks of completing first-line platinum-based regimen) ES-SCLC. Those with a best response of progressive disease to first-line therapy per RECIST 1.1 or more than 1 line of cytotoxic therapy are excluded. Prior immunotherapy is allowed.

Participants receive talazoparib 0.75 mg daily on 28-day cycles with temozolomide 37.5 mg/m2 on days 1 to 5. A total of 15 patients are planned to be enrolled in the first part of a 2-stage design; if 3 or more responses are seen, an additional 13 participants will be enrolled. At the cut-off (30 March 2019), 10 patients had been treated on protocol with 8 evaluable for treatment response (median age 66 years).

As best response, 2 patients had a confirmed partial response (1 with a 50% reduction lasting 8 months), 3 had stable disease, and 2 patients had progressive disease (in 1 case this led to death; see Figure) [2]. At least grade 1 thrombocytopenia was seen in nearly all patients, but most cases self-resolved within 2 weeks of holding drug. In 3 patients, high grade haematologic events led to dose-reduction of temozolomide. There was 1 patient who withdrew consent, based on haematologic toxicities, and 1 patient was hospitalised for atypical pneumonia related to cytopenia. Thus, the combination of talazoparib and temozolomide which is used as second-line therapy in ES-SCLC, is tolerable and has shown promising preliminary results. The trial is currently ongoing, and will continue to enrol patients [2].

Figure. Percentage of change from baseline [2]

1. Wainberg ZA, et al. Cancer Res 2016;76(14 Suppl):Abstract CT011.
2. Goldman J, et al. P2.12-09 WCLC 2019.

Posted on 8 November 201925 March 2024