Primary analysis from the phase 2 study of continuous talazoparib (TALA) plus intermittent low-dose temozolomide (TMZ) in patients with relapsed or refractory extensive-stage small cell lung cancer (ES-SCLC).

• DOI: 10.1200/jco.2022.40.16_suppl.8517
• Publication Date: 2022-06-06T17:17:10Z
• Authors: Jonathan W. Goldman; Amy Lauren Cummings; Melody A. Mendenhall; Maria A Velez; Sunil Babu; Tirrell T. Johnson; Juan M. Alcantar; Shaker R. Dakhil; David E. Kanamori; William E. Lawler; Sidharth Anand; James Chauv; Edward B. Garon; Dennis J. Slamon
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

8517 Background: TALA exhibits cytotoxic effects by inhibiting poly (ADP-ribose) polymerase (PARP) proteins 1 and 2 in addition to “trapping” PARP on DNA. TMZ has been shown to increase antitumor response when combined with TALA in SCLC models (Wainberg AACR 2016). TALA plus TMZ as second-line therapy for ES-SCLC may improve disease-related outcomes. Methods: This is a phase 2, open-label, single-arm study of the safety and efficacy of TALA plus TMZ in patients with ES-SCLC, relapsed or refractory to a first-line platinum-based regimen. Participants receive TALA 0.75 mg (or 0.5 mg if creatinine clearance < 60 mL/min) po daily on 28-day cycles with TMZ 37.5 mg/m2 po on days 1-5. The primary endpoint is objective response rate (ORR) based on RECIST 1.1 criteria, versus a historical control of 15% ORR in second-line topotecan, with the null hypothesis rejected for 8 or more confirmed responses among 28 evaluable subjects (29% ORR). Secondary endpoints include progression-free survival, overall survival, duration of response, and time to response. Exploratory endpoints include biomarker studies such as status of DNA damage response genes (DDR) and patient reported outcomes. A Simon two-stage design was utilized to reach a total accrual of 28 evaluable patients. Results: Thirty-one subjects were enrolled, of which 3 were non-evaluable due to ineligibility (1) or early withdrawal of consent prior to first disease assessment (2). Eleven of 28 evaluable subjects (39.3%) achieved a confirmed partial response. The ORR was similar among platinum-refractory (3/6), -resistant (4/9), and -sensitive subgroups (4/13). The median time to response was 1.8 months (m), duration of response 5.8 m, progression free survival 4.5 m, and overall survival 11.9 m. Adverse events (AEs) were manageable, with grade ≥ 3 AEs being thrombocytopenia (61.3%), anemia (54.8%), neutropenia (41.9%), and atypical pneumonia (3.2%), which responded well to dose-hold or dose-reduction and transfusion or growth factor support as needed. Cell free DNA and tissue analysis demonstrated no germline DDR mutations among the trial subjects, but somatic DDR mutations at baseline and acquired during treatment were common. Three subjects remain on study treatment. Conclusions: The study exceeded its target response rate. This is the second trial to demonstrate a benefit of PARP inhibition with low-dose TMZ in SCLC (see Farago Cancer Discovery 2019). A phase 3 study is appropriate to confirm the benefit of this approach compared to currently approved options. Clinical trial information: NCT03672773.