Talazoparib plus temozolomide for extensive-stage relapsed or refractory small cell lung cancer
Recent data from the phase II UCLA/TRIO-US L-07 trial demonstrated that the combination of talazoparib and temozolomide results in an objective response rate (ORR) of 39.3% in patients with extensive-stage small cell lung cancer who relapsed or were refractory to a frontline platinum-based chemotherapy regimen. These results compared favourably to the historical control of a 15% ORR achieved with second-line topotecan. As such, the study exceeded its target response rate.
In small-cell lung cancer models, talazoparib (TALA), a potent PARP inhibitor, exhibits cytotoxic effects by inhibiting PARP proteins 1 and 2, and trapping PARP on DNA while temozolomide (TMZ) potentiates antitumour response by contributing to genomic instability. The phase II UCLA/TRIO-US L-07 study was investigator-initiated to determine if TALA plus TMZ may improve disease-related outcomes as second line therapy for ES-SCLC.
Study design
This is a phase II, 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 (PFS), overall survival (OS), duration of response (DoR), and time to response (TTR). Exploratory endpoints include biomarker studies such as status of DNA damage response genes (DDR) and patient-reported outcomes. A Simon two-stage design was utilised to reach a total accrual of 28 evaluable patients.
Results
Thirty-one subjects were enrolled, of which three were non-evaluable due to ineligibility (N=1) or early withdrawal of consent prior to first disease assessment (N= 2). The median age (range) among the 28 evaluable patients was 65.5 (46-89) years. Moreover, 57.1% of patients were male, 71.4% were White, and 64.3% were former smokers. Most patients (92.9%) received one prior regimen, and 7.1% received two prior regimens. All patients previously received cytotoxic chemotherapy, 71.4% had prior immunotherapy, 57.1% received prior radiotherapy, and 3.6% previously received rovalpituzumab tesirine. Eleven of those 28 patients (39.3%) achieved a confirmed partial response. A 12th patient came off trial before the response could be confirmed. Median TTR was 1.8 months, DoR was 4.3 months, PFS was 4.3 months and OS was 11.9 months. The ORR was similar among platinum-refractory (3/6), -resistant (4/9), and –sensitive subgroups (4/13). Adverse events (AEs) were manageable, with grade ≥ 3 AEs being thrombocytopenia (60.7%), anaemia (53.6%), neutropenia (32.1%), a decreased white blood cell count (17.9%) and atypical pneumonia (3.6%), which responded well to dose-hold or dose-reduction and transfusion or growth factor support as needed.
For 27 response evaluable patients, 78 ctDNA samples were collected. Among them, 22 patients (81.5%) had disease control, including 11 with confirmed partial response (PR). All those with PRs and ctDNA burden > 0.2% at baseline experienced a ctDNA decrease at 8 weeks. There were no patients with germline DDR mutations. The most common baseline somatic alterations were mutations in TP53 (23 patients, 85.2%), RB1 (8 patients, 29.6%), ATM (5 patients, 18.5%), and BRCA2 (5 patients, 18.5%). Somatic DDR mutations were found in 18/27 (66.7%) patients. Among those with ≧2 time points collected, 13/17 (76.4%) patients had ≧ 1 treatment-emergent mutation, most commonly in ATM (7 patients). Treatment emergent mutations of any type associated with disease control (p= 0.042) with a trend towards improved PFS (5.8 vs. 3.5 months). Finally, patient-reported outcomes demonstrated mostly low severity and non-progressive symptoms.
Conclusion
The UCLA/TRIO-US L-07 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). Adverse events were mostly haematologic and manageable. There were no germline DDR mutations among the trial subjects. The development of new mutations on treatment may associate with disease control. A phase III study is appropriate to confirm the benefit of this approach compared to currently approved options.
Reference
Goldman J, Cummings A, Mendenhall M, et al. Phase 2 study analysis of talazoparib (TALA) plus temozolomide (TMZ) for extensive-stage small cell lung cancer (ES-SCLC). Presented at IASLC 2022; Abstract OA12.03.
