Talazoparib Plus Low-Dose Temozolomide Improves ORR Over Historical Control in R/R ES-SCLC

Jonathan W. Goldman, MD

The combination of talazoparib (Talzenna) and temozolomide elicited an objective response rate (ORR) of 39.3% in patients with extensive-stage small cell lung cancer (ES-SCLC) who were relapsed or refractory to a frontline platinum-based chemotherapy regimen, according to data from a phase 2 UCLA/TRIO-US L-07 trial (NCT03672773) presented during the 2022 World Conference on Lung Cancer.¹

Eleven of the 28 evaluable patients achieved a confirmed partial response (PR) to the doublet; the twelfth patient came off the trial before response to treatment could be confirmed. The median time to response (TTR) was 1.8 months and the median duration of response (DOR) was 4.3 months. Moreover, the median progression-free survival (PFS) with the combination was 4.3 months, and the median overall survival (OS) was 11.9 months.

Notably, the ORR, which was based on RECIST v1.1 criteria, compared favorably with the historical control of a 15% ORR achieved with second-line topotecan. As such, the study exceeded its target response rate, according to Jonathan W. Goldman, MD, lead study author and assistant professor at David Geffen School of Medicine of UCLA.

“This is the second trial to demonstrate a benefit of PARP inhibition with low-dose temozolomide in SCLC,” Goldman said in a presentation of the data. “A phase 3 study is appropriate to confirm the benefit of this approach compared with currently approved options.”

In prior models of this disease, talazoparib was found to have cytotoxic effects by inhibiting PARP proteins 1/2 and trapping PARP on DNA, as temozolomide potentiated antitumor response by contributing to genomic instability.

In the investigator-initiated, Simon 2-stage, open-label, single-arm phase 2 trial, Goldman and colleagues sought to understand whether second-line treatment with the doublet could improve disease-associated outcomes in patients with ES-SCLC.

To be eligible for enrollment, patients were required to have cytologically or histologically confirmed, relapsed/refractory ES-SCLC.² They needed to have measurable disease per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1. If they had a best response of progressive disease (PD) to frontline platinum-doublet chemotherapy, received more than 1 line of cytotoxic therapy, prior PARP inhibition or temozolomide, they were excluded.

Study participants were given a daily dose of talazoparib at 0.75 mg in combination with temozolomide at 37.5 mg/m² on days 1 through 5 as part of 28-day treatment cycles.

The primary objective of the trial was to examine the ORR achieved with the doublet vs the control of second-line topotecan. Null hypothesis was rejected if 8 or more confirmed responses were identified among 28 evaluable patients (ORR of 29%). Secondary objectives included DOR, TTR, PFS, and OS. Key exploratory end points include patient-reported outcomes (PROs) and a biomarker analysis.

A total of 28 patients were enrolled to the trial, with a median age of 65.5 years (range, 46-89). Moreover, 57.1% of patients were male, 71.4% were White, and 64.3% were former smokers. Most patients (92.9%) received 1 prior regimen, and 7.1% received 2 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 (Rova-T).

Additional data presented from the trial during the meeting showed that the ORR achieved with the doublet was comparable in those with platinum-refractory disease (n = 6) platinum-resistant disease (n = 9), and platinum-sensitive disease (n = 13).

In the cohort with platinum-refractory disease, 3 patients achieved a PR to talazoparib/temozolomide, 2 had stable disease (SD), and 1 had PD. In those with platinum-resistant disease, 4 achieved PRs to treatment, 2 had SD, 2 had PD, and 1 was not evaluated. Lastly, in the platinum-sensitive cohort, 4 patients achieved a PR with the doublet, 7 had SD, and 2 had PD.

For a total of 27 patients who were determined to be evaluable for response to treatment, investigators collected 78 circulating tumor DNA (ctDNA) samples. Of these patients, 81.5% experienced disease control with the doublet; this included 11 patients with a confirmed PR. Notably, all patients who achieved PRs to treatment and who had a ctDNA burden of greater than 0.2% at baseline experienced a decrease in ctDNA at 8 weeks.

No patients were found to have germline DDR mutations. The most frequently observed somatic alterations at baseline were in TP53 (85.2%), RB1 (29.6%), ATM (18.5%), and BRCA2 (18.5%). Moreover, 66.7% of patients were noted to have somatic DDR mutations.

In those who had ctDNA collected for at least 2 time points (n = 17), 76.4% were found to have at least 1 treatment-emergent mutation, and this was most frequently in ATM (n = 7).

Notably, treatment-emergent mutations of any kind may be linked with disease control (P = .042), according to Goldman, with a trend toward better PFS if present vs not, at 5.8 months (95% CI, 3.9-8.2) vs 3.5 months (95% CI, 1.8–not reached), respectively (P = .099).

PRO data indicated mostly low severity, non-progressive symptoms, according to Goldman.

Regarding safety, the most common hematologic adverse effects (AEs) reported with the combination included anemia (60.7%), decreased neutrophil count (39.3%), decreased platelet count (67.9%), and decreased white blood cell count (21.4%). The most frequent non-hematologic AEs reported with talazoparib/temozolomide were fatigue (28.6%), diarrhea (14.3%), and nausea (14.3%).

Grade 3 or 4 AEs included anemia (53.6%), decreased neutrophil count (32.1%), decreased platelet count (60.7%), decreased white blood cell count (17.9%), and atypical pneumonia (3.6%).

References

1. 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: International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract OA12.03
2. Talazoparib and low-dose temozolomide in treating participants with relapsed or refractory extensive-stage small cell lung cancer. ClinicalTrials.gov. Updated February 8, 2022. Accessed August 8, 2022. https://clinicaltrials.gov/ct2/show/NCT03672773