Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical
Nobuyuki Takahashi1,2, Zhonglin Hao3, Liza C Villaruz4
1National Cancer Institute, Center for Cancer Research, Bethesda, Maryland.
Importance:
Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan.
Objective:
To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC.
Design, Setting, And Participants:
Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible.
Interventions:
Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy.
Main Outcomes And Measures:
The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI.
Results:
Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]).
Conclusions And Relevance:
In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS.
Trial Registration:
ClinicalTrials.gov Identifier: NCT03896503.
Insights
In relapsed small cell lung cancer (SCLC), adding berzosertib to topotecan did not improve progression-free survival. However, this combination therapy significantly improved overall survival for patients with SCLC.
Area of Science:
- Oncology
- Clinical Trials
- Pharmacology
Background:
- Small cell lung cancer (SCLC) is an aggressive cancer with limited treatment options for relapsed cases.
- Replication stress is a key feature of SCLC, suggesting potential therapeutic targets like ATR kinase.
- Berzosertib, an ATR kinase inhibitor, has shown promise in preclinical studies for SCLC.
Purpose of the Study:
- To evaluate the efficacy and safety of combining berzosertib with topotecan in patients with relapsed SCLC.
- To determine if this combination improves progression-free survival (PFS) and overall survival (OS) compared to topotecan alone.
Main Methods:
- An open-label, phase 2 randomized clinical trial was conducted with 60 patients with relapsed SCLC.
- Patients were randomized to receive either topotecan alone or topotecan plus berzosertib.
- The primary endpoint was PFS, with OS as a key secondary endpoint. Survival outcomes were analyzed using Kaplan-Meier and Cox proportional hazards models.
Main Results:
- No significant difference in PFS was observed between the combination arm and topotecan alone (median PFS: 3.9 vs 3.0 months; HR, 0.80; P=.44).
- Overall survival was significantly longer in the group receiving berzosertib plus topotecan (median OS: 8.9 vs 5.4 months; HR, 0.53; P=.03).
- Adverse event profiles were comparable between the two treatment groups, with similar rates of thrombocytopenia and nausea.
Conclusions:
- Adding berzosertib to topotecan did not improve PFS in patients with relapsed SCLC.
- The combination of berzosertib and topotecan demonstrated a significant improvement in overall survival.
- This suggests a potential role for ATR inhibition in combination with chemotherapy for relapsed SCLC, warranting further investigation.
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