Key Points
Question
Does the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan therapy benefit patients with relapsed small cell lung cancer (SCLC)?
Findings
In this phase 2 multi-institutional randomized clinical trial of 60 adults with relapsed SCLC, the addition of berzosertib to topotecan therapy did not increase progression-free survival but significantly prolonged overall survival.
Meaning
The findings of the randomized clinical trial indicate that the addition of berzosertib to topotecan therapy does not improve progression-free survival among patients with relapsed SCLC.
Abstract
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
This randomized clinical trial compares the improvement in clinical outcomes following the administration of topotecan alone with that of berzosertib plus topotecan among patients with relapsed small cell lung cancer.
Introduction
Small cell lung cancer (SCLC) is the most fatal and metastatic form of lung cancer, constituting approximately 14% of all lung cancers, and kills at least 250 000 people globally each year.1 This cancer is usually detected after tumors have already widely metastasized.2 Although administration of anti-programmed death-ligand 1 antibody combined with platinum and etoposide is the current standard treatment,3,4 responses to this regimen are typically brief. There are few effective treatments after failure of first-line therapies. Topotecan is the most widely used agent globally. However, clinical benefit is modest, with response rates of approximately 16%.5 Lurbinectedin received conditional approval by the US Food and Drug Administration for second-line treatment, with response rates of 35%.6 However, combination therapy with lurbinectedin and doxorubicin did not improve overall survival (OS) over topotecan.7 There has been only minimal improvement in survival since the 1980s.8
Genomic instability is an enabling characteristic of cancer, which by generating genetic diversity expedites the acquisition of multiple other hallmark capabilities.9 Replication stress, defined as the slowing or stalling of replication fork progression and DNA synthesis is a major driver of genomic instability.10 We reasoned that SCLC, being a smoking-related cancer, which is marked by extensive chromosomal rearrangements and high mutation rate, frequent inactivation of tumor suppressor genes TP53 and RB1,11 extra-chromosomal amplification of MYC genes,12 and hyper-transcription, depends on an effective cellular response to replication stress to sustain its rapid proliferation.13 Ataxia telangiectasia and Rad3-related (ATR) is a master regulator of the replication stress response, stabilizing the genome when DNA replication is compromised.14 Enhancing replication stress in tumors that are already under high replication stress through ATR inhibition can induce cell death by mitotic catastrophe.10,15
In a phase 1 clinical trial, we combined the first-in-class ATR inhibitor berzosertib with topotecan, which produces replication stress by trapping topoisomerase I (TOP1) cleavage complexes.10,16 The combination enhanced replication stress and produced durable responses in patients with chemotherapy refractory cancers while being tolerable.16 In a single-arm phase 2 trial, the combination yielded partial responses in 36% of patients with relapsed SCLC, meeting the primary objective.17 Building on these findings, we launched a randomized, phase 2 trial, reported here, asking whether administration of berzosertib would enhance the activity of topotecan therapy and show superior efficacy compared with topotecan alone in patients with relapsed SCLC.
Methods
Study Design and Participants
This open-label, 2-arm, phase 2 randomized clinical trial was conducted in 16 cancer centers in the United States, including the Center for Cancer Research, National Cancer Institute (NCI), all participating as members of the NCI Cancer Therapy Evaluation Program. The Trial Protocol is provided in Supplement 1. The study schema is shown in eFigure 1 in Supplement 2. All patients provided written informed consent and consented to mandatory collection of archival tumor tissue and pretreatment tumor biopsy for exploratory correlative studies. The trial was approved by each participating site’s institutional review board or ethics committee, conducted in accordance with the Declaration of Helsinki18 and Good Clinical Practice standards, and reported following the Consolidated Standards of Reporting Trials (CONSORT) guideline.
Eligible patients were 18 years or older, had histologically confirmed SCLC at diagnosis with relapse at study entry, an unlimited number of previous treatments with disease progression, measurable lesions according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2, and normal organ and marrow functions as defined in the protocol. Patients previously treated with topotecan were not eligible. Race and ethicity data were assessed to address whether the efficacy and safety were observed across different races and ethnicity. The information collection was not required by a funding agency and was collected by self-report. We used categories of Asian, African American, White, and others.
Randomization
Eligible patients were enrolled by investigators and randomly assigned 1:2 to receive topotecan alone (group 1) or in combination with berzosertib (group 2). Patients and investigators were not masked to treatment assignment, which was performed centrally through the Theradex Interactive Web Response System. Randomization was stratified by sensitivity to first-line treatment with platinum-based chemotherapy, depending on whether patients had SCLC that was sensitive (progression or relapse ≥90 days after completion of chemotherapy) or resistant (<90 days) to platinum-based chemotherapy.19
Treatment
Berzosertib was provided by the NCI Cancer Therapy Evaluation Program, and topotecan was obtained commercially. After randomization, treatment was started within 30 days. Berzosertib, 210 mg/m2 intravenously on days 2 and 5, was administered concurrently with topotecan, 1.25 mg/m2 intravenously on days 1 through 5, in 21-day cycles. The dose and timing of administration were based on safety, pharmacodynamic activity, and antitumor efficacy in a dose escalation study16 and a single-arm phase 2 study.17 Hematopoietic growth factor support was allowed.
Treatment continued until disease progression, unacceptable toxic effects, patient withdrawal from study, intercurrent illness that prevented further treatment, or changes in the participant’s condition that rendered the treatment unacceptable. Toxic effect–related dose delays of up to 21 days were allowed. Depending on the grade of the adverse event, topotecan could be reduced to 1 mg/m2 or 0.75 mg/m2, and berzosertib could be reduced to 158 mg/m2 or 105 mg/m2. Dose reductions were required for grade 4 hematologic adverse events, prolonged grade 3 neutropenia lasting more than 21 days, and grade 3 nonhematologic adverse events. Crossover from the topotecan group to the topotecan plus berzosertib group was allowed for patients who developed disease progression.
Study Evaluation
History and physical examination were conducted at baseline and before each cycle. Complete blood cell counts and serum laboratory values were obtained at baseline, day 8, and day 15 for the first cycle, and prior to each cycle thereafter. Radiographic evaluation was performed at baseline and every 2 cycles. Toxic effects were graded using NCI Common Terminology Criteria for Adverse Events, version 4.0. After stopping study treatment, patients were followed up every 3 months until death.
Outcomes
The primary end point was progression-free survival (PFS), defined as the time from randomization until investigator-assessed progressive disease or death (regardless of cause). Secondary end points were OS (time from randomization to death, regardless of cause), objective response rate (ORR, percentage of participants with a complete or partial response), and duration of response.
Statistical Analysis
The primary objective of the trial was to determine if treatment with the combination of berzosertib and topotecan would result in an improvement in PFS compared with topotecan alone among patients with relapsed SCLC. Previous study results indicated that treatment with single-agent topotecan resulted in a median PFS of approximately 3 months (median, 3.0-4.3 months for patients with platinum-sensitive SCLC, and 1.5-2.6 months for patients with platinum-resistant SCLC).20,21,22,23,24 The present study was designed to have 85% power to detect an improvement of median PFS from either 2.5 or 3 months with topotecan alone to 5 or 6 months with topotecan plus berzosertib, using a log-rank test at the 1-sided α level of 0.10. Randomly assigning 54 patients (36 patients in the combination treatment group and 18 patients in the topotecan treatment group) for 2 years and following up for up to an additional 12 months, with 48 total progression events, would satisfy those criteria. Analyses of PFS, OS, and safety were performed for all patients who received at least 1 dose of study treatment. Analyses of other secondary efficacy end points were also performed for all patients who received at least 1 dose of study treatment, including those with measurable disease who were not assessable for objective response because of early discontinuation of protocol therapy. 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 overall and within selected subgroups. We also examined the treatment effects on OS and PFS in a 2 platinum-sensitivity strata using Kaplan-Meier curves. A multivariable Cox model was created for OS to assess the impact of treatment after adjusting for demographic and clinical characteristics after obtaining the results from the univariate survival analyses. The final Cox model was determined by backward selection. Patients who withdrew from treatment for reasons unrelated to disease progression were included and censored at the date that they were no longer receiving protocol treatments in the PFS analysis. An interim futility analysis was performed at 24 PFS events to stop study enrollment in case of futility. All statistical analyses were performed with R software, version 4.1.0 (R Foundation for Statistical Computing).
Results
Patient Characteristics
Between December 1, 2019, and December 31, 2022, 83 patients from 16 centers across the United States were screened. In total, 23 patients (28%) did not meet screening criteria, mostly due to abnormal results in screening tests or disease progression before treatment initiation. Among 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male and 27 [45%] female; <5 were Asian, 5 were African American, and 54 were White), 20 were randomly assigned to receive the single-agent topotecan (group 1) and 40 to receive a combination of topotecan and berzosertib (group 2) (Figure 1). Baseline characteristics for each treatment group are given in Table 1. Most patients (46 of 60, 77%) had symptoms related to SCLC (ie, ECOG PS ≥1). Approximately half of all patients had liver metastases. All patients had received platinum-based chemotherapy at diagnosis, and 60% had additionally received immunotherapy, the current standard care for SCLC3,4; 20% had received lurbinectedin.6 The median number of prior treatments was 2 (range, 1-5). Just over half of all patients (31 of 60, 52%) had platinum-resistant SCLC, and they were equally distributed in both groups as a prespecified stratification factor for randomization (Table 1). All 60 randomly assigned patients received at least 1 dose of treatment and were included in the PFS and OS analyses. Patients with at least 1 diagnostic imaging scan beyond baseline were evaluated for response (total of 57: 18 in group 1, and 39 in group 2). Safety was assessed in all 60 patients who received at least 1 dose of study treatment.
Figure 1. Study Flow Diagram.
Table 1. Baseline Clinical Characteristics of Patients.
| Characteristic | Participants, No, (%) | ||
|---|---|---|---|
| Group 1, topotecan alone, (n = 20) | Group 2 (topotecan + berzosertib) (n = 40) | Total (n = 60) | |
| Age at inclusion, median (range), y | 59 (34-72) | 60 (46-79) | 59 (34-79) |
| Sex, No. | |||
| Male | 9 | 24 | 33 |
| Female | 11 | 16 | 27 |
| ECOG PS (0/1/2), No. | 3/13/4 | 11/25/4 | 14/38/8 |
| Race and ethnicity, No. | |||
| African American | 0 | 5 | 5 |
| Asian | 0 | <5 | <5 |
| White | 20 | 34 | 54 |
| Liver metastasis at inclusion | 11 (55) | 20 (50) | 31 (52) |
| Brain metastasis at inclusion | 1 (5) | 3 (8) | 4 (7) |
| Type of previous treatment for brain metastasis (WBRT/SRS/surgery), No. | 2/1/0 | 7/6/1 | 9/7/1 |
| Prophylactic WBRT | 2 (10) | 3 (8) | 5 (8) |
| Previous systemic therapy | |||
| No. of treatments, median (range) | 2 (1-5) | 2 (1-4) | 2 (1-5) |
| Platinum-based chemotherapy | 20 (100) | 40 (100) | 60 (100) |
| Platinum-immunotherapy combination in first-line treatment | 10 (50) | 26 (65) | 36 (60) |
| Lurbinectedin | 3 (15) | 9 (23) | 12 (20) |
| Immunotherapy in second or later line | 7 (35) | 12 (30) | 19 (32) |
| Platinum rechallenge | 3 (15) | 5 (13) | 8 (13) |
| Investigational drugs | 5 (25) | 7 (18) | 12 (20) |
| Platinum sensitivity | |||
| Sensitive, No.a | 9 | 20 | 29 |
| Resistant, No.b | 11 | 20 | 31 |
| Time from diagnosis to treatment, median (range), mo | 9.7 (4.2-110.8) | 10.6 (5.0-48.8) | 10.4 (4.2-110.8) |
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; WBRT, whole brain radiation therapy; SRS, stereotactic radiosurgery.
Platinum sensitive defined as relapse or disease progression 90 or more days after first-line platinum-based chemotherapy.
Platinum resistant defined as relapse or disease progression less than 90 days after or during first-line chemotherapy.19
Efficacy
After a median (IQR) follow-up of 21.3 (18.1-28.3) months, most patients discontinued treatment due to disease progression (15 of 20, 75% in group 1, topotecan alone; 35 of 40, 88% in group 2, topotecan and berzosertib). No statistical difference in PFS was demonstrated between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months in group 1 vs 3.9 [95% CI, 2.8-4.6] months in group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44) (Figure 2A). In group 1, the PFS probability for 4 months was 42.1% (95% CI, 20.4%-62.5%) and for 6 months was 15.8% (95% CI, 3.9%-34.9%). In group 2, the PFS probability for 4 months was 45.0% (95% CI, 29.3%-59.5%) and for 6 months was 27.5% (95% CI, 14.9%-41.7%). One patient (5%) in group 1 and 3 patients (8%) in group 2 had disease progression only in the brain. Ten patients (17%) remained alive (3 in group 1, and 7 in group 2) at the time of data cutoff. The OS was longer with the combination therapy: 5.4 (95% CI, 3.2-6.8) months in group 1 vs 8.9 (95% CI, 4.8-11.4) months in group 2; the HR was 0.53 (95% CI, 0.29-0.96; P = .03) (Figure 2B). In group 1, the OS probability for 6 months was 44.4% (95% CI, 21.6%- 65.1%) and for 12 months was 11.1% (95% CI, 1.9%-29.8%). In group, 2 the OS probability for 6 months was 62.5% (95% CI, 48.2%-77.6%) and for 12 months was 29.6% (95% CI, 16.4%-44.1%). The final multivariable Cox model demonstrated that the administration of the combination of berzosertib and topotecan remained well associated with better OS after adjustment for sex, the only other factor that remained in the final model (eTable 1 in Supplement 2). In an unplanned post hoc analysis, the depth of the target lesion response was significantly associated with better OS among patients in the combination treatment group (eFigure 8 in Supplement 2).
Figure 2. Progression-Free Survival and Overall Survival Among Patients Treated With Topotecan Alone (Group 1) or Topotecan Plus Berzosertib (Group 2).
Plus signs represent censored.
Of 57 evaluable patients, a numerically higher ORR was observed among patients receiving the combination therapy: 1 of 18 (6%; 95% CI, 0.1%-27.3%) in group 1 vs 10 of 39 (26%; 95% CI, 13.0%-42.1%) in group 2 (P = .15) (eTable 2 in Supplement 2). The median duration of response was 3.3 months in group 1 (n = 1) and 9.3 months (95% CI, 0.3-0.6 months) in group 2 (n = 10) (P = .45) (eFigure 2 in Supplement 2). Of 20 patients in group 1, 11 (55.0%) crossed over to group 2 to receive the combination treatment at disease progression; however, most of these patients (9 of 11 [81.8%]) had further disease progression within 1 or 2 cycles of the treatment, and none of them had an objective response after crossover.
The PFS, OS, and ORR were examined in the subgroups of platinum-sensitive SCLC and platinum-resistant SCLC. As with the overall cohort, PFS was similar between patients in group 1 and group 2 in platinum-sensitive (median, 5.5 [95% CI, 1.2-9.6] months vs median, 4.4 [95% CI, 3.0-8.2] months; HR, 1.20 [95% CI, 0.50-2.84], P = .69) and in platinum-resistant (median, 2.1 [95% CI, 0.9-4.1] months vs median 2.7 [95% CI, 1.5-5.4] months; HR, 0.58 [95% CI, 0.27-1.27], P = .17) subgroups (eFigure 3 in Supplement 2). There was a numerically longer median OS in group 2, both in platinum-sensitive (6.5 months in group 1 vs 9.6 months in group 2) and in platinum-resistant (4.6 months in group 1 vs 6.1 months in group 2) subgroups (eFigure 4 in Supplement 2).The ORR was numerically higher in the group 2 platinum-sensitive subgroup (1 of 8 [12%] vs 7 of 20 [35%], P = .37). Three of 19 patients with platinum-resistant tumors (16%) achieved a partial response in group 2, whereas 0 of 10 patients in group 1 had a partial response (eTable 3 and eFigure 5 in Supplement 2). Antitumor responses were observed with the combination treatment irrespective of platinum sensitivity (Figure 3). No particular subgroup showed improved PFS in group 2 over group 1. The OS improvement observed with the combination treatment was irrespective of clinical subgroup, including age, sex, ECOG PS, prior therapy, and platinum sensitivity (eFigure 6 in Supplement 2).
Figure 3. Best Response and Duration of Antitumor Efficacy Among Patients Treated With Topotecan Alone or With a Combination of Topotecan and Berzosertib.
Platinum-sensitive disease was defined as relapse or disease progression 90 or more days after first-line platinum-based chemotherapy. Platinum-resistant disease was defined as relapse or disease progression at less than 90 days or during first-line chemotherapy.19 Top and bottom blue lines indicate 30% increase or 20% decrease as tumor size change from baseline. The arrowhead indicates an increase from baseline of more than 100%.
aNot assessed per protocol.
bClinical progression.
Safety
All 60 patients enrolled and randomly assigned received at least 1 cycle of treatment. Of 20 patients in group 1, 5 (25%) received 5 or more cycles of treatment, compared with 20 of 40 patients (50%) in group 2. The frequencies of grade 3 or 4 treatment-related adverse events were similar between groups 1 and 2: thrombocytopenia (11 of 20 [55%] vs 20 of 40 [50%]), anemia (9 of 20 [45%] vs 18 of 40 [45%]), lymphopenia (8 of 20 [40%] vs 6 of 40 [15%]), and neutropenia (7 of 20 [35%] vs 12 of 40 [30%]). Gastrointestinal tract symptoms of any grade, such as nausea (9 of 20 [45%] vs 14 of 40 [35%]), vomiting (5 of 20 [25%] vs 7 of 40 [18%]), anorexia (5 of 20 [25%] vs 8 of 40 [20%]), and diarrhea (6 of 20 [30%] vs 7 of 40 [18%]) were also observed, although most of these symptoms were mild and tolerable and considered grade 1 or 2 (Table 2; eFigure 7 in Supplement 2). One patient each in group discontinued treatment because of unacceptable toxic effects (grade 3 or higher myelosuppression persisting despite 2 dose reductions of topotecan and berzosertib) considered to be related to treatment. Eight patients (4 each in group) died during the study: 1 in each group due to events unrelated to treatment (infection without neutropenia and myocardial infarction). The other 6 patients died due to disease progression. Seven of 20 patients (35%) in group 1 and 15 of 40 patients (38%) in group 2 required at least 1 dose reduction, mostly because of myelosuppression.
Table 2. Treatment-Related Adverse Events.
| Adverse event | Adverse events, No. (%)a | |||||
|---|---|---|---|---|---|---|
| Any grade | Grade 3 or 4 | |||||
| Group 1 (n = 20) | Group 2 (n = 40) | Total (N = 60) | Group 1 (n = 20) | Group 2 (n = 40) | Total (N = 60) | |
| Hematologic | ||||||
| Thrombocytopenia | 16 (80) | 30 (75) | 46 (77) | 11 (55) | 20 (50) | 31 (52) |
| Anemia | 14 (70) | 27 (68) | 41 (68) | 9 (45) | 18 (45) | 27 (45) |
| Lymphopenia | 11 (55) | 21 (52) | 32 (53) | 8 (40) | 6 (15) | 14 (23) |
| Neutropenia | 11 (55) | 19 (48) | 30 (50) | 7 (35) | 12 (30) | 19 (32) |
| Nonhematologic | ||||||
| Fatigue | 12 (60) | 14 (35) | 26 (43) | 3 (15) | 1 (3) | 4 (8) |
| Nausea | 9 (45) | 14 (35) | 23 (38) | 0 (0) | 0 (0) | 0 (0) |
| ALP increased | 9 (45) | 8 (20) | 17 (28) | 0 (0) | 0 (0) | 0 (0) |
| Anorexia | 5 (25) | 8 (20) | 13 (22) | 1 (5) | 0 (0) | 1 (2) |
| Hypokalemia | 7 (35) | 6 (15) | 13 (22) | 0 (0) | 0 (0) | 0 (0) |
| Diarrhea | 6 (30) | 7 (18) | 13 (22) | 0 (0) | 0 (0) | 0 (0) |
| Hypomagnesemia | 4 (20) | 8 (20) | 12 (20) | 1 (5) | 0 (0) | 1 (2) |
| Vomiting | 5 (25) | 7 (18) | 12 (20) | 0 (0) | 0 (0) | 0 (0) |
| ALT increased | 5 (25) | 6 (15) | 11 (18) | 0 (0) | 0 (0) | 0 (0) |
| Hypophosphatemia | 3 (15) | 5 (13) | 8 (13) | 0 (0) | 0 (0) | 0 (0) |
| Hyponatremia | 2 (10) | 5 (13) | 7 (12) | 0 (0) | 1 (3) | 1 (2) |
| Total bilirubin increased | 3 (15) | 3 (8) | 6 (10) | 0 (0) | 0 (0) | 0 (0) |
| AST increased | 2 (10) | 4 (10) | 6 (10) | 0 (0) | 0 (0) | 0 (0) |
| Alopecia | 2 (10) | 4 (10) | 6 (10) | 0 (0) | 0 (0) | 0 (0) |
| Muscle weakness | 2 (10) | 3 (8) | 5 (8) | 1 (5) | 0 (0) | 1 (2) |
| Hypocalcemia | 2 (10) | 3 (8) | 5 (8) | 1 (5) | 0 (0) | 1 (2) |
| Respiratory infection | 3 (15) | 1 (3) | 4 (7) | 3 (15) | 1 (3) | 4 (7) |
| Urinary tract infection | 1 (5) | 0 (0) | 1 (2) | 1 (5) | 0 (0) | 1 (2) |
| Sepsis | 1 (5) | 0 (0) | 1 (2) | 1 (5) | 0 (0) | 1 (2) |
| Skin infection | 1 (5) | 0 (0) | 1 (2) | 1 (5) | 0 (0) | 1 (2) |
| Hypertension | 0 (0) | 1 (3) | 1 (2) | 0 (0) | 1 (3) | 1 (2) |
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Any grade adverse event that occurred in more than 10% of total patients or any grade 3 or 4 adverse event.
Discussion
This multicenter, open-label, phase 2, randomized clinical trial was designed on the rationale that SCLC is a tumor with high replication stress and that TOP1 inhibitors exacerbate replication stress by trapping TOP1 cleavage complexes on DNA, further enhancing dependency on ATR.10,16,17 The results of this trial showed that the addition of the ATR inhibitor berzosertib to topotecan for treatment of patients with relapsed SCLC did not improve PFS compared with topotecan therapy alone. The combination therapy significantly improved OS and was well tolerated. A similar proportion of patients in both treatment groups experienced treatment-related moderate to severe adverse events and dose reductions.
The duration of OS from treatment initiation was significantly longer among patients who received the combination therapy compared with patients who received treatment with topotecan alone (Figure 2B). While the details of postprogression therapy were not collected for this trial, it is unlikely that such treatments, which are largely ineffective for SCLC, may have prolonged OS.1 Overall survival benefits without apparent benefit in PFS are typically described with immunotherapies25; traditional RECIST criteria fail to properly capture the atypical immunotherapy response patterns. Such considerations are less relevant in the context of the cytotoxic therapies that we tested here. It is also controversial whether PFS is a true surrogate marker for OS in SCLC.26,27 Intriguingly, in an unplanned post hoc analysis, the depth of the target lesion responses was significantly associated with better OS among patients in the combination treatment group, suggesting that the deeper tumor regression by the combination therapy of berzosertib and topotecan may have eventually contributed to OS improvement, as has been reported previously in the setting of metastatic colorectal cancer.28 Those observations should be examined and validated in further studies. Notably, a trial of the combination therapy in second-line treatment of platinum-resistant SCLC29 was terminated early due to an insufficient number of responses,30 suggesting that line of treatment and platinum sensitivity are important determinants of response and need to be taken into account as stratifying factors.
Molecular understanding of human SCLC has evolved since the present trial started enrollment, from a single disease to one that is marked by a high degree of intratumoral heterogeneity, harboring cells of neuroendocrine and nonneuroendocrine states.15,17,31,32,33 The SCLC subtypes, defined by the dominant cell states in each tumor, exhibit distinct therapeutic vulnerabilities.17,32 Immunogenic plasticity and Notch signaling of nonneuroendocrine SCLC underlie responses to immune checkpoint blockade.32 Neuroendocrine SCLC subtypes are more likely to have an upregulation of DNA damage response genes and replication stress, rendering them susceptible to DNA repair-targeted agents.17 The present study incorporated mandatory tumor biopsies and is, to our knowledge, one of the few contemporary studies to do so in relapsed SCLC. Ongoing tissue and circulating free DNA-based studies, including whole-exome and transcriptome sequencing, are seeking to identify genomic determinants of response and biomarkers of replication stress in these tumors.10
Limitations
One of the main limitations of this study is the small sample size. This trial was a hypothesis-generating study powered to detect an improvement in median PFS at a 1-sided α significance level of 0.10. The study was open label, although it is reassuring that the group receiving topotecan alone showed a median PFS that was consistent with that previously reported for similar patient populations.5 A placebo-controlled blinded study will be needed to confirm the OS benefit.
Conclusions
The findings of this randomized clinical trial suggest that further investigation of concurrent ATR and TOP1 inhibition is warranted, using newer and more potent ATR inhibitors and support stratification based on platinum-free interval, number of previous lines of therapies, neuroendocrine differentiation, and replication stress levels. In addition to better definition of patient populations using biomarkers, tumor-targeted delivery of TOP1 inhibitors using antibody drug conjugates will enable improved tolerability of such combinations.34,35
Trial Protocol
eFigure 1. Trial Schema
eFigure 2. Duration of Response (DOR)
eFigure 3. Progression-Free Survival Grouped by Platinum Sensitivity
eFigure 4. Overall Survival Grouped by Platinum Sensitivity
eFigure 5. Best Response in All Patients (A) and Grouped by Platinum Sensitivity (B, C)
eFigure 6. Subgroup Analysis of Progression-Free Survival (PFS, A) and Overall Survival (OS, B) Based on Clinical Characteristics
eFigure 7. Comparisons of Hematological (A) and Non-Hematological (B) Adverse Events (AEs) in Patients Who Were Treated With Topotecan Alone (Arm 1) and Topotecan and Berzosertib (B)
eFigure 8. Overall Survival in Patients Who Received Combination of Topotecan and Berzosertib According to Depth of Antitumor Response
eTable 1. Cox Regression Analysis of Overall Survival
eTable 2. Objective Response
eTable 3. Best Response Grouped by Platinum Sensitivity
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eFigure 1. Trial Schema
eFigure 2. Duration of Response (DOR)
eFigure 3. Progression-Free Survival Grouped by Platinum Sensitivity
eFigure 4. Overall Survival Grouped by Platinum Sensitivity
eFigure 5. Best Response in All Patients (A) and Grouped by Platinum Sensitivity (B, C)
eFigure 6. Subgroup Analysis of Progression-Free Survival (PFS, A) and Overall Survival (OS, B) Based on Clinical Characteristics
eFigure 7. Comparisons of Hematological (A) and Non-Hematological (B) Adverse Events (AEs) in Patients Who Were Treated With Topotecan Alone (Arm 1) and Topotecan and Berzosertib (B)
eFigure 8. Overall Survival in Patients Who Received Combination of Topotecan and Berzosertib According to Depth of Antitumor Response
eTable 1. Cox Regression Analysis of Overall Survival
eTable 2. Objective Response
eTable 3. Best Response Grouped by Platinum Sensitivity
Data Sharing Statement
