Dataset Information

A randomised phase 2b study comparing the efficacy and safety of belotecan vs. topotecan as monotherapy for sensitive-relapsed small-cell lung cancer.

ABSTRACT:

Background

This study compared the efficacy/safety of the camptothecin analogues belotecan and topotecan for sensitive-relapsed small-cell lung cancer (SCLC).

Methods

One-hundred-and-sixty-four patients were randomised (1:1) to receive five consecutive daily intravenous infusions of topotecan (1.5 mg/m²) or belotecan (0.5 mg/m²), every 3 weeks, for six cycles. Main outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), tolerability and toxicity. The study statistical plan was non-inferiority design with ORR as the endpoint.

Results

In the belotecan vs. topotecan groups, ORR (primary endpoint) was 33% vs. 21% (p = 0.09) and DCR was 85% vs. 70% (p = 0.030). PFS was not different between groups. Median OS was significantly longer with belotecan than with topotecan (13.2 vs. 8.2 months, HR = 0.69, 95% CI: 0.48-0.99), particularly in patients aged <65 years, with more advanced disease (i.e., extensive-stage disease, time to relapse: 3-6 months), or Eastern Cooperative Oncology Group performance status 1 or 2. More belotecan recipients completed all treatment cycles (53% vs. 35%; p = 0.022).

Conclusions

The efficacy/safety of belotecan warrants further evaluation in Phase 3 trials. Belotecan potentially offers an alternative to topotecan for sensitive-relapsed SCLC, particularly in patients aged <65 years, with more advanced disease, or poor performance.

SUBMITTER: Kang JH

PROVIDER: S-EPMC7884704 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

A randomised phase 2b study comparing the efficacy and safety of belotecan vs. topotecan as monotherapy for sensitive-relapsed small-cell lung cancer.

Kang Jin-Hyoung JH Lee Ki-Hyeong KH Kim Dong-Wan DW Kim Sang-We SW Kim Hye Ryun HR Kim Joo-Hang JH Choi Jin-Hyuk JH An Ho Jung HJ Kim Jin-Soo JS Jang Joung-Soon JS Kim Bong-Seog BS Kim Heung Tae HT

British journal of cancer 20201116 4

<h4>Background</h4>This study compared the efficacy/safety of the camptothecin analogues belotecan and topotecan for sensitive-relapsed small-cell lung cancer (SCLC).<h4>Methods</h4>One-hundred-and-sixty-four patients were randomised (1:1) to receive five consecutive daily intravenous infusions of topotecan (1.5 mg/m<sup>2</sup>) or belotecan (0.5 mg/m<sup>2</sup>), every 3 weeks, for six cycles. Main outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survi ...[more]

PMID: 33191408

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Project description:ImportancePatients 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.ObjectiveTo investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC.Design, setting, and participantsBetween 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.InterventionsEligible 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 measuresThe 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.ResultsOf 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 relevanceIn 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 registrationClinicalTrials.gov Identifier: NCT03896503.

Project description:BackgroundTo undertake a systematic review of the available data for oral and intravenous topotecan in adults with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first line regimen is not considered appropriate.MethodsWe searched six databases from 1980 up to March 2009 for relevant trials regardless of language or publication status. Relevant studies included any randomised trial of any chemotherapeutic treatment against any comparator in this licensed indication. Where possible we used opposite quantitative methods. Where meta-analysis was considered unsuitable for some or all of the data, we employed a narrative synthesis method. For indirect comparisons we used the method of Bucher et al., where available data allowed it, otherwise we used narrative descriptions.ResultsSeven unique studies met the inclusion criteria, four of which could be used in our analyses. These included one study comparing oral topotecan plus best supportive care (BSC) to BSC alone, one study comparing intravenous topotecan to cyclophosphamide, adriamycin and vincristine (CAV), and two studies comparing oral topotecan with intravenous topotecan. All four studies appear to be well conducted and with low risk of bias. Oral topotecan plus BSC has advantages over BSC alone in terms of survival (hazard ratio = 0.61; 95% CI, 0.43 to 0.87) and quality of life (EQ-5 D difference: 0.15; 95% CI, 0.05 to 0.25). Intravenous topotecan was at least as effective as CAV in the treatment of patients with recurrent small-cell lung cancer and resulted in improved quality-of-life with respect to several symptoms. CAV was associated with significantly less grade 4 thrombocytopenia compared with IV topotecan (risk ratio = 5.83; 95% CI, 2.35 to 14.42). Survival (hazard ratio = 0.98; 95% CI, 0.77 to 1.25) and response (pooled risk ratio = 1.04; 95% CI, 0.58 to 1.85) data were similar for the oral and IV topotecan groups. Symptom control was also very similar between the trials and between the oral and IV groups. Toxicity data showed a significant difference in favour of oral topotecan for neutropenia (pooled risk ratio = 0.65; 95% CI, 0.47 to 0.89). Indirect evidence showed that oral topotecan was at least as good as or better than CAV on all outcomes (survival, response rates, toxicities, and symptoms) that allowed indirect comparisons, with the only exception being grade four thrombocytopenia which occurred less often on CAV treatment.ConclusionsConcerning topotecan both the oral and intravenous options have similar efficacy, and patient preference may be a decisive factor if the choice would be between the two formulations. The best trial evidence for decision making, because it was tested versus best supportive care, exists for oral topotecan. Indirectly, because we have two head-to-head comparisons of oral versus intravenous topotecan, and one comparison of intravenous topotecan versus CAV in similar patients as in the trial against best supportive care, one might infer that IV topotecan and CAV could also be superior to best supportive care, and that oral topotecan has similar effects to CAV with possibly better symptom control. From the evidence discussed above, it is evident that oral topotecan has similar efficacy to IV topotecan (direct comparison) and CAV (indirect comparison). There is no further evidence base of direct or possible indirect comparisons for other comparators than CAV of either oral or IV topotecan.

Project description:ImportanceProbation is a cornerstone of efforts to reduce mass incarceration. Although it is understudied, specialty probation could improve outcomes for the overrepresented group of people with mental illness.ObjectiveTo test whether specialty probation yields better public safety outcomes than traditional probation.Design, setting, and participantsA longitudinal observational study with group matching on age, sex, race/ethnicity, probation time, and offense at 2 urban agencies that exemplify specialty and traditional probation. Enrollment began October 19, 2005; follow-up data were complete January 26, 2013. Participants were 359 diverse probationers with serious mental health problems and functional impairment. Probationers and officers were assessed 3 times (for probationers, 6-month retention, 315 of 359 [88%]; 12-month retention 304 of 359 [85%]) and follow-up records were obtained. Machine learning algorithms were combined with a targeted maximum likelihood estimation, a double robust estimator that accounts for associations between confounders and both treatment assignment and outcomes. Statistical analysis was conducted from January 1, 2016 to May 5, 2017.InterventionsSpecialty probationers were assigned to small, homogeneous caseloads supervised by experts. Prior data indicate that specialty officers had better relationships with probationers, participated more in probationers' treatment, and relied more on positive compliance strategies than traditional officers.Main outcomes and measuresViolence during 1 year, determined by probationer report, officer report, and records, and rearrest during a period of 2 to 5 years, according to Federal Bureau of Investigation records.ResultsParticipants were 183 specialty (73.8% of 248 eligible) and 176 traditional (56.6% of 311 eligible) probationers (205 men and 154 women; mean [SD] age, 36.9 [10.6]). Although specialty probation had no significant effect on violence (odds ratio, 0.97; 95% CI, 0.69-1.36), the odds of rearrest were 2.68 times higher for traditional probationers than for specialty probationers (95% CI, 1.86-3.84; P < .001). At 2 years, estimated probabilities of rearrest were 28.6% for specialty probationers and 51.8% for traditional probationers. Survival analyses indicate that arrest effects endured up to 5 years.Conclusions and relevanceAlthough it did not specifically reduce violence, well-implemented specialty probation appears to be effective in reducing general recidivism. Reform efforts for people with mental illness could leverage probation-a ubiquitous and revitalized node of the justice system.

Dataset Information

A randomised phase 2b study comparing the efficacy and safety of belotecan vs. topotecan as monotherapy for sensitive-relapsed small-cell lung cancer.

Background

Methods

Results

Conclusions

Publications

A randomised phase 2b study comparing the efficacy and safety of belotecan vs. topotecan as monotherapy for sensitive-relapsed small-cell lung cancer.

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