Combination lurbinectedin and doxorubicin versus physician's choice of chemotherapy in patients with relapsed small-cell lung cancer (ATLANTIS): a multicentre, randomised, open-label, phase 3 trial
Mené sur 613 patients atteints d'un cancer du poumon à petites cellules récidivant (durée médiane de suivi : 24,1 mois), cet essai multicentrique de phase III compare l'efficacité, du point de vue de la survie globale, et la toxicité d'un traitement combinant lurbinectédine et doxorubicine par rapport à une chimiothérapie de deuxième ligne choisie par le médecin (topétécan ou chimiothérapie de type CAV)
Background : Lurbinectedin is a synthetic marine-derived anticancer agent that acts as a selective inhibitor of oncogenic transcription. Lurbinectedin monotherapy (3·2 mg/m2 every 3 weeks) received accelerated approval from the US Food and Drug Administrationon the basis of efficacy in patients with small-cell lung cancer (SCLC) who relapsedafter first-line platinum-based chemotherapy. The ATLANTIS trial assessed the efficacyand safety of combination lurbinectedin and the anthracycline doxorubicin as second-linetreatment for SCLC.
Methods : In this phase 3, open-label, randomised study, adult patients aged 18 years or olderwith SCLC who relapsed after platinum-based chemotherapy were recruited from 135 hospitals across North America, South America, Europe, and the Middle East. Patients were randomly assigned (1:1) centrally by dynamic allocation to intravenous lurbinectedin 2·0 mg/m2 plus doxorubicin 40·0 mg/m2 administered on day 1 of 21-day cycles or physician's choice of control therapy (intravenous topotecan 1·5 mg/m2 on days 1–5 of 21-day cycles; or intravenous cyclophosphamide 1000 mg/m2, doxorubicin 45·0 mg/m2, and vincristine 2·0 mg on day 1 of 21-day cycles [CAV]) administered until disease progression or unacceptable toxicity. Primary granulocyte-colony stimulating factorprophylaxis was mandatory in both treatment groups. Neither patients nor clinicians were masked to treatment allocation, but the independent review committee, which assessedoutcomes, was masked to patients' treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02566993, and with EudraCT, 2015-001641-89, and is complete.
Findings : Between Aug 30, 2016, and Aug 20, 2018, 613 patients were randomly assigned to lurbinectedin plus doxorubicin (n=307) or control (topotecan, n=127; CAV, n=179) and comprised the intention-to-treat population; safety endpoints were assessed in patients who hadreceived any partial or complete study treatment infusions (lurbinectedin plus doxorubicin,n=303; control, n=289). After a median follow-up of 24·1 months (95% CI 21·7–26·3),303 patients in the lurbinectedin plus doxorubicin group and 289 patients in the controlgroup had discontinued study treatment; progressive disease was the most common reasonfor discontinuation (213 [70%] patients in the lurbinectedin plus doxorubicin group vs 152 [53%] in the control group). Median overall survival was 8·6 months (95% CI 7·1–9·4)in the lurbinectedin plus doxorubicin group versus 7·6 months (6·6–8·2) in the controlgroup (stratified log-rank p=0·90; hazard ratio 0·97 [95% CI 0·82–1·15], p=0·70).12 patients died because of treatment-related adverse events: two (<1%) of 303 inthe lurbinectedin plus doxorubicin group and ten (3%) of 289 in the control group.296 (98%) of 303 patients in the lurbinectedin plus doxorubicin group had treatment-emergentadverse events compared with 284 (98%) of 289 patients in the control group; treatment-relatedadverse events occurred in 268 (88%) patients in the lurbinectedin plus doxorubicingroup and 266 (92%) patients in the control group. Grade 3 or worse haematologicaladverse events were less frequent in the lurbinectedin plus doxorubicin group thanthe control group (anaemia, 57 [19%] of 302 patients in the lurbinectedin plus doxorubicingroup vs 110 [38%] of 288 in the control group; neutropenia, 112 [37%] vs 200 [69%]; thrombocytopenia, 42 [14%] vs 90 [31%]). The frequency of treatment-related adverse events leading to treatmentdiscontinuation was lower in the lurbinectedin plus doxorubicin group than in thecontrol group (26 [9%] of 303 patients in the lurbinectedin plus doxorubicin group vs 47 [16%] of 289 in the control group).
Interpretation : Combination therapy with lurbinectedin plus doxorubicin did not improve overall survival versus control in patients with relapsed SCLC. However, lurbinectedin plus doxorubicin showed a favourable haematological safety profile compared with control.
The Lancet Respiratory Medicine , résumé, 2021