Pneumologie 2012; 66 - V94
DOI: 10.1055/s-0032-1302561

Randomized phase 3 trial of amrubicin versus topotecan as second-line treatment for small cell lung cancer (SCLC)

J von Pawel 1, R Jotte 2, DR Spigel 3, MA Socinski 4, MER O'Brien 5, E Paschold 6, J Mezger 7, M Steins 8, L Bosquée 9, J Bubis 10, K Nackaerts 11, JM Trigo 12, P Clingan 13, W Schuette 14, P Lorigan 15, M Reck 16, M Domine 17, F Shepherd 18, R McNally 19, M Renschler 19
  • 1Asklepiosfachkliniken München Gauting
  • 2US Oncology, Housten TX
  • 3Sarah Cannon Research Institute, Nashville TN
  • 4Lineberger Comprehensive Cancer Center, Chapel Hill NC
  • 5Royal Marsden NHS Foundation Trust, Surrey
  • 6Piedmont Hematology Oncology Associates, Winston-Salem NC
  • 7St. Vincentius-Kliniken, Karlsruhe
  • 8Thoraxklinik am Universitätsklinikum Heidelberg
  • 9C.H.U. Sart-Tilman, Liège, Belgium
  • 10Florida Oncology Associates, Orange Park
  • 11University Hospital Gasthuisberg, Leuven
  • 12Hospital Universitario Virgen de la Victoria, Malaga Spain
  • 13Southern Medical Day Care Centre, Wollongong
  • 14Krankenhaus Martha-Maria Halle-Doelau
  • 15Christie Hospital NHS Foundation Trust, Manchester
  • 16Krankenhaus Großhansdorf, Zentrum für Pneumologie und Thoraxchirurgie
  • 17Universidad Autónoma de Madrid
  • 18Princess Margaret Hospital, Toronto
  • 19Celgene Corporation, Summit NJ

Aims: Amrubicin, a 3rd gen. anthracycline and potent topoisomerase II inhibitor, has shown activity in SCLC. ACT-1 compared the safety and efficacy of amr vs. topo for 2nd line treatment of SCLC.

Methods: 637 pts were random. 2:1 amr 40mg/m2 IV d 1–3 (n=424) vs. topo 1.5mg/m2 IV d 1–5 (n=213) with proph. WBC growth factors and antibiotics required in last 1/3 of trial. Endpoints: OS (primary), RR, PFS, and safety. Subgroup analyses used protocol-defined definitions: refract. pts had PD as best response to 1st line therapy or progressed <90 days. QoL was assessed by mean change in LCSS, Symptom Burden (LCSS SB) score, and EQ –5D.

Results: Baseline characteristics were similar in both groups: med. age 62 vs. 61 years; pts <65 years 60% vs. 65%; men 58% vs. 60%; PS sens. 30% vs. 34%; refractory 47% vs. 45%.

Hazard ratio (HR) <1 and odds ratio (OR for RR only) >1 favors amrubicin. CI=confidence interval

N

Amrubicin

Topotecan

HR/OR

95% CI

P-Value

OS (mo)

637

7.5

7.8

0.88

0.73–1.06

0.17

12-mo OS (%)

28

25

18-mo OS (%)

16

9

24-mo OS (%)

9

3

OS (Cox Model)

637

-

-

0.82

0.68–0.99

0.036

RR (%)

637

31

17

2.22

1.47–3.36

0.0002

PFS (mo)

637

4.1

3.6

0.83

0.70–0.99

0.041

Duration of Response (mo)

637

4.7

4.2

Subgroups

OS sensitive pts (mo)

342

9.2

10

0.94

0.72–1.21

0.62

OS refractory pts (mo)

295

6.2

5.7

0.77

0.59–1.0

0.047

12-mo OS (%)

17

7

18-mo OS (%)

12

0

PFS sensitive pts (mo)

342

5.5

4.3

0.73

0.57–0.94

0.012

PFS refractory pts (mo)

295

2.8

2.6

0.96

0.75–1.24

0.74

ORR sensitive pts (%)

342

41

23

2.31

1.39–3.82

0.001

ORR refractory pts (%)

295

20

9

2.43

1.13–5.25

0.024

Covariates in the Cox model are PS 0 (yes, no), age, response to 1st line platinum-based therapy (refr., sens.), and disease stage (lim., ext.).

Pts treated with amr had better symptom control and QoL: LCSS 0.2 vs. 5.6 and LCSS-SB -0.1 vs. 5.2 for amr and topo, respectively, all P<0.05. Grade ¾ AEs in amr and topo groups, respectively, were: neutropenia (41% vs. 53%), thrombocytopenia (21% vs. 54%), anemia (16% vs. 30%), infections (16% vs. 10%), febrile neutropenia (10% vs. 4%), all P<0.05, and cardiac disorders (5% vs. 5%; P=0.84).

Conclusions: Amrubicin is active in 2nd treatment of SCLC with significantly improved RR and PFS versus topotecan. While the primary endpoint was not met, survival trended in favor of amrubicin (HR 0.88), especially in refractory patients (HR 0.77). Preliminary QoL results favored amrubicin.