Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed,...

27
Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum- sensitive Ovarian Cancer Eric Pujade-Lauraine on behalf of all GCIG collaborators CALYPSO trial

Transcript of Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed,...

Page 1: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Carboplatin & Pegylated Liposomal Doxorubicin (PLD)

versus Carboplatin & Paclitaxel

in Relapsed, Platinum-sensitive

Ovarian CancerEric Pujade-Lauraineon behalf of all GCIG collaborators

CALYPSO trial

Page 2: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Background

• Despite response to 1st-line treatment, relapse is eventual for most patients with advanced ovarian cancer (AOC)

• Choice of relapsed disease treatment is dependent on interval since prior platinum-based therapy – Relapse within 6 months: platinum-resistant

disease– Relapse over 6 months: platinum-sensitive

disease

• Carboplatin-paclitaxel is standard in platinum-sensitive disease

Page 3: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Rationale for PLD-Carboplatin Doublet

• Due to risk of cumulative neuropathy and of hair loss, other carboplatin combinations have been explored

• Pegylated liposomal doxorubicin (PLD) is a rational choice for combined therapy– PLD outperformed topotecan in platinum-

sensitive population in large randomized trial (significant benefit in PFS and OS)1,2

– Phase II trial of PLD-carboplatin verified safety and efficacy3

1Gordon et al. J Clin Oncol. 2001;19:3312-3322; 2Gordon et al. ECCO 12. September 2003 (poster); 3Ferrero et al. Ann Oncol. 2007;18:263-268.

Page 4: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

CALYPSO Study Schema

Ovarian cancer in late relapse (> 6 months) after 1st- or 2nd-line

platinum-based therapy (previous taxane

required)

International, Intergroup, Open-label, Randomized Phase III Study

Stratification:

•Therapy-free interval (6-12 mo vs > 12 mo)

•Measurable disease (yes vs no)

•Center

RANDOMIZE

Experimental arm: CD

PLD 30 mg/m2 IV d 1

Carboplatin AUC 5 d 1

Control arm: CP

Paclitaxel 175 mg/m2 IV d 1

Carboplatin AUC 5 d 1

Q 28 days x 6 courses*

Q 21 days x 6 courses*

*or progression in patients with SD or PR

Page 5: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Key Eligibility Criteria

• Age ≥ 18 years• ECOG performance status ≤ 2• Histologically proven diagnosis of cancer of

the ovary, fallopian tube, or extra-ovarian papillary serous tumors

• Disease progression > 6 months after 1st- or 2nd-line platinum-based therapy

• Previous taxane exposure• Measureable disease (RECIST criteria) or CA

125 assessable disease (GCIG criteria) or histologically proven diagnosis of relapse

Page 6: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Endpoints. Statistical discussions

Primary endpoint• Progression-free survival (PFS)

Statistical considerations• Two-arm, parallel, NON-INFERIORITY study design• Statistical assumptions based on PFS from

ICON4/AGO-OVAR 2.2 trial1 • Declare non-inferior if HR one-side 95% CI <1.23

(CD:CP) for PFS• Power of 90% and one-sided confidence level of

95%• Number of events required : 745

1Parmar et al. Lancet. 2003;361:2099-2106.

Page 7: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Endpoints

Secondary endpoints• Qualitative and quantitative toxicities• Quality of life (EORTC QLQ-C-30 version

3.0 and OV-28 questionnaire version 1.0)

• Overall survival (OS)

Page 8: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Accrual

N=976

Page 9: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

CALYPSO Worldwide CollaborationAustria, Australia, Belgium, Canada, Denmark, Finland, France,

Germany, Italy, New Zealand, Saudi Arabia, Spain, Sweden, Switzerland, Turkey

Page 10: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Accrual by Groups

49

76

317

227

71

17

22

137

60

Page 11: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Baseline Characteristics (1)

CharacteristicCD (n=466) CP (n=508)

Number of patients (%)

Age, medianECOG performance status* 0 1 2Primary site of disease Ovarian

Papillary/Serous histology Initial FIGO stage* I/II III/IVNumber of previous lines One Two

60.5

286 (61)159 (34)13 (3)

415 (89)334 (72)

52 (11)401 (86)

408 (88) 58 (12)

61.0

317 (62)164 (32)15 (3)

451 (89)366 (72)

59 (12)427 (84)

421 (83) 87 (17)

* Missing values to attain 100%.

Page 12: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Baseline Characteristics (2)

CharacteristicCD (n=466) CP (n=508)

Number of patients (%)

Prior taxane

Interval since prior therapy, median 6-12 months > 12 months

Measurable disease Yes No

Tumour size < 5 cm > 5 cm

Number of sites 1 > 1

462 (99)

162 (35)304 (65)

281(60)185 (39)

377(81) 89(19)

217(47)249 (53)

500 (99)

182 (36)326 (64)

321 (63)188 (37)

419 (82) 90 (18)

245(48)264(52)

Page 13: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Treatment Exposure

CD (n=465)** CP (n=501)**

Total treatment duration, median wk* 21 16

Relative dose intensity % Carbo: 99PLD: 99

Carbo: 99Paclitaxel: 98

Patients with ≥ 6 cycles, n (%)* 395 (85) 392 (78)

Patients with ≥ 9 cycles, n (%) 36 (8) 36 (7)

* P< 0.001; ** Patients receiving at least one cycle

Page 14: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Hematologic Toxicity

Toxicity, grade(gr)

CD (n=464)

CP (n=500) P Value

Number of patients (%)

Neutropenia, gr 3

gr 4

144 (31)

20 (4)

121 (24)

108 (22)

<0.01

Febrile neutropenia, gr 3-4

10 (2) 21 (4) NS

Infection, gr 3-4 11 (3) 14 (3) NS

Thrombocytopenia, gr 3-4 73 (16) 31 (6) <0.01

Bleeding, gr 3-4 3 (0.6) 0 (0) NS

Anemia, gr 3-4 37 (8) 27 (5) NS

NS=not significant.

Page 15: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Selected Non-Hematologic Toxicities During Treatment

*P< 0.001

CD (n=466) CP (n=501)Grade 2 Grade3/4 Grade 2 Grade 3/4

Nausea/vomiting* 31% 4% 20% 4%

Constipation 19% 2% 20% 2%

Diarrhea 4% 2% 6% 2%

Arthralgia/myalgia* 4% 0% 18% 1%

Hand-foot syndrome* 11% 2% 2% 0%

Mucositis* 13% 2% 6% 1%

Fatigue 31% 7% 34% 7%

Cardiac disorders 2% 1% 3% 1%

Page 16: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Selected Non-Hematologic Toxicities During Treatment

CD (n=466) CP (n=501)

Alopecia grade 2* 7% 84%

Alopecia

*P< 0.001

Page 17: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Long-Lasting Toxicity

CD (n=466) CP (n=501)

Grade 2 Grade 3/5 Grade 2 Grade 3/5

Neuropathy* 4% 1% 24% 4%

Neuropathy score over time

EORTC OV28 – QoL Peripheral Neuropathy

*P< 0.001

Page 18: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Early Treatment Discontinuation

ReasonCD (n=466) CP (n=501)

Number of patients (% of total)

Toxicity*

Patient/investigator choice

Progressive disease

Intercurrent disease

TOTAL*

27 (6)

16 (3)

26 (6)

1 (<1)

70 (15)

73 (15)

14 (3)

22 (4)

1 (<1)

110 (22)

* P< 0.001

Page 19: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Carboplatin Hypersensitivity Reactions

CD (n=466) CP (n=501)

Grade 2 Grade 3/5 Grade 2 Grade 3/5

Hypersensitivity* 3% 2% 10% 9%

One drug stopped - 2%

Both drugs stopped 1% 4%

*P< 0.001

Protocol included EORTC guidelines for re-challenge after a hypersensitivity reaction to carboplatin

Page 20: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Follow-up and Number of Events

• Median follow-up 22 months

• Number of events – Progressions or deaths 824 (85%)– Deaths 322 (33%)

Page 21: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Progression-Free Survival (ITT)

CD CP

Median PFS, mo 11.3 9.4

HR (95% CI) 0.82 (0.72, 0.94)

Log-rank p-value (superiority) 0.005

P-value (non-inferiority) <0.001

Page 22: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Symmetry of Tumor Assessments

Page 23: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Sensitivity PFS analysis

Page 24: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Multivariate Analysis of Baseline Predictive Factors on PFS

Significant predictors of PFS included

Baseline Factor NMultivariate Cox Regression Model

HR 95% CI P-value

Therapy-free interval

6-12 mo 342 1.00(0.48, 0.65) < 0.001

> 12 mo 617 0.56

Measurable Disease

No 362 1.00(1.27, 1.70) < 0.001

Yes 597 1.47

CA 125< 100 316 1.00

(1.52, 2.07) < 0.001≥100 643 1.77

Treatment arm

CP 499 1.00(0.71, 0.93) 0.003

CD 460 0.80

Page 25: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Key findings• In patients with platinum-sensitive relapsing ovarian

cancer, the combination of PLD-carboplatin was not inferior in term of PFS to paclitaxel-carboplatin, and even was found significantly superior– 18% reduction in risk of recurrence (HR 0.82; P=0.005)

• Overall survival data immature, with only 322 deaths to date

• Paclitaxel-carboplatin associated with more severe toxicity (carboplatin hypersensitivity), alopecia, and long-lasting toxicity (neuropathy)

• Moderate reversible HFS, mucositis, and nausea/vomiting more frequent with PLD

Page 26: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Conclusions

• Carboplatin-PLD demonstrated a superior therapeutic index (benefit/risk ratio) versus current standard, carboplatin-paclitaxel

• PLD- carboplatin offers an evidence-based option for patients with platinum-sensitive recurrent ovarian cancer

Page 27: Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer Eric Pujade-Lauraine.

Study Office B. Votan G. Elser G. Andersen M. Bacon J. Martin B. Volger A. Demeester J. Bryce R. Fossati N. Le Fur P. Schantl C. Jeppesen C. Goudreau K. Carlton J. Ulmer

Investigators

Acknowledgement Patients and their families, and …

E. Pujade -LauraineA. LortholaryF. JolyB.WeberL. GladieffA. FloquetR. LargillierM. FabbroA. Goupil R. DelvaE. GuardiolaF. PriouG.De RauglaudreD. Coeffic …

E. EisenhauerL. ElitP. SauthierJ. BentleyA. OzaH. ChalchalA. SugimotoM. HeywoodP. BessetteD. PopkinL. KaizerW. GotliebP. Walde …

G. KristensenJ. KaernR. SandveiJ. HerrstedtE. Aavall -LundqvistT. HogbergB. LundK. BomanH. HavsteenM. HansenJ. Maenpaa …

J. PfistererJ. SehouliA. Du BoisP. WimbergerB. SchmalfeldtJ. HuoberS. MahnerM. Gropp M. ThillK. BaumannA. BurgesA. StaehleR. KreienbergA. BelauM. Beckmann S. LoiblA. HasenburgG. EmonsW. AulitzkyL. Spaetling …

C. MarthA. ZeimetA. ReinthallerL. Angleitner -BoubenizekH. SchauerP. SeveldaE. Petru…

I. VergoteN. ReedK. Van EygenP. OttevangerM. Van der BurgA. Casado Herraez

S. PignataG. ScambiaR. SorioE. BredaA. De Matteis

A. FerreroN. ColomboN. DonadelloD. Gueli AllettiA. LissoniS. Siena

DSMBM. Gore

M. BradyM. Seiden

P. VaseyB. FitzharrisM. BuckT. BonaventuraM. VaughanM. DavyA. O’DonnellC. SteerM. QuinnM. Friedlander A. GoldrickF. Kirsten …

Supported by

Shering Plough InternationalS. Stopatschinskaja C. DohertyB. Winograd B. Hartley

K. Djazouli

K. RehmanM. FehrG. Tulunay

StatisticsV. GebskiC. Brown

Data ManagementH. Karsenty L. Bertel, B. VoulazS. Perrin

Web siteD. Pihan

Coordinating Centre

A. BonvoisinE. PlançonF. PinotN. Chiannilkulchai

GINECO AGO-OVAR NSGO NCIC-CTG ANZGOG AGO-Austria EORTC MITO MANGO

Safety OfficeS. Azouz

T. Tran