DYNAMO: A PHASE 2 STUDY DEMONSTRATING THE CLINICAL ACTIVITY OF DUVELISIB IN PATIENTS WITH DOUBLE-REFRACTORY INDOLENT NON-HODGKIN LYMPHOMA

Presented at 14-ICML, 14 June 2017, Lugano Switzerland

Zinzani, Pier Luigi Institute of Hematology Serágnoli, University of Bologna, ItalyWagner-Johnston, Nina Siteman Cancer Center, Washington University, St Louis, USAMiller, Carole Saint Agnes Hospital, Baltimore, USA Ardeshna, Kirit University College London, London, UK Tertreault, Scott Florida Cancer Specialists, Tallahassee, USA Assouline, Sarit Jewish General Hospital, Montreal, CanadaMayer, Jiri Interni hematologicka a onkologicka klinika-FN Brno, Czech RepublicMichele Merli Ospedale Di Circolo e Fondazione Macchi U.O. Ematologia, Varese, Italy Lunin, Scott Florida Cancer Specialist, Fort Myers, USAPettitt, Andrew University of Liverpool, UK Nagy, Zsolt Semmelweis Egyetem, I. sz. Belgyogyaszati Klinika, Budapest, HungaryTournilhac, Oliver CHU Estaing - Service d'hématologie, Clermont-Ferrand, France

Abou-Nassar, Karim Centre intégré de santé et de services sociaux de l'Outaouais, Canada

Crump, Michael Princess Margaret Cancer Center, Toronto, CanadaJacobsen, Eric Beth Israel Deaconess Medical Center, Boston, USA De Vos, Sven Ronald Reagan UCLA Medical Center, Los Angeles, USA Kelly, Virginia Verastem Inc, Needham, USA Flinn, Ian Tennessee Oncology, Nashville, USA

Authors Institutions

DUVELISIB: AN ORAL DUAL INHIBITOR OF PI3K-DELTA AND PI3K-GAMMA

• Duvelisib synergistically targets both malignant B cells (PI3K-δ) and the supportive microenvironment (PI3K-γ)

• Robust clinical activity was observed in Phase 1 study in advanced B- and T-cell lymphomas (Flinn ASH 2014; O’Brien ASH 2014; Horwitz ASH 2014)

STUDY OVERVIEW

Duvelisib 25 mg BID Continuously

Single arm n=129 Treatment until

progression or unacceptable

toxicity

Response Assessments

• Baseline, Cycles 3, 5, 7, 10, every 4 cycles thereafter

• Cycle = 28 days

Criteria

IWG (Cheson 2007), as assessed by independent review committee (IRC)

Primary EndpointORR = best response of CR or PR per IRC

Key Secondary Endpoints• Duration of response (DOR)

• Progression-free survival (PFS)

• Overall survival (OS)

• Safety

• Accrual complete• Final Analysis: April 2016• Mature Follow-up: March 2017

KEY ELIGIBILITY CRITERIA

• 3 iNHL disease subtypes:

− follicular lymphoma (FL) (n=83)

− small lymphocytic lymphoma (SLL) (n=28)

− marginal zone lymphoma (MZL) (n=18)

• Patients were double-refractory to rituximab (monotherapy or in combination) and to chemotherapy or radioimmunotherapy

- Refractory = no response on prior therapy, or PD within 6 months of last dose of prior therapy

- Chemotherapy = alkylating agent or purine analogue

• No eligibility restrictions for cytopenias

STUDY ENROLLMENT BY REGION / COUNTRY

WESTERN EUROPEItaly 21United Kingdom 11France 6Belgium 2Spain 2

EASTERN EUROPEBelarus 10Czech Republic 9Hungary 7Bulgaria 5Georgia 1

NORTH AMERICAUnited States 46Canada 9

BASELINE CHARACTERISTICS

CATEGORY OVERALLN = 129

FLN = 83

SLLN = 28

MZLN = 18

Age, median (range) 65 (30-90) 64 (30-82) 63 (48-83) 67 (41-90)

Male, % 68 68 68 72

ECOG - 0/1/2, % 47 / 48 / 5 51 /42/ 7 43 / 54 / 4 33 / 67 / 0

Years since diagnosis, median (range)

5 (0.3-27) 4 (0.3-27) 6 (0.9-17) 2 (0.8-10)

Bulky Disease (≥ 5 cm), % 40 37 46 39

Elevated LDH, % 67 75 57 44

High FLIPI (3-5 factors), % N/A 66 N/A N/A

PRIOR ANTICANCER TREATMENT

CATEGORY OVERALLN = 129

FLN = 83

SLLN = 28

MZLN = 18

Number of Prior Anticancer Regimens

Median 3 3 3 2

Min, Max 1, 18 1, 10 1, 18 1, 8

≤ 2, % 37 35 28 61

> 2, % 63 65 72 39

Time since completion of last therapy (months)

Median 4 3 3 7

Min, Max 0, 121 0, 121 1, 74 1, 58

REFRACTORY TO SELECT PRIOR ANTICANCER THERAPY

CATEGORY

OverallN=129

%

FL N=83

%

SLLN=28

%

MZLN=18

%

Refractory to last therapy 96 94 100 100

Refractory to at least 2 therapies 77 81 71 67

Rituximab 98 99 100 94

Alkylating Agent and/or Purine Analogue 92 90 96 94

Rituximab + Alkylating Agent 91 89 96 89

Bendamustine + rituximab 43 43 43 39

R-CHOP 28 31 18 28

R-CVP 26 24 32 28

OVERALL RESPONSE RATE

OVERALLN = 129

FLN = 83

SLLN = 28

MZLN = 18

ORR per IRC 47% 43% 68% 33%

P-value p = 0.0001 -- -- --

95% CI (38-56) -- -- --

Complete Response 1% 1% 0 0

Partial Response 47% 42% 68% 33%

ORR per Investigator 60% 53% 86% 50%

Complete Response 3% 2% 4% 6%

Partial Response 57% 51% 82% 44%

• Rapid time to response: median 2 months (range: 1.4 – 12)

• Primary endpoint met at final analysis

• Median time on duvelisib: 7 months (range: 0.4-35)

PERCENT CHANGE IN NODAL TARGET LESIONS

88% of patients had reduction in target lymph nodes (IRC data)

DURATION OF RESPONSE

PopulationMedian

(months)95% CI

All iNHL 9.9 4.5, 10.3FL 7.9 4.1, 12.6SLL 10.1 4.2, 10.5MZL 8.3 1.3, NE

PROGRESSION-FREE SURVIVAL

PopulationMedian

(months)95% CI

All iNHL 9.0 6.7, 11.8FL 8.3 4.2, 11.0SLL 11.7 5.8, 12.1MZL 14.3 3.6, NE

OVERALL SURVIVAL

PopulationMedian

(months)95% CI

All iNHL 27.8 20.8, NEFL 27.8 20.1, NESLL 28.9 15.2, NEMZL NE 12.4, NE

MOST COMMON AEs (N=129) (≥15% ANY GR, OR >5% GR 3-4)

Preferred Term All Grades %

Gr 3 %

Gr 4 %

Hematologic Neutropenia 33 14 16Anemia 25 12 2Thrombocytopenia 23 6 9

Nonhematologic Diarrhea 47 14 1Nausea 30 2 0Cough 28 0 0Fatigue 28 5 0Pyrexia 25 0 0Rash 19 5 0Vomiting 19 4 0Peripheral edema 17 2 0Headache 16 0 0Decreased appetite 15 1 0Febrile neutropenia 9 7 2

Investigations ALT increased 14 5 1Lipase increased 9 3 4

ADVERSE EVENTS OF INTEREST

• Few discontinuations due to severe AEs of interest

• Serious opportunistic infections < 4%: PCP (unconfirmed) (n=1); CMV (n=2); fungal pneumonia (n=2)

• Deaths attributed to treatment (n=6)*

*colitis (n=1); toxic epidermal necrolysis/sepsis syndrome (n=1); drug reaction/eosinophilia/systemic symptoms (n=1); pneumonitis/pneumonia (n=1); viral infection (n=1); septic shock (n=1)

DYNAMO STUDY CONCLUSIONS

• Duvelisib monotherapy is clinically active in double-refractory iNHL

– ORR of 47% per IRC; ORR of 60% per Investigator

– 88% of patients had tumor reduction

– Responses were durable (median 10 months)

• Duvelisib has a manageable safety profile

• In long-term follow-up (median 18 months), duvelisib remains well tolerated

• Duvelisib showed favorable risk-benefit in double-refractory iNHL, and may represent an important treatment option for these patients

THANK YOU

We would like to acknowledge the participating institutions, their study investigators and clinical staff, for the successful conduct of the study.

Most importantly, we sincerely thank our patients and their families for their participation in this clinical study.