Adjuvant Therapy for Pancreatic Cancer: Is …...– APACT is the first adjuvant trial in pancreatic ductal adenocarcinoma to use independently assessed DFS as the primary endpoint

1

Adjuvant Therapy for Pancreatic Cancer: Is mFOLFIRINOX the New Standard?

Bassel F. El-Rayes, M.D.

Professor and Vice Chair

Director of the GI Oncology Program

Associate Cancer Center Director

Winship Cancer Institute of Emory University

Atlanta, Ga.

2

What is the Data Supporting FOLFIRINOX as Adjuvant Therapy?

3Winship Cancer Institute | Emory University

PRODIGE 24/CCTG PA.6 Trial: Study Design

Presented by Thierry Conroy ASCO 2018; published in NEJM Dec 20, 2018.

Stratification: • Center

• Resection margin (R0 vs R1)

• CA19-9 level (≤ 90 vs 91-179 U/mL)

• pN0 (< 12 vs ≥ 12 examined nodes)

vs pN1

R0 or R1 resected

pancreatic cancer

Postoperative

CT-scan mandatory

CA19-9 level < 180 U/mL

within 12 weeks

after surgery

R

A

N

D

O

M

I

Z

E

- 6 months of chemotherapy- CT scans: every 3 months

NCT01526135 mFOLFIRINOXOxaliplatin 85 mg/m², leucovorin 400 mg/m²,

Irinotecan 180 mg/m²*, all at D1

Fluorouracil continuous IV infusion 2.4 g/m² over

46 hours

Every 2 weeks; 12 cycles *Reduced to 150 mg/m² after patient 162

Gemcitabine1000 mg/m2, qw 3/4 weeks;

6 cycles

For both arms:

1:1

CT = computed tomography; IV = intravenous


Key Inclusion Criteria

• Histologically confirmed resected pancreatic ductal adenocarcinoma

• Macroscopically complete resection (R0 or R1 resection)

• Patients able to receive chemotherapy within 12 weeks after resection

• ECOG PS 0-1

• Ages 18 to 79 years

• No prior radiotherapy or chemotherapy

• Adequate hematologic/blood chemistry levels

• Patient information and written informed consent

Conroy T, et al. J Clin Oncol. 2018;36(suppl): LBA4001; Conroy T, et al. N Engl J Med. 2018;379:2395-2406.

ECOG PS = Eastern Cooperative Oncology Group Performance Status


Key Exclusion Criteria

• Metastatic disease or macroscopic incomplete tumor removal (R2 resection)

• Postoperative CA 19-9 ≥ 180 U/ml assessed within 21 days of randomization

• Symptomatic heart failure or coronary heart disease

• Major comorbidity, active infection, history of HIV, or uncontrolled diabetes

• Inflammatory bowel disease, or occlusion or subocclusion of the intestine, or severe

postoperative uncontrolled diarrhea

• Concomitant occurrence of another cancer or significant history of cancer



Endpoints

Primary: DFS

Secondary:

• Toxicity (NCI-CTC version 4.0 grading)

• OS

• Cancer SS

• MFS


DFS = disease-free survival; MFS = metastasis-free survival; OS = overall survival; SS = specific survival

Baseline Characteristics: Patients

CharacteristicmFOLFIRINOX

N = 247

Gemcitabine

N = 246P

Median age (years)

[range]

63

[30-79]

64

[30-81].09

Gender male 57.5 % 55.6 % .67

ECOG PS 0

1

49.8 %

50.2 %

52.5 %

47.5 %

.55

Diabetes 25.3 % 26.6 % .44


Baseline Characteristics: Pancreatic Tumors

CharacteristicsmFOLFIRINOX

N = 247

Gemcitabine

N = 246P

Median size of primary tumor [mm, range] 30 [8-90] 30 [6-120] .50

T1-2/T3-4 (%) 12.5/87.5 9.8 /90.2 .33

N0/N1 (%) 22.3 /77.7 24.5 /75.5 .60

Stage: I/IIA/IIB/III-IV (%) 4.9/17.4 /74.1/3.6 5.7/19.1 /72.8/2.4 .81

Tumor grading :

well/moderately/poorly differentiated (%)30.6/54.1/15.3 33.9/53.7/12.5 .58

Whipple resection procedure (%) 82.1 76.8 .53

R1 resection (%) 40.1 45.7 .24

Venous resection (%) 21.3 28.2 .08

Lymphovascular emboli (%) 73.7 63.1 .02


Treatment Completion, 6 Months

mFOLFIRINOX

(n = 238)

Gemcitabine

(n = 243)P

All cycles of chemotherapy 66.4% 79.0% .002

Planned administrations

Median No. administrations

12

12 [1-12]

18

18 [1-18]─

No. administrations delayed 14.4% 3.9% < .001

Relative dose intensity > 0.70 48.7% 91.4% < .001

Early stop

due to:

- relapse

- toxicity

- principal investigator’s decision

- patient decision

80 (33.6%)

15 (6.3%)

21 (8.8%)

7 (2.9%)

13 (5.4%)

51 (21.0%)

26 (10.7%)

11 (4.5%)

2 (0.8%)

2 (0.8%)

.002



Disease-Free Survival

0.00

0.25

0.50

0.75

1.00

Dis

ease

-fre

e s

urv

iva

l

247 210 156 118 80 60 46 29 21 11 2B:mFolfirinox

246 205 127 85 59 34 24 15 10 7 3A:Gemcitabine

Number at risk

0 6 12 18 24 30 36 42 48 54 60

Time (months)

A :Gemcitabine B:mFolfirinox

HR=0.58 CI95%[0.46-0.73]Stratified HR = 0.58 [95%CI: 0.46-0.73],

P < .0001


No DFS events: 314

Median DFS:• 21.6 months [95% CI: 17.7-27.6]

with mFOLFIRINOX

• 12.8 months [95% CI: 11.7-15.2]

with gemcitabine

3-year DFS: • 39.7% [95% CI: 32.8-46.6]

with mFOLFIRINOX

• 21.4% [95% CI: 15.8-27.5]

with gemcitabine

CI = confidence interval; HR = hazard ratio


Overall SurvivalMedian overall survival:

• 54.4 months [95% CI: 41.8–NR]

with mFOLFIRINOX

• 35.0 mos [95% CI: 28.7–43.9]

with gemcitabine

3-year overall survival:

No OS events = 192

• 63.4% (mFOLFIRINOX) vs

48.6 % gemcitabine

0.00

0.25

0.50

0.75

1.00

Overa

ll su

rviv

al

247 223 210 165 119 91 68 46 32 16 4B:mFolfirinox

246 233 215 171 120 81 55 33 18 9 4A:Gemcitabine

Number at risk

0 6 12 18 24 30 36 42 48 54 60

Time (months)

A :Gemcitabine B:mFolfirinox

HR=0.64 CI95%[0.48-0.86]Stratified HR = 0.64,

[95%CI: 0.48-0.86], P = .003


NR = not reached

12

What Other Options Are Available for Adjuvant Therapy?


Postoperative Adjuvant Therapy Trials

Ahn D, et al. Cancer Treat Rev. 2016;42:10-17.

Study Treatment

R1,

%

LN+,

%

Locoregional

Recurrence,

%

Median

OS,

Mos P

Median

DFS,

Mos P

Gr 3/4

AEs,

%

ESPAC-1 (N = 289) 5-FU

CRT

19

19

53

50

35 20.1

15.9.009

15.2

10.7.04

4

6

ESPAC-3 (N = 1149) 5-FU

Gem

14

15

62

60NR

23.0

23.6.39

14.1

14.3.53

14

7.5

RTOG 9704 (N = 451) 5-FU/CRT

Gem/CRT

33

35

65

68

30

31

16.9

18.8.15

11.1

11.2NR

62

79

CONKO-001 (N = 354) Gem

Observation

19

15

71

73

34

41

22.8

20.2.01

13.4

6.7< .001

5

1

JSAP-02 (N = 378) Gem

Observation

19

8

67

70

23

32

22.3

18.4< .001

11.4

5.0.01

26

NR

GITSG (N = 43) CRT

Observation

19

24

29

27

15

15

20

11.03

11

9.01

7

--

CONKO-005 (N = 436) Gem

Gem/erlotinib

0

0

66

64

NR

NR

26.5

24.6.406

11.6

11.6.291

45.4

63.0

AE = adverse event; CRT = chemoradiation therapy

14Winship Cancer Institute | Emory UniversityOettle H, et al. JAMA. 2013;310:1473-1481.

CONKO 001: Gemcitabine vs Observation in Patients With Resected Pancreatic Cancer


Median DFS

Gemcitabine: 13.4 months (95% CI, 11.6-15.3)

Observation: 6.7 months (95% CI, 6.0-7.5)

Hazard ratio, 0.55 (95% CI, 0.44-0.69)

Oettle H, et al. JAMA. 2013;310:1473-1481.

CONKO-001: DFS and OS

Median OS

Gemcitabine: 22.8 months (95% CI, 18.5-27.2)

Observation: 20.2 months (95% CI, 17.7-22.8)

Hazard ratio, 0.76 [95% CI, 0.61-0.95]

DFS OS

16Winship Cancer Institute | Emory UniversityNeoptolemos J, et al. Lancet. 2017;389:1011-1024.

ESPAC 4: Gemcitabine vs Gemcitabine Capecitabine in Resected Pancreatic Cancer


ESPAC-4: Survival by Treatment

Neoptolemos J, et al. Lancet. 2017;389:1011-1024.

18Winship Cancer Institute | Emory UniversityNeoptolemos J, et al. Lancet. 2017;389:1011-1024.

ESPAC-4: Survival by Treatment

Abstract 4000

APACT: Phase III, Multicenter, International, Open-Label, Randomized

Trial of Adjuvant nab-Paclitaxel Plus Gemcitabine vs Gemcitabine for Surgically

Resected Pancreatic Adenocarcinoma

Margaret A. Tempero,1 Michele Reni,2 Hanno Riess,3 Uwe Pelzer,3 Eileen M. O’Reilly,4 Jordan Winter,5

Do-Youn Oh,6 Chung-Pin Li,7 Giampaolo Tortora,8,9 Heung-Moon Chang,10 Charles D. Lopez,11

Josep Tabernero,12 Eric Van Cutsem,13 Philip Philip,14 David Goldstein,15 Jordan D. Berlin,16

Stefano Ferrara,17 Mingyu Li,17 Brian Lu,17 Andrew Biankin18


APACT: Study Design

*No prior neoadjuvant, radiation, or systemic therapy

Phase III, multicenter, international, open-label, randomized trial

Patients ≥ 18 years of

age with confirmed

resected PDAC

(T1-3, N0-1, M0);

R0/R1; ECOG PS 0

or 1; CT without

evidence of disease

CA19-9 < 100 U/mL;

no prior therapy*

Ran

dom

ized 1

:1

Follow-up

Radiological evaluation

for ≤ 5 years after

last dose or until

recurrence, new cancer

therapy, or death; safety

assessment for 28 days

after last dose

nab-P + gem

nab-P 125 mg/m2 q w 3/4 +

Gem 1000 mg/m2 q w 3/4

× 6 cycles

Gem

Gem 1000 mg/m2 q w 3/4

× 6 cycles

End of treatment

Treat for 6 cycles

unless recurrence,

death, unacceptable

toxicity, consent

withdrawal, or

patient/physician

decision

• Randomized as early as possible after adequate recovery from surgery, but no later than 12 weeks

after surgery

• Stratification: resection status (R0 vs R1); lymph node status (LN+ vs LN−); geographic region (North

America, Europe, and Australia vs Asia Pacific)

Tempero M, et al. J Clin Oncol. 2019;37(suppl): Abstract 4000.

LN = lymph node; PDAC = pancreatic ductal adenocarcinoma


APACT: Statistical Design

Sample Size and Power Considerations

Endpoint nab-P + gem Gem

Primary (independently assessed DFS)

Median, months 18.5 13.5

HR for disease recurrence or death 0.73

Events required for 90% power at 2-sided α of 0.05, n 438

Secondary (OS)

Events to be analyzed as supportive analysis, n ≈ 630

Type 1 error control for OS None

• Primary endpoint: independently assessed DFS

– APACT is the first adjuvant trial in pancreatic ductal adenocarcinoma to use independently

assessed DFS as the primary endpoint

– Central review was conducted by radiologists not involved in the trial without clinical or

laboratory data

• Secondary endpoints: OS; safety

• Exploratory endpoints: Tumor & blood biomarker analysis; quality of life

• Prespecified sensitivity analyses included: investigator-assessed DFS



Selected Baseline Characteristics (ITT Population)Characteristic nab-P + Gem Gem Total

(n = 432) (n = 434) (N = 866)Age, median (range), years 64.0 (34 - 83) 64.0 (38 - 86) 64.0 (34 - 86)

Sex, male, n (%) 228 (53) 253 (58) 481 (56)

ECOG PS, n (%)

0

1

252 (58)

180 (42)

268 (62)

166 (38)

520 (60)

346 (40)

Resection status, n (%)

R0 (tumor-free margin)

R1 (microscopically positive margin)

327 (76)

105 (24)

334 (77)

100 (23)

661 (76)

205 (24)

Nodal status, n (%)

Lymph node negative

Lymph node positive

121 (28)

311 (72)

122 (28)

312 (72)

243 (28)

623 (72)

Baseline CA19-9

n

Median, U/mL

423

14.31

429

12.90

852

13.65

Tumor grade, n (%)

Well differentiated

Moderately differentiated

Poorly differentiated

Undifferentiated

Other/unknown

49 (11)

264 (61)

101 (23)

1 (< 1)

17 (4)

55 (13)

241 (56)

115 (26)

2 (< 1)

21 (5)

104 (12)

505 (58)

216 (25)

3 (< 1)

38 (4)


ITT = intent to treat


Treatment Exposure and Dose Modifications (Treated Population)

Parameters nab-P + Gem Gem

Treatment exposure (n = 429) (n = 423)

Treatment duration, median (range), weeks 24.0 (0.7 - 33.0) 24.0 (1.3 - 31.9)

Treatment cycles, median (range), n 6.0 (1 - 6) 6.0 (1 - 6)

nab-P Gem

Relative dose intensity, median, % 75.1 80.0 91.2

Cumulative dose, median, mg/m2 1500 13,200 15,000

Dose modifications

Patients with ≥ 1 dose reduction, n (%) 273 (64) 266 (62) 213 (50)

• Overall, 69% of patients completed 6 treatment cycles (nab-P + gem, 66%; gem, 71%)

• 59% of patients on nab-P + gem received dosing of nab-P in cycle 6



Primary Endpoint:Independently Assessed DFS (ITT Population)

24

Median independently assessed DFS

nab-P + gem: 19.4 months

Gem: 18.8 months

(HR 0.88; 95% CI, 0.729 - 1.063; stratified log-rank P = .1824)

Number of events: 439

0

10

20

30

40

50

60

70

80

90

100

Pro

ba

bil

ity o

f D

FS

, %

30 6 9 12 18 21 24 30 33 36 39 42 484515 27 51 54

MonthsPatients at risk

391

368

432

434

338

309

279

235

236

183

167

147

138

127

121

116

99

98

88

88

54

59

43

42

20

15

2

1

14

10

204

157

112

105

2nab-P + Gem

Gem

nab-P + gem

Gem



Prespecified Sensitivity Analysis: Investigator Assessed DFS (ITT Population)

Median investigator assessed DFS

nab-P + Gem: 16.6 months

Gem: 13.7 months

(HR 0.82; 95% CI, 0.694 - 0.965; nominal P = .0168)

Number of events: 571

0

10

20

30

40

50

60

70

80

90

100

Pro

ba

bil

ity o

f D

FS

, %

30 6 9 12 18 21 24 30 33 36 39 42 484515 27 51 54

Months

406

384

432

434

355

330

287

247

246

202

183

159

160

142

141

127

118

106

98

92

59

59

46

42

24

14

2

1

16

9

216

175

128

116

2

nab-P + gem

Gem

Patients at risk

nab-P + Gem

Gem



Secondary Endpoint:Interim OS (ITT population)

26

Median interim OS (68% mature)

nab-P + gem: 40.5 months

Gem: 36.2 months

(HR 0.82; 95% CI, 0.680 - 0.996; nominal P = .045)

Number of events: 427; Median follow-up, 38.5 months

0

10

20

30

40

50

60

70

80

90

100

Months

Pro

ba

bil

ity o

f O

S, %

30 6 9 12 18 21 24 30 33 36 39 42 484515 27 51 54 57

427

415

432

434420

404

406

384

385

354

344

301

307

275

284

262

252

228

219

198

162

153

113

101

73

64

12

12

40

29

366

320

264

249

3

2 1

Patients at risk

nab-P + Gem

Gem

nab-P + gem

Gem



Safety (Treated Population)

Event, n (%) nab-P + Gem Gem

Safety summary (n = 429) (n = 423)

Patients with ≥ 1 grade ≥ 3 TEAE 371 (86) 286 (68)

Patients with ≥ 1 serious TEAE 176 (41) 96 (23)

Grade ≥ 3 hematologic TEAEs (occurring in ≥ 5% of patients in either treatment arm)

Any hematologic TEAEs 250 (58) 204 (48)

Neutropenia 212 (49) 184 (43)

Anemia 63 (15) 33 (8)

Leukopenia 36 (8) 20 (5)

Febrile neutropenia 21 (5) 4 (1)

Grade ≥ 3 nonhematologic TEAEs (occurring in ≥ 5% of patients in either treatment arm)

Peripheral neuropathy (SMQ)* 64 (15) 0

Fatigue 43 (10) 13 (3)

Diarrhea 22 (5) 4 (1)

Asthenia 21 (5) 8 (2)

Hypertension 17 (4) 27 (6)

*Reported as a group term.

MedDRA = Medical Dictionary for Regulatory Activities; SMQ = standardized MedDRA query; TEAE = treatment-emergent adverse event.

• TEAEs led to death in 2 patients in each arm

• Ten patients (16%) with grade ≥ 3 peripheral neuropathy improved to grade ≤ 1

• The incidence of TEAEs of special interest—gastrointestinal events, hepatic toxicity, and sepsis—was generally low in

both arms


Conclusions

• The outcome of the gemcitabine single-agent arm has improved over time

– Better supportive care and patient selection

• mFOLFIRINOX is a very effective adjuvant therapy regimen with median OS in the range of 54 months and HR 0.64

– This regimen needs to be considered standard of care for patients with good performance status and who have recovered well post operatively

• Gemcitabine-based regimens have activity and should be considered standard for patients with borderline PS or prolonged recovery from surgery

– Gemcitabine capecitabine or gemcitabine nab-paclitaxel for patients with moderate PS (HR 0.8)

– Single-agent gemcitabine for patients with poor PS


Thanks

Adjuvant Therapy for Pancreatic Cancer: Is …...– APACT is the first adjuvant trial in pancreatic ductal adenocarcinoma to use independently assessed DFS as the primary endpoint

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