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Melanoma: novità ESMO 2017

Vincenzo Picone

Istituto dermopatico dell’Immacolata (IDI)

AGENDA

Metastatico

• CheckMate 067

Adiuvante

• LBA7_PR - BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+

melanoma at high risk for recurrence. K. Lewis et al.

• LBA6_PR COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma. A. Hauschild et al.

• LBA8_PR - Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: A randomized, double-blind, phase 3 trial (CheckMate 238). J. Weber

CheckMate 067: Phase III Trial of Nivo + Ipi vs Nivo vs Ipi for First-line Treatment of Mel

• Coprimary endpoints: PFS, OS

• Secondary endpoints: ORR, tumor PD-L1 expression and efficacy, safety

Nivo 1 mg/kg + Ipi 3 mg/kg q3w for 4 doses, then Nivo 3 mg/kg q2w

(n = 314)

Nivo 3 mg/kg q2w + Placebo (n = 316)

Wolchok JD, et al. ASCO 2015. Abstract LBA1; Larkin j,et al. N Engl J Med 2015;373:23-34 Stratified by

 PD-L1 expression (< 5% vs ≥ 5%),

 BRAF status, and

 AJCC M stage

Ipi 3 mg/kg q3w for 4 doses + Placebo (n = 315)

Until disease progression or

unacceptable toxicity Previously untreated pts

with unresectable stage III/IV melanoma and

ECOG PS 0-1 (N = 945)

CheckMate 067: Pt Population Baseline Characteristics

Characteristic Nivo + Ipi (n = 314)

Nivo (n = 316)

Ipi (n = 315) Median age, yrs (range) 61 (18-88) 60 (25-90) 62 (18-89)

Male, % 66 64 64

ECOG PS 0, % 73 75 71

AJCC M1c stage, % 58 58 58

LDH, %

> ULN

≥ 2 x ULN

36 12

35 12

37 10

Brain metastases, % 4 3 5

PD-L1 expression* ≥

5% 22 25 24

BRAF V600 mutant 32 32 31

*PD-L1 expression measured by IHC using a validated automated assay with the PD-L1 clone 28-8.

CheckMate 067: ORR and PFS for Nivo + Ipi and Nivo Alone vs Ipi Alone

The study was not powered for a comparison between the NIVO+IPI and NIVO arms, but descriptive analyses are presented at ESMO congress Madrid 2017

CheckMate 067: OS for Nivo + Ipi and Nivo Alone vs Ipi Alone

*Stratified log-rank P < .00001 vs Ipi.

†Exploratory endpoint. Study not powered to detect a statistical difference between Nivo + Ipi and Nivo.

CheckMate 067: Subsequent Therapies and Safety

Subsequent Therapies

• Subsequent systemic therapies were received by: 32% in the NIVO+IPI arm, 46% in the NIVO arm, and 63% in the IPI arm

• The median time to subsequent systemic therapy was not reached for the NIVO+IPI arm, 25.5 months for the NIVO arm, and 8.1 months for the IPI arm Safety summary

The majority of NIVO+IPI treatment-related grade 3/4 select (immune-mediated) AEs resolved within 3 to 4 weeks of intervention, using established safety guidelines

CheckMate 067: conclusions

• NIVO+IPI and NIVO significantly improved OS vs IPI in patients with untreated MEL

• In descriptive analyses performed at 3 years, NIVO+IPI demonstrated numerically higher efficacy than NIVO alone, with a 15% relative reduced risk of death, with the median DOR not reached

• Based on descriptive analyses, difference in OS and PFS favoring NIVO+IPI vs NIVO alone was observed across clinically relevant subgroups, including M1c disease, elevated lactate dehydrogenase (LDH), and those with PD-L1-expressing and -non-expressing tumors

• Safety profile of NIVO+IPI was consistent with earlier experience and, similar to both the NIVO and IPI arms, the majority of treatment-related grade 3/4 select AEs with NIVO+IPI resolved within 3 to 4 weeks of intervention using established safety guidelines

• Based on available data, NIVO+IPI continues to offer unsurpassed OS and PFS benefit over other available first-line agents, with the potential for patients to remain treatment-free after discontinuation of therapy

AGENDA

Metastatico

• CheckMate 067

Adiuvante

• LBA7_PR - BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+ melanoma at high risk for recurrence. K. Lewis et al.

• LBA6_PR COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma. A. Hauschild et al.

• LBA8_PR - Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: A randomized, double-blind, phase 3 trial (CheckMate 238). J. Weber

• The 5y recurrence rate for resected stage IIIB melanoma is 68% and for stage IIIC is 89%¹

• Despite the high rate of recurrence, more than two-thirds of patients do not receive adjuvant therapy for resected stage III melanoma ^2,3

• Interferon is approved in both the USA and the EU as adjuvant therapy for resected highrisk melanoma, but it is not widely used ⁴

• The absolute differences in EFS at 5 and 10 years were 3.5% and 2.7%, and for OS were 3.0% and 2.8% respectively in favour of IFN-α. ⁶

• Ipilimumab at 10 mg/kg was approved in the USA in 2015 for adjuvant therapy of resected stage III melanoma based on an improvement in RFS vs placebo in a randomized, phase 3 trial (EORTC 18071) ⁴

• 5 yrs OS 65,4% vs 54,4% (HR = 0.72, P = 0.001)⁵

• 5 yrs RFS 40.8% vs 30.3% (HR, 0.76; P<0.001)

• However, >50% of patients treated experienced a grade 3/4 adverse event ⁵

• There is a need to improve the risk-benefit ratio of adjuvant treatment given the toxicity observed with the approved ipilimumab adjuvant regimen of 10 mg/kg,^4,5

ADJUVANT: BACKGROUND

1. Romano E et al. J Clin Oncol. 2010;28:3042-3047. 2. Harlan LC et al. Melanoma Res. 2011;21:547-554. 3. Mohr P (discussant). Presented at ASCO 2017. 4. Eggermont AMM et al. Lancet Oncol. 2015;16:522-530. 5. Eggermont AMM et al. N Engl J Med. 2016;375:1845-1855; 6.

Natalie j et al. Eur J Canc Sept 2017

STUDY RATIONALE: MELANOMA ^V600+

• Oncogenic BRAF mutations are found in ≈ 40%

of melanomas and cause constitutive activation of the MAPK pathway^1,2

• In phase 3 trials (COMBI-d and COMBI-v),

treatment with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with unresectable or metastatic BRAF V600E/K–mutant melanoma^3,4

• Dabrafenib plus trametinib is approved for this patient population in many countries

pERK RAS

MEK

mutBRAF Dabrafenib vemurafenib MAPK Pathway

Trametinib cobimetinib

• MAPK, mitogen-activated protein kinase; mut, mutated.

• 1. Long GV, et al. J Clin Oncol. 2011;29:1239-1246; 2. Jakob JA, et al. Cancer. 2012;118:4014-4023; 3. Long GV, et al. N Engl J Med. 2014;371:1877-1888; 4. Robert C, et al. N Engl J Med. 2015;372:30-39.

Proliferation, Survival, Invasion, Metastasis

A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Vemurafenib

(RO5185426) Adjuvant Therapy in Patients With Surgically Resected, Cutaneous BRAF-Mutant Melanoma at High Risk for Recurrence (BRIM8)

Karl Lewis,¹ Michele Maio,² Lev Demidov,³ Mario Mandalà,⁴ Paolo A. Ascierto,⁵ Christopher Herbert,⁶ Andrzej Mackiewicz,⁷ Piotr Rutkowski,⁸ Alexander Guminski,⁹ Grant Goodman,¹⁰ Brian Simmons,¹⁰ Chenglin Ye,¹⁰ Yibing Yan,¹⁰ Dirk Schadendorf¹¹

1University of Colorado Comprehensive Cancer Center, Aurora, CO, USA;²Division of Medical Oncology and Immunotherapy, Center for Immuno- Oncology, University Hospital of Siena, Siena, Italy; ³N N Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russia; ⁴Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy; ⁵Melanoma Unit, Cancer Immunotherapy and Innovative

Therapies, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; ⁶Bristol Haematology and Oncology Centre, Bristol, UK; ⁷Department of Cancer Immunology, Poznan University for Medical Sciences, Med-POLONIA, Poznan, Poland; ⁸Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute – Oncology Center, Warsaw, Poland; ⁹Melanoma Translational Research Group, Melanoma Institute Australia, Wollstonecraft, NSW, Australia; ¹⁰Genentech, Inc., South San Francisco, CA, USA; ¹¹Department of Dermatology, University Hospital Essen,

Essen, Germany; German Cancer Consortium, Heidelberg, Germany

BRIM8: Study Design

Cohort 1 = 314 (Stage IIC, IIIA^a, IIIB)

Stratified by disease stage and geographic region

Placebo

x 52 weeks | (n=157)

Vemurafenib 960 mg BID x 52 weeks | (n=157)

Cohort 2 = 184 (Stage IIIC)

Stratified by

geographic region

Placebo x 52 weeks | (n=91)

Vemurafenib 960 mg BID x 52 weeks | (n=93) 1:1

1:1

• Primary endpoint

– DFS

• Secondary endpoints

– DMFS – OS – Safety – HRQoL

• A two cohort design was implemented to address the concern that the IIIc patients would drive the analysis as they would have faster events than the other stage patients

• At data cutoff, median follow up was 31 months in Cohort 1 and 34 months in Cohort 2

BID, twice daily; DFS, disease-free survival; DMFS, distant metastasis-free survival; HRQoL. Health-related quality of life; OS, overall survival. Patients with stage IIIA melanoma were eligible if they had one or more nodal metastasis >1 mm in diameter.

Phase III, international, multicenter, double-blind, randomized, placebo-controlled study

BRIM8: Primary DFS endpoint (Cohort 1, stage IIC–IIIB)

aCannot be considered significant because primary endpoint was not met in Cohort 2.CI, confidence interval; DFS, disease-free survival; HR, hazard ratio, NE, not estimable.

Patients at risk, n 100

80

60

40

20

0

0 9 18 27 36 48

Patients Alive and Disease-Free (%)

Time (months) Vemurafenib

Placebo Censored

84.3%

66.2%

72.3%

56.5%

+

3 6 12 15 21 24 30 33 39 42 45 51

+ + + +

+ +

+ + +

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

+

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

+ + + + +

Vemurafenib 157 146 137 129 120 115 107 94 72 49 38 31 26 18 15 4 2 − Placebo 157 129 118 106 100 94 90 79 65 43 35 31 28 22 12 3 1 −

Vemurafenib (n = 157)

Placebo (n = 157)

Events, n (%) 45 (29) 72 (46)

Median DFS, months (95% CI)

NE 36.9

(21.4 – NE) Hazard ratio (95% CI)

log-rank P-value

0.54 (0.37 to 0.78) p = 0.0010^a

• One year of adjuvant vemurafenib results in 46% DFS risk reduction in stage IIC-IIIB BRAF^V600 melanoma, demonstrating a substantial clinical benefit vs placebo

BRIM8: Primary DFS endpoint (Cohort 2, stage IIIC)

CI, confidence interval; DFS, disease-free survival; HR, hazard ratio, NE, not estimable.

Patients at risk, n 100

80

60

40

20

0

0 9 18 27 36 48

Patients Alive and Disease-Free (%)

Time (months) Vemurafenib

Placebo Censored

78.9%

58.0%

46.3%

47.5%

+

3 6 12 15 21 24 30 33 39 42 45 51

+ + +

+

+

+ + + + + + + + +

+ + + + + + + +

+ + + + + + + + + + + +

+

+ + + + + + +

+ + + + + + + +

+ + + + + + + + + + + +

+ +

Vemurafenib 93 87 85 76 70 61 57 44 29 16 15 13 11 7 5 1 − − Placebo 91 71 59 54 51 45 43 39 31 21 16 13 11 8 7 5 1 −

Vemurafenib (n = 93)

Placebo (n =91)

Events, n (%) 52 (56) 53 (58)

Median DFS, months (95% CI)

23.1 (18.6 – 26.5)

15.4 (11.1 – 35.9) Hazard ratio (95% CI)

log-rank P-value

0.80 (0.54 to 1.18) p = 0.2598

• One year of adjuvant vemurafenib increased median DFS vs placebo in stage IIIc BRAF^V600 melanoma demonstrating a biologic effect, however it did not significantly reduce DFS risk

BRIM8: Distant metastasis-free survival (DMFS)

+ + +

+ + + + + +

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

+ + + + + + + + + + 100

80

60

40

0 20

Vemurefenib 93 89 86 78 73 65 59 45 30 19 16 13 1 1 7 5 1 Placebo 91 79 70 64 58 48 46 42 33 22 17 13 12 8 7 5 1

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Patients at risk, n

83.2%

77.0%

57.5%

62.4%

Patients Alive and Without Distant Metastasis (%)

Vemurafenib Placebo Censored +

Time (months) +

+ + + + + + +

+ + + + + + + + + + + +

+ + + + + + + + + + +

+ + +

+ + + + +

+ + + + + +

100

80

60

40

0 20

Patients at risk, n

Vemurafenib 157 147 139 132 122 1 18 1 10 98 76 52 40 33 27 18 15 4 2 Placebo 157 140 133 125 1 13 101 96 83 67 44 36 31 28 22 12 3 1

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months)

Patients Alive and Without Distant Metastasis (%)

88.9%

79.5%

81.0%

66.9%

Vemurafenib Placebo Censored +

+ +

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

+ + +

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

+ + +

+ +

Cohort 2 (IIIC) Vemurafenib (n = 93)

Placebo (n = 91)

Events, n (%) 38 (41) 37 (41)

Median DMFS, months (95% CI)

37.2 (22.1 – NE)

30.7 (24.5 – NE) Hazard ratio

(95% CI)

log-rank P-value

0.91 (0.57 to 1.44) p = 0.6815^a

Cohort 1 (IIC – IIIB)

Vemurafenib (n = 157)

Placebo (n = 157)

Events, n (%) 34 (22) 52 (33)

Median DMFS, months (95% CI)

NE NE

(36.9 – NE) Hazard ratio

(95% CI)

log-rank P-value

0.58 (0.37 to 0.90) p = 0.0133^a

^aCannot be considered significant because primary endpoint was not met in Cohort 2.

• Secondary endpoint of DMFS is consistent with the primary endpoint in both cohorts

Cohort 2 (stage IIIC) Cohort 1 (stage IIC – IIIB)

BRIM8: Adjuvant vemurafenib was tolerable and had a manageable safety profile

Vemurafenib (n = 247)

Placebo (n = 247)

Dose intensity, median % 82 99

Treatment duration, median days 364 364

Any grade AEs, n (%) 246 (100) 219 (89)

Grade 3-4 AEs, n (%) 141 (57) 37 (15)

Grade 5 AEs, n (%) 1 (<1)^a 0

Treatment discontinuation for AEs, n (%) 49 (20)^b 5 (2.0) ^b

aRefers to a case of a patient who died 2 months after hospitalization for hypertension; brain imaging revealed haemorrhage in a cerebral lesion consistent with metastasis. The patient had surgery for the cerebral

hemorrhage and was subsequently discharged. The death was not considered to be related to the study drug.

bTreatment discontinuation for AEs by cohort, n (%) C2: 13 (14%) vemurafenib, vs 0 placebo ; C1: 34 (22%) vemurafenib, vs 5 (3%) placebo.

• The majority of patients in both cohorts received their planned treatment

BRIM8: conclusions

• One year of adjuvant vemurafenib provided a substantial DFS benefit (46% reduction vs placebo) in patients with stage IIC-IIIB BRAF

melanoma

• In stage III C BRAF

melanoma adjuvant vemurafenib increased median DFS demostrating a biological effect, but did not significantly reduce DFS risk

• Secondary endpoints and subgroup analyses were consistant with the primary endpoint in both cohorts

• Adjuvant vemurafenib was tolerable and had a manegeable safety profile consistent with that previously observed in clinical studies

– The incidence of cuSCC/KA is consistent with the known safety profile for vemurafenib

– No non-cuSCC or GI malignancies were reported

• OS data were immature and furter follow up is ongoing

cuSCC, cutaneous squamous cell carcinoma;DFS, disease-free survival; GI, gastrointestinal; KA, keratoacanthoma; OS, overall survival.

AGENDA

Metastatico

• CheckMate 067

Adiuvante

• LBA7_PR - BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+

melanoma at high risk for recurrence. K. Lewis et al.

• LBA6_PR COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma. A. Hauschild et al.

• LBA8_PR - Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: A randomized, double-blind, phase 3 trial (CheckMate 238). J. Weber

COMBI-AD: ADJUVANT DABRAFENIB PLUS TRAMETINIB FOR RESECTED

STAGE III BRAF V600–MUTANT MELANOMA

Axel Hauschild, Mario Santinami, Georgina V. Long, Victoria Atkinson, Mario Mandalà, Vanna

Chiarion-Sileni, James Larkin, Marta Nyakas, Caroline Dutriaux, Andrew Haydon, Caroline Robert, Laurent Mortier, Jacob Schachter, Ran Ji, Pingkuan Zhang, Bijoyesh Mookerjee, Jeff Legos,

Richard Kefford, Reinhard Dummer, John M. Kirkwood

COMBI-AD: STUDY DESIGN

Key eligibility criteria

• Completely resected, high-risk stage IIIA (lymph node metastasis > 1 mm), IIIB, or IIIC cutaneous melanoma

• BRAF V600E/K mutation

• Surgically free of disease ≤ 12 weeks before randomization

• ECOG performance status 0 or 1

• No prior radiotherapy or systemic therapy

R A N D O M I Z A T I O N Stratification

• BRAF mutation status (V600E, V600K)

• Disease stage (IIIA, IIIB, IIIC)

1:1

Dabrafenib 150 mg BID + trametinib 2

mg QD (n = 438)

2 matched placebos

(n = 432)

Follow- up^b until

end of study^c

• Primary endpoint: RFS^d

• Secondary endpoints: OS, DMFS, FFR, safety

N = 870

BID, twice daily; DMFS, distant metastasis–free survival; ECOG, Eastern Cooperative Oncology Group; FFR, freedom from relapse; OS, overall survival; QD, once daily; RFS, relapse-free survival. ^a Or until disease recurrence, death, unacceptable toxicity, or withdrawal of consent; ^b Patients were followed for disease recurrence until the first recurrence and thereafter for survival;

c The study will be considered complete and final OS analysis will occur when ≈ 70% of randomized patients have died or are lost to follow-up; ^d New primary melanoma considered as an event.

Treatment: 12 months^a

BASELINE DEMOGRAPHICS AND PATIENT CHARACTERISTICS ^a

• ^a Reported for patients with available data; ^b One patient had both BRAF V600E and BRAF V600K mutations and was included in the V600K subset.

Dabrafenib Plus Trametinib

(n = 438) Placebo

(n = 432) Total (N = 870)

Median age (range), years 50 (18-89) 51 (20-85) 50 (18-89)

Male, n (%) 195 (45) 193 (45) 388 (45)

BRAF mutation status, n (%) V600E

V600K^b 397 (91)

41 (9) 395 (91)

37 (9) 792 (91)

78 (9)

ECOG performance status of 0, n (%) 402 (92) 390 (90) 792 (91)

Disease stage, n (%) IIIA

IIIB IIIC

III (unspecified)

83 (19) 169 (39) 181 (41) 5 (1)

71 (16) 187 (43) 166 (38) 8 (2)

154 (18) 356 (41) 347 (40) 13 (1) N of positive lymph nodes, n (%)

1 2 or 3 ≥ 4

177 (40) 158 (36) 73 (17)

183 (42) 150 (35) 72 (17)

360 (41) 308 (35) 145 (17) Type of lymph involvement, n (%)

Microscopic Macroscopic Not reported

152 (35) 158 (36) 128 (29)

157 (36) 161 (37) 114 (26)

309 (36) 319 (37) 242 (28) Primary tumour ulceration, n (%)

Yes No

179 (41) 253 (58)

177 (41) 249 (58)

356 (41) 502 (58)

COMBI-AD: Relapse-free survival (primary endpoint)

438 413 405 392 382 373 355 336 325 299 282 276 263 257 233 202 194 147 116 110 66 52 42 19 7 2 0 432 387 322 280 263 243 219 203 198 185 178 175 168 166 158 141 138 106 87 86 50 33 30 9 3 0 0

Months From Randomization

Dabrafenib plus trametinib Placebo

No. at Risk

0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Proportion Alive and Relapse Free ^{1 y, 88%}

2 y, 67%

3 y, 58%

1 y, 56%

2 y, 44%

3 y, 39%

Group

Events, n (%)

Median (95% CI), mo

HR (95% CI) Dabrafenib

plus trametinib

166 (38) NR

(44.5-NR) 0.47 (0.39-0.58);

P < .001 Placebo 248 (57) 16.6

(12.7-22.1)

P = .0000000000000153

NR, not reached.

RELAPSE-FREE SURVIVAL BY SUBGROUP

Macrometastasis and no ulceration (n = 201) Micrometastasis and no ulceration (n = 165)

0.01 0.10 1.00

0.51 0.37

0.52 0.51 0.33

0.43 0.49 0.43

0.44

10.00 HR

Favors Dabrafenib Plus Trametinib Favors Placebo

V600K (n = 78) V600E (n = 792) Male (n = 482) Female (n = 388)

< 65 years (n = 712)

≥ 65 years (n = 158) Disease stage IIIA (n = 154) Disease stage IIIB (n = 356) Disease stage IIIC (n = 347) Micrometastasis (n = 309) Macrometastasis (n = 319)

Macrometastasis and ulceration (n = 116) Micrometastasis and ulceration (n = 143)

1 Nodal metastatic mass (n = 360) 2–3 Nodal metastatic masses (n = 308)

≥4 Nodal metastatic masses (n = 145)

0.45 0.50 0.44 0.38

0.51 0.55 0.43

0.48 0.54

FREEDOM FROM RELAPSE

438 413 405 392 382 373 355 336 325 299 282 276 263 257 233 202 194 147 1 16 1 10 66 52 42 19 7 2 0 432 387 322 280 263 243 219 203 198 185 178 175 168 166 158 141 138 106 87 86 50 33 30 9 3 0 0

Proportion With Freedom From Relapse

Dabrafenib plus trametinib Placebo

No. at Risk

3 y, 59%

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Months From Randomization

1 y, 88%

2 y, 67%

1 y, 56%

2 y, 44%

3 y, 39%

Group

Events, n (%)

Median (95% CI), mo

HR (95% CI) Dabrafenib

plus trametinib

165 (38) NR (44.5-NR)

0.47 (0.39-0.57);

nominal P < .001 Placebo 247 (57) 16.6

(12.7-22.3)

DISTANT METASTASIS–FREE SURVIVAL

438 413 407 390 381 373 353 336 327 302 285 278 265 258 235 203 195 146 1 16 1 10 66 52 42 19 7 2 0 432 392 330 282 265 247 221 206 201 187 179 176 169 168 159 144 140 107 88 87 51 33 30 9 3 0 0

Proportion Alive and Distant Metastasis Free _{1 y, 91%}

2 y, 77%

3 y, 71%

1 y, 70%

2 y, 60% 3 y, 57%

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Months From Randomization

Dabrafenib plus trametinib Placebo

No. at Risk

Group

Events, n (%)

Median (95% CI), mo

HR (95% CI) Dabrafenib

plus trametinib

110 (25) NR (NR-NR)

0.51 (0.40-0.65);

nominal P < .001 Placebo 152 (35) NR

(41.2-NR)

OVERALL SURVIVAL

(FIRST INTERIM ANALYSIS)

438 426 416 414 408 401 395 387 381 376 370 366 362 352 328 301 291 233 180 164 105 82 67 28 12 5 0 432 425 415 410 401 386 378 362 346 337 328 323 308 303 284 269 252 202 164 152 94 64 51 17 7 1 0

0 0 0

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54

Proportion Alive

2 y, 91%

3 y, 86%

1 y, 94%

2 y, 83%

3 y, 77%

Months From Randomization

Group

Events, n (%)

Median (95% CI), mo

HR (95% CI) Dabrafenib

plus trametinib

60 (14) NR

(NR-NR) 0.57 (0.42-0.79);

P = .0006^a Placebo 93 (22) NR

(NR-NR)

Dabrafenib plus trametinib Placebo

No. at Risk

a Prespecified significance boundary (P = .000019).

SAFETY SUMMARY

• AE, adverse event; SAE, serious adverse event.

•

Most common AEs leading to treatment discontinuation in the dabrafenib plus trametinib arm were pyrexia (9%) and chills (4%)

AE Category, n (%)

Dabrafenib Plus Trametinib

(n = 435)

Placebo (n = 432)

Any AE 422 (97) 380 (88)

AEs related to study treatment 398 (91) 272 (63)

Any grade 3/4 AE 180 (41) 61 (14)

Any SAE 155 (36) 44 (10)

SAEs related to study treatment 117 (27) 17 (4)

Fatal AEs related to study drug 0 0

AEs leading to dose interruption 289 (66) 65 (15)

AEs leading to dose reduction 167 (38) 11 (3)

AEs leading to treatment discontinuation^a

114 (26) 12 (3)

CONCLUSIONS

• This is the first randomized study of combination BRAF and MEK inhibition as melanoma adjuvant therapy

• Dabrafenib plus trametinib significantly reduced the risk of disease recurrence vs placebo in patients with resected high-risk, stage III, BRAF V600E/K–mutant melanoma (RFS HR, 0.47 [95% CI, 0.39-0.58]; P < .001)

– Estimated 1-, 2-, and 3-year RFS rates with dabrafenib plus trametinib were 88%, 67%, and 58%, respectively

– Similar RFS benefit was observed across patient subgroups, including all stage categories

• In addition to RFS, OS improvement with dabrafenib plus trametinib was demonstrated (HR, 0.57 [95% CI, 0.42-0.79])

– Similar rates of post-recurrence therapy in each arm attributes OS improvement to adjuvant dabrafenib plus trametinib treatment

• Manageable safety profile with combination dabrafenib and trametinib

• Dabrafenib plus trametinib is a novel adjuvant treatment option for BRAF V600–mutant melanoma

AGENDA

Metastatico

• CheckMate 067

Adiuvante

• LBA7_PR - BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+

melanoma at high risk for recurrence. K. Lewis et al.

• LBA6_PR COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma. A. Hauschild et al.

• LBA8_PR - Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: A randomized, double-blind, phase 3 trial (CheckMate 238). J. Weber

Adjuvant Therapy With Nivolumab Versus Ipilimumab After Complete Resection of Stage

III/IV Melanoma: A Randomized, Double-blind, Phase 3 Trial (CheckMate 238)

Jeffrey Weber,¹ Mario Mandala,² Michele Del Vecchio,³ Helen Gogas,⁴ Ana M. Arance,⁵

C. Lance Cowey,⁶ Stéphane Dalle,⁷ Michael Schenker,⁸ Vanna Chiarion-Sileni,⁹ Ivan Marquez-Rodas,¹⁰ Jean-Jacques Grob,¹¹ Marcus Butler,¹² Mark R. Middleton,¹³ Michele Maio,¹⁴ Victoria Atkinson,¹⁵

Paola Queirolo,¹⁶ Veerle de Pril,¹⁷ Anila Qureshi,¹⁷ James Larkin,¹⁸* Paolo A. Ascierto¹⁹*

1NYU Perlmutter Cancer Center, New York, New York, USA; ²Papa Giovanni XIII Hospital, Bergamo, Italy; ³Medical Oncology, National Cancer Institute, Milan, Italy; ⁴University of Athens, Athens, Greece; ⁵Hospital Clínic de Barcelona, Barcelona, Spain; ⁶Texas Oncology-Baylor Cancer Center, Dallas, Texas, USA; ⁷Hospices Civils de Lyon, Pierre Bénite, France; ⁸Oncology Center Sf Nectarie Ltd., Craiova, Romania; ⁹Oncology Institute of Veneto IRCCS, Padua, Italy; ¹⁰General University Hospital Gregorio Marañón, Madrid, Spain; ¹¹Hôpital de la Timone, Marseille, France;

12Princess Margaret Cancer Centre, Toronto, Ontario, Canada; ¹³Churchill Hospital, Oxford, United Kingdom; ¹⁴Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; ¹⁵Gallipoli Medical Research Foundation and Princess Alexandra Hospital, Woolloongabba, and University of Queensland, Greenslopes, Queensland, Australia; ¹⁶IRCCS San Martino-IST, Genova, Italy; ¹⁷Bristol-Myers

Squibb, Princeton, New Jersey, USA; ¹⁸Royal Marsden NHS Foundation Trust, London, UK; ¹⁹Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; *Contributed equally to this study.

CA209-067: Study Design

CA209-238: Study Design

Patients with high-risk, completely resected stage IIIB/IIIC or stage

IV melanoma

Enrollment period: March 30, 2015 to November 30, 2015

Follow-up Maximum treatment duration of

1 year NIVO 3 mg/kg IV Q2W

and

IPI placebo IV Q3W for 4 doses then Q12W from week 24

IPI 10 mg/kg IV Q3W for 4 doses then Q12W from week 24

and

NIVO placebo IV Q2W 1:1

n = 453

n = 453

Stratified by:

1) Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c 2) PD-L1 status at a 5% cutoff in tumor cells

Key Eligibility Criteria

• At least 15 years of age

• Eastern Cooperative Oncology Group performance status score of 0 or 1

• Histologically confirmed melanoma metastatic to regional lymph nodes or with distant metastases surgically rendered free of disease

– Stage IIIB, IIIC, or stage IV melanoma by the American Joint Committee on Cancer 2009 classification, 7th edition

– Complete regional lymphadenectomy or resection was required within 12 weeks of randomization

• Patients with ocular/uveal melanoma, systemic corticosteroid use

>10 mg/day of prednisone or equivalent, or previous systemic therapy for melanoma were excluded

– Acral and mucosal melanoma were allowed

Study Overview

Primary endpoint

• RFS: time from randomization until first recurrence (local, regional, or distant metastasis), new primary melanoma, or death

Secondary endpoints

• OS

• Safety and tolerability

• RFS by PD-L1 tumor expression

• HRQoL

Current interim analysis

• Primary endpoint (RFS), safety, and HRQoL

– DMFS (exploratory)

• Duration of follow-up: minimum 18 months; 360 events

DMFS = distant metastasis-free survival; HRQoL = health-related quality of life

Baseline Patient Characteristics

•

•

•

NIVO (n = 453)

IPI (n = 453)

Median age, years 56 54

Male, % 57 59

Stage, IIIB+IIIC, % 81 81

Macroscopic lymph node involvement (% of

stage IIIB+IIIC) 60 58

Ulceration (% of stage IIIB+IIIC) 42 37

Stage IV, % 18 19

M1c without brain metastases (% stage IV) 17 17

PD-L1 expression ≥5%, % 34 34

BRAF mutation, % 41 43

LDH ≤ ULN, % 91 91

Primary Endpoint: RFS

RFS (%)

Months

0 10 20 30 40 50 60 70 80 90 100

0 3 6 9 12 15 18 21 24 27

453 399 353 332 311 291 249 71 5 0

NIVO

453 364 314 269 252 225 184 56 2 0

IPI

Number of patients at risk NIVO IPI

NIVO IPI

Events/patients 154/453 206/453 Median (95% CI) NR NR (16.6,

NR) HR (97.56% CI) 0.65 (0.51, 0.83) Log-rank P value <0.0001

66%

53%

71%

61%

PD-L1 Expression Level <5% PD-L1 Expression Level ≥5%

NIVO IPI

Events/patients 114/275 143/286 Median (95% CI) NR 15.9 (10.4, NR) HR (95% CI) 0.71 (0.56, 0.91)

NIVO IPI

Events/patients 31/152 57/154

Median (95% CI) NR NR

HR (95% CI) 0.50 (0.32, 0.78)

Subgroup Analysis of RFS: PD-L1 Expression Level

RFS (%)

Months 0

10 20 30 40 50 60 70 80 90 100

0 3 6 9 12 15 18 21 24 27

NIVO IPI

275 242 204 189 171 159 129 41 3 0

NIVO

286 219 184 153 139 124 100 31 2 0

IPI

Number of patients at risk

RFS (%)

Months

152 135 130 125 122 114 105 26 2 0

NIVO

154 133 120 108 105 93 78 21 0 0

IPI

Number of patients at risk

64%

54%

0 10 20 30 40 50 60 70 80 90 100

0 3 6 9 12 15 18 21 24 27

NIVO IPI

82%

74%

Stage III Stage IV

Subgroup Analysis of RFS: Disease Stage

RFS (%)

Months 0

10 20 30 40 50 60 70 80 90 100

0 3 6 9 12 15 18 21 24 27

367 322 290 272 257 239 203 58 3 0

NIVO

366 299 259 223 208 186 152 45 1 0

IPI

Number of patients at risk

72%

62%

RFS (%)

Months 0

10 20 30 40 50 60 70 80 90 100

0 3 6 9 12 15 18 21 24 27

82 73 59 56 51 49 43 12 2 0

NIVO

87 65 55 46 44 39 32 11 1 0

IPI

Number of patients at risk

63%

58%

NIVO IPI

Events/patients 120/367 163/366 Median (95% CI) NR NR (16.6,

NR) HR (95% CI) 0.65 (0.52, 0.83)

NIVO IPI

Events/patients 33/82 43/87 Median (95% CI) NR (15.9,

NR) 16.8 (8.5, NR) HR (95% CI) 0.70 (0.45, 1.10)

NIVO IPI

NIVO IPI