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Metastatic Melanoma, Checkmate 0671

A 3-arm, phase 3 study in the first-line
treatment of metastatic melanoma1,2

Checkmate 067: OPDIVO® + YERVOY® or OPDIVO monotherapy vs
YERVOY
Checkmate 067: OPDIVO® + YERVOY® or OPDIVO monotherapy vs
YERVOY

The primary endpoints compared OPDIVO + YERVOY with YERVOY, and OPDIVO monotherapy with YERVOY.1,2

Key exclusion criteria1

  • Patients with active brain metastasis, ocular melanoma, autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive result for hepatitis B or C, and a history of HIV1

*The recommended dose of OPDIVO is 1 mg/kg administered as an intravenous infusion over 30 minutes, followed by YERVOY 3 mg/kg administered as an intravenous infusion over 90 minutes on the same day, q3w for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier. After completing 4 doses of the combination, administer OPDIVO as a single agent, either 240 mg q2w or 480 mg q4w, administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity. Review the Prescribing Information for YERVOY for additional information prior to initiation.1

AJCC=American Joint Committee on Cancer; DOR=duration of response; HIV=human immunodeficiency virus; IV=intravenous; M=metastases; ORR=overall response rate; OS=overall survival; PD-L1=programmed death-ligand 1; PFS=progression-free survival; q2w=every 2 weeks; q3w=every 3 weeks; q4w=every 4 weeks.


Overall survival analysis at ~6.5 years

49% of ITT and 57% BRAF MT patients were still alive at ~6.5 years3,4

mOS at ~6.5 years (95% CI, months)3:

OPDIVO + YERVOY: 72.1 (38.2–NR)

OPDIVO: 36.9 (28.3–58.7)

YERVOY: 19.9 (16.8–24.6)


Patients were stratified by BRAF status at baseline.2
OS analysis of this pre-specified subpopulation was conducted but not powered to detect statistical differences.3

In BRAF MT patients at ~6.5 years (95% CI)3:

  • mOS (months):

OPDIVO + YERVOY: NR (50.7–NR)

OPDIVO: 45.5 (26.4–NR)

YERVOY: 24.6 (17.9–31.0)

In BRAF WT patients at ~6.5 years (95% CI)3:

  • mOS (months):

OPDIVO + YERVOY: 39.1 (27.5–NR)

OPDIVO: 34.4 (24.1–59.2)

YERVOY: 18.5 (14.1–22.7)


  • HR vs YERVOY

OPDIVO + YERVOY: 0.58 (0.45–0.74)

OPDIVO: 0.63 (0.50–0.80)


mOS=median OS; MT=mutant; NR=not reached; WT=wild type.


PFS analysis at ~6.5 years

34% of ITT and 37% BRAF MT patients still progression free at ~6.5 years2,3

In ITT patients (95% CI)1,3,4:

  • HR vs YERVOY at primary analysis of 9 months:

OPDIVO + YERVOY: 0.42 (0.34–0.51); P<0.0001; OPDIVO: 0.57 (0.47–0.69); P<0.0001

HR vs YERVOY at ~6.5 years: OPDIVO + YERVOY: 0.42 (0.35–0.51); OPDIVO: 0.53 (0.44–0.64)

  • mPFS at primary analysis of 9 months:

OPDIVO + YERVOY: 11.5 (8.9–16.7); OPDIVO: 6.9 (4.3–9.5); YERVOY: 2.9 (2.8–3.4)

  • mPFS at ~6.5 years:

OPDIVO + YERVOY: 11.5 (8.7–19.3); OPDIVO: 6.9 (5.1–10.2); YERVOY: 2.9 (2.8–3.2)

  • PFS rate at ~6.5 years:

OPDIVO + YERVOY: 34% (29–40)

OPDIVO: 29% (23–34)

YERVOY: 7% (4–11)


Patients were stratified by BRAF status at baseline.2
PFS analysis of this pre-specified subpopulation was conducted but not powered to detect statistical differences.5

In BRAF MT patients at ~6.5 years (95% CI)3:

  • mPFS (months):

OPDIVO + YERVOY: 16.8 (8.3–32.0)

OPDIVO: 5.6 (2.8–9.5)

YERVOY: 3.4 (2.8–5.2)

In BRAF WT patients at ~6.5 years (95% CI)3:

  • mPFS (months):

OPDIVO + YERVOY: 11.2 (7.0–18.1)

OPDIVO: 8.2 (5.1–19.6)

YERVOY: 2.8 (2.8–3.1)

  • HR vs YERVOY

OPDIVO + YERVOY: 0.41 (0.33–0.52)

OPDIVO: 0.47 (0.38–0.59)


This study was not designed to compare OPDIVO + YERVOY with OPDIVO.

CI=confidence interval; HR=hazard ratio; ITT=intention to treat; mPFS=median progression-free survival.


Select Important Safety Information

Serious Adverse Reactions
In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%).


Analysis of OPDIVO + YERVOY: Patients alive and treatment-free at ~6.5 years3,4

In the ITT population at ~6.5 years3,4::

  • OPDIVO: 69% of surviving patients were treatment-free and never received subsequent systemic therapy (n=84/122), 7% were still on study therapy (n=8/122), and 25% received subsequent systemic therapy (n=30/122)
  • YERVOY: 43% of surviving patients were treatment-free and never received subsequent systemic therapy (n=27/63) and 57% received subsequent systemic therapy (n=36/63)
  • Of patients who were living and treatment-free: 58.9% on OPDIVO + YERVOY, 33.3% on OPDIVO, and 44.4% on YERVOY discontinued due to toxicity; 5.4% on OPDIVO + YERVOY, 7.1% on OPDIVO, and 7.4% on YERVOY discontinued due to disease progression. Patients also discontinued for other reasons

In the BRAF MT population at ~6.5 years3,4::

  • OPDIVO: 64% of surviving patients were treatment-free and never received subsequent systemic therapy (n=28/44), 5% were still on study therapy (n=2/44), and 32% received subsequent systemic therapy (n=14/44)
  • YERVOY: 41% of surviving patients were treatment-free and never received subsequent systemic therapy (n=11/27) and 59% received subsequent systemic therapy (n=16/27)
  • Of patients who were living and treatment-free: 53.8% on OPDIVO + YERVOY, 41.7% on OPDIVO, and 44.4% on YERVOY discontinued due to toxicity; 7.7% on OPDIVO + YERVOY, 12.5% on OPDIVO, and 11.1% on YERVOY discontinued due to disease progression. Patients also discontinued for other reasons

*Percentages may not total 100 after rounding.


Select Important Safety Information

Common Adverse Reactions
In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%).


ITT population: At ~6.5 years, overall survival by response type3,6

These data are a post hoc descriptive analysis of ~6.5-year overall survival outcomes in confirmed responders from the time of patient randomization.

ORR in ITT patients at 9-month primary analysis (95% CI)1:

  • OPDIVO + YERVOY: 50% (44–55); P<0.0001, CR: 9%, PR: 41%
  • OPDIVO: 40% (34–46); CR: 9%, PR: 31%
  • YERVOY: 14% (10–18); CR: 2%, PR: 12%

ITT response analysis at ~6.5 years (95% CI)6: In the OPDIVO arm:

  • ORR: 42% (36-47); CR: 17%, PR: 25%
  • 92% (71–98) of complete responders were alive*
  • 76% (66–83) of partial responders were alive*

OPDIVO mDOR at ~6.5 years: 77.21 (95% CI: 7.52–NA)6

In the YERVOY arm:

  • ORR: 15% (11–19); CR: 5%, PR: 10%
  • 50% (11–80) of complete responders were alive*
  • 62% (44–75) of partial responders were alive*

*Rates are based on Kaplan-Meier estimates of overall survival analysis from month 12 by confirmed BOR per Investigator RECIST 1.1. To address guarantee-time bias, landmark analysis excluded patients who had an event during the first 12 months.3

BOR=best overall response; CR=complete response; mDOR=median duration of response; PR=partial response.


BRAF MT population: At ~6.5 years, overall survival by response type6

This is a post hoc, exploratory analysis where patients were grouped by response category based on assessment at 12 months.

Patients were stratified by BRAF status at baseline.2
PFS analysis of this pre-specified subpopulation was conducted but not powered to detect statistical differences.5

BRAF MT response analysis at ~6.5 years (95% CI)6:

OPDIVO:
  • ORR: 37% (27-47); CR: 12%, PR: 25%
  • 100% (100–100) of complete responders were alive*
  • 65% (44–79) of partial responders were alive*

YERVOY:
  • ORR: 15% (9–24); CR: 5%, PR: 10%
  • 50% (1–91) of complete responders were alive*
  • 81% (42–95) of partial responders were alive*

OPDIVO mDOR at ~6.5 years: 55.0 (95% CI: 13.7–78.4)6

ORR in BRAF WT patients at ~6.5 years (95% CI)6:

  • OPDIVO + YERVOY: 46% (39–53); CR: 17%, PR: 29%
  • OPDIVO: 44% (37–51); CR: 19%, PR: 25%
  • YERVOY: 14% (10–20); CR: 5%, PR: 9%

*Rates are based on Kaplan-Meier estimates of overall survival analysis from month 12 by confirmed BOR per Investigator RECIST 1.1. To address guarantee-time bias, landmark analysis excluded patients who had an event during the first 12 months.6

Adjuvant Treatment of Melanoma

The only head-to-head clinical trial to
evaluate a current standard of care vs an
active comparator1-4*

Checkmate 2381,5:

Checkmate 238: OPDIVO® vs Ipilimumab in adjuvant treatment of melanoma
Checkmate 238: OPDIVO® vs Ipilimumab in adjuvant treatment of melanoma

Similar to the real-world population, Checkmate 238 included 42% BRAF mutant patients1,6

*At median follow-up of 5.3 years, OS of 65% was observed (95% CI: 60.8-69.6). OS HR (95% CI) of YERVOY vs placebo: HR=0.72 (0.58-0.88); P<0.002. The OS at 4 years for ipilimumab was 76.6% (95% CI: 72.2-80.3).5,7

AJCC=American Joint Committee on Cancer; HR=hazard ratio; IV=intravenous; NED=no evidence of disease; OS=overall survival; PD-L1=programmed death-ligand 1; q2w=every 2 weeks; q3w=every 3 weeks; q12w=every 12 weeks; RFS=recurrence-free survival.

Select Important Safety Information

Common Adverse Reactions
In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients
(n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash
(35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%),
nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The
most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).


OPDIVO: Durable RFS benefit and the longest
follow-up for any PD-1 agent in the adjuvant
setting5

Recurrence-free survival results through 4 years

Checkmate 238: RFS results through 4 years
Checkmate 238: RFS results through 4 years

Already a standard of care in BRAF wild type, now offer OPDIVO to your BRAF mutant patients

  • Median RFS, mos (95% CI):
  • 18 months (ITT); OPDIVO 3 mg/kg: NR (NR-NR); ipilimumab 10 mg/kg: NR (16.6-NR)1
  • 4 years (ITT): OPDIVO 3 mg/kg: 52.4 (42.5-NR); ipilimumab 10 mg/kg: 24.1 (16.6-35.1)5
  • RFS by BRAF status was an exploratory pre-specified subgroup analysis at 18 months and at 4 years5,10
  • 4-year RFS in patients receiving ipilimumab was 44% for BRAF MT and 39% for BRAF WT9
  • 4-year BRAF MT; NR for OPDIVO (35.0-NR), 25.5 for ipilimumab(15.9-NR; n=194)10
  • 4-year BRAF WT: 46.8 for OPDIVO (36.3-NR), 16.6 for ipilimumab(11.6-35.1; n=212)10
  • *These data are based on RFS Kaplan-Meier estimates.5
  • ITT=intention to treat; MT=mutation; WT=wild type.

Select Important Safety Information

Serious Adverse Reactions
In Checkmate 238, serious adverse reactions occurred in 18% of patients
receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in
25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and
4 adverse reactions reported in ≥2% of OPDIVO-treated patients were
diarrhea and increased lipase and amylase.

Recurrence-free survival results across BRAF status9

BRAF mutant

Checkmate 238: RFS results in BRAF mutant
Checkmate 238: RFS results in BRAF mutant

BRAF wild type

Checkmate 238: RFS results in BRAF wild type

4-years RFS in BRAF WT patients receiving ipilimumab was 39%

Checkmate 238: RFS results in BRAF wild type

Through 4 years, RFS rates are numerically similar across BRAF status

RFS by BRAF status was an exploratory pre-specified analysis at 18 months and 4 years5,10

*Unstratified hazard ratio.5

Learn About Safety
References
  1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
  2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535-1546.
  3. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. CheckMate 067: 6.5-year outcomes in patients with advanced melanoma. Presented at: ASCO 2021; June 4-8. 2021; Virtual. Abstract 9506.
  4. Data on file. EBD 2630. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
  5. Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480-1492.
  6. Data on file. NIVO 648. Princeton, NJ: Bristol-Myers Squibb Company; 2019.
References
  1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
  2. YERVOY [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
  3. TAFINLAR [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation.
  4. KEYTRUDA [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.
  5. Ascierto PA, Del Vecchio M, Mandalá M, et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial [published online ahead of print September 19, 2020]. Lancet Oncol. 2020;21(11):1465-1477. doi: 10.1016/S1470-2045(20)30494-0.
  6. Cheng L, Lopez-Beltran A, Massari F, MacLennan GT, Montironi R. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Mod Pathol. 2018;31(1):24-38.
  7. Eggermont AMM, Chiarion-Sileni V, Grob
    J-J, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med.
    2016;375:1845-1866.
  8. Weber J, Del Vecchio M, Mandalá M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III/IV melanoma: 3-year efficacy and biomarker results from the phase 3 CheckMate 238 trial. Presented at: ESMO Congress 2019;
    September 27-October 1, 2019; Barcelona, Spain. Abstract 2801.
  9. Weber J, Del Vecchio M, Mandalá M. Adjuvant nivolumab versus ipilimumab in resected stage III/IV melanoma: 4-year recurrence-free and overall survival results from CheckMate 238. Presented at: ESMO Congress 2020. Abstract 10760.
  10. Weber J, Mandalá M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma [published online ahead of print September 10, 2017]. N Engl J Med. 2017;377(19):1824-1835.