check point inhibitors when to use combination or single

Check Point Inhibitors

When to Use Combination or

Single Agent Therapy?

Sanjiv S. Agarwala, MDProfessor of Medicine

Temple University School of Medicine

Chief, Oncology & Hematology

St. Luke’s Cancer Center, Bethlehem, PA

Check-Point Inhibitors

Approved for Melanoma

• Anti CTLA4 (ipilimumab)

• Anti PD-1 (pembrolizumab, nivolumab)

• Combination anti CTLA-4 and anti-PD1

(ipilimumab and nivolumab)

Overview

• Data with ipilimumab monotherapy

• Data with anti-PD1 monotherapy

• Data with Combination ipi-nivo

• Choosing the right treatment

CTLA-4 Affects The Priming Phase of

T-Cell Activation1

CTLA-4 = cytotoxic T-lymphocyte antigen 4.

1. Pardoll DM. Nat Rev Cancer. 2012;12:252–264; 2. Ribas A. N Engl J Med. 2012;366:2517–2519; 3. Topalian SL et al. Curr Opin Immunol.

2012;24:207–212.

Dendritic cell Inactivated T cell

Priming (Early Stage)

Phase of Activation

CTLA-4

• In healthy tissues, CTLA-4 is

thought to function as a

dominant “off switch” broadly

shutting down T-cell activity

to prevent autoimmunity1-3

Clinical Results with Ipilimumab (2nd and 1st line)Ipilimumab vs vaccine and Ipi + DTIC vs DTIC

HR: 0.66 and 0.68Pre-treated ptsIpi 3 mg/kg +/- gp100

HR: 0.72First line

Ipi 10 mg/kg + DTIC

Hodi FS, et al. N Engl J Med. 2010;363:711-23. Robert C, et al. N Engl J Med. 2011;364:2517-26.

Maio et al, J Clin Oncol 2015

5-year Survival: DTIC +/-Ipilimumab

0 1 2 3 4 5 6 7 8 9 10

100

90

80

70

60

0

50

40

30

20

10

Ove

rall

Su

rviv

al (%

)

Years

IPI (Pooled analysis)1

N=1,861

7

Immune Checkpoint Inhibitors Provide Durable Long-term Survival for Patients with Advanced Melanoma

1. Schadendorf et al. J Clin Oncol 2015;33:1889-1894; 2. Current analysis; 3. Poster presentation by Dr. Victoria Atkinson at SMR 2015 International Congress.

Ipilimumab Summary

• Superior to chemotherapy

• Durable Benefit of 20%

• Approximately 35% grade 3-4 IRAE

Overview





PD-1 affects Mainly the Effector Phase of T-cell Activity

Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Cancer,1 copyright 2012.

PD-1 = programmed cell death protein 1; TCR = T-cell receptor; MHC = major histocompatibility complex; PD-L1 = programmed cell death ligand 1;

PD-L2 = programmed cell death ligand 2.

1. Pardoll DM. Nat Rev Cancer. 2012;12:252–64.

Dendritic cell Naïve T cell Activated T cell Tumor cell

PD-1

Antigen

PD-1PD-L2

MHCTCR

• Emerging research has

identified PD-1 as an

immune checkpoint

pathway that tumor cells

may exploit to evade

immune surveillance

• Tumor cells may block

immune responses via the

PD-1 immune checkpoint

pathway by expressing the

dual PD-1 ligands, PD-L1

and PD-L2

Priming Phase of

ActivationEffector Phase

PD-L1

KEYNOTE-001: Melanoma Cohorts

KN-001: Pembrolizumab All Pts (n=655)

KEYNOTE-001 – 5 Year Survival (ASCO 2018)

ASCO 2018 13

KEYNOTE-001 – 5 Year Duration of Response

2018-06-04ASCO 2018 14

Keynote-006 Front-line Pembrolizumab vs Ipilimumab

• Primary end points: PFS and OS• Secondary end points: ORR, duration of

response, safety

Patients

• Unresectable, stage III or IV melanoma

• ≤1 prior therapy, excluding anti–CTLA-4,

PD-1, or PD-L1 agents

• Known BRAF statusb

• ECOG PS 0-1

• No active brain metastases

• No serious autoimmune disease

Pembrolizumab

10 mg/kg IV Q2W

Pembrolizumab

10 mg/kg IV Q3W

R

1:1:1

Stratification factors:

• ECOG PS (0 vs 1)

• Line of therapy (first vs second)

• PD-L1 status (positivec vs negative)

Ipilimumab

3 mg/kg IV Q3W

x 4 doses

aPatients enrolled from 83 sites in 16 countries.bPrior anti-BRAF targeted therapy was not required for patients with normal LDH levels and no clinically significant tumor-related symptoms or evidence of rapidly progressing disease.cDefined as membranous PD-L1 expression in ≥1% of tumor cells as assessed by IHC using the 22C3 antibody.

Baseline Characteristics

Response (irRC, investigator review)<br />Median Follow-Up 45.9 (0.3-50.0) Months

Duration of Response (irRC, investigator)

Overall Survival<br />Median Follow-Up 45.9 (0.3-50.0) Months

Progression-Free Survivala<br />Median Follow-Up 45.9 (0.3-50.0) Months

Poststudy Drug Therapya

Disposition of Patients Completing <br />≥94 Weeks of Pembrolizumab Treatment

Abstract 9503, 2018 ASCO Annual Meeting

PFSa in Patients Who Completed Protocol-Specified Time on Pembrolizumab (n = 103)


Duration of Response in Patients With ≥94 Weeks of Pembrolizumaba (n = 103)


Outcome of 19 Progressors After ≥94 Weeks of Pembrolizumab (n = 103)


Pattern of Recurrence and Response in Patients on 2nd Course of Pembrolizumab


Immune Mediated AEs and Infusion Reactions for Patients on 1st and 2nd Course of Pembrolizumab


Treatment Exposure and Duration of Response in Patients on 2nd Course of Pembrolizumab


PD-1 Monotherapy: Summary

• Superior to ipilimumab

• Lower toxicity

• Durable benefit – double that of

ipilimumab

Overview





Blocking CTLA-4 and PD-1

Nivolumab

Pembrolizumab

Spartalizumab

Ipilimumab and TremelimumabAtezolizumab

Durvalumab

Avelumab

CM-67 Response to treatment

Database lock May 24, 2017 Wolchok, NEJM, 2017

CM-67 Progression-Free Survival

Database lock May 24, 2017

NIVO+IPI (N=314) NIVO (N=316) IPI (N=315)

Median PFS, mo (95% CI)11.5

(8.7–19.3)6.9

(5;1–9.7)2.9

(2.8–3.2)

HR (95% CI) vs. IPI0.43

(0.35–0.52)0.55

(0.45–0.66)--

HR (95% CI) vs. NIVO0.78

(0.64–0.96)-- --

Wolchok, NEJM, 2017

CM-67 Overall Survival

Database lock May 24, 2017

*P<0.0001

NIVO + IPI (N=314)

NIVO (N=316) IPI (N=315)

Median OS, months (95% CI) 38.2-NR37.6

(29.1-NR)19.9

(16.9-24.6)

HR (99.5% CI) vs. IPI0.55

(0.45–0.69)*0.65

(0.53–0.80)*-

HR (99.5% CI) vs. NIVO0.85

(0.68-1.07)- -

Wolchok, NEJM, 2017

Combo Ipi-Nivo Summary

• Superior to ipilimumab monotherapy

• Improves RR and PFS over nivolumab

alone

• OS improvement over nivo not statistically

significant

• Toxicity is higher (~55% grade 3-4)

Overview





Decision Point….

Immunotherapy

PD-1 alonePD-1/CTLA-4

Combination

Checkmate 067: Safety Summary• With an additional 19 months of follow-up, safety was consistent with the initial report1

• Most select AEs were managed and resolved within 3-4 weeks (85–100% across organ categories)

• ORR was 70.7% for pts who discontinued NIVO+IPI due to AEs, with median OS not reached

40

NIVO+IPI(N=313)

NIVO

(N=313)IPI

(N=311)

Patients reporting event, % Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4

Treatment-related adverse event (AE)

95.8 58.5 86.3 20.8 86.2 27.7

Treatment-related AE leading to discontinuation

39.6 31.0 11.5 7.7 16.1 14.1

Treatment-related death, n (%) 2 (0.6)a 1 (0.3)b 1 (0.3)b

aCardiomyopathy (NIVO+IPI, n=1); Liver necrosis (NIVO+IPI, n=1). Both deaths occurred >100 days after the last treatment.bNeutropenia (NIVO, n=1); colon perforation (IPI, n=1).1

1. Larkin J, et al. NEJM 2015;373:23‒34.

Skin (n=18)

Skin (n=5)

Gastrointestinal (n=46)

Gastrointestinal (n=7)

Endocrine (n=15)

Endocrine (n=2)

Hepatic (n=60)

Hepatic (n=8)

Pulmonary (n=3)

Pulmonary (n=1)

Renal (n=6)

Renal (n=1)0 10 20 30 40 50 60Weeks

5.6 (0.1 – 55.0)

19.4 (1.3 – 50.9)

7.4 (1.0 – 48.9)

26.3 (13.1 – 57.0)

12.1 (2.9 – 17.0)

28.6 (19.1 – 38.1)

7.4 (2.1 – 48.0)

14.1 (1.9 – 25.1)

3.7 (3.7 – 9.4)

6.7 (6.7 – 6.7)

11.3 (3.3 – 23.7)

50.9 (50.9 – 50.9)

NIVO+IPI

NIVO

Checkmate 067: SafetyOnset Grade 3–4 Treatment-Related Select AEs

Circles represent medians; bars signify ranges

Larkin J et al ECC 2015

Toxicity EarlierLonger Time to Resolution

Can a biomarker help us

decide?

Keynote 001 Pembrolizumab

PD-L1 Expression and Response

APS, Allred proportion score.Analysis cut-off date: October 18, 2014.

PD-L1 Positive

1-10% Staining

APS = 2

PD-L1 Negative

0% Staining

APS = 0

PD-L1 Positive

10-33% Staining

APS = 3

PD-L1 Positive

66-100% Staining

APS = 5

0

10

20

30

40

50

60

70

80

90

100

OR

R, %

(9

5%

CI)

ORR, RECIST v1.1

APS 0n = 28

APS 1n = 24

APS 2n = 72

APS 3n = 54

APS 4n = 32

APS 5n = 34

PositiveNegative

Daud A et al, ASCO 2015

<1% PD-L1 NIVO+IPI NIVO IPI

Median OS, mo

(95% CI)

NR

(26.5–NR)

23.5

(13.0–NR)

18.6

(13.7–23.2)

HR (95% CI)

vs NIVO

0.74

(0.52–1.06)─ ─

≥1% PD-L1 NIVO+IPI NIVO IPI

Median OS, mo

(95% CI)NR NR

22.1

(17.1–29.7)

HR (95% CI)

vs NIVO

1.03

(0.72–1.48)─ ─

OS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 39363330272421181512963

60%

49%

41%

OS

(%

)

Months

0

10

20

30

40

50

60

70

80

90

100

0 39363330272421181512963

113 0IPI 11032434450576171798796

117 0NIVO 216505557596265737686103

123 0NIVO+IPI 4186672747479828291102113

164 0IPI 2216474778389102115126138155

171 0NIVO 13698109112117122131139148158165

155 0NIVO+IPI 3278599101102105112116127132144

67%

67%

48%

OS by Tumor PDL-1 Expression at a 1% Cutoff

45

PD-L1 Expression Level <1% PD-L1 Expression Level ≥1%

Patients at risk: Patients at risk:

• ORR of 65.2% for NIVO+IPI and 55.0% for NIVO • ORR of 54.5% for NIVO+IPI and 35.0% for NIVO

Subgroup

Patients Unstratified Hazard Ratio Unstratified Hazard Ratio (95% CI)

NIVO+IPI NIVO PFS OS PFS OS

Overall 314 316 0.77 0.89

<65 years 185 198 0.74 0.81

≥65 years 129 118 0.82 0.99

BRAF Mutant 102 98 0.60 0.71

BRAF Wild-type 212 218 0.86 0.97

ECOG PS = 0 230 237 0.79 0.91

ECOG PS = 1 83 78 0.72 0.82

M0/M1a/M1b 129 132 0.67 0.84

M1c 185 184 0.83 0.90

LDH ≤ ULN 199 197 0.72 0.89

LDH > ULN 114 112 0.79 0.86

LDH > 2 x ULN 37 37 0.70 0.71

PD-L1 ≥5% 68 80 0.87 1.05

PD-L1 <5% 210 208 0.73 0.84

PFS and OS Subgroup Analyses (All Randomized Patients)Descriptive comparison between NIVO+IPI and NIVO

46NIVO+IPI NIVO

20 1

NIVO+IPI NIVO

20 1

The Facts & The Choice….

• Monotherapy with PD-1 works well

– Low toxicity

– 4 year survival in KN-06 is 44%

• Combination Ipi-Nivo also works well!

– Superior to monotherapy for RR and PFS

– But not statistically superior for OS

– Higher Toxicity

The Bottom Line…

• Treatment must be individualized

• It is not an exact science

• Choices will depend upon many factors

– Patients wishes

– Availability and other practical issues

Decision Point….

Age, PS

Tumor PDL-1

Combination

Ipi- Nivo

Monotherapy

Pembro or Nivo

Older Patient,

PS 1 or higher

Younger Patient

Good PS

PDL-1 < 5%

If you cannot make up your mind…

• Have a caipirinha before making your

decision!

check point inhibitors when to use combination or single

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