immunotherapy – the changing face of cancer treatment keynot… · impact of immunotherapy on...

Immunotherapy – The Changing Face of Cancer Treatment

Nadeem Ikhlaque MD

Medical Oncologist and Hematologist

Director Lung cancer program

Franciscan Physician Network

Disclosures

• Speakers Forum and Advisory board member for BMS and Lilly pharmaceuticals

• Advisory board member for Cardinal Oncology

Gratitude

Objectives

Impact of immunotherapy on cancer treatment.

Mechanism of action.

FDA approved indications of Immunotherapy.

Toxicity associated with immunotherapy and how it differs from conventional chemotherapy.

Management of immune related side affects

Long term follow up

Cancer treatment

Surgery

Radiation Therapy

Chemotherapy

Targeted therapy

Immunotherapy

Objectives

Impact of immunotherapy on cancer treatment.

Mechanism of action.

FDA approved indications of Immunotherapy.

Toxicity associated with immunotherapy and how it differs from conventional chemotherapy.

Management of immune related side affects

Long term follow up

Locally Adv. or Met. Urothelial Cancer

1L/2L pembrolizumab,

1L/2L after platinum salt:

• atezolizumab, avelumab, durvalumab, or nivolumab

Copyright Photo: pixologic / 123RF

U.S. FDA Approved Immune-Checkpoint Inhibitors1-7

Merkel Cell Carcinoma

2L avelumab or pembrolizumab

Cutaneous Squamous Cell Carcinoma

1L cemiplimab

Malignant Melanoma

Adjuvant ipilimumab, nivolumab, or pembrolizumab

1L ipilimumab, nivolumab, or pembrolizumab

1L combination nivolumab + ipilimumab

Hepatocellular Carcinoma

2L nivolumab or pembrolizumab after sorafenib

Adv. Renal Cell Carcinoma

1L nivolumab plus ipilimumab

2L nivolumab after anti-angiogenic therapy

MSI-H or dMMR Cancers

2L nivolumab in CRC

2L nivolumab plus ipilimumab in CRC

2L pembrolizumab in any MSI-H/dMMR cancer

Squamous Cell Head & Neck Cancer

1L/2L after platinum chemotherapy:

• nivolumab or pembrolizumab

Cervical Cancer

2L pembrolizumab CPS≧1

Small Cell Lung Cancer

3L nivolumab

Non-Small Cell Lung Cancer

Maintenance durvalumab after chemoradiation

1L pembrolizumab TPS≧50%

1L non-squamous NSCLC

• pembrolizumab + pemetrexed & platinum-salt

• atezolizumab + bevacizumab, paclitaxel & carboplatin

1L squamous NSCLC

• pembrolizumab + carboplatin & (nab-)paclitaxel in

2L pembrolizumab TPS≧1%

2L atezolizumab or nivolumab

Gastric & GEJ Carcinoma

3L pembrolizumab CPS≧1

Classical Hodkin Lymphoma

4L pembrolizumab

3L/4L nivolumab after auto-HSCT and BV

PMBCL

3L pembrolizumab

Updated on 09-Mar-2019 - citations on last page - ©medi-paper.com

Triple-Negative Breast Cancer

1L atezolizumab + paclitaxel protein-bound PD-L1≧1%

Small cell lung Cancer

Triple Negative Breast Cancer

Renal Cell Carcinoma

Gratitude

Objectives

Impact of immunotherapy on cancer treatment.

Mechanism of action.

FDA approved indications of Immunotherapy.

Toxicity associated with immunotherapy and how it differs from conventional chemotherapy.

Management of immune related side affects

Long term follow up

Immune System

CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment

Ribas. NEJM. 2012;366:2517. Slide credit: clinicaloptions.com

Anti–PD-1:Cemiplimab-rwlcNivolumabPembrolizumab

Anti–PD-L1:AtezolizumabAvelumabDurvalumab

Anti–CTLA-4:Ipilimumab

Priming Phase (Lymph Node) Effector Phase (Peripheral Tissue)

T-Cell Migration

Turning on T cellsCheckpoint Blockade Inhibitors

T Cell

Tumor Cell

PD-1

PD-L1

Checkpoint Blockade InhibitorsTurning on T cells

T Cell

Tumor Cell

T Cell

Tumor Cell

PD-1

PD-L1

Turning on T cellsCheckpoint Blockade Inhibitors

T Cell

Tumor Cell

T Cell

Tumor Cell

PD-1

PD-L1

Molecular Determinants of Response to PD-1 and PD-L1 Blockade in Patients With Advanced NSCLC

Rivzi. JCO. 2018;36:633. Slide credit: clinicaloptions.com

• In patients with advanced NSCLC (N = 240):

• TMB assessed by next-generation sequencing

• Tumor PD-L1 expression assessed by IHC (n = 84)

No durable benefitDurable clinical benefit (duration of PR/SD > 6 mos)

0

5

10

15

20

25

TMB HighPD-L1 High

50.0%(10 of 20)

35.3%(6 of 17)

TMB LowPD-L1 High

29.4%(5 of 17)

TMB HighPD-L1 Low

18.2%(4 of 22)

TMB LowPD-L1 Low

Objectives

Impact of immunotherapy on cancer treatment.

Mechanism of action.

FDA approved indications of Immunotherapy.

Toxicity associated with immunotherapy and how it differs from conventional chemotherapy.

Management of immune related side affects

Long term follow up

Gratitude

Gratitude

Rise of Immunotherapy

20142011

• Long-term disease control against recalcitrant cancers

• Game-changing discoveries – more coming

Ipilimumab

introduced for

melanoma

Pembrolizumab,

nivolumab

approved for

melanoma

2015-2016

PD-1/L-1 drugs

benefit even

more of

cancers

2016 ASCOAdvance of the Year

Locally Adv. or Met. Urothelial Cancer

1L/2L pembrolizumab,

1L/2L after platinum salt:

• atezolizumab, avelumab, durvalumab, or nivolumab

Copyright Photo: pixologic / 123RF

U.S. FDA Approved Immune-Checkpoint Inhibitors1-7

Merkel Cell Carcinoma

2L avelumab or pembrolizumab

Cutaneous Squamous Cell Carcinoma

1L cemiplimab

Malignant Melanoma

Adjuvant ipilimumab, nivolumab, or pembrolizumab

1L ipilimumab, nivolumab, or pembrolizumab

1L combination nivolumab + ipilimumab

Hepatocellular Carcinoma

2L nivolumab or pembrolizumab after sorafenib

Adv. Renal Cell Carcinoma

1L nivolumab plus ipilimumab

2L nivolumab after anti-angiogenic therapy

MSI-H or dMMR Cancers

2L nivolumab in CRC

2L nivolumab plus ipilimumab in CRC

2L pembrolizumab in any MSI-H/dMMR cancer

Squamous Cell Head & Neck Cancer

1L/2L after platinum chemotherapy:

• nivolumab or pembrolizumab

Cervical Cancer

2L pembrolizumab CPS≧1

Small Cell Lung Cancer

3L nivolumab

Non-Small Cell Lung Cancer

Maintenance durvalumab after chemoradiation

1L pembrolizumab TPS≧50%

1L non-squamous NSCLC

• pembrolizumab + pemetrexed & platinum-salt

• atezolizumab + bevacizumab, paclitaxel & carboplatin

1L squamous NSCLC

• pembrolizumab + carboplatin & (nab-)paclitaxel in

2L pembrolizumab TPS≧1%

2L atezolizumab or nivolumab

Gastric & GEJ Carcinoma

3L pembrolizumab CPS≧1

Classical Hodkin Lymphoma

4L pembrolizumab

3L/4L nivolumab after auto-HSCT and BV

PMBCL

3L pembrolizumab

Updated on 09-Mar-2019 - citations on last page - ©medi-paper.com

Triple-Negative Breast Cancer

1L atezolizumab + paclitaxel protein-bound PD-L1≧1%

Name Company Target Indications Details

Nivolumab

(Opdivo®)2

Bristol-Myers

Squibb

PD-1 • Adj./1L Inoperable or metastatic melanoma • Single agent in BRAF-WT and BRAF-MU or in combination with

ipilimumab

• Adj. treatment of melanoma • Patients with lymph node involvement or metastatic disease, and

• Underwent complete resection

• 2L metastatic NSCLC • Irrespective of PD-L1 expression

• Failure on platinum chemotherapy

• Failure on EGFR/ALK targeted agent (if indicated)

• 3L metastatic SCLC • Progression on at least two lines of prior treatment

• Including: one line of platinum-based therapy

• 1L advanced, intermediate or poor risk renal cell carcinoma • In combination with ipilimumab

• 2L advanced renal cell carcinoma • After prior treatment with anti-angiogenic drug

• 3L/4L classical Hodgkin lymphoma • Adult patients

• After prior auto-HSCT and (4L-only) brentuximab vedotin (BV)

• 1L recurrent or metastatic head and neck squamous cell carcinoma • PD on or after (adjuvant) platinum chemotherapy

• 1L/2L locally advanced or metastatic urothelial carcinoma • Failure on prior platinum chemotherapy

• PD<12 months after (neo)adjuvant platinum chemotherapy

• MSI-H or dMMR metastatic colorectal cancer • Single agent or in combination with ipilimumab

• Adult and paediatric patients (≧12 years)

• PD following fluoropyrimidine, oxaliplatin, and irinotecan

• 2L heptocellular carcinoma • PD on prior sorafenib

Ipilimumab

(Yervoy®)3

Bristol-Myers

Squibb

CTLA4 • 1L inoperable or metastatic melanoma • Adult and paediatric patients (≧12 years)

• Single agent or in combination with nivolumab (see Opdivo® USPI)

• Adjuvant treatment of stage IIIa cutaneous melanoma • Patients with pathological involvement of the regional lymph nodes >1 mm

who underwent complete resection, including total lymphadenectomy

• 1L advanced, intermediate or poor risk renal cell carcinoma • In combination with nivolumab

• MSI-H or dMMR metastatic colorectal cancer • Single agent or in combination with nivolumab

• Adult and paediatric patients (≧12 years)

• PD following fluoropyrimidine, oxaliplatin, and irinotecan

U.S. FDA Approved Immune-Checkpoint Inhibitors

Updated on 09-Mar-2019 - citations on last page - ©medi-paper.com

U.S. FDA Approved Immune-Checkpoint InhibitorsName Company Target Indications Details

Pembrolizumab

(Keytruda®)1

Merck (MSD) PD-1 • Adj. treatment of melanoma • Patients with lymph node involvement, and

• Underwent complete resection

• 1L inoperable or metastatic melanoma • Single agent

• 1L metastatic Merkel cell carcinoma • Adult and paediatric patients

• 2L metastatic NSCLC with PD-L1 expression • Failure on platinum-doublet chemotherapy

• Failure on EGFR/ALK targeted agent (if indicated)

• TPS≧1%

• 1L metastatic non-squamous NSCLC • In combination with pemetrexed and a platinum chemotherapy

• No known EGFR/ALK tumour-driver mutations

• 1L metastatic squamous NSCLC • In combination with carboplatin and paclitaxel or nab-paclitaxel

• 1L metastatic NSCLC with high PD-L1 expression • No known EGFR/ALK tumour-driver mutations

• TPS≧50%

• 1L/2L recurrent or metastatic head and neck squamous cell carcinoma • PD on or after (adjuvant) platinum chemotherapy

• 4L refractory classical Hodgkin lymphoma • Adult and paediatric patients with disease relapse after 3 prior treatments

• 3L refractory PMBCL • Adult and paediatric patients relapsed ≧2 or more prior lines of therapy.

• Limitation of use: not recommended when PMBCL patient requires

urgent cytoreductive therapy

• 1L/2L locally advanced or metastatic urothelial carcinoma • Ineligible for cisplatin chemotherapy and a CPS≥1

• Ineligible for platinum chemotherapy irrespective of PD-L1 expression

• PD on prior platinum chemotherapy

• PD<12 months after (neo)adjuvant platinum chemotherapy

• MSI-H or dMMR cancers • Adult and paediatric patients

• PD in solid tumours following prior treatment and no other, satisfactory

alternative treatment options

• Colorectal cancer progressed following FOLFOXIRI

• Limitation of use: safety and effectiveness not established in paediatric

patients with MSI-H CNS cancers

• Recurrent locally advanced or metastatic gastric GEJ adenocarcinoma • CPS≥1

• Disease progression ≥2 prior lines of therapy, including fluoropyrimidine-

and platinum-containing chemotherapy

• PD following HER2-targeted therapy, if indicated

• Recurrent or metastatic cervical cancer • CPS≥1 and PD on chemotherapy

• 2L heptocellular carcinoma • Pretreated with sorafenib

Updated on 09-Mar-2019 - citations on last page - ©medi-paper.com

U.S. FDA Approved Immune-Checkpoint InhibitorsName Company Target Indications Details

Atezolizumab

(Tecentriq®)4

Roche & Genentech PD-L1 • 1L/2L locally advanced or metastatic urothelial carcinoma • Ineligible for cisplatin chemotherapy and PD-L1 expression (PD-L1

stained tumour-infiltrating immune cells [IC] covering ≥ 5% of the tumor

area)

• Ineligible for platinum chemotherapy regardless of PD-L1 expression

• Failure on prior platinum chemotherapy

• PD<12 months after (neo)adjuvant platinum chemotherapy

• 1/L metastatic non-squamous NSCLC • In combination with bevacizumab, paclitaxel, and carboplatin

• No EGFR or ALK genomic tumour aberrations

• 2/L metastatic NSCLC • Irrespective of PD-L1 expression

• Failure on platinum chemotherapy

• Failure on targeted agent (if applicable)

• 1/L unresectable locally advanced or metastatic triple-negative breast

cancer

• In combination with paclitaxel protein-bound

• PD-L1 stained tumour-infiltrating immune cells (IC) of any intensity

covering ≥1% of the tumour area

Avelumab

(Bavencio®)5

Merck Serono &

Pfizer

PD-L1 • 1L metastatic Merkel cell carcinoma • Adult and paediatric patients (≧12 years)

• 1L/2L locally advanced or metastatic urothelial carcinoma • Failure on prior platinum chemotherapy

• PD<12 months after (neo)adjuvant platinum chemotherapy

Durvalumab

(Imfinzi®)6

AstraZeneca PD-L1 • 1L/2L locally advanced or metastatic urothelial carcinoma • Failure on prior platinum chemotherapy

• PD<12 months after (neo)adjuvant platinum chemotherapy

• Maintenance for unresectable, stage III NSCLC • No PD following concurrent platinum-based chemotherapy and radiation

therapy

Cemiplimab

(Libtayo®)7

Sanofi PD-L1 • 1L metastatic cutaneous squamous cell carcinoma (CSCC) • Not amenable for curative surgery or curative radiation

Updated on 09-Mar-2019 - citations on last page - ©medi-paper.com

ASCO 2019 Lung - NSCLC Immunotherapy (1)

REF Study Study details Line Drug Biomarker/Subgroup N Primary endpoint Secondary endpoints

21 Lung-MAP S1400INCT02785952(N=350)

Phase III, randomisedStage IV SQ-NSCLC

≥2ndnivolumab+ipilimumab

nivolumab

AllPD-L1 ≥5PD-L1 <5TMB ≥10TMB <10AllPD-L1 ≥5PD-L1 <5TMB ≥10TMB <10

125

127

mOS 10.0 mo NS14.1 mo NS8.3 mo NS13.1 mo NS7.6 mo NS11.0 mo NS12.0 mo NS10.3 mo NS11.4 mo NS10.0 mo NS

IA mPFS / ORR3.8 mo NS / 18%3.9 mo NS 4.4 mo NS4.2 mo NS1.9 mo NS2.9 mo NS / 19%2.9 mo NS1.6 mo NS3.4 mo NS2.7 mo NS

22 KEYNOTE-189NCT02578680(N=616)

Phase III, double-blind, randomisedStage IV NSQ-NSCLC

1st Arm A: pembrolizumab + pemetrexed + carboplatin or cisplatinArm B: placebo + pemetrexed + carboplatin or cisplatin

Arm A + Arm BAll

- TPS ≥50%

- TPS 1%–49%

- TPS <1%

410206

616

202

186

190

mOS: 22.0 mo mOS: 10.7 mo

HR Arm A vs Arm BOS: 0.56 (0.45, 0.70)PFS: 0.48 (0.40, 0.58)OS: 0.59 (0.39, 0.88)PFS: 0.36 (0.26, 0.51)OS: 0.62 (0.42, 0.92)PFS: 0.51 (0.36. 0.73)OS: 0.52 (0.36, 0.74)PFS: 0.64 (0.47, 0.89)

HR Arm A vs Arm B

PFS2: 0.47 (0.33, 0.69)

PFS2: 0.59 (0.41, 0.86)

PFS2: 0.46 (0.33, 0.66)

23 KEYNOTE-001NCT01295827(N=550)

Phase Ib, open-label, randomisedlaNSCLC or mNSCLC

≥1stpembrolizumab All

Treatment-naïve- TPS ≥50%- TPS 1%–49%Prior treatment(s)- TPS ≥50%- TPS 1%–49%- TPS <1%

550101275244913816890

ORR / median DoR

42% / 16.8 mo

23% / 38.9 mo

mOS / OS-rate 36- / 60-mo

22.3 mo / 37& / 23.2%35.4 mo / 48.1% / 29.6%19.5 mo / 27.5% / 15.7%10.5 mo / 20.9% / 15.5%15.4 mo / 30.4% / 25.0%8.5 mo / 16.9% / 12.6%8.6 mo / 11.1% / 3.5%

Abbreviations and citations on final slideData based on public abstracts and clinicaltrials.gov information

Abbreviations and Citations

Abbreviations Citations

1L: first-line 1 Prescribing information pembrolizumab (Keytruda®), revised: 02/2019

2L: second-line 2 Prescribing information nivolumab (Opdivo®), revised: 02/2019

3L: third-line 3 Prescribing information ipilimumab (Yervoy®), revised: 07/2018

4L: fourth-line 4 Prescribing information atezolizumab (Tecentriq®), revised: 03/2019

Adv: advanced 5 Prescribing information avelumab (Bavencio®), revised: 10/2018

ALK: anapaestic lymphoma kinase 6 Prescribing information durvalumab (Imfinzi®), revised: 02/2018

auto-HSCT: autologous haematopoietic stem cell transplantation 7 Prescribing information cemiplimab (Libtayo®), revised: 09/2018

BV: brentuximab vedotin

CNS: central nervous system

CPS: combined proportion score

dMMR: mismatch-repair deficient

EGFR: epidermal growth factor receptor

GEJ: gastroesophageal junction

HER2: human epidermal growth factor receptor 2

Met: metastatic

MSI-H: microsatellite instability-high

Mu: mutation

NSCLC: non-small cell lung cancer

PMBCL: primary mediastinal B-cell lymphoma

PD: progression disease

PD-1: programmed death 1

PD-L1: programmed death ligand 1

TPS: tumour proportion score

WT: wild-type

Updated on 09-Mar-2019 - ©medi-paper.com

Objectives

Impact of immunotherapy on cancer treatment.

Mechanism of action.

FDA approved indications of Immunotherapy.

Toxicity associated with immunotherapy and how it differs from conventional chemotherapy.

Management of immune related side affects

Long term follow up

Objectives

Impact of immunotherapy on cancer treatment.

Mechanism of action.

FDA approved indications of Immunotherapy.

Toxicity associated with immunotherapy and how it differs from conventional chemotherapy.

Management of immune related side affects

Long term follow up

Objectives

Impact of immunotherapy on cancer treatment.

Mechanism of action.

FDA approved indications of Immunotherapy.

Toxicity associated with immunotherapy and how it differs from conventional chemotherapy.

Management of immune related side affects

Long term follow up

Gratitude

Gratitude