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Immunotherapy – The Changing Face of Cancer Treatment
Nadeem Ikhlaque MD
Medical Oncologist and Hematologist
Director Lung cancer program
Franciscan Physician Network
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Disclosures
• Speakers Forum and Advisory board member for BMS and Lilly pharmaceuticals
• Advisory board member for Cardinal Oncology
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Gratitude
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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
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Cancer treatment
Surgery
Radiation Therapy
Chemotherapy
Targeted therapy
Immunotherapy
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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
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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%
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Small cell lung Cancer
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Triple Negative Breast Cancer
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Renal Cell Carcinoma
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Gratitude
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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
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Immune System
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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
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Turning on T cellsCheckpoint Blockade Inhibitors
T Cell
Tumor Cell
PD-1
PD-L1
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Checkpoint Blockade InhibitorsTurning on T cells
T Cell
Tumor Cell
T Cell
Tumor Cell
PD-1
PD-L1
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Turning on T cellsCheckpoint Blockade Inhibitors
T Cell
Tumor Cell
T Cell
Tumor Cell
PD-1
PD-L1
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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
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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
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Gratitude
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Gratitude
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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
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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%
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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
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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
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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
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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
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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
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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
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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
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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
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Gratitude
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Gratitude