personalized treatment in the era of molecular biology by suman … · 2015-11-30 · geftinib egfr...
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Personalized treatment in the era of molecular biologyBy Suman Rao, MD
Overview of Biomarkers: What is a Biomarker?
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal
or abnormal process, or of a condition or disease
M2.T.LC.BioMOA.7
DRIVER Mutations DRIVER mutations-
useful biomarkers for predicting efficacy of targeted therapy
somatic genome alterations occur in the genome of cancer cells within genes that
encode for proteins critical to cell growth and survival. impart an oncogene-addicted biology to the
transformed cell, meaning that the mutated protein causes reliance within the cancer cell to receive a signal from the driver in order to survive
Chemotherapy A meta-analysis incorporated individual patient data
from 2714 cases enrolled on 16 randomized trials
Conducted before driver mutations Chemotherapy associated with improved survival , 1
year survival rate 29 versus 20 percent . Independent of histology , PFS, age Led to use of 4 cycles of platinum doublet
chemotherapy followed by observation as standard Also has been proven to improve Quality of life
Patient 1 53 year old grandmother , smoked a PPD for 30 years.
Quit 3 years ago Presented with dyspnea, chest pain, weight loss rapidly
progressive Was in wheel chair due to dyspnea. Multiple neck
lymph nodes on exam CT scan with right plural effusion Molecular testing negative. PD1 negative
Carbo/Pemetrexed/BevacizumabBefore treatment After treatment
Antiangiogenesis agents Bevacizumab – Direct inhibitor of Vascular endothelial
growth factor receptor I Ramucirumab – inhibitor of Vascular endothelial
growth factor II
VEGF inhibition Vascular endothelial growth factor (VEGF) is a potent
endothelial-specific angiogenic factor. In NSCLC, high levels of VEGF expression are associated with a poor prognosis.
bevacizumab, a recombinant humanized monoclonal antibody (MoAb) that binds VEGF, thereby preventing its interaction with the VEGF receptor.
Bevacizumab ECOG trial E4599, 878 patients randomized to
paclitaxel plus carboplatin or the same plus Bevacizumab followed by Bevacizumab maintanence .
Bevacizumab significantly increased ORR (35 versus 15 percent), OS (median 12.3 versus 10.3 months), one-year and two-year survival rates (51 versus 44 and 23 versus 15 percent, respectively), and PFS (6.2 versus 4.5 months).
Bevacizumab Meta-analysis based upon four trials bevacizumab
increased both PFS and OS compared with chemotherapy ( hazard ratio for death or progression 0.90 and 0.72 respectively)
Increases Grade 3 toxicity Greater efficacy in adenocarcinoma Not clear if there is additional benefit with
maintanence chemotherapy
VEGF inhibitor side effects Fatigue Dysphonia Hypertension
Monitor and treat early Polycythemia Bleeding
Mostly minor , maybe up to 30% 3.5 % incidence of major bleeding problems
Nephrotic syndrome Delayed wound healing
Overview of Biomarkers: Prognostic vs Predictive
Prognostic: A biomolecule that predicts outcome of disease’s progression/survival independent of therapy Indicator of the innate tumor aggressiveness
Predictive: A biomolecule that predicts for differential treatment benefit (therapeutic efficacy) Interaction with therapy on patients’ outcome
Biomarkers can be both prognostic and predictive
Bepler G, et al. Cancer Control. 2008;15(2):130-139.M2.T.LC.BioMOA.8
Overview of Biomarkers: Adenocarcinoma NSCLC1999 2005-20122004
Unknown75%
Unknown60%
Unknown35%
KRAS
KRAS
KRAS
EGFR
EGFR
ALKPIK3CA
BRAFMETHER2
MEKROS1
RET
Kris MG, et al. IASLC. 2012 (Breakout Session I).M2.T.LC.BioMOA.9
Patient 2 64 year old , just retired teacher , non smoker. Planned
vacations with husband . Presented with cough, dyspnea treated 3 times for
pneumonia. Chest X ray was negative CT scan showed extensive bilateral disease Needed ICU management post bronchoscopy,
discharged on Home O2 therapy Molecular testing positive for EGFR mutation Exon 19
ErlotinibBefore Treatment After Treatment
ErlotinibBefore Treatment After Treatment
EGFR Mutations: Frequency According to Clinical Characteristics in NSCLC
Mitsudomi T, et al. Int J Clin Oncol. 2006;11:190-198.Retrospective review of 2880 cases
Ethnicity:Asian
Gender: female
Smoking history:never smoker
Histology:adenocarcinoma
Wild-type
MUT+38%
WT62%
MUT+30%WT
70%
WT68%
MUT+32% WT
53%MUT+
47%
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EGF EGF
Intracellular
Extracellular
EGFRactivatingmutations (eg L858R)WT
EGFR
Sensitive Hypersensitive
EGFR TKI
EGFR TKI
Mutant EGFR kinase domain has higher affinity for erlotinib than for
ATP vs WT EGFR kinase domain
EGFR Mutations: Receptor Biology – Erlotinib Sensitivity in WT vs Mutated EGFR
1. Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139. 2. Paez JG, et al. Science. 2004;304:1497-1500. 3. Carey KD, et al. Cancer Res. 2006;66:8163-8171.
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EGFR MUTANT Lung Cancer 15 % of lung cancers carry this mutation Higher in non smokers Seen in 60 % of Asians with lung cancer Targetable mutations are in Exon 19/21
EGFR inhibitors Erlotinib Gefitinib Afatinib In studies ( after progression on first line)
Rocelitinib Osimertinib just approved
Geftinib IPASS trial, 1217 patients randomly assigned to geftinib or
carboplatin plus paclitaxel Asian Adenocarcinoma Either never smokers or former light smokers. PFS significantly better with gefitinib (12-month
progression-free rate 25 versus 7 percent, HR for progression 0.74).
OS was not statistically significant (median 18.8 versus 17.4 months, HR for death 0.90, 95% CI 0.79-1.02)
Geftinib EGFR mutations were present in 60 percent of the 437 patients. For patients with EGFR mutation
PFS was significantly prolonged with geftinib median 9.5 versus 6.3 months HR for progression 0.48)
OS was not increased (median 22 months in both groups, HR 1.00)
For those without an EGFR mutation PFS was significantly shorter with gefitinib (median 1.5 versus
6.5 months, HR 2.85 for progression ) OS was not statistically significant (median 11.2 versus 12.7
months, HR for death 1.18)
Erlotinib OPTIMAL trial – 154 patients randomized to Erlotinib vs Gemcitabine plus
Carboplatin Erlotinib improved PFS (13.1 versus 4.6 months, HR 0.16) ORR (83 versus 36 percent). Overall survival was not significantly different (22.8 versus 27.2 months,
HR 1.19 ), EURTAC trial – 174 patients randomized to erlotinib or a platinum-based
chemotherapy doublet PFS , increased with erlotinib (9.7 versus 5.2 months, HR 0.37). no difference in OS in the erlotinib versus chemotherapy (19.3 versus 19.5
months, HR 1·04.
ENSURE trial – 275 patients randomized to erlotinib or gem and cisplatinerlotinib improved PFS (11.0 versus 5.5 months, HR 0.34. Median OS
similar in the two groups (26.3 versus 25.5 months, HR 0.91, 95% CI 0.63-1.31).
Afatinib LUX LUNG 3 Trials
PFS significantly with Afatinib (median 11.1 months versus 6.9 months, 12 month progression-free rate 51 versus 21 percent, HR for progression 0.58
ORR was significantly increased with afatinib (56 versus 23 percent). Time to symptom progression and quality of life were also significantly improved with afatinib
Side effects Skin rash
Acneform Pustular Exfoliative/ dry
Diarrhea Pneumonitis Hepatotoxicity
EGFR Inhibitor Side effects TREATMENT of Rash
Mild Sunscreen 1% cortisone cream Clindamycin gel 1%
Moderate 2.5% Hydrocortisone or Floucinonide cream Clindamycin gel Doxycycline 100 mg bid
Severe Dose reduction Doxycycline 100 mg bid
Diarrhea Imodium , aggressive use Lomotil Dose reductions Drug holidays
Patient 3 66 year old RN, just retired, never smoker. Asian
heritage Cough about 8 months prior, small lung lesion, missed Presented with increased cough, dyspnea. Multiple
bone metastases on imaging, then admitted to back pain
Molecular testing was negative for EGFR, QNS for ALK 2nd bronchoscopy , testing positive for ALK
CrizotinibBefore Treatment After Treatment
ALK mutations 3-8% of unselected adenocarcinoma of lung Younger, non smokers Crizotinib is the first line treatment of choice 2nd generation such as Ceritinib already approved
CRIZOTINIB Phase III trial 347 patients ,previously treated with
platinum-based chemotherapy regimen, received crizotinib, pemetrexed or docetaxel
Cross over to Crizotinib at progression PFS increased with crizotinib compared with
chemotherapy (median 7.7 versus 3 months, hazard ratio [HR] for progression 0.49.
The ORR significantly increased (65 versus 20 percent). median time to response 6.3 versus 12.6 weeks and of longer duration (32 versus 24 weeks).•
No significant difference in overall survival (median 20.3 versus 22.8 months, HR for death 1.02).Likley because of crossover effect
Crizotinib 2nd trial, 343 chemotherapy naïve patients randomized to
crizotinib or chemotherapy with pemetrexed plus either cisplatin or carboplatin
Crossover to crizotinib was permitted for those treated with chemotherapy.
PFS, was significantly prolonged with crizotinib compared with chemotherapy (median 10.9 versus 7 months, HR 0.45)
The ORR also significantly increased (74 versus 45 percent).
OS was not significantly different (HR 0.82). However, majority of patients crossed over to Crizotinib.
Ceritinib 246 patients with ALK positive NSCLC treated with
ceritinib. 163 previously treated with an ALK inhibitor ORR was 58%, 55 % in those with prior crizotinib, 66 % in
ALK inhibitor naïve patients. Median duration of response 10 months in the entire
cohort, 7.4 months with prior crizotinib treatment. The median PFS for the entire cohort was 8.2 months,
including 6.9 months for those previously treated with an ALK inhibitor and not estimable (lower bound of 95% CI 8.3 months) for those not previously on ALK inhibitor.
Patient 4 69 year old Grandmother , never smoked Actively taking care of her 2 young grand kids Treated with chemotherapy with Carboplatin.
Pemetrexed for adenocarcinoma that was EGFR/ ALK negative and progressed
Presented in wheelchair with left hip pain, severe cough, hemoptysis
PembrolizumabBefore Treatment After Treatment
Patient 5 56 year old woman , 2 PPD for 40 years Working full time, has teenage children Husband post transplant for lymphoma, doing well Presented with large neck nodes, headaches, facial
swelling, cough, weight loss PD1 positive , but negative for EGFR/ ALK
PembrolizumabBefore Treatment After Treatment
PembrolizumabBefore Treatment After Treatment
Multiple opportunities for intervention exist for immune therapy in cancer
42
Dendritic cells
T cells
Major components of the immune-suppressed tumor microenvironment include myeloid-derived suppressor cells and regulatory T cells, as well as associated soluble factors
Microenvironment
The generation of tumor-reactive T cells to eradicate tumors is the mainstay of immuno-oncology. Activated, antigen-specific T-cells can be derived by multiple means:
• Checkpoint inhibitors can relieve immune tolerance and rescue antitumor effector T cell, while costimulatory antibodies can promote activation
Dendritic cells lay at the intersection of innate and adaptive immunity, both capturing antigens in the periphery
and presenting them to T cells to induce activation and promote a
specific and targeted immune response
Prepared by Merck and DAVA OncologyConfidential – not for distribution
Immunological checkpoints normally regulate immune responses
CTLA-4: development of tolerance, blunts antitumor responses
Anti–CTLA-4 effects: prevents development of tolerance, augments antitumor responses, exacerbates autoimmune disease
43
Cancer evades the immune system by engaging CTLA-4 and PD-1
PD-1 (CD279): suppresses T-cell activation in peripheral tissues during inflammation or immune activation, restricting tissue damage
Anti–PD-1 effects: enhanced immune tumor recognition, restricts tumorigenesis and invasiveness
Harvey, Clin Pharmacol Ther. 2014; 96: p214; DAVA Oncology Lung Compass. 2014
Prepared by Merck and DAVA OncologyConfidential – not for distribution
Immune checkpoints function to prevent overactivation and the ensuing damage to healthy tissue
44
Priming phase(Lymph node)
CD28
CTLA4
B7
B7
TCRMHC
Dendritic cell
T cell
Activation
Anergy
Effector phase(Periphery)
B7
PD-1 PD-L1
CD28
TCR MHC
Cancer cell
T cell
Activation
Tolerance
CTLA-4 is exclusively expressed on T cells, and functions primarily at the early stages of T-cell activation. The major physiological role of CTLA-4 is likely downregulation of CD4(+) helper T cells.
PD-1 is expressed on T cells as well as other activated lymphocytes, in contrast to CTLA-4. PD-1 inhibitory signaling is thought to prevent autoimmunity by limiting the activity of T cells in the periphery.
T-cell activation is dependent on a balance between co-stimulatory signals, such as that provided by CD28, as well as co-inhibitory signals, as supplied by immune checkpoint molecules.
Pardoll, Nat Rev Cancer. 2012; 12: p252
Prepared by Merck and DAVA OncologyConfidential – not for distribution
The PD-1 Pathway Controls Immune Tolerance and is ‘Hijacked’ by Cancers to Block Immune Rejection
45
PD-1 is expressed on T-lymphocytes to maintain immune tolerance
- PD-1 knock-out mice develop spontaneous autoimmunity
- Genetic variants of PD-1 are linked to human disease (e.g. rheumatoid arthritis, diabetes)
PD-L1 (PD-1 ligand) is expressed by many human cancers to ‘hijack’ the PD-1 pathway
- Aberrant PD-L1 expression correlates with poor prognosis and poor survival in most solid cancers
- PD-1 expression marks anergic tumor-infiltrating lymphocytes
Strong functional evidence indicates that the PD-1 pathway is also utilized by pathogenic viruses (HIV, HBV, HCV) to evade immunity
Prepared by Merck and DAVA OncologyConfidential – not for distribution
Nivolumab Mechanism of Action PD-1 expression on tumor-infiltrating lymphocytes is associated with decreased cytokine
production and effector function10
Nivolumab binds PD-1 receptors on T cells and disrupts negative signaling triggered byPD-L1/PD-L2 to restore T-cell antitumor function11–13
MHC
PD-L1
PD-1 PD-1
PD-1 PD-1
T-cellreceptorT-cell
receptor
PD-L1PD-L2
PD-L2
MHC
CD28 B7
T cell
NFκBOther
PI3KDendritic
cellTumor cell
IFNγ
IFNγR
Shp-2Shp-2
Nivolumab: PD-1 Receptor Blocking Ab
CheckMate 057 (NCT01673867) Study Design
PD-L1 expression measured using the Dako/BMS automated IHC assay14,15
Fully validated with analytical performance having met all pre-determined acceptance criteria for sensitivity, specificity, precision, and robustness
aMaintenance therapy included pemetrexed, bevacizumab, or erlotinib (not considered a separate line of therapy); b Per RECIST v1.1 criteria as determined by the investigator.
Rand
omiz
e 1:1
• Stage IIIB/IV non-SQ NSCLC• Pre-treatment (archival or recent) tumor
samples required for PD-L1
• ECOG PS 0–1
• Failed 1 prior platinum doublet
• Prior maintenance therapy alloweda
• Prior TKI therapy allowed for knownALK translocation or EGFR mutation
N = 582
Nivolumab3 mg/kg IV Q2W
until PD orunacceptable toxicity
n = 292
Docetaxel75 mg/m2 IV Q3W
until PD orunacceptable toxicity
n = 290
• Primary Endpoint– OS
• Additional Endpoints– ORRb
– PFSb
– Safety– Efficacy by tumor PD-L1
expression– Quality of life (LCSS)
Patients stratified by prior maintenance therapy and line of therapy (second- vs third-line)
Overall Survival
Symbols represent censored observations.
Nivolumab
(n = 292)
Docetaxel(n = 290)
mOS, mo 12.2 9.4
HR = 0.73 (96% CI: 0.59, 0.89); P = 0.0015
Nivolumab
Docetaxel
1-yr OS rate = 51%
1-yr OS rate = 39%
292 232 194 169 146 123 62 32 09
290 244 194 150 111 88 34 10 05
Nivolumab
Docetaxel
Number of Patients at Risk
OS
(%)
Time (months)
100
90
80
70
60
50
40
30
10
0
20
27211815129630 24
100
90
80
70
60
50
40
30
10
0
20
Progression-free Survival
Symbols represent censored observations.
Nivolumab
(n = 292)
Docetaxel
(n = 290)
mPFS, mo
2.3 4.2
HR = 0.92 (95% CI: 0.77, 1.11); P = 0.3932
27211815129630 24
PFS
(%)
Time (months)
292 128 82 58 46 35 17 7 02
290 156 87 38 18 6 2 1 01
Nivolumab
Docetaxel
Number of Patients at Risk
Nivolumab
Docetaxel
1-yr PFS rate = 19%
1-yr PFS rate = 8%
NivoDoc
NivoDoc
100
90
80
70
60
50
40
30
10
0
20
Time (months)
100
90
80
70
60
50
40
30
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0
20
24211815129630 27Time (months)
24211815129630 27
Symbols represent censored observations.
OS by PD-L1 Expression
mOS (mo)
Nivo
10.4
Doc 10.1
mOS (mo)
Nivo
17.2
Doc
9.0
mOS (mo)
Nivo
9.9
Doc 10.3
mOS (mo)
Nivo
19.4
Doc
8.0
Time (months)
≥5% PD-L1 expression level
<5% PD-L1 expression level
mOS (mo)
Nivo
18.2
Doc
8.1
mOS (mo)
Nivo
9.7
Doc
10.1
≥1% PD-L1 expression level
HR (95% CI) = 0.59 (0.43, 0.82)
Time (months)
<1% PD-L1 expression level
OS
(%)
HR (95% CI) = 0.90 (0.66, 1.24)
HR (95% CI) = 0.43 (0.30, 0.63)
HR (95% CI) = 1.01 (0.77, 1.34)
OS
(%)
Time (months)
Time (months)
≥10% PD-L1 expression level
<10% PD-L1 expression level
HR (95% CI) = 0.40 (0.26, 0.59)
HR (95% CI) = 1.00 (0.76, 1.31)
24211815129630 27
100
90
80
70
60
50
40
30
10
0
20
100
90
80
70
60
50
40
30
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0
20
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24211815129630 27
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20
SummaryNivolumab is the first PD-1 inhibitor to demonstrate a survival benefit versus
standard-of-care docetaxel in previously-treated patients with advanced SQ NSCLC 41% reduction in risk of death (HR 0.59; P = 0.00025)
1-yr OS: 42% vs 24%
mOS: 9.2 vs 6.0 mo
Nivolumab demonstrated superiority over docetaxel across all secondary efficacy endpoints ORR: 20% vs 9% (P = 0.0083)
1-yr PFS: 21% vs 6.4%; mPFS: 3.5 vs 2.8 mo (HR 0.62; P = 0.0004)
Nivolumab benefit wasindependent of PD-L1 expression
The safety profile of nivolumab was favorable versus docetaxel and consistent with prior studies
Nivolumab received FDA approval in the US on March 4, 2015 for metastatic SQ-NSCLC with progression on or after platinum-based chemotherapy
Treatment-related AEs Reported in ≥10% of Patients
a No grade 5 events were reported at DBL; 1 grade 5 event was reported for nivolumab post-DBL.
Nivolumab (n = 287) Docetaxel (n = 268)Any Grade,
%Grade 3–4,a
%Any Grade,
%Grade 3–4,a
%Total patients with an event 69 10 88 54
Fatigue 16 1 29 5Nausea 12 1 26 1Decreased appetite 11 0 16 1Asthenia 10 <1 18 2Diarrhea 8 1 23 1Peripheral edema 3 0 10 <1Myalgia 2 <1 11 0Anemia 2 <1 20 3Alopecia <1 0 25 0Neutropenia <1 0 31 27Febrile neutropenia 0 0 10 10Leukopenia 0 0 10 8
Pembrolizumab (MK-3475) (formerly lambrolizumab)
Humanized IgG4k antibody variable region (mouse anti-human PD-1 antibody grafted into human IgG4
Ig) Very high affinity: Kd=28pM PD-L1 IC50 0.1-0.3nM PD-L2 IC50 0.5-0.9nM Does not engage Fc receptors or activate complement, so reduced ADCC
53 Prepared by Merck and DAVA OncologyConfidential – not for distribution
Mechanism of action of pembrolizumab (MK-3475)
54
PD-1
Tumorcell
PD-L1
AnergicT cell
Tumorcell
ActivatedT cell
Tumorcell
1. MK-3475 binds PD-1
2. Bound MK-3475 blocks the interaction between PD-1 and PD-L1
3. Anergic MK-3475–bound cells become activated
4. Activated cells promote immune-mediated tumor cell killing
MK-3475
Control mAb treated Anti–PD-1 treated
CD8b CD8bMC38 Mouse Colon Adenocarcinoma Model
Pink = CD8b T-cell infiltrate
ActivatedT cell
Prepared by Merck and DAVA OncologyConfidential – not for distribution
55
Keynote - 024Phase III Study of Pembrolizumab Monotherapy vs. a Platinum-Based Doublet in First-Line PD-L1(+)a “Strong” Stage IV NSCLC
Patients: • Stage IV NSCLC• Measurable disease• ECOG PS 0-1• PD-L1 IHC strong
(defined as staining in ≥50% of tumor cells)
• ALK translocation negative
• No EGFR sensitizing mutation
• No untreated CNS metastases
R1:1
N=300
Pembrolizumab200 mg q3w
Up to 2 years
Platinum Doubletq3w, 4-6 cycles
paclitaxel/carboplatinpemetrexed/carboplatin
pemetrexed/cisplatin gemcitabine/carboplatin
gemcitabine/cisplatin (nonsquamous Hx, +/-
pemetrexed maintenance)
PD
PD
Primary Endpoint: PFSSecondary Endpoints: OS, ORR
OffStudy
Cross-over
OffStudy
* Positive defined as proportion score (PS) of >1%, where weakly positive is 1-49% and strongly positive is ≥50% .
25% of NSCLC patients are PD-L1(+) “strong”
Prepared by Merck and DAVA OncologyConfidential – not for distribution
Keynote-001: estimated prevalence of PD-L1 for NSCLC
56
In 824 samples evaluated by clinical trial assay:
Prevalence
39.2% 37.6% 23.2%
PD-L1 ≤ 1% PD-L1 ≥ 50%PD-L1 = 2 to 49%
NEJM.org, April 19, 2015
PFS Overall Survival
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Pembrolizumab FDA approved based on KEYNOTE-001 trial
ORR of 20% among 495 previously treated and treatment-naive patients
The overall response rate was much higher, at 45.2%, among a cohort of patients with high PD-L1-expressing NSCLC.
Pembrolizumab Median duration of response 12.5 months , regardless
of the degree of PD-L1 expression. Median overall survival was 12.0 months (95% confidence interval [CI], 9.3 - 14.7 months) for all patients, 9.3 months (95% CI, 8.4 - 12.4 months) for previously treated patients, and 16.2 months (95% CI, 16.2 months - not reached) for previously untreated patients.
Pembrolizumab: Selected ASCO 2015
15 Abstracts presented:1 phase III trial:
KEYNOTE-040: Pembrolizumab vs standard therapy in metastatic head and neck cancer
4 phase II trials: KEYNOTE-002: Pembrolizumab vs chemotherapy for ipi-refractory
advanced melanoma SARC-028: Pembrolizumab in patients with advanced sarcoma KEYNOTE-001: Population pharmacokinetics Safety and efficacy in melanoma patients with untreated brain
metastases
10 phase I trials
59 Prepared by Merck and DAVA OncologyConfidential – not for distribution
Treatment-related Select AEs
Includes events reported in ≥2.5% of patients.a No grade 5 events were reported at DBL;1 grade 5 event for nivolumab was reported post-DBL.
Nivolumab (n = 287) Docetaxel (n= 268)Any Grade Grade 3–4a Any Grade Grade 3–4a
Endocrine, %Hypothyroidism 7 0 0 0
Gastrointestinal, %Diarrhea 8 1 23 1
Hepatic, %ALT increasedAST increased
33
0<1
11
<10
Pulmonary, %Pneumonitis 3 1 <1 <1
Skin, %RashPruritusErythema
981
<100
314
000
Hypersensitivity/Infusion reaction, %
Infusion-related reaction 3 0 3 <1• Select AEs: AEs with potential immunologic etiology that require frequent monitoring/intervention
Pembrolizumab irAE Package Insert warnings and precautions
61
Hypophysitis
Skin: Dermatitis, SJS, vitiligo, rash,
Pneumonitis
Hepatitis
EyeUveitis
Colitis Nephritis
MyocarditisPericarditis
Adrenal insufficienc
y
HyperthyroidHypothyroid
Hematologic
Keytruda® PI, Merck ECI Guidance v5
Neurologic: Guillain-Barré
Prepared by Merck and DAVA OncologyConfidential – not for distribution
Timing of irAEs with pembrolizumab
62
1. Wide range of time to onset2. Late development of toxicities can occur even AFTER drug
discontinuation3. Onset not related to duration of therapy
Oncology Nov 2014; Keytruda PI
Prepared by Merck and DAVA OncologyConfidential – not for distribution
Ramucirumab in addition to Docetaxel in second line lung cancer improved OS VEGF 2 receptor
Cetuximab has had mixed results FLEX study showed improved OS, but not PFS BMS 099 study did not show improvement in PFS/OS
PIPELINE drugs Targeting Kras mutations RET mutations NCI Match trial Small cell lung cancer ?
PD1 inhibitors Notch inhibitors
Overview of Biomarkers: Factors to Guide Personalized Therapy in NSCLC
Clinical Factors Histologic Factors
Molecular Factors
Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.M2.T.LC.BioMOA.5