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%

M2.T.LC.BioMOA.29

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.

M2.T.LC.BioMOA.25

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

10

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

10

0

20

24211815129630 27

24211815129630 27

100

90

80

70

60

50

40

30

10

0

20

24211815129630 27

100

90

80

70

60

50

40

30

10

0

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

Prepared by Merck and DAVA OncologyConfidential – not for distribution

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