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How do we implement immunotherapy in

routine practice? Lessons from the lung

cancer experience

Pr Alexis Cortot, M.D., Ph.D.

Thoracic Oncology Department, CHRU Lille

Institut of Biology, Lille

TAO

Paris, 9 décembre 2016

Disclosures

• Advisory boards : BMS, Roche, Astra-Zeneca, MSD

Le contenu et /ou les opinions exprimées lors de cette présentation, notamment

celui ou celle relatifs à la stratégie thérapeutique ont été réalisées en toute

indépendance.

Efficacy of IO in non small cell lung cancer

CHECKMATE-017 – Nivolumab

Squamous Cell Carcinoma

KEYNOTE-010 – Pembrolizumab

PD-L1 >1%, all histologies


Non-squamous

OAK – Atezolizumab

All histologies

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24 27

SG

Temps (mois)

Nb à risque

Atezolizumab 425 363 305 248 218 188 157 74 28 1

Docetaxel 425 336 263 195 151 123 98 51 16 0

Atezolizumab

Docetaxel

Nivolumab

Docetaxel

1-yr OS rate = 51%

1-yr OS rate = 39%

OS (

%)

Time (months)

100

90

80

70

60

50

40

30

10

0

20

27211815129630 24

Efficacy of IO in non small cell lung cancer






Non-squamous


Non-squamous

Nivolumab

Docetaxel

1-yr OS rate = 51%

1-yr OS rate = 39%

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

27211815129630 24

PF

S (

%)

Nivolumab

Docetaxel

1-yr PFS rate = 19%

1-yr PFS rate = 8%

OS PFS

Choosing Immunotherapy

• What information do we need to choose immunotherapy as 2nd

line therapy?

� SCC : go for it!

� Non-squamous :

• Smoking status?

• EGFR mutational status?

• Threatening tumor?

N Unstratified HR (95% CI)

Overall 582 0.75 (0.62, 0.91)

Age Categorization (years)

<65 339 0.81 (0.62, 1.04)

≥65 and <75 200 0.63 (0.45, 0.89)

≥75 43 0.90 (0.43, 1.87)

Gender

Male 319 0.73 (0.56, 0.96)

Female 263 0.78 (0.58, 1.04)

Baseline ECOG PS

0 179 0.64 (0.44, 0.93)

≥1 402 0.80 (0.63, 1.00)

Smoking Status

Current/Former Smoker 458 0.70 (0.56, 0.86)

Never Smoked 118 1.02 (0.64, 1.61)

EGFRMutation Status

Positive 82 1.18 (0.69, 2.00)

Not Detected 340 0.66 (0.51, 0.86)

Not Reported 160 0.74 (0.51, 1.06)

1.0 2.0 4.0

Nivolumab Docetaxel

0.50.25

N Unstratified HR (95% CI)

Overall 582 0.75 (0.62, 0.91)

Age Categorization (years)

<65 339 0.81 (0.62, 1.04)

≥65 and <75 200 0.63 (0.45, 0.89)

≥75 43 0.90 (0.43, 1.87)

Gender

Male 319 0.73 (0.56, 0.96)

Female 263 0.78 (0.58, 1.04)

Baseline ECOG PS

0 179 0.64 (0.44, 0.93)

≥1 402 0.80 (0.63, 1.00)

Smoking Status

Current/Former Smoker 458 0.70 (0.56, 0.86)

Never Smoked 118 1.02 (0.64, 1.61)

EGFRMutation Status

Positive 82 1.18 (0.69, 2.00)

Not Detected 340 0.66 (0.51, 0.86)

Not Reported 160 0.74 (0.51, 1.06)

1.0 2.0 4.0

Nivolumab Docetaxel

0.50.25

Borghaei et al. N Engl J Med 2015

Choosing Immunotherapy

Champiat et al. CCR 2016

Precautions for use

• Age

Borghaei et al. N Engl J Med 2015; Herbst et al. Lancet 2016

Precautions for use

• Autoimmune disorders

Khan et al. JAMA Oncol 2016; Johnson et al. JAMA Oncol 2015

Precautions for use

• Brain mets

– No active brain mets in the

RCT

– Phase II showing efficacy of

pembro in small BM,

asymptomatic, no

corticosteroids, from

melanoma and NSCLC

Goldberg et al. Lancet Oncol 2016

Precautions for use

• Concomitant therapies

– Anti-PD1/PD-L1 agents are not metabolized by cytochrome P450

– Corticosteroids

• Corticosteroids and immunosuppressive drugs may reduce efficacy of IO

• Should be avoided except for treating AEs

– Radiation therapy

• Not recommended concurrently, wait at least 2 weeks

• May increase the risk of radiation pneumonitis

• May increase efficacy of IO; ongoing trials

What do we need before starting immunotherapy?

• Inform the patient

– Key messages :

• Explanations on mechanism of action

• Inform about the possibility of long response, and the

risk of progression

• Inform about the safety profile, need for reactivity

– Documents, patient alert card

What do we need before starting immunotherapy?

• Radiological Exams

– Recent Chest CT-scan

• Will serve as baseline exam

• Looking for signs of ILD

– Recent CNS imaging

• Biological Exams

– Detect any abnormality

– Will serve as baseline reference

• ECG

The day of treatment

• Check clinical parameters

– Signs of tumor progression (PS, pain, weight loss, …)

– Signs of adverse events, including but not limited to :

• Diarrhea (colitis)

• Dyspnea (ILD)

• Fatigue (endocrinopathy)

• Rash

• ...


• Check biological and radiological parameters

– Before each cycle :

• CBC, coagulation

• Liver enzymes, bilirubin

• Serum electrolytes

• Glycemia

• Renal function

– TSH, T4 every 4 weeks

– Chest X-Ray


• Once the green light has been given :

– In the Oncology Pharmacy :

• Preparation : 3 min

• Sterilization : 15-30 min

• Control : 5 min

– In the Oncology Department :

• Duration of administration : 60 min

• Flushing: 15 min

Monitoring of a patient treated with immunotherapy

• Clinical parameters

– Alert in case of frequent or prolonged diarrhea

– Alert in case of any unusual symptoms

• Biological parameters

• Keep monitoring even after treatment termination

• Inform patient, nurses, general practitioner, ER physicians

• « Dream team » of organ specialists implicated in the management of irAEs

How to assess efficacy of immunotherapy?

• Unconventional patterns of response

– Pseudoprogression

– Delayed response

• Specific criteria (irRC, iRECIST)





• Specific criteria :

– Apperance of a new lesion is not considered

as Progressive Disease (included in the total

tumor burden)

– PD must be confirmed at least 4 weeks later


Continue IO in case of PD on the first

assessment, and maintained PS





• Specific criteria :

– Apperance of a new lesion is not considered

as Progressive Disease (included in the total

tumor burden)

– PD must be confirmed at least 4 weeks later

• Be cautious in case of discordance

between radiological and clinical response

Conclusion

Implementing immunotherapy into daily practice is feasible but requires

preparation and an adapted organization :

• Correct choice of treatment

• Toxicity

– Know the immune-related toxicity

– Educate patients, nurses, practitioners

– Adapt your tools to immunotherapy (lab tests prescription, clinical reports, …)

– Identify key organ specialists

• Assessment of tumor response