CÁNCER DE PULMÓN:

Irrupción de la inmunooncología Rosario García Campelo

Servicio de Oncología Médica, Hospital Universitario A Coruña

NSCLC 5 year survival rate SEER cancer statistics

LUNG CANCER IS

A DEVASTATING DISEASE

RET: Cabozantinib : RR=40%

ALK: 65%RR to Crizotinib: ~70% RR to 2° Gen TKI

Ceritinib in resistant cancers

METex14: RR >50% to

Crizotinib

HER2 mutation: >50% RR to Afatinib; ~20% to Dacomitinib

BRAF (V600E): >60% RR to BRAF + MEK

inhibitor combo

Translating Genomic Profiling Data into Therapeutic Strategies (Lung Adenocarcinoma)

KRAS: 35% RR to MEK

inhibitors + Chemotherapy

ROS1: 70% RR to Crizotinib

HER2 mutation

EGFR: RR>70% to 1°-2° Gen TKIs;

~60% RR to 3° Gen TKIs in resistant cancers

Cancer is a failure of the inmune system

ARE WE CURING ANYBODY? WHAT ABOUT IO?

Ascierto AL, Frontiers in Oncol 2015

Molecular characteristics of long-term survivors (≥5y) to nivolumab therapy - CA209-003 Study

Brahmer et al. AACR 2017

Slide 4

KEYNOTE 001 3 YEARS SURVIVAL RATE

Leighl N et al. ASCO 2017

Anti-PD1 and anti-PDL1 therapies in previously treated advanced NSCLC

Brahmer, et al. N Engl J Med 2015 373(2): 123–35; Borghaei, et al. N Engl J Med 2015 373(17): 1627–39 Herbst, et al. Lancet 2016 387(10027): 1540–50; Barlesi, et al. ESMO 2016 (Abs.LBA44)

NSCLC Stage IV (2L/3L)

1. Nivolumab SqCC N=272 2. Nivolumab NSq N=582 3. Pembrolizumab >1% N=1024 4. Atezolizumab Any N=1225

Docetaxel

Checkpoint inhibitor

R 1:1

POSITIVE TRIALS

Nivolumab 2nd line therapy 2 year survival rate

Barlesi F et al. ESMO 2016

Keynote 010: OS in the Total Populationa

Herbst R, et al. WCLC 2016. 6769 – RS Herbst

Overa

ll S

urv

ival,

%

Docetaxel 75 mg/m2 (n = 343)

Pembrolizumab 2 mg/kg Q3W (n = 344)

Pembrolizumab 10 mg/kg Q3W (n = 346)

No. at risk

Docetaxel

Pembro 2 mg/kg Q3W

Pembro 10 mg/kg Q3W

216

261

259

129

176

195

84

135

259

40

88

100

20

46

57

6

12

15

0

0

1

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30 35

Pembro

2 mg/kg Q3W

n = 344

Pembro

10 mg/kg

Q3W

n = 346

Docetaxel

n = 343

Events, n (%) 233 (68) 214 (62) 257 (75)

OS, median

mo

(95% CI)

10.5

(9.6-12.4)

13.4

(11.2-17.0)

8.6

(7.9-9.8)

HR (95% CI) 0.72

(0.60-0.86)

0.60

(0.49-0.72) —

P value

(vs docetaxel) 0.00017 <0.00001 —

24-mo OS rate,

%

(95% CI)

30.1

(25.0-35.4)

37.5

(32.2-42.9)

14.5

(10.5-19.2) Median follow-up:b

2.1 years

(range, 1.5-3.0 years)

aStratified HR for ITT and TC1/2/3 or IC1/2/3. Unstratified HR for other subgroups. TC, tumor cells; IC, tumor-infiltrating immune cells; OS, overall survival. Barlesi et al. ESMO 2016 LBA44

Overall survival, ITT (n = 850) and PD-L1 subgroups

Atezolizumab

Docetaxel

Median 9.6 mo

(95% CI, 8.6, 11.2)

Median 13.8 mo

(95% CI, 11.8, 15.7)

Ove

rall

Su

rviv

al (%

)

Months

HR, 0.73a

(95% CI, 0.62, 0.87)

P = 0.0003

Minimum follow up = 19 months

42

5

36

3

30

5

24

8

21

8 188

15

7 74 28 1

42

5

33

6

26

3

19

5

15

1

123 98 51 16 0

No. at risk

Atezolizumab

Docetaxel

0.2 2

Subgroup

TC1/2/3 or IC1/2/3a

TC0 and IC0

ITTa

TC3 or IC3

TC2/3 or IC2/3

Median OS, mo

n = 425 n = 425

9.6

8.9

10.3

10.8

8.9

13.8

12.6

15.7

16.3

20.5 0.41

0.67

0.74

0.75

0.73

0.2 1 2

In favor of

docetaxel

Hazard Ratioa

In favor of

atezolizumab

Docetaxel Atezolizumab

OS HR

OAK: OS ITT POPULATION

Gadgeel et al. WCLC 2016

REGULATORY STATUS

CHANGING THE STATE OF THE ART…

14

What about IO in 1st line setting? Raising the bar

POSITIVE

NEGATIVE

A NEW ERA IN LUNG CANCER TREATMENT… Keynote 024, Pembrolizumab in PD-L1 positive patients

Reck M, et al. NEJM 2016

PFS 10.3 vs 6m HR 0.5 6 months OS 80% vs 72.4% HR 0.6

Cross over > 60%

BIRCH: updated OS and PFS

• NE, not estimable

• Data cutoff date: August 1, 2016

Garassino, et al. WCLC 2016 (Abs. OA03.02)

Peters S, et al. J Clin Oncol 2017

TC2/3 or IC2/3 (n=138) PD-L1 on ≥5% of TCs or ICs

TC3 or IC3 (n=65) PD-L1 on ≥10% of TCs or ≥50% of ICs

• Stage IV NSCLC

• No prior treatment

• Squamous or non-squamous histology

• PD-L1 IHC TC1/2/3 or IC1/2/3 status

• ECOG PS 0–1

(n=400)

R

Until PD or loss of

clinical benefit

Until PD

Atezolizumab 1,200mg q3w

1 2 PFS (co-primary)

OS (co-primary)

ORR, DoR and time in response, TTD in patient-reported symptoms, PK, AEs

Endpoints

PD-L1 TC1/2/3 or IC1/2/3 by IHC

IMpower110: phase III study of first-line atezolizumab monotherapy

Pemetrexed or gemcitabine + carboplatin or cisplatin

(4 or 6 cycles)

Optional pemetrexed maintenance

THESE ARE PRACTICE CHANGING DATA!!!!

20

Dabraf

+

Trame

BRAF M+

Chemo

IN THE NEAR FUTURE...

I-O Agents Have a Unique Mechanism of Action, Offering the Opportunity for Combination With Other Agents

1. Drake C. Ann Oncol. 2012;23(suppl 8):viii41–viii46. 2. Hannani D, et al. Cancer J. 2011;17:351–358. 3. Ménard C, et al. Cancer Immunol Immunother. 2008;57:1579–1587. 4. Ribas A, et al. Curr Opin Immunol. 2013;25:291–296.

I-O

22 LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES

Keynote 021: Pembro + CT NSCLC

Langer C, et al. Lancet Oncol 2016

There are several ongoing phase III studies of

anti-PDL1/PD1 therapy in first-line NSCLC

Study name Study description Monotherapy Chemotherapy

combination Anti-CTLA4

combination

Atezolizumab

IMpower110 Atezolizumab monotherapy (squamous and non-squamous) TC1/2/3 or IC1/2/3 (TC or IC ≥1%)

IMpower130 Atezolizumab + platinum doublet chemotherapy (non-squamous)

IMpower131 Atezolizumab + platinum doublet chemotherapy (squamous)

IMpower132 Atezolizumab + platinum doublet chemotherapy (non-squamous)

IMpower150 Atezolizumab + platinum doublet chemotherapy ± bevacizumab (non-squamous)

Pembrolizumab

KEYNOTE-024 Pembrolizumab monotherapy (squamous and non-squamous) TPS ≥50%

KEYNOTE-042 Pembrolizumab monotherapy (squamous and non-squamous) TPS ≥1%

KEYNOTE-407 Pembrolizumab + platinum doublet chemotherapy (squamous)

KEYNOTE-189 Pembrolizumab + platinum doublet chemotherapy (non-squamous)

Nivolumab

CheckMate 026 Nivolumab monotherapy (squamous and non-squamous) TC ≥1% (TC ≥5% as co-primary endpoint)

CheckMate 227 Nivolumab monotherapy or + ipilimumab or + platinum doublet chemotherapy (squamous and non-squamous) PD-L1+ only for monotherapy arm

Durvalumab

MYSTIC Durvalumab monotherapy or + tremelimumab (squamous and non-squamous)

NEPTUNE Durvalumab + tremelimumab (squamous and non-squamous)

Avelumab

JAVELIN Lung 100 Avelumab monotherapy (squamous and non-squamous)

Phase 1 CheckMate 012 Study Design: First-Line Nivolumab ± Ipilimumab in NSCLC

• Updated datad presented here reflect:

– Median follow-up: monotherapy, 22 months; Q12W and Q6W cohorts, 16 months

– Change in median follow-up from prior disclosure: monotherapy, 8 months;10 Q12W cohort, 3 months;11 Q6W cohort, 4 months11

Primary endpoint: safety and tolerability

Secondary endpoints: ORR (RECIST v1.1) and PFS rate at 24 weeks assessed by investigators

Exploratory endpoints: OS, efficacy by PD-L1 expression

Stage IIIB/IV NSCLC (any histology), no prior chemotherapy for advanced disease, ECOG PS 0 or 1

Nivolumab 3 mg/kg IV Q2Wa

Nivolumab 3 mg/kg IV Q2W +

Ipilimumab 1 mg/kg IV Q12Wb

Nivolumab 3 mg/kg IV Q2W +

Ipilimumab 1 mg/kg IV Q6Wb

Until disease progressionc or unacceptable toxicity

ClinicalTrials.gov number NCT01454102; aTreatment allocation not randomized; bTreatment allocation randomized; earlier cohorts evaluated other dosing schedules/regimens11 cPatients tolerating study treatment permitted to continue treatment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefit dBased on a September 2016 database lock

OS in all treated patients and by PD-L1 expression

Goldman J, et al. ASCO 2017

Patient selection for IO Resistance mechanisms

Treatment duration Toxicity

PATIENT SELECTION FOR IO: AN URGENT ISSUE

• PATIENT/ HOST CHARACTERISTICS – Response to previous therapies – PS – Smoking status – SNPs – Increased neutrophil/lymphocyte ratio – Liver metastases – LDH

• PHENOTYPE AND GENOMIC MARKERS – PDL-1 expression – TILs – Microbiome – INF- GAMMA – TML – MSI – Driver mutations

Abdel-Rahman et al. Critical Rev in Oncol and Hem 2016

PDL1 <1%

PDL1 ≥1%

Metanalysis of 2nd line studies showed OS benefit only for patients whose tumors express PD-L1≥1%

Keynote-010 and Oak studies were not included in the metanalysis

Although PD-L1 expression is not the

perfect biomarker, it seems…

The higher the expression the higher the

likelihood and magnitude of the benefit

PFS by Tumor Mutation Burden Tertile CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC

Carbone D et al. NEJM 2017

TMB is associated with improved efficacy of Atezolizumab in 1L and 2L NSCLC patients

Less benefit from Checkpoint inhibitors in metastatic EGFR mutated NSCLC

Khoon C, et al. J Thorac Oncol 2016

High CD73 expression correlates with Low PD-L1 protein expression

Rizvi N et al. ASCO 2017

Do KRAS co-mutations impact clinical response to

immunotherapy?

• Retrospective review of KRAS mutant lung

adenocarcinoma pts treated with immune

checkpoint inhibitors

• 162 Kras- mutant tumors included in the

analysis

Datasets:

Skoulidis et al. ASCO 2017

Significantly shorter

median progression-free

survival with

immunotherapy

in the KL subgroup

BIOMARKERS FOR IO

EGFR

STK11

TP53

KRAS

Mutational load

PD-L1 expression

CD8+ T cell density

Low immunogenicity

Suppress T-cell Activity

DNA replication and damage repair

Increase

Response to PD-1 Blockade

Predict

Koyama S et al. Cancer Res. 2016 Topalian SL et al. Nat Rev Cancer. 2016 Skoulidis F et al. Cancer Discov. 2015 Rizvi NA et al. Science. 2015

Background

Because of the multifactorial nature of cancer-immune interactions, combinations of biomarker assays will by definition be required.

Duration of treatment, treatment beyond progression, best sequence,

retreatment after irAEs….

61 years old male

Active smoker 50 paq/year

May 2014: Stage IV squamous Cell Lung Cancer

He started Nivo in June 2015…

Acute infusion reactions…

• 1st Nivolumab dose: – After 5-6 minutes of nivolumab infusion, intense pruritus and urticaria

– Infusion interruption, iv fluids and antihistamines

• 2nd Nivolumab dose (premedicated) – After 20 minutes of nivolumab infusion, intense pruritus, urticaria (2-6 cm

wheals in neck and thorax), dizzines, hypotension and dyspnea

– Infusion interruption, iv fluids, antihistamines and systemica steroids

– Prolonged reaction (>45 minutes)

• No subsequent dosing

2 months after stopping Nivo…

PR after 24 minutes of anti PD-1 infusion….Still almost CR after months without any treatment…

NSCLC receiving Patients with irAE had longer median OS (13.2 vs 5.8 months, p = 0.018). Owen et al, ASCO 2017

Are irAEs related to outcome in IO treated patients?

Weber et al. J Clin Oncol 2016

Slide 11

How safe is retreatment after irAEs?

Slide 12

Slide 13

Herbst R, et al. WCLC 2016

KEYNOTE 010 1st Treatment Duration and Time to Last Scan (RECIST v1.1, Central Imaging Review; N = 47)

6769 – RS Herbst

•Median time off

therapy 3.8

(range), months

(<0.1-11.0)

•All patients alive as of

cutoff date

0 5 10 15 20 25 30 35

Time, months

+ Last dose

++

++++++

++

+

+

+

+

+++

++++

++

+

++++

+++

++++

++

+++++

+++

++ Time on therapy

Time to last scan

Outcomes of 5-Year Survivors (n = 16) CA209-003 5-Year Update: Phase 1 Nivolumab in Advanced NSCLC

Brahmer J, et al. AACR 2017

• 12 (75%) patients had a PR (including both early and late responses), 2 (12%) had SD, and 2 (12%) had PD as BOR • One patient had a non-conventional response <2 months after initial progression

Time since treatment initiation (months)

SD

SD

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

OS off nivolumab

Time on nivolumab

Alive as of database lock

PR

Adverse event leading to discontinuation

PD

Non-conventional response

Completed maximum cycles of treatment per

protocol

22 0 12 24 36 48 60 72 84 96

Gandara et al. ASCO 2017

Treatment beyond progression…

• Median duration of Atezo postPD: 3 cycles

• 4% (16 pts) > 12 months

Optimizing IO therapy: Keynote 024 progression after the next line of therapy (PFS2)

PFS2 significantly better for patients in the pembro arm vs CT arm

Brahmer J, et al. ASCO 2017

Some take home messages

IO, A GAME CHANGER

• IO WORKS…AND IT WORKS REALLY WELL…IN A RELATIVELY SMALL PROPORTION OF PATIENTS

• We are just at the very beginning….

• New combinations of IO are in the horizon…

• CT+IO…I´d like to see phase III results

• Patient selection for therapy: IT´S AN URGENT ISSUE – PD-L1 IHC plus TML…probably better than one

– Economical toxicity…

• Defining duration of IO therapy: IT´S ALSO AN URGENT ISSUE