Stage IV NSCLC

Rachel Dear Medical oncologist

SVH/TKCC 20 May 2016

Lung cancer is a major health burden

• One of the most common cancers & leading cause of cancer death in Australia, US & worldwide

• In 2012, there were 10,926 new cases of lung cancer diagnosed in Australia (6,462 males & 4,464 females) – 5th most commonly diagnosed cancer

• In 2013, there were 8,217 deaths from lung cancer in Australia (4,995 males & 3,222 females) – highest number of deaths from cancer in Australia

• Overall 5YS 15% http://www.aihw.gov.au/cancer/lung/

NSCLC: AJCC/IASLC Staging

Edge SB, AJCC Cancer Staging Manual.

7th ed. New York, NY: Springer; 2010. p. 253-270.

Lung Cancer Staging: Differences Between the AJCC Cancer Staging Manual, 6th and 7th Editions

AJCC 6th Edition AJCC 7th Edition

T descriptor

T1 ≤ 3 cm T1a: ≤ 2 cm T1b: > 2 cm but ≤ 3 cm

T2 3 cm or: Invades visceral pleura Atelectasis of less than entire lung Proximal extent at least 2 cm from carina

T2a: > 3 cm but ≤ 5 cm T2b: > 5 cm but ≤ 7 cm Or tumors ≤ 7 cm with invasion of visceral pleura, atelectasis of less than entire lung, proximal extent at least 2 cm from carina

T3 Tumors with invasion of chest wall, diaphragm, mediastinal pleura

Tumors > 7 cm or with: Direct invasion of chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, main bronchus < 2 cm from carina (without involvement of carina) Tumor nodules in same lobe as primary tumor

T4 Tumor of any size with: Invasion of mediastinum, heart, great vessels, trachea, esophagus Malignant pleural or pericardial effusions Tumor nodules in the same lobe as the primary

Tumor of any size with: Invasion of mediastinum, heart, great vessels, trachea, esophagus Metastatic tumor nodules in different lobe from primary tumor

N descriptor No changes

M descriptor

M1 Distant metastasis: metastatic tumor nodules in a different lobe from the primary tumor

Subdivided into: M1a: Malignant pleural or pericardial effusion pleural nodules, nodules in contralateral lung M1b: Distant metastasis

Changes in staging are shown in italics.

Treatment decision making

Chemotherapy Targeted Therapy Immunotherapy

Histologic subtyping for

chemotherapy

Genomics-driven TKIs:

EGFR ALK ROS1

Anti–PD-1 Anti–PD-L1 Anti–CTLA-4

1. How do we optimize therapy in individual patients – 1st, 2nd, 3rd line?

2. How do we use new diagnostic testing platforms for targeted therapy or immunotherapy to achieve the best results? eg next generation sequencing in tissue or cell-free DNA in plasma

Biopsy

• Need enough tissue for histologic subtype & molecular analysis • Histology - squamous or non-squamous? • Molecular testing in all non-squamous

– EGFR mutation, ALK and ROS1 translocations – Should other genes be evaluated? KRAS, BRAF, HER2, RET, others? – Should these genes be evaluated in squamous cancers?

• Re-biopsy at time of progression – To determine resistance in EGFR-mutated and ALK+ cases

• Bone biopsy – not good for molecular testing due to decalcification and degradation

of DNA

• Liquid biopsies - cell-free DNA in plasma is starting to be used

Histologically Distinct Subtypes of NSCLC

American Cancer Society. Non-small-cell lung cancer.

Rekhtman N, et al. Mod Pathol. 2011;24:1348-1359.

Small cell (~ 10% to 15%) NSCLC (85% to 90%) Others (< 5%)

(eg, carcinoid)

Large cell

(15%)

Adenocarcinoma

(40%)

Squamous cell carcinoma

(25% to 30%)

TTF-1 (+/-) NS (+/-) CG (+/-) p63 (-) CK7 (-) CK20 (-)

TTF-1 (+) p63 (-) CK7 (+) CK20 (-)

TTF-1 (-) p63 (+) CK7 (-) CK20 (-) CK5/6 (+)

Lung cancer

Adenocarcinoma vs squamous Adenocarcinoma Squamous

Age Bimodal with

younger subset ~ Older

Male/ female

↑ Females ↑ Males

Smoking Never-smoker subset ~ Smokers

Therapies contra- indicated

No Yes

(Pem) (Bev)

Biomarker-driven targeted therapy

Yes

No

Improved survival Yes No

Evolution of NSCLC subtyping from histologic to molecular

Li JCO 31:1039-1049, 2013

First targeted therapy ALK EGFR

Considerations for 1st line therapy

• Clinical features – Performance status

– Age/comorbidities/

smoking status

– Nutritional status (weight loss)

– Haemoptysis

– CNS metastases

– Previous chemotherapy in adjuvant or locally advanced setting

• Histologic subtyping – Adenocarcinoma,

squamous, other

– Non-squamous vs squamous

• Molecular subtyping – EGFR mutation,

ALK/ROS1 or

– Next generation sequencing

Who should have molecular testing? • Adenocarcinoma component

• Pure SCC diagnosis in some clinical settings1

– Young, never, or light smoker

– SCC on resection specimen unlikely to harbor ALK or EGFR mutation2

Next-generation sequencing may be used to detect a broader array of mutations and gene rearrangements3

Broad molecular testing can detect a wider range of mutations, eg BRAF, KRAS, ROS, MET, HER23

• Primary tumors and metastatic lesions equally suitable[1]

– Discordance between mutation status of primary tumor and metastases is uncommon4

1. Lindeman NI, J Thorac Oncol. 2013;8:823-859.

2. D’Angelo SP, J Clin Oncol. 2011;29:2066-2070.

3. NCCN. Clinical practice guidelines in oncology: NSCLC. v4.2016.

4. Yatabe Y, J Clin Oncol. 2011;29:2972-2977.

Pack-Yrs2 EGFR

Mutation, %

95% CI

Never 52 48-56

1-5 34 25-43

6-10 34 26-44

11-15 18 11-26

16-25 11 7-16

26-50 8 6-11

51-75 9 5-13

> 75 4 2-8

TREATMENT BASED ON HISTOLOGY

Chemotherapy in NSCLC: a MA using updated data on individual patients from 52 RCTs

Cisplatin-based trials, HR 0.73 (P<0.0001), absolute 1YS survival improved by 10% ie 5% to 15%, Increased median OS by 1.5 months (range 1 month to 2.5 months) NSCLC collaborative group BMJ 1995;311:899

Chemotherapy in Addition to Supportive Care Improves Survival in Advanced NSCLC: A

Systematic Review and MA of Individual Patient Data From 16 RCTs

Reduced risk of death HR 0.77 (0.71 to 0.83, P <0.0001), 1YS increased from 20% to 29% ie 9% and median survival by 1.5 months (from 4.5 m to 6m) NSCLC collaborative group J Clin Oncol 2008 26: 4617-4625

Benefits of chemotherapy

• In advanced NSCLC, systemic chemotherapy – Improves survival and – Maintains QOL compared with best supportive care

• Studies which prospectively evaluate intrathoracic tumour-related symptoms demonstrate an improvement from baseline scores with palliative chemotherapy

• Elderly- doublet chemo improves OS in fit elderly (no major comorbidities) and PS of 0-2

• Cis/pemetrexed VS cis/gemcitabine – No difference in OS – Cis/gem superior OS if squamous cell histology – Cis/pemetrexed superior OS if adenocarcinoma

• Cisplatin versus carboplatin • 4-6 cycles

NSCLC MA Collaborative Group J Clin Oncol 2008 Georgoulias V J Clin Oncol 2004

Advanced-stage,

previously

untreated NSCLC

pts

(N = 1725)

Cisplatin 75 mg/m2 on Day 1 + Gemcitabine 1250 mg/m2 on Days 1 and 8

Six 3-wk cycles

Cisplatin 75 mg/m2 on Day 1 + Pemetrexed 500 mg/m2 on Day 1

Six 3-wk cycles

Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

First-line Cisplatin + Pemetrexed or Gemcitabine in Advanced NSCLC

Stratified by:

• ECOG PS (0 vs 1)

• Disease stage (IIIB vs IV)

• Brain metastases (yes vs no)

• Sex (male vs female)

• Pathologic diagnosis (histologic vs cytologic)

• Treatment centre

Phase III trial

First-line Cisplatin + Pemetrexed or Gemcitabine in Advanced NSCLC: OS

Scagliotti GV, J Clin Oncol. 2008;26:3543-3551.

OS Pemetrexed/

Cisplatin

N=839

Gemcitabine/

Cisplatin

N=830

HR (95% CI)

Median OS, mos

(95% CI) 10.3 (9.8-11.2) 10.3 (9.6-10.9) 0.94 (0.84-1.05)

Nonsquamous 11.8 (10.4-13.2) 10.4 (9.6-11.2) 0.81 (0.70-0.94)

Squamous 9.4 (8.4-10.2) 10.8 (9.5-12.1) 1.23 (1.00-1.51)

Median PFS, mos 4.8 5.1 1.04

OS 12 mos 43% 42%

OS 24 mos 19% 14%

Treat J 2012 Lung Cancer 76:222-7 MA of 3 P3 RCTs non-squamous pem/cis median OS 11m compared to gem/carbo 8m. If squamous vin/cis best, and gem/cis better than pem/cis

Sandler A, N Engl J Med. 2006;355:2542-2550.

Paclitaxel-carboplatin alone or with bevacizumab for NSCLC (E4599)

Paclitaxel 200 mg/m2 on Day 1 +

Carboplatin AUC 6 on Day 1

for six 3-wk cycles; no crossover to bevacizumab permitted

(n = 444)

Paclitaxel 200 mg/m2 on Day 1 +

Carboplatin AUC 6 on Day 1

for six 3-wk cycles +

Bevacizumab 15 mg/kg on Day 1

every 3 wks until PD or unacceptable toxicity

(n = 434)

Endpoint, % PC BPC Significance

ORR (CR + PR) 15.0 35.0 P < .001

Median OS, mos 10.3 12.3 HR: 0.79; P = .003

Median PFS, mos 4.5 6.2 HR: 0.66; P < .001

Pts with recurrent or

advanced

nonsquamous NSCLC,

no prior chemotherapy

(N = 878)

Paclitaxel-carboplatin alone or with bevacizumab for NSCLC

Sandler A NEJM 2006 355:2542-50

Median OS 12.3m vs 10.3 m Median PFS 6.2 m vs 4.5 m

Socinski MA, J Clin Oncol. 2012;30:2055-2062.

Phase III Study: Carboplatin + Either nab-Paclitaxel or Paclitaxel

Pts with stage IIIb/IV NSCLC, ECOG PS 0-1, no previous chemotherapy

(N = 1052)

nab-Paclitaxel 100 mg/m2 on Days 1, 8, 15 + Carboplatin AUC 6 on Day 1

No premedication

Paclitaxel 200 mg/m2 on Day 1 + Carboplatin AUC 6 on Day 1

Premedication: dexamethasone, antihistamines

Stratified by stage (IIIb vs IV), age (< 70 yrs vs > 70 yrs), sex, histology (squamous vs nonsquamous),

geographic region

21-day cycles

Endpoint, % PC (n = 531) nPC (n = 521) Significance

ORR (CR + PR) 25 33 P < .005

Median OS, mos 11.2 12.1 HR: 0.922;

P = .271

Median PFS, mos 5.8 6.3 HR: 0.902;

P < .214

SQUIRE: Necitumumab ± Gem + Cisplatin for First-line Squamous NSCLC

• Necitumumab FDA approved (11/15) in combination with gem + cisplatin for first-line squamous, but not nonsquamous, NSCLC

• Open-label, randomized phase III trial

• Primary endpoint: OS

Pts 18 yrs of age or

older with stage IV

squamous NSCLC; no

previous chemo;

ECOG PS 0-2;

functiadequate organ

on

(N = 1093)

Necitumumab

800 mg IV Days 1, 8 +

Gemcitabine

1250 mg/m2 IV Days 1, 8 +

Cisplatin

75 mg/m2 IV on Day 1

(n = 545)

Gemcitabine 1250 mg/m2 IV Days 1, 8 +

Cisplatin 75 mg/m2 IV Day 1

(n = 548)

Thatcher N, Lancet Oncol. 2015;16:763-774.

Maximum 6 3-wk cycles

Necitumumab

only

continued

until PD or

toxicity

Gandara DR, Clin Lung Cancer. 2012;13:321-325.

Maintenance Options After Platinum-Based Therapy With Non-progressive NSCLC

Platinum doublet

x 4-6 cycles

Platinum Doublet

x 4-6 cycles

Platinum doublet

x 4-6 cycles

Same drug(s)

Different drug(s)

Different drug(s)

Continuation maintenance

“Switch” maintenance

Second-line therapy

First-line Therapy What Comes After

First-line Therapy

Options: bevacizumab, pemetrexed

Options: pemetrexed, docetaxel, erlotinib

CR/PR/SD

CR/PR/SD

PD

PARAMOUNT: maintenance

pemetrexed versus placebo

Paz-Ares LG J Clin Oncol 2013 31:2895-2902

Second-line chemotherapy

• Seminal study showed docetaxel improved OS versus BSC – Median survival of 7m versus 4.6 m, P=0.047

• Pemetrexed versus docetaxel, no difference in OS, 1YS 30% in both arms – Docetaxel more likely to have FN, infections,

hospitalizations – Pemetrexed benefit in non-squamous not squamous

Shepherd FA, J Clin Oncol 18(10): 2095-2103 Hanna N, J Clin Oncolo 22(9): 1589-1597

REVEL: Ramucirumab + Docetaxel vs Docetaxel in Pts With PD After Chemo: OS

Garon EB, Lancet. 2014;384:665-673.

0 3 6 9 12 15 18 21 24 27 30 33 36 0

20

40

60

80

100

OS

(%)

Mos

Ram + doc Pbo + doc Censored

Ram + doc

Pbo + doc

Ram + doc vs placebo + doc:

HR: 0.857 (95% CI: 0.759-0.979; P = .0235)

10.5 (9.5-11.2) 9.1 (8.4-10.0)

Median OS, Mos (95% CI)

FDA approved ramucirumab (12/14) in combination with docetaxel in metastatic

NSCLC with disease progression on or after platinum-based chemotherapy

First-line treatment metastatic adenocarcinoma

• First-line carbo/pemetrexed or carbo/paclitaxel – 4 cycles

• exceeding this only adds expense and toxicity shown in MA

– +/- bevacizumab (Roche access program)

• Maintenance - 3 options are being compared in the ongoing ECOG-E5508 trial (NCT01107626) – Pemetrexed (as per PARAMOUNT)

– Bevacizumab (as per ECOG4599)

– Bevacizumab + pemetrexed (as per Pointbreak, Avaperl)

Long-term toxicity of maintenance 1. pem-related fatigue

• POINTBREAK trial the median time on maintenance therapy in both arms was less than 6 months, but some patients receive more prolonged treatment, which often is complicated by the presence of troublesome side effects

• Pem-fatigue common usually starts the first few days after treatment and lasts several more

• reduces the dose or increases the interval between treatments (take extra week off), particularly for patients who are receiving more prolonged therapy

Long-term toxicity of maintenance 2. bev-related HT and PU

• Grade 3 or 4 proteinuria occurs in about 6% – Can follow the serum albumin as a measure of urine

protein loss, – urine protein levels – hold treatment and then restart – Aim to avoid nephrotic-range proteinuria

• Most hold treatment for Stage 1 HT 155/90 while others continue bev and treat the hypertension but will hold the drug for greater blood pressure elevations – Start with ACEI then add CCB if needed – hypertension may be correlated with greater antitumor

benefit

Metastatic adenocarcinoma in elderly patients

• Age is just a number and that fit elderly patients without significant comorbidities with normal renal and hepatic function can receive therapies similar to those used for younger patients

• Choice of chemotherapy? Doublet – >80 years: carboplatin/pem induction followed by pem

maintenance can be used

• Bevacizumab? Pooled analysis of patient age in the ECOG-E4599 and POINTBREAK trials that reported good safety and efficacy up to age 75 but a higher rate of treatment complications beyond that point

First line treatment of metastatic squamous cell carcinoma (mSCLC)

• Carboplatin (or cisplatin)/gemcitabine – Carboplatin (or cisplatin)/paclitaxel

– Carboplatin (or cisplatin)/vinorelbine

• Maintenance – Evidence base supporting its role in squamous cell

disease is much weaker

– Consider gemcitabine or docetaxel - but this approach has not been rigorously tested in squamous cancer - a valid extrapolation from the studies in non-squamous disease

TREATMENT BASED ON EGFR MUTATIONS

Kris MG, JAMA. 2014;311:1998-2006

Lung Cancer Mutation Consortium: Single Driver Mutations in NSCLC

• Mutations found in 64% (466/733) of tumors completely tested

No mutation detected

KRAS 25%

EGFR 17%

EML4-ALK 8%

Double mutants 3%

BRAF 2%

PIK3CA < 1%

ERBB2 3%

MEK1 < 1%

NRAS < 1%

AKT1 0%

MET AMP < 1%

Pao W, J Clin Oncol. 2005;23:2556-2568.

Wu YL, J Thorac Oncol. 2007;2:430-439.

EGFR Mutations: Context

• Found in 10% to 15% of NSCLC pts

• More common in never-smokers, adenocarcinomas, females, Asians

• Predominantly located in EGFR exons 18-21 – 85% of EGFR mutations are either deletions in exon 19

or a single point mutation in exon 21 (L858R)

• The specific EGFR mutation identified is important – There are sensitive mutations, primary resistance

mutations (often exon 20), and acquired resistance mutations (T790M)

Previously untreated

pts with stage IIIB/IV

NSCLC;

adenocarcinoma,

never or ex-light

smokers, WHO PS 0-2

(N = 1217)

Up to six

3-wk cycles

Gefitinib 250 mg/day PO

(n = 609)

Paclitaxel 200 mg/m2 IV on Day 1 +

Carboplatin AUC 5-6 mg/mL/min IV on Day 1

(n = 608)

Mok TS, N Engl J Med. 2009;361:947-957.

IPASS: First-line Gefitinib vs Paclitaxel/ Carbo in Stage IIB/IV NSCLC

• Primary endpoint: PFS

• Secondary endpoints: OS, ORR, quality of life, symptom reduction, safety

• Study conducted in Asian countries

Phase III trial

IPASS: Gefitinib vs Paclitaxel/Carbo in NSCLC: PFS by EGFR Status

• Randomized phase III trial; previously untreated pts with advanced NSCLC (N = 1217)

• PFS: Gefitinib superior to carboplatin/paclitaxel in ITT population

• EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vs carboplatin/paclitaxel

Mok TS, N Engl J Med. 2009;361:947-957.

EGFR Mutation Positive

HR: 0.48 (95% CI: 0.36-0.64; P < .001)

Pro

bab

ilit

y o

f P

FS

Mos Since Randomization

1.0

0.8

0.6

0.4

0.2

0 0 4 8 12 16 20 24

EGFR Mutation Negative

HR: 2.85 (95% CI: 2.05-3.98; P < .001)

Pro

bab

ilit

y o

f P

FS

Mos Since Randomization

1.0

0.8

0.6

0.4

0.2

0 0 4 8 12 16 20 24

Gefitinib

Pac/carbo

Gefitinib

Pac/carbo

First-line erlotinib trials

EURTAC Rosell Lancet Oncol 2012;13:239-46

PFS 10m vs 5m

PFS 13m vs 5m

OPTIMAL Zhou Lancet Oncol 2011; 12:735-42

LL3 and LL6: First-line Afatinib vs CT in Pts With Advanced EGFR+ NSCLC

• Phase III trials in stage IIIB/IV EGFR mutation–positive NSCLC (LL3, N = 307; LL6, N = 364)

• In both studies, pts with EGFR exon 19 mutations had significantly longer PFS and OS with afatinib

1. Sequist L, J Clin Oncol. 2013;31:3327-3334.

2. Wu YL, Lancet Oncol. 2014;15:213-222.

3. Sequist L, Chicago Multidisciplinary Symposium in Thoracic Oncology 2014.

Abstract 9.

Median PFS, Mos LUX-Lung 3[1] LUX-Lung 6[2]

Afatinib 11.1 11.0

Chemotherapy 6.9 5.6

HR 0.58 (P = .001) 0.28 (P < .001)

Median OS With EGFR del(19), Mos[3]

LUX-Lung 3 (Global Population)

LUX-Lung 3 (Non-Asian Population)

LUX-Lung 6 (Asian Population)

Afatinib 33.3 mos 33.6 mos 31.4 mos

Chemotherapy 21.1 mos 20.0 mos 18.4 mos

HR 0.54 (P = .002) 0.45 (P = .031) 0.64 (P = .023)

First-line Treatment With EGFR TKIs vs Chemotherapy in EGFR-Mutated NSCLC

Study Treatment N Median PFS, Mos Median OS, Mos

Maemondo[1] Gefitinib vs carboplatin/

paclitaxel 230

10.8 vs 5.4

(P < .001)

30.5 vs 23.6

(P = .31)

Mitsudomi[2,3] Gefitinib vs

cisplatin/docetaxel 172

9.2 vs 6.3

(P < .0001)

35.5 vs 38.8

(HR: 1.19)

OPTIMAL[4,5] Erlotinib vs

carboplatin/gemcitabine 165

13.1 vs 4.6

(P < .0001)

22.8 vs 27.2

(HR: 1.19)

EURTAC[6]

Erlotinib vs

platinum-based

chemotherapy

174 9.7 vs 5.2

(P < .0001)

19.3 vs 19.5

(P = .87)

LUX-Lung 3[7,8] Afatanib vs

cisplatin/pemetrexed 345

11.1 vs 6.9

(P = .001)

28.2 vs 28.2

(P = .39)

LUX-Lung 6[8,9] Afatinib vs

cisplatin/gemcitabine 364

11.0 vs 5.6

(P < .0001)

23.1 vs 23.5

(P = .61)

1. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 2. Mitsudomi T, et al.

Lancet Oncol. 2010;11:121-128. 3. Mitsudomi T, et al. ASCO 2012. Abstract 7521.

4. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 5. Zhou C, et al. Ann Oncol.

2015;26:1877-1883. 6. Rosell R, et al. Lancet Oncol. 2012;13:239-246. 7. Sequist LV, et

al. J Clin Oncol. 2013;31:3327-3334. 8. Yang JC, et al. Lancet Oncol. 2015;16:118-119.

9. Wu YL, et al. Lancet Oncol. 2014;15:213-222.

Platinum doublet MS 10-12m EGFR TKI MS 24m

EGFR Inhibitors and Skin Rash

• EGFR inhibitors most commonly characterized by papulopustular reaction

• Mostly mild to moderate; requires therapeutic intervention in ~ 30% of pts

• Proactive management may decrease severity and maximize treatment outcome

• EGFR-associated rash in NSCLC

– Predictive of response to EGFR TKIs

– Prognostic factor

– Associated with longer PFS, OS

Melosky B, et al. Curr Oncol. 2009;16:16-26.

Lacouture ME, et al. Oncology. 2007;21(11 suppl 5):17-21.

Liu HB, et al. PLoS One. 2013;8:e55128.

EGFR Inhibitor–Associated Skin Rash: Management

Preventive Recommended Not Recommended Comments

Topical Hydrocortisone 1% cream with

moisturizer, sunscreen BID

Pimecrolimus 1% cream

Tazarotene 0.05%

cream

Sunscreen as single

agent

Systemic Minocycline 100 mg/day

Doxycycline 100 mg BID

Tetracycline 500 mg BID Doxycycline is preferred

in pts with renal

impairment; minocycline

is less photosensitizing

Treatment Recommend Not Recommended Comments

Topical Alclometasone 0.05% cream

Fluocinonide 0.05% cream BID

Clindamycin 1%

Vitamin K1 cream

Systemic Doxycycline 100 mg BID

Minocycline 100 mg/day

Isotretinoin at low doses

(20-30 mg/day)

Acitretin Photosensitizing agents

Lacouture ME, et al. Support Care Cancer. 2011;19:1079-1095.

Disease Progression on EGFR TKI in NSCLC with Mutated EGFR

PD: Clinical appearance

• Rapid global progression

• Slow growth globally

• Growth in several areas, but not all

PD: Molecular

• Unknown (other pathways)

• EGFR T790M (exon 20)

• MET amplification

• PIK3CA

Camidge DR, Nat Rev Clin Oncol. 2014;11:473-481.

T790M

~ 40% to 55%

T790M +

EGFR amp

~ 10%

Other

EGFR mut

1% to 2%

SCLC

with

PI3K

~ 4%

SCLC

~ 6%

PIK3CA

~ 1% to 2%

MET amp

~ 5%

BRAF

~ 1%

HER2 Amp

~ 8% to 13%

EMT

~ 1% to 2%

Unknown

~ 15% to 20%

IMPRESS: Cis/Pem ± Gefitinib in Stage IIIb/IV NSCLC With EGFR Mut and PD

• Gefitinib FDA approved (10/15) for tx of pts with metastatic NSCLC with EGFR exon 19 deletion or exon 21 (L858R) substitution mutations

• Primary endpoint: PFS

• Secondary endpoints: OS, ORR, DCR, safety/tolerability, QoL

• Exploratory endpoints: biomarkers

• Randomization did not include stratification factors; analyses adjusted for age (< vs ≥ 65 yrs) and prior gefitinib response (SD vs PR/CR)

Soria JC, Lancet Oncol. 2015;16:990-998.

Cisplatin 75 mg/m2 +

Pemetrexed 500 mg/m2 (≤ 6 cycles) +

Gefitinib 250 mg

(n = 133)

Cisplatin 75 mg/m2 +

Pemetrexed 500 mg/m2 (≤ 6 cycles) +

Placebo 250 mg

(n = 132)

Pts with stage IIIb/IV

NSCLC, EGFR mutations,

chemo naive, response

≥ 4 mos with first-line

gefitinib, PD < 4 wks prior

to randomization

(N = 265)

Phase III trial

Gefitinib (n = 133)

Placebo (n = 132)

1.0

0.8

0.6

0.4

0.2

0

0 2 4 6 8 10 12 14

Pro

ba

bil

ity o

f P

FS

Mos of Randomization Pts at Risk, n

Gefitinib

Placebo

133

132

110

100

88

85

40

39

25

17

12

5

6

4

0

0

IMPRESS: Cis/Pem ± Gefitinib in Stage IIIb/IV NSCLC With EGFR Mut and PD: PFS

Soria JC, et al. Lancet Oncol. 2015;16:990-998.

Outcome Gefitinib (n = 133)

Placebo (n = 132)

HR

Median PFS, mos 5.4 5.4 0.86* (P = .27)

Events, % 74 81

Median OS, mos 14.8 17.2 1.62

(P = .03)

*HR < 1 implies lower risk of progression with gefitinib.

Osimertinib (AZD9291): Novel EGFR TKI in EGFR-Mutated NSCLC

• Osimertinib FDA approved (11/15) for advanced EGFR T790M–positive NSCLC after PD on prior EGFR TKI

– Approval based on AURA and AURA2 single-arm phase II studies of osimertinib in advanced/metastatic NSCLC with EGFR T790M

– Companion diagnostic test for EGFR mutation also approved

AURA

(N = 201)

AURA2

(N = 210)

Median age, yrs 62 64

Osimertinib dose, mg/day 80 80

ORR, % 61 71 (including 2 CRs)

Disease-control rate, % -- 92 at 6 weeks

Median PFS, mos Not reached 8.6

Median DOR, mos Not reached 7.8

Mitsudomi T, WCLC 2016. Abstract 1406.

Yang JC, WCLC 2016. Abstract 943.

Third-Generation EGFR TKIs

EGFR TKI N T790M- ORR,* %

T790M+ ORR, %

Toxicity

Rociletinib (CO-1686)[1]

63 29 59 Hyperglycemia

HM61713[2] 48 (300 mg) 62 (800 mg)

-- 29 55

Dyspnea/rash

EGF816X[3] 53 -- 60 Rash

ASP8273[4]

47 ~ 33 61 Hyponatremia/

diarrhea

1. Sequist LV, N Engl J Med. 2015;372:1700-1709.

2. Park K, ASCO 2015. Abstract 8084.

3. Tan DS, ASCO 2015. Abstract 8013.

4. Goto Y, ASCO 2015. Abstract 8014.

*T790M- subgroups are very small pt populations.

Multiple other agents in early development

TREATMENT BASED ON ALK TRANSLOCATION AND ROS1 FUSION

1. American Cancer Society. http://www.cancer.org.

2. Soda M, Nature. 2007;448:561-566.

3. Shaw AT, J Clin Oncol. 2009;27:4247-4253.

ALK Rearrangement: Context

• ALK (anaplastic lymphoma kinase) rearrangements found in approximately 5% of NSCLC adenocarcinoma pts[1,2]

• Younger pts with light/never-smoking history; males > females[1,3]

• Predominantly a fusion of ALK with partner oncogenes, particularly EML4[2,3]

• Occurs in similar pt subgroup as pts with EGFR mutations, but EGFR mutations and ALK rearrangements are predominantly mutually exclusive[1-3]

PROFILE 1014: Crizotinib vs Pemetrexed/ Platinum* in Advanced ALK+ NSCLC

• Phase III trial (N = 343) ALK-positive pts with nonsquamous NSCLC and no prior systemic treatment for advanced disease

• PFS benefit seen across all subgroups

– Eg, age, sex, smoker, time since diagnosis

• ORR: 74% with crizotinib vs 45% with chemo (P < .001)

Solomon BJ, N Engl J Med. 2014;371:2167-2177.

PFS

*Carboplatin or cisplatin.

100

80

60

40

0

20

0 5 10 15 20 25 30 35

PF

S (

%)

172

171

120

105 65

36

38

12 19

2

7

1

1

0

0

0

Crizotinib

(n = 172)

Chemotherapy

(n = 172)

Events, n (%) 100 (58) 137 (80)

Median, mos 10.9 7.0

HR (95% CI) 0.45 (0.35-0.60)

P < .001

Ceritinib in ALK+ NSCLC: Best % Change From Baseline in Target Lesions

• Other second-generation ALK inhibitors in development: alectinib, brigatinib, lorlatinib

Shaw AT, N Engl J Med. 2014;370:1189-1197.

100

80

60

40

20

0

-20

-40

-60

-80

-100

Best

% C

ha

ng

e F

rom

Baseli

ne

PFS event

ORR (CR + PR), % Overall 58

Previous crizotinib 57 No crizotinib 60

ASCEND-1: Ceritinib in ALK-Positive NSCLC

• Phase I trial; tx (N = 246): 750 mg/day (MTD from dose-escalation phase)

• Antitumor activity independent of prior ALK inhibitor treatment

Kim DW, ASCO 2014. Abstract 8003.

PFS Most common grade

3/4 AEs: increased ALT (27%) and AST (13%)

Most common AEs (all grades): diarrhea (86%), nausea (80%), vomiting (60%)

100

80

60

40

0

20

0 3 6 9 12 15 18

PF

S (

%)

ALK inhibitor treated (n = 163)

ALK inhibitor naive (n = 83)

All (N = 246)

Median: nonestimable

(95% CI: 8.31 - nonestimable)

PFS rate at 12 mos: 61.3%

Median: 8.21 mos

(95% CI: 6.70-10.12)

PFS rate at 12 mos: 39.1% Median: 6.90 mos

(95% CI: 5.39-8.41)

PFS rate at 12 mos: 28.4%

Mos

Ceritinib in ALK-Rearranged NSCLC: Phase II Studies (ASCEND-2 and -3)

Outcome Previously Treated With Chemo + Crizotinib (ASCEND-2)[1]

(N = 140)

No Prior ALK Inhibitor (ASCEND-3)[2] (N = 124)

ORR, n (%) 54 (38.6; 52.5% if no brain mets) 79 (63.7; 58% with brain mets)

Median OS, mos 14.9 Not reached; 12-mo OS 81.5%

Median PFS, mos 5.7 (11.3 if no brain mets) 11.1 (10.6 with brain mets)

Median DoR, mos 9.7 (10.3 if no brain mets) 9.3 (9.1 with brain mets)

Serious tx-related AEs, n (%)

24* (17.1) 10 (8.1)

1. Mok T, et al. ASCO 2015. Abstract 8059.

2. Felip E, et al. ASCO 2015. Abstract 8060.

*Pneumonia, nausea, vomiting in 3 pts (2.1%); pericarditis abdominal pain, pyrexia, pneumonitis in 2 pts

(1.4%), other serious AEs in 1 pt.

Alectinib in Crizotinib-Refractory ALK-Positive NSCLC: Phase II Studies

• Alectinib FDA approved (12/15) for pts with ALK-positive, metastatic NSCLC who have progressed on or are intolerant to crizotinib

• At baseline, 61% of pts in Ou study and 55% in Shaw study had CNS metastases

Outcome Ou (N = 138)[1] Shaw (N = 87)[2]

ORR, % 50 48

Previous chemo 45 NR

CNS mets 57 75

Median PFS, mos 8.9 8.1

CNS progression at Mo 12, %

24.8 NR

Median DOR, mos 11.2 13.5

CNS mets 10.3 11.1

CNS DCR, % 83 89

1. Ou S, et al. J Clin Oncol. 2015;[Epub ahead of print].

2. Shaw AT, et al. Lancet Oncol. 2015;[Epub ahead of print].

Activity of Crizotinib in Pts With ROS1 Fusions: Best Overall Response

• Based on this study, the FDA approved (03/16) crizotinib for pts with ROS1-positive, metastatic NSCLC.

Shaw AT, N Engl J Med. 2014;371:1963-1971.

80

60

40

20

0

-20

-40

-60

-80

-100

Ch

an

ge

Fro

m B

as

eli

ne

(%

)

PD

SD

PR

CR

(N = 50) 100

IMMUNOTHERAPY IN NSCLC

PD-1 as a Target in Cancer Therapy

McDermott DF, Cancer Med. 2013;2:662-673.

Nivolumab

Pembrolizumab

Pidilizumab

Atezolizumab

Durvalumab

Avelumab

PD-L1 PD-1

Tumor or APC

CD80 CD86 CD28

Activated T Cell

Initial immune response

Cytokines Proliferation Activation

Exhausted T Cell

Persistent antigen stimulation

CD80 CD86

CD28

Tumor or APC

CheckMate-017: Nivolumab vs Docetaxel in Previously Treated Squamous NSCLC

• Nivolumab FDA approved (3/15) in met squamous NSCLC on/after PD on platinum-based chemo; data from CheckMate-063,-017

• Open-label, randomized phase III trial

• Primary endpoint: OS

• Secondary endpoint: ORR, PFS, PD-L1 expression, QoL

Stage IIIB/IV squamous

NSCLC, after failure of

1 previous platinum-

based tx, ECOG PS 0-1

(N = 272)

Nivolumab

3 mg/kg IV q2w

(n = 135)

Docetaxel 75 mg/m2 IV q3w

(n = 137)

Brahmer J, N Engl J Med. 2015;373:123-135.

100

80

60

40

20

0

CheckMate-017: Nivolumab vs Docetaxel Efficacy

Brahmer J, N Engl J Med. 2015;[Epub ahead of print].

0 3 6 9 12 15 18 21 24

Mos

Pro

ba

bil

ity o

f S

urv

iva

l

(% o

f P

ts)

Median OS,

Mos (95% CI)

9.2 (7.3-13.3)

6.0 (5.1-7.3)

Nivolumab

Docetaxel

HR: 0.59 (95% CI: 0.44-0.79; P < .001)

1-Yr OS, %

(95% CI)

42 (34-50)

24 (17-31)

CheckMate-057: Nivolumab vs Docetaxel in R/R Nonsquamous NSCLC

• FDA expanded approval (10/15) of nivolumab to nonsquamous NSCLC PD on/after platinum-based chemo with data from CheckMate-057

• Primary endpoint: OS

• Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression, safety, QoL

Borghaei H, N Engl J Med. 2015;373:1627-1639.

Pts with stage IIIB/IV

nonsquamous NSCLC and

ECOG PS 0-1 who failed 1

prior platinum doublet

chemotherapy ± TKI therapy

(N = 582)

Nivolumab 3 mg/kg IV q2w

(n = 292)

Docetaxel 75 mg/m2 IV q3w

(n = 290)

Until disease progression or unacceptable

toxicity

Stratified by previous maintenance therapy (yes vs no) and line of therapy (second vs third line)

CheckMate-057: Efficacy of Nivolumab vs Docetaxel in Nonsquamous NSCLC

Borghaei H, N Engl J Med. 2015;373:1627-1639.

100

80

60

40

20

0 0 3 6 9 12 15 18 21 24 27

OS

Mos

OS

(%

)

1-yr OS: 39%

1-yr OS: 51%

Nivolumab

Docetaxel

Median OS, mos 12.2 9.4

HR: 0.73 (96% CI: 0.59-0.89; P = .002)

Nivolumab

(n = 292) Docetaxel

(n = 290)

PD-L1 Expression Level Nivolumab

Median OS, Mos

Docetaxel

Median OS, Mos

Unstratified HR

(95% CI)

Interaction

P Value

≥ 1%

< 1%

17.2

10.4

9.0

10.1

0.59 (0.43-0.82)

0.90 (0.66-1.24) .06

≥ 5%

< 5%

18.2

9.7

8.1

10.1

0.43 (0.30-0.63)

1.01 (0.77-1.34) < .001

≥ 10%

< 10%

19.4

9.9

8.0

10.3

0.40 (0.26-0.59)

1.00 (0.76-1.31) < .001

Nivolumab vs Docetaxel in Previously Treated NSCLC: Response by Histology

1. Borghaei H, N Engl J Med. 2015;373:1627-1639.

2. Brahmer J, N Engl J Med. 2015;373:123-135.

ORR, % Nivolumab Docetaxel P Value

Nonsquamous

(CheckMate 057)[1] 19 12 .02

Squamous

(CheckMate 017)[2] 20 9 .008

KEYNOTE-001: Subanalysis of Phase I Pembrolizumab Trial in NSCLC

• Administered tumor assessment: imaging every 9 wks

– Primary: RECIST v.1.1 (independent central review)

– Secondary: immune-related response criteria (investigator assessed)

• Tumor biopsy

– Tumor biopsy within 60 days prior to first dose of pembrolizumab required

– Tumor PD-L1 expression determined by prototype assay to inform enrollment; samples were independently reanalyzed using clinical trial IHC assay

Garon EB, N Engl J Med. 2015; 372:2018-2028.

Treatment-naive

or previously

treated advanced

NSCLC

(N = 495)

Pembrolizumab IV

2 mg/kg q3w (n = 6)

Mandatory tumor biopsy

Pembrolizumab IV 10 mg/kg q3w (n = 287)

Pembrolizumab IV

10 mg/kg q2w (n = 202)

CR, PR, SD

PD, unacceptable

AE, or investigator

decision

Continue dosing

and assessments

every 9 wks

Off study

Pembrolizumab FDA approved (10/15) in met NSCLC expressing PD-L1, based on

FDA-approved test, with PD on/after platinum based on KEYNOTE-001 data

Keynote-001: Pembrolizumab Efficacy by PD-L1 Expression

PFS OS

Proportion score for 356 pts in training, validation groups with slides sectioned ≤ 6 mos of staining

100

80

60

40

20

0

PF

S,

%

100

80

60

40

20

0

OS

, %

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Mos

0 4 8 12 16 20 24

Mos

28

PS ≥ 50% (n = 119)

PS < 1% (n = 76)

PS 1% - 49% (n = 161)

PS ≥ 50% (n = 119)

PS < 1% (n = 76)

PS 1% - 49% (n = 161)

ORR by RECIST Pts, n All Cohorts, % (95% CI)

Percent PD-L1 staining

≥ 50% 73 45.2 (33.5-57.3)

1% - 49% 103 16.5 (9.9-25.1)

< 1% 28 10.7 (2.3-28.2)

Garon EB, N Engl J Med. 2015;372:2018-2028.

Summary of PD-1/PD-L1 Blockade Immune-Mediated AEs

Occasional

• Fatigue, headache, arthralgia, fevers, chills, lethargy

• Rash: maculopapular, pruritus, vitiligo

– Topical treatments

• Diarrhea/colitis

– Initiate steroids early, taper slowly

• Hepatitis, liver/pancreatic enzyme abnormalities

• Infusion reactions

• Endocrinopathies: thyroid, adrenal, hypophysitis

Rare

• Pneumonitis

– Grade 3/4 toxicity uncommon

– Low-grade incidence reversible with steroids and discontinuation

• Anemia

Weber JS, J Clin Oncol. 2012;30:2691-2697.

Weber JS, J Clin Oncol. 2015;33:2092-2099.

Management of Immune-Related AEs

• All healthcare team members should be educated about potential AEs

• Rapid and timely diagnostic and therapeutic intervention is imperative for optimal control of irAEs

– Persistent grade 2 irAEs and grade 3/4 irAEs are treated with steroids

– Early discontinuation of steroids may predispose to relapse

• Re-initiation of treatment may be possible with optimal management

• Approximately 5% to 10% of pts experience evidence of enlarging tumor lesions prior to a response

– Pseudoprogression can be managed by continuing treatment and monitoring closely

Optimal management is attainable through continued communication

between all members of the healthcare team and individual pts

Checkpoint Inhibition: Managing Grade 3/4 Treatment-Related AEs

Grade 3/4 pneumonitis, nephritis,

enterocolitis, hepatitis, or infusion-

related reaction

New or worsening neuropathy

Any life-threatening or grade 4 AE

Any severe or grade 3 recurrent AE

Hepatitis associated with AST/ALT > 5 x ULN

AST/ALT ≥ 50% ↑ from baseline lasting

≥ 1 wk*

Total bilirubin > 3 x ULN

*In pts with liver metastasis who begin treatment with grade 2 elevation of AST/ALT. †Pts receiving ipilimumab may tolerate treatment with PD-1/PD-L1 inhibitor alone. ‡Steroids do not appear to accelerate the rate of improvement.

Initiate steroid therapy

Permanently discontinue PD-1 tx

If no improvement in colitis or pneumonitis, infliximab or mycophenolate†

If no improvement in hepatitis, consider mycophenolate; infliximab contraindicated

Grade 4 elevation of pancreatic

enzymes

Usually resolves with tx interruption‡

Conclusions

• For the vast majority of pts, histology still guides therapeutic choice

• For pts with stage IV NSCLC and adenocarcinoma component, molecular testing is the standard of care

• Important to factor pt age, performance status, management of treatment-related AEs

• New FDA approvals for treatment of metastatic NSCLC: ramucirumab, nivolumab, gefitinib, pembrolizumab, osimertinib, necitumumab, alectinib, crizotinib (new indication for ROS1-positive pts)

Future

• First-line treatment will involve a checkpoint inhibitor — for now an anti-PD-1 or anti-PD-L1 monoclonal antibody, perhaps even combined with a CTLA-4 inhibitor with the goal of generating long-term remission or maybe even cure

References

• http://www.aihw.gov.au/cancer/lung/ • Edge SB, AJCC Cancer Staging Manual.

7th ed. New York, NY: Springer; 2010. p. 253-270. • Li JCO 31:1039-1049, 2013 • Lindeman NI, J Thorac Oncol. 2013;8:823-859. • D’Angelo SP, J Clin Oncol. 2011;29:2066-2070. • NCCN. Clinical practice guidelines in oncology: non-small-cell lung cancer. v4.2016. • Yatabe Y, J Clin Oncol. 2011;29:2972-2977. • NSCLC MA Collaborative Group J Clin Oncol 2008 • Georgoulias V J Clin Oncol 2004 • NSCLC collaborative group BMJ 1995;311:899 • NSCLC collaborative group J Clin Oncol 2008 26: 4617-4625 • Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551 • Treat J 2012 Lung Cancer 76:222-7: • Sandler A, N Engl J Med. 2006;355:2542-2550. • Socinski MA, J Clin Oncol. 2012;30:2055-2062. • Thatcher N, Lancet Oncol. 2015;16:763-774 • Gandara DR, Clin Lung Cancer. 2012;13:321-325. • Paz-Ares LG J Clin Oncol 2013 31:2895-2902 • Sandler A NEJM 2006 355:2542-50

References

• Shepherd FA, J Clin Oncol 18(10): 2095-2103 • Hanna N, J Clin Oncol 22(9): 1589-1597 • Garon EB, Lancet. 2014;384:665-673. • Kris MG, JAMA. 2014;311:1998-2006 • Pao W, J Clin Oncol. 2005;23:2556-2568. • Wu YL, J Thorac Oncol. 2007;2:430-439 • Mok TS, N Engl J Med. 2009;361:947-957 • Zhou Lancet Oncol 2011; 12:735-42 • Rosell Lancet Oncol 2012;13:239-46 • Sequist L, J Clin Oncol. 2013;31:3327-3334. • Wu YL, Lancet Oncol. 2014;15:213-222 • Camidge DR, Nat Rev Clin Oncol. 2014;11:473-481 • Soria JC, Lancet Oncol. 2015;16:990-998. • Sequist LV, N Engl J Med. 2015;372:1700-1709. • Soda M, Nature. 2007;448:561-566 • Shaw AT, J Clin Oncol. 2009;27:4247-4253. • Solomon BJ, N Engl J Med. 2014;371:2167-2177 • Shaw AT, N Engl J Med. 2014;370:1189-1197 • Shaw AT, N Engl J Med. 2014;371:1963-1971. • McDermott DF, Cancer Med. 2013;2:662-673. • Brahmer J, N Engl J Med. 2015;373:123-135 • Borghaei H, N Engl J Med. 2015;373:1627-1639 • Garon EB, N Engl J Med. 2015; 372:2018-2028. • Weber JS, J Clin Oncol. 2012;30:2691-2697