is advanced lung cancer becoming a chronic disease?

Is advanced lung cancer becoming a chronic disease?

James Chung-Man HO (何重文) M.D. FRCP Associate Professor, The University of Hong Kong

Honorary Consultant, Department of Medicine Specialist in Respiratory Medicine Queen Mary Hospital, Hong Kong

1

Disclosures • Received honoraria for lectures or

served as advisory board consultant for AstraZeneca, BMS, Roche, Boehringer Ingelheim, Eli Lilly, Pfizer, and MSD

• Received research funding from Roche and AstraZeneca

Outline of Lecture

• Lung cancer statistics • Advances in anticancer

options • Current management

algorithm of advanced non-small cell lung cancer

• Conclusions

3

Incidence rate: 2014

5 HK Cancer Registry

Mortality rate: 2014

6 HK Cancer Registry

Incidence of lung cancer in HK: Male (ASR)

7

↓ 18%

HK Cancer Registry

Mortality of lung cancer in HK: Male (ASR)

8

↓ 27%

HK Cancer Registry

Incidence of lung cancer in HK: Female (ASR)

9

↓ 9%

HK Cancer Registry

Incidence of lung cancer in HK: Female (ASR)

10

↓ 15%

HK Cancer Registry

Survival rates for lung cancer (stage III/IV): QMH Resp

11

N=44 N=54 N=66 N=79 N=71

61-83% adenocarcinoma Mean age 60-64 yrs

Unpublished data

PKC: clinical presentation • M/62 • Chronic cough • Chest Xray: L lung shadow in Aug

2013 • Workup confirmed lung

adenocarcinoma (EGFR L858R + T790M) 13

Driver mutations in NSCLC are heavily influenced by ethnicity

14

France1

China3

EGFR 40%

Unknown 29%

KRAS 7%

EML4-ALK 7%

MET 5%

BRAF 2%

PTEN 6%

Japan2

1. Barlesi F et al. Lancet 2016;387:1415–26; 2. Mitsudomi T. Jpn J Clin Oncol 2010;40:101–6; 3. Wu YL, Ann Oncol 2011;22 (suppl 9):Abstract 33.

Spectrum of EGFR Mutations

15

Tyrosine Kinase Domain Exons 18-24

Exon 18

EGFR Gene

Exon 19 Exon 20 Exon 21

G719C G719S G719A

5%

Del E746-A750 Del E746_S752>V Del E746_T751>A

Del E746_T751 Del L747_A750>P

Del L747_E749 Del L747_P753>Q Del L747_P753>S

Del L747_S752 Del L747_T751>P

Del L747_T751 Del S752_I759

& additional deletions

~45%

T790M D770_N771 (ins NPG) D770_N771 (ins SVQ)

D770_N771 (insG) S768I

~5%

L858R L861Q

~45%

Lynch et al., 2004 Paez et al., 2004 Sharma et al., 2007 Hirsch and Bunn, 2009

Sensitivity

Resistance

PFS = progression-free survival; OS = overall survival. .

EGFR TKIs vs Chemotherapy in EGFR M+ NSCLC (1L)

EGFR TKI Trial N EGFR

mutaiton ORR* (%)

PFS* (months)

OS* (months)

First Generation

TKI

Gefitinib

IPASS 1217 261 71 vs 47 P<0.001

9.5 vs 6.3 HR 0.48 (0.36-0.64)

21.6 vs 21.9 HR 1.00 (0.76-1.33)

NEJ002 224 224 74 vs 31 P<0.001

10.8 vs 5.4 HR 0.32 (0.24-0.44)

27.7 vs 26.6 HR 0.89 (0.63-1.24)

WJTOG 3405 172 172 62 vs 32

P<0.0001 9.2 vs 6.3

HR 0.0.5 (0.34-0.71) 36 vs 39

HR 1.19 (0.77-1.83)

Erlotinib

EURTAC 173 173 58 vs 15 P-value NR

9.7 vs 5.2 HR 0.37 (0.25-0.54)

22.9 vs 19.6 HR 0.92 (0.63-1.35)

OPTIMAL 165 154 83 vs 36 P<0.0001

13.1 vs 4.6 HR 0.16 (0.10-0.26)

22.8 vs 27.2 HR 1.19 (0.83-1.71)

ENSURE 217 216 63 vs 34 P=0.0001

11.0 vs 5.6 HR 0.42 (0.27-0.66)

26.3 vs 25.5 HR 0.91 (0.61-1.31)

Second Generation

TKI Afatinib

LUX-Lung 3 345 308 69 vs 44 P=0.001

13.6 vs 6.9 HR 0.41 (0.31-0.56)

31.6 vs 28.2 HR 0.78 (0.58-1.06)

LUX-Lung 6 364 324 74 vs 31 P<0.0001

13.7 vs 5.6 HR 0.26 (0.19-0.36)

23.6 vs 23.5 HR 0.83 (0.62-1.09)

*Results described refer to common mutations only

Mok TS et al. N Engl J Med. 2009;361:947-57; Fukuoka M et al. J Clin Oncol. 2011;29:2866-74; Maemondo M et al. N Engl J Med. 2010;362:2380-98; Mitsudomi T et al. Lancet Oncol. 2010;11:121-8; Yoshioka H et al. J Clin Oncol. 2014;32(suppl):abstract 8117; Rosell R et al. Lancet Oncol. 2012;13:239-46; Leon L et al. ESMO 2014. Abstract 1273P; Zhou CC et al. Lancet Oncol. 2011;12:735-42; Zhou CC et al. J Clin Oncol. 2012;30(suppl):abstract 7520; Wu YL et al. Ann Oncol. 2015;26:1883-9; Sequist LV et al. J Clin Oncol. 2013;31:3327-34; Wu YL et al. Lancet Oncol. 2014;15:213-22; Yang JC et al. Lancet Oncol 2015;16:141-51.

PFS in EGFR mutation positive and negative lung adenoca: IPASS

Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT population

Mok TS et al. NEJM 2009;361:947-57

HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001

No. events gefitinib, 97 (73.5%) No. events C/P, 111 (86.0%) Median PFS G, 9.5 months Median PFS C/P, 6.3 months

Gefitinib (n=132) Carboplatin/paclitaxel (n=129)

EGFR mutation positive

132 71 31 11 3 0 129 37 7 2 1 0

108 103

0 4 8 12 16 20 24

Gefitinib C/P

0.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty o

f pr

ogre

ssio

n-fr

ee

surv

ival

Patients at risk : Months

EGFR mutation negative

HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001

No. events gefitinib , 88 (96.7%) No. events C/P, 70 (82.4%) Median PFS G, 1.5 months

Median PFS C/P, 5.5 months

91 4 2 1 0 0 85 14 1 0 0 0

21 58

0 4 8 12 16 20 24 0.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty o

f pr

ogre

ssio

n-fr

ee

surv

ival

Gefitinib (n=91) Carboplatin/paclitaxel (n=85)

Months

PKC: clinical presentation • LU lobectomy in private in Aug 2013 • Adjuvant chemotherapy x 4 cycles in

Aug-Nov 2013 • PET-CT in July 2014: disease

recurrence with L pleural nodules/effusion

• Started Tarceva in Oct-Dec 2014 no response

18

PKC: clinical presentation • Referred to QMH for clinical trial

option • VATS pleural biopsy in Jan 2015:

confirmed adenocarcinoma (EGFR L858R + T790M)

• Considered for AURA 3 trial

19

Mechanisms of Acquired Drug Resistance to EGFR TKIs

T790M mutation is the most common mechanism

Managing acquired resistance is a challenge in the treatment of patients with EGFR M+ NSCLC

1.Stewart EL et al. Transl Lung Cancer Res 2015;4:67–81; 2.Wu SG et al. Oncotarget 2016;7:12404–13. 3.Sacher AG et al. Cancer 2014;120:2289–98.

Three Generations of EGFR TKIs: Potency and Specificity

Gefitinib

EGFRm

T790M

Wt

Afatinib Osimertinib

EGFRm

T790M

T790M

Wt

Wt

EGFRm 1x

10x

100x

Rel

ativ

e IC

50

Li D, et al. Oncogene. 2008;27:4702-4711. Ranson M, et al. WCLC 2013. Abstract MO21.12. Moyer JD, et al. Cancer Res. 1997;57:4838-4848. Kancha RK, et al. Clin Cancer Res. 2009;15:460-467.

T790M

EGFRm

Wt

Erlotinib

AURA (Ph I/II) & AURA 2 (Ph II): Osimertinib (80 mg QD) for EGFR T790M Resistance

Efficacy Parameter AURA (Ph II extension,

T790M+) (N=201)

AURA 2 (Ph II, T790M+) (N=210)

Overall (N=411)

Objective Response Rate* (95% CI)

57% (50, 64)

61% (54, 68)

59% (54, 64)

Complete Response 0 1% 0.5%

Partial Response 57% 60% 59%

Duration of Response

• 96% of patients in both trials had ongoing responses at the time of primary analysis

• mDOR had not been reached with duration of ongoing responses ranging from 1.1 to 5.6 months

*Objective response rate determined by RECIST v1.1 as assessed by Independent review

US approval of Osimertinib for EGFR T790M+ NSCLC on 13 Nov 2015

Janne et al. N EnglJ Med. 2015;372:1689.

PKC: clinical presentation • Eligible for AURA 3 trial • Received AZD9291 (osimertinib)

since Feb 2015 • Very well tolerated • CT reassessment: partial response • Last follow-up on 13 Apr 2017

23

PKC: CT thorax Jan 2015 Feb 2016

24

PKC: CT thorax Jan 2015 Feb 2016

25

AURA 3: PFS

26 Mok TS et al. NEJM 2017;376:629-40

27

Mok TS et al. NEJM 2017;376:629-40

WYC: clinical presentation

28

Incidental finding of left lung shadow

on chest X-ray in 2008 during routine body

check

PET-CT: primary tumour in left

hilar node, two satellite

nodules in LUL, mediastinal

lymph nodes

Mediastinoscopy in private hospital:

adenocarcinoma EGFR WT, T4N2

Referred to hospital authority

oncology unit

• Male, 36 years-old • Ex-light smoker • Performance score: 0


29

Advised chemoradiotherapy

treatment

July 2008

CT of thorax

Multiple tumors: ~8 cm mass in LUL; bilateral multiple

lung nodules, multiple mediastinal and

supraclavicular nodes

April 2010

Patient returned: cough, mild shortness

of breath

Patient refused

treatment

6 cycles of chemotherapy with

carboplatin/paclitaxel + bevacizumab (SOC)

April 2010

Stable disease

October 2010

Progressive disease: stable extracranial disease but new

metastases in the brain


30

Nov 2010 Dec 2010

WBRT (concurrent with

pemetrexed)

5 cycles of pemetrexed

(every three weeks)

PET-CT

PD + new bone metastases

(L4 vertebra and right ilium)

March 2011

Erlotinib

Progressive disease

Assessed for eligibility to

PROFILE 1005: ALK positive

tumour

June 2011

EML4-ALK fusion oncogene Anaplastic lymphoma kinase (ALK):

normally not expressed in lung Echinoderm microtubule associated

protein-like 4 (EML4) EML4-ALK fusion first discovered

in 2007: inversion of chromosome 2 [Inv(2) (p21p23)]

N terminus: EML4 C terminus: entire intracellular

tyrosine kinase domain of ALK Variants: different truncations of

EML4 (at least 9) Other fusion partners with ALK:

TRK-fused gene KIF5B

EML4-ALK fusions → ligand-independent activation of kinase

Soda M et al. Nature 2007;448:561-66 Koivunen JP et al. CCR 2008;14:4275-83

~ 3-7% in NSCLC

Predictive biomarkers for ALK

FISH IHC

Typical population with ALK fusion Neversmokers or ex-light smokers Adenocarcinoma Young age of onset Solid pattern with abundant signet ring cells EGFR WT

IPASS population

IPASS population with EGFR WT, around 33% will have EML4-ALK

IPASS population in Asians ~ 60% EGFR activating mutations

Mok TS et al. NEJM 2009;361:947-57

PROFILE 1005: study design

34

• Phase II, single-arm, multicenter study; ~1,100 patients1,2

1. Riely G, et al. Abstract 166. Presented at IASLC Chicago Multidisciplinary Symposium in Thoracic Oncology 2012, Chicago,

Illinois, 6–8 September, 2012; 2. Kim D, et al. Ann Oncol 2012;23(Suppl 9):ix402:Abstract 1230PD.

Crizotinib 250 mg BID PO; continuous daily dosing

Key eligibility criteria: ●ALK-positive NSCLC by central laboratory

– Local test allowed on case-by-case basis per protocol amendment (January 2011)

●ECOG PS: 0–3

●≥1 prior line of chemotherapy

●Stable/controlled brain metastases allowed

Primary endpoints: ● ORR ● Safety/tolerability Secondary endpoints include: ● OS ● PFS ● Duration of response ● Time to response ● PRO/HRQoL

Treatment

PROFILE 1014: study design

35 aStratification factors: ECOG PS (0/1 vs 2), Asian vs non-Asian race, and

brain metastases (present vs absent); cAssessed by IRR Solomon BJ, et al. N Engl J Med 2014;371:2167−77.

Key entry criteria ● ALK-positive by

central FISH testing

● Locally advanced, recurrent, or metastatic non-squamous NSCLC

● No prior systemic treatment for advanced disease

● ECOG PS 0−2 ● Measurable disease ● Stable treated brain

metastases allowed

N=343

Crizotinib 250 mg BID PO,

continuous dosing (N=172)

Pemetrexed 500 mg/m2

+ cisplatin 75 mg/m2 or carboplatin AUC

5–6 q3w for ≤6 cycles (N=171)

Endpoints

● Primary – PFS (RECIST v1.1,

by IRR)

● Secondary – ORR – OS – Safety – PROs

(EORTC QLQ-C30, QLQ-LC13, EQ-5D)

R A N D O M I Z E a

Accrual period: January 2011 − July 2013

Crossover to crizotinib permitted after progression

PROFILE 1014: primary endpoint – PFS by IRR (ITT population)

36 Solomon BJ, et al. N Engl J Med 2014;371:2167−77. a2-sided stratified log-rank test

Crizotinib (n=172)

Chemotherapy (n=171)

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

Median, mo 10.9 7.0

HR (95% CI) 0.45 (0.35−0.60)

pa <0.001

Crizotinib Chemotherapy

No. at risk: Crizotinib 172 120 65 38 19 7 1 0 Chemotherapy 171 105 36 12 2 1 0 0

Time (months) 0 35

PFS

prob

abilit

y (%

)

100

80

60

40

20

0 20 15 10 5 25 30

WYC: clinical course

37

July 2011

Enrolled in PROFILE 1005

September 2011

Crizotinib

Partial response, stable in the brain

Scan at baseline Scan after 2 months


38

September 2011

Crizotinib

Partial response, stable in the brain

Scan after 2 months

October 2012

Small new right high parietal brain lesion (2.3 x 3.2 x 2.5 mm)

detected


39

September 2011

Crizotinib

Partial response

April 2013

Progressive thoracic disease

Stable brain disease

October 2012

Continue crizotinib

New brain metastasis

Acquired Resistance in ALK+ NSCLC • ALK-rearranged (ALK+) NSCLC is sensitive to

crizotinib1–3

• Most patients develop resistance to crizotinib4,5

– Usually within 1–2 years – CNS relapses are common6

• Mechanisms of resistance are diverse4,5

– ALK resistance mutations – Alternative signalling pathways

amp, amplification; mut, mutation. 1. Camidge DR, et al. Lancet Oncol. 2012;13:1011-1019; 2. Kim D-W, et al. ESMO; 2012. Abstract 1230PD; 3. Shaw AT, et al. ESMO; 2012. Abstract LBA1_PR; 4. Katayama R, et al. Sci Transl Med. 2012;4:120ra17; 5. Doebele RC, et al. Clin Cancer Res. 2012;18:1472-1482; 6. Takeda M, et al. J Thorac Oncol. 2013;8:654-657.

2nd generation TKI ceritinib: ASCEND-5

41

• Phase III, randomized (1:1), controlled, multicenter study; 231 patients

Scagliotti, G. Abstract LBA42. Presented at ESMO 2016 Congress in Copenhagen, Denmark, 9 October, 2016.

Kim, DW. Lancet Oncol. 2016;17:452-63

Ceritinib (750 mg/d) Key eligibility criteria: ●ALK-positive NSCLC by central laboratory

●≥1 prior line of chemotherapy

●Previous treatment with an ALK inhibitor

●ECOG PS: 0–3

●Stable/controlled brain metastases allowed

Primary endpoint (PFS) results: Median 5.4 vs 1.6 months, HR=0.49, (P<0.001)

Chemotherapy (pemetrexed [500 mg/m2] or

docetaxel [75 mg/m2])

Previous exploratory data from the Phase 1 ASCEND-1 trial also reported improved intracranial responses to ceritinib in patients with brain metastases

No. of patients at risk Ceritinib Chemo

ASCEND 5: PFS

42

115 116

87 45

68 26

40 12

31 9

18 6

12 2

9 2

4 2

3 0

2 0

1 0

0 0

0

20

40

60

80

100

Censoring times

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

Prob

abili

ty o

f PFS

(%)

Time (Months)

Ceritinib 750 mg (N=115)

Chemotherapy (N=116)

Events, n (%) 83 (72.2) 89 (76.7)

Median (95% CI), months 5.4 (4.1, 6.9) 1.6 (1.4, 2.8)

Hazard ratio (95% CI) 0.49 (0.36, 0.67)

Log-rank p-value < 0.001

Scagliotti G et al. ESMO 2016


43

April 2013

Progressive thoracic disease by CT scan

May 2013

Ceritinib through the CLDK378A2201 trial

Stable disease; transient interruption

due to hepatitis

Stable response to ceritinib

44

May 2013 July 2013

WYC: February 2014

45

• Suspected progressive disease (left upper lung collapse and consolidation)

• Referred to MRI for neck and shoulder pain which showed new brain metastasis (15 mm lesion in medulla)


46

Stereotactic radiotherapy for brainstem lesion

February 2014

Continue treatment with ceritinib post-progression

April 2014

Progressive thoracic disease and new brain

metastasis

Stable disease in thorax and CNS

Medullary lesion post-stereotactic radiotherapy

47

3 months 11 months

July 2014 March 2015


48

February 2014

Continue treatment with ceritinib post-progression

April 2014

Stereotactic radiotherapy for brainstem lesion

Progressive thoracic disease and new brain

metastasis

Stable disease in thorax and CNS

March 2015

Ceritinib withheld due to increased ALT

for 2 weeks

PD in CNS

Alectinib • Alectinib has demonstrated high potency and

selectivity, and promising antitumor effects in NSCLC

• Preclinical studies: active against several mutant forms of ALK that confer resistance to crizotinib, including the gatekeeper mutation L1196M – Phase III ALUR results suggest longer PFS with

alectinib compared with chemotherapy in pretreated patients

– Ongoing Phase III study (ALEX)

49 Wong KM et al. Drugs Today (Barc) 2015;51:161–70.

Wolf, J. Ann Oncol 2016;27(suppl_6): 1290TiP http://www.roche.com/media/store/releases/med-cor-2017-04-03.htm

J-ALEX: Phase III study design

50 Kim YH, et al. Presented at the IASLC 17th World Conference on Lung Cancer.

December 4–7, Vienna, Austria, 2016. Presentation No. 5597. Nokihara T, et al. Presented at ASCO Annual Meeting. June 3–7, Chicago, IL, 2016.

Stratification factors:

R 1:1

Key Entry Criteria • Stage IIIB/IV or recurrent

ALK-positive NSCLC • ALK centralized testing (IHC and FISH or RT-PCR) • ECOG PS 0-2 • ≥1 measurable lesion

assessed by investigator • Treated/asymptomatic brain

metastases allowed • ≤1 prior chemotherapy

Alectinib 300 mg BID PO, 28-day cycle

(N=100)

Crizotinib 250 mg BID PO, 28-day cycle

(N=100)

Endpoints •Primary - PFS assessed by IRF*

•Secondary - OS - ORR - PK - HRQoL - Time to CNS progression - Safety

Clinical stage (IIIB/IV vs recurrent) Prior chemotherapy (0 vs 1) ECOG PS (0/1 vs 2)

Objective: To demonstrate superiority in PFS with alectinib compared with crizotinib in previously untreated patients or patients received one line of chemotherapy, based on

independent review

● Randomized controlled multi-center open-label Phase III study comparing the efficacy and safety of alectinib versus crizotinib (44 sites)

J-ALEX: PFS by CNS disease

51 Kim YH, et al. Presented at the IASLC 17th World Conference on Lung Cancer. December 4–7, Vienna, Austria, 2016. Presentation No. 5597.

Without CNS disease at baseline With CNS disease at baseline

100

80

60

40

20

0

PFS

rate

(%)

0 6 12 18 27 24 21 3 9 15 1

Alectinib Crizotinib

Time (months) No. of patients at risk

40 28

22 12

63 48

28 16

5 3

80 63

89 75

89 74

100

80

60

40

20

0

PFS

rate

(%)

0 6 12 18 27 24 21 3 9 15 1


Time (months) No. of patients at risk

9 12

5 2

13 17

8 5

4 1

13 23

14 29

14 28

1

Alectinib (N=89)

Crizotinib (N=75)

Event 24 (27.0%) 42 (56.0%) Median [95% CI] 20.3 [17.5 ; -] 10.0 [8.2 ; 13.9] P-Value 0.0001 HR [95% CI]a 0.37 [0.22 ; 0.62]

Alectinib (N=14) Crizotinib (N=29)

Event 1 (7.1%) 16 (55.2%) Median [95% CI] - [- ; -] 10.2 [6.5 ; 14.2] P-Value 0.0062 HR [95% CI]a 0.09 [0.01 ; 0.74]



Alectinib demonstrated greater efficacy in patients with CNS disease versus crizotinib

However, it should be noted that there was an imbalance in patients with brain metastases at baseline (crizotinib = 29 vs alectinib = 14) as

this was not a stratification factor for randomization


52

March 2015

Decrease in multiple brain lesions including

brainstem

Continued on ceritinib

May 2015

Applied for compassionate use of

alectinib

Continued on ceritinib

December 2015

PD in medullary lesion

Initiated alectinib

Response to alectinib in CNS

53

June 2016 December 2015

WYC experienced occasional, transient myosistis on alectinib

WYC: Summary of therapy progress

54

Erlotinib

Aug 2010

Ceritinib

May 2013

Alectinib Chemotherapy

Mar–June 2011

ALK mutation identified

Dec 2015

Stereotactic radiotherapy

Progression

Partial response

Stable disease

Progression

Crizotinib

July 2011

WBRT

Progression Progression

Progressive CNS disease

Patient passed away:

19 Apr 2017

~ 6 years

NCCN guideline version 5.2017 NSCLC: 1L

Metastatic disease

Adenoca Large cell

NSCLC NOS

Squamous cell ca

Molecular testing

(EGFR, ALK, ROS1);

EGFR +

ALK +

ROS1 +

PD-L1 + EGFR/ALK/ROS1 –ve or unknown

PD-L1/ EGFR/ALK/ROS1 –ve or unknown

Consider molecular

testing (EGFR, ALK,

ROS1) esp. in nonsmokers,

small bx, mixed

histologies; 55

Emerging 1L treatment algorithm

Advanced lung adenoca/selected squamous

cell ca

Specific TKIs

EGFR/ALK/ROS1 driven

EGFR/ALK/ROS1 WT

PD-L1 ≥ 50%

Pembro

PD-L1 1-49%

Chemotherapy options 1.pem/platinum (nonsquamous) 2.Bev + chemo

(nonsquamous) 3.Gem or taxane

/platinum (squamous) Based on KEYNOTE 024 data and NCCN guideline

EGFR/ALK/ROS1 / PD-L1 –ve or

unknown

∗ Non-small cell lung cancer is a heterogeneous disease with diverse molecular profile

∗ Early detection of actionable targets (e.g. EGFR mutations, ALK or ROS1 rearrangement) allows specific targeted therapies

∗ Emerging anticancer therapies (esp. targeted therapy and immunotherapy) significantly improve the general outlook for advanced lung cancer

∗ Advanced lung cancer is now becoming a chronic disease

Conclusions

∗ Respiratory team (medical and nursing): QMH ∗ Co-investigators of clinical trials ∗ Research nurse (Christina Yan) ∗ Research coordinators (Vivian Li, Joy Zhang) ∗ All patients and their families taking part in clinical

trials

Acknowledgements

is advanced lung cancer becoming a chronic disease?

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