Nuovi dati NSCLC

III III SESSIONE: TUMORI TORACICI

NUOVI DATI NSCLC

B. Di Cocco

UOC Oncologia

Osp S.M. Goretti ASL Latina

Study Design

• At database lock (May 15, 2017), minimum/median follow-up time post-randomization was 10.0/14.9 months

aConventional systemic therapies, excluding immuno-oncology therapies; ^bTreatment until PD, unacceptable toxicity, or withdrawal of consent;

treatment beyond investigator-assessed PD permitted; ^cAll patients on treatment at 1 year were randomized regardless of response status; ^dPrimary endpoint was incidence of high-grade select treatment-related AEs^1,2; ^eResponses were investigator-assessed every 8 weeks ± 5 days from week 9 1. Hussein M, et al. Oral presentation at IASLC 16th World Conference on Lung Cancer; September 6–9, 2015; Denver, CO, USA.

Abstract ORAL02.02. 2. Waterhouse D, et al. Poster presentation at ASCO Annual Meeting; June 3–7, 2016; Chicago, IL, USA. Abstract 3059.

Exploratory endpoints

: safety/efficacy

with continuous vs 1-year treatment, efficacy, other (eg, biomarkers, PK) Key eligibility criteria

• Advanced/

metastatic NSCLC

• ≥1 prior systemic therapy

• ECOG PS 0−2

• Treated CNS

metastases allowed Stop nivolumab

Continuous nivolumab Nivolumab

3 mg/kg IV Q2W Treatment for 1 year

R

Nivolumab retreatment

allowed at PD

Patient Flow and Analysis Populations

Stop nivolumab Continuous nivolumab

1,245 patients treated

220 patients on treatment at

1 year

76 had response or SD at randomization

87 had response or SD at randomization

R

Efficacy analyses

aMain US cohort; 1,025 patients discontinued prior to 1 year due to progression, death, study withdrawal, toxicity, or other reasons;

bAll 220 patients continuing on treatment at 1 year were randomized regardless of response status; 57 of these 220 patients had PD and were randomized as allowed per protocol; safety analyses were based on all 220 patients, 107 in the continuous arm and 113 in the stop arm; ^c8 patients discontinued treatment due to patient request or withdrawal of consent; ^d12 patients discontinued treatment due to patient request or withdrawal of consent

Baseline Patient Characteristics (Efficacy Analyses) ^a

Continuous treatment (n = 76) 1-year treatment

(n = 87) Median age, years (range)

≥70 years, % 67 (50−92)

41

67 (49−86) 40

Female, % 51 45

ECOG PS,

% 0−1

2

91 8

95 2

Current or former/never smoker, % 96/4 97/3

Squamous histology, % 34 47

PD-L1 status,

% Quantifiable <1%

≥1%

≥50%

53 32 68 28

60 25 75 23 Prior lines of therapy,

%

1 2 ≥3

41 33 26

40 28 29

CR or PR prior to randomization,

% 70 56

aPatients who did not have PD at randomization; ^bWith optional retreatment allowed at PD; ^cNot reported: continuous, n = 1; 1-year,

n = 2; ^dUsing Dako PD-L1 IHC 28-8 pharmDx assay; ^ePercentage of patients with quantifiable PD-L1 expression; ^fNot reported: continuous, n = 0;

1-year, n = 3; ^gCRs: continuous, n = 8; 1-year, n = 2

PFS From Randomization ^a

aPatients who did not have PD at randomization; minimum/median follow-up time post-randomization, 10.0/14.9 months

bWith optional retreatment allowed at PD NR = not reached; tx = treatment

Median, months (95% CI)

PFS rate, % 6-month 1-year

Continuous tx NR (NR) 80 65

1-year tx^b 10.3 (6.4, 15.2) 69 40

HR: 0.42 (95% CI: 0.25, 0.71)

No. at risk 1-year tx Continuous tx

87 50 43 33 21 16 5 1 0

76 60 53 49 35 22 10 3 0

No. at risk 1-year tx Continuous tx

87 50 43 33 21 16 5 1 0

76 60 53 49 35 22 10 3 0

Time post-randomization (months)

0

20 40 60 80 100

0 3 6 9 12 15 18 21 24

PFS From Randomization by Response Status ^a

Median, months (95% CI)

NR (NR)

10.6 (4.8, NA)

HR: 0.45 (95% CI: 0.24, 0.85)

Median, months (95% CI)

NR (5.6, NA)

9.6 (4.5, 12.6)

HR: 0.44 (95% CI: 0.17, 1.09)

CR/PR SD

aBest overall response prior to randomization; minimum/median follow-up time post-randomization, 10.0/14.9 months; ^bWith optional retreatment allowed at PD; ^cTwo patients who stopped treatment had CR prior to randomization; both patients lost CR (6 and 13 months after stopping treatment) with progression due to new lesions; NA = not available

1-year tx 49 29 26 20 14 11 3 1 0

Continuous tx 53 45 41 39 28 17 7 2 0 No. at risk

0 20 40 60 80 100

0 3 6 9 12 15 18 21 24

Time post-randomization (months)

38 21 17 13 7 5 2 0 0

23 15 12 10 7 5 3 1 0

0 20 40 60 80 100

0 3 6 9 12 15 18 21 24

Time post-randomization (months)

n HR (95% CI)

Overall 163 0.42 (0.25, 0.71)

<70 years

≥70 years

97 66

0.28 (0.13, 0.60) 0.66 (0.32, 1.37)

ECOG PS 0−1

152 0.43 (0.25, 0.73)

Male Female

85 78

0.37 (0.18, 0.74) 0.56 (0.25, 1.25) Former/current smoker

157 0.42 (0.25, 0.72) Squamous histology

Non-squamous histology

67 96

0.41 (0.18, 0.93) 0.46 (0.23, 0.92) Second-line treatment

Third-line treatment

Fourth-/later-line treatment/unknown

66 49 48

0.34 (0.14, 0.82) 0.65 (0.27, 1.56) 0.35 (0.13, 0.95)

<1% PD-L1 expression

≥1% PD-L1 expression

≥50% PD-L1 expression

PD-L1 not quantifiable/not reported

26 66 23 71

0.35 (0.11, 1.17) 0.36 (0.15, 0.86) 0.15 (0.03, 0.76) 0.51 (0.23, 1.12)

0 1 2

Favors continuous tx Favors stopping tx

PFS From Randomization by Subgroup ^a

• HR = 0.43 (95% CI: 0.25, 0.76) when adjusted for gender, histology, best overall response, and PD-L1 status using multivariate analysis

aPatients who did not have PD at randomization; minimum/median follow-up time post-randomization, 10.0/14.9 months; ^bHR not calculated for patients with ECOG PS 2 due to small sample size (n = 8); 3 patients had unreported ECOG PS; ^cHR not calculated for

never-smokers/patients with unknown smoking status due to small sample size (n = 6)

OS From Randomization ^a

aPatients who did not have PD at randomization; minimum/median follow-up time post-randomization, 10.0/14.9 months

bWith optional retreatment allowed at PD

Median, months (95% CI)

OS rate, % 6-month 1-year

Continuous tx NR (NR) 97 88

1-year tx^b 23.2 (23.2, NA) 95 81 HR: 0.63 (95% CI: 0.33, 1.20)

74 72 67 62 41 29 7 2 0

79 74 70 61 38 23 4 0 0

No. at risk

1-year tx Continuous tx

87 76

Time post-randomization (months)

0

20 40 60 80 100

0 3 6 9 12 15 18 21 24 27

Retreatment in 1-Year Treatment Arm

aMain US cohort; 1,025 patients discontinued prior to 1 year due to progression, death, study withdrawal, toxicity, or other reasons;

bAll 220 patients continuing on treatment at 1 year were randomized regardless of response status; 57 of these 220 patients had PD and were randomized as allowed per protocol; safety analyses were based on all 220 patients, 107 in the continuous arm and 113 in the stop arm; ^c8 patients discontinued treatment due to patient request or withdrawal of consent; ^d12 patients discontinued treatment due to patient request or withdrawal of consent

Stop nivolumab

Continuous nivolumab

1,245 patients treated

220 patients on treatment

at 1 year

76 had response or SD at randomization

87 had response or SD at randomization R

Efficacy analyses

43 (49%) had PD after stopping

nivolumab

34 (79%) were retreated with

nivolumab

Data at time of analysis (database lock May 15, 2017)

Tumor Burden Change of Target Lesions in Retreated Patients

aPatients with PD in target lesions only; ^bn = 11: 1 patient without further assessment after retreatment start was excluded

Type of PD n (%)

Target lesions only 12 (35)

Non-target lesions only 1 (3)

New lesions only 14 (41)

Target lesions and new lesions 4 (12) Non-target lesions and new lesions 1 (3) Target lesions, non-target lesions, and

new lesions 2 (6)

Tumor burden change in target lesions following retreatment

● Start of retreatment

% change truncated to 100%

Days since randomization

−100

−80

−60

−40

−20 0 20 40 60 80 100

0 100 200 300 400 500

Continuous treatment (n = 107)

1-year treatment

(n = 113)

Any grade, % Grade 3–4, % Any grade, % Grade 3–4, %

Treatment-related AEs 39 8 25 4

Treatment-related SAEs 5 4 2 1

Select treatment-related AEs 33 2 17 2

Treatment-related AEs leading to

discontinuation 7 5 3 1

Summary of Safety Post-Randomization ^a

• Few new-onset events occurred after 1 year

• No treatment-related deaths were reported among randomized patients

• No new safety signals were observed

aAll randomized patients

bAEs in this group include those during retreatment

Summary

• CheckMate 153 is the first randomized study to evaluate duration of therapy with a PD-1/PD-L1 inhibitor

• Among patients still on nivolumab at 1 year, PFS was significantly improved for those treated continuously vs stopping: PFS HR = 0.42 (95% CI: 0.25, 0.71)

• OS HR = 0.63 (95% CI: 0.33, 1.20), showing a trend favoring continuous nivolumab; follow-up for OS is ongoing

• The frequency of treatment-related AEs was numerically higher with continuous

vs 1-year treatment, but overall, few new-onset events occurred after 1 year

Three-Year Follow-up From CheckMate 017/057: Nivolumab Versus Docetaxel in Patients With Previously Treated Advanced

Non-Small Cell Lung Cancer

• Enriqueta Felip,

Scott Gettinger,

Marco Angelo Burgio,

Scott J. Antonia,

Esther Holgado,

David Spigel,

Oscar Arrieta,

Manuel Domine,

Osvaldo Arén Frontera,

Julie Brahmer,

Laura Q. Chow,

Lucio Crinò,

Charles Butts,

Bruno Coudert,

Leora Horn,

Martin Steins,

William J. Geese,

Ang Li,

Diane Healey,

Everett E. Vokes

•¹Hospital Universitari Vall d’Hebron, Barcelona, Spain; ²Yale Cancer Center, New Haven, CT, USA; ³IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; ⁴H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; ⁵Hospital De Madrid, Norte Sanchinarro, Madrid, Spain; ⁶Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA; ⁷Instituto Nacional de Cancerología, Mexico City, Mexico; ⁸Fundación Jiménez Díaz, Madrid, Spain; ⁹Centro Internacional de Estudios Clinicos, Santiago, Chile;

10The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; ¹¹University of Washington, Seattle, WA, USA;

12Cross Cancer Institute, Edmonton, AB, Canada; ¹³Centre Georges François Leclerc, Dijon, France; ¹⁴Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; ¹⁵Thoraxklinik, Heidelberg University Hospital, Heidelberg, Germany; ¹⁶Bristol-Myers Squibb, Princeton, NJ, USA;

17University of Chicago Medicine & Biological Sciences, Chicago, IL, USA

• Nivolumab, an anti–programmed death (PD)-1 antibody, is approved in many countries for the treatment of patients with advanced non-small cell lung cancer (NSCLC) and disease progression during or after platinum-based chemotherapy ^1,2

• Approval was based on data from 2 pivotal phase 3 trials in previously treated patients with squamous (SQ) NSCLC (CheckMate 017) or non-SQ NSCLC (CheckMate 057), which showed nivolumab significantly prolonged overall survival (OS) and had a favorable safety profile compared with docetaxel ^3,4

–Treatment benefit was observed in patients with SQ or non-SQ NSCLC, including those with <1% PD-1 ligand 1 (PD-L1) expression ^3-6 ; higher levels of PD-L1 expression were associated with a greater magnitude of benefit in non- SQ NSCLC ⁴

• Here, we present updated efficacy and safety data from CheckMate 017 and

CheckMate 057 based on >3 years of follow-up

CheckMate 017 and 057 study designs

aThe protocols of both studies were amended in September 2016, when minimum follow-up was approximately 2.5 years, allowing patients to switch to nivolumab 480 mg Q4W starting 2 weeks after their last 3-mg/kg Q2W dose; ^bAfter completion of the primary analyses,^3,4 patients in the docetaxel arms who ended treatment at any time during the studies were allowed to cross over to nivolumab

ALK = anaplastic lymphoma kinase; ECOG PS = Eastern Cooperative Oncology Group performance status; EGFR = epidermal growth factor receptor; IV = intravenous; LCSS = Lung Cancer Symptom Scale; ORR = objective response rate; PFS = progression-free survival; Q3W = every 3 weeks; TKI = tyrosine kinase inhibitor

Nivolumab 3 mg/kg IV Q2W until progressive disease or

unacceptable toxicity (n = 292)

Docetaxel 75 mg/m² IV Q3W until progressive disease or

unacceptable toxicity^b (n = 290) Nivolumab 3 mg/kg IV Q2W until progressive disease or

unacceptable toxicity (n = 135) CheckMate 017 (NCT01642004; N = 272)

CheckMate 057 (NCT01673867; N = 582) Key eligibility criteria

• Stage IIIB/IV SQ NSCLC

• ECOG PS 0–1

• 1 prior platinum-based chemotherapy

• Pretreatment (archival or fresh) tumor samples required for PD-L1 analysis

Key eligibility criteria

• Stage IIIB/IV non-SQ NSCLC

• ECOG PS 0–1

• 1 prior platinum-based chemotherapy

• Pretreatment (archival or fresh) tumor samples required for PD-L1 analysis

• Prior maintenance therapy allowed

• Prior TKI therapy allowed for known ALK translocation or EGFR mutation

Endpoints

• Primary

‒ OS

• Additional

‒ PFS

‒ ORR

‒ Efficacy by tumor PD-L1 expression

‒ Safety

‒ Quality of life (LCSS) Optional switch to flat

dose nivolumab 480 mg Q4W allowed after

September 2016^a

Optional switch to flat dose nivolumab 480 mg

Q4W allowed after September 2016^a Docetaxel 75 mg/m² IV Q3W

until progressive disease or unacceptable toxicity^b

(n = 137)

OS (3 years’ minimum follow-up)

CI = confidence interval; HR = hazard ratio

292 194 148 112 82 58 49 39 7 0

290 195 112 67 46 35 26 16 1 0

135 86 57 38 31 26 21 16 8 0

137 69 33 17 11 10 8 7 3 0

CheckMate 057 (non-SQ NSCLC) CheckMate 017 (SQ NSCLC)

No. of patients at risk Nivolumab

Docetaxel

No. of patients at risk Nivolumab

Docetaxel

0 6 12 18 24 30 36 42 48 54

Δ10%

Nivolumab (n = 135) Docetaxel (n = 137)

1-y OS = 42%

2-y OS = 23%

3-y OS = 16%

1-y OS = 24%

2-y OS = 8% 3-y OS = 6%

HR (95% CI): 0.62 (0.48, 0.80) 10

0 80 60 40 20 0

Months

Δ18%

Δ15%

0 6 12 18 24 30 36 42 48 54 Months

1-y OS = 51%

2-y OS = 29%

3-y OS = 18%

1-y OS = 39%

2-y OS = 16%

3-y OS = 9%

Nivolumab (n = 292) Docetaxel (n = 290)

HR (95% CI): 0.73 (0.62, 0.88) 10

0 80 60 40 20 0

Δ12%

Δ13%

Δ9%

3-year OS rates nivolumab vs docetaxel CheckMate 017 were 16% versus 6%

CheckMate 057 were 18% versus 9%

PFS ^a (3 years’ minimum follow-up)

a

Investigator-assessed NC = not calculable

292 82 47 39 29 20 18 10 2 0

290 89 22 7 4 3 1 0 0 0

135 48 24 17 16 13 10 7 3 0

137 27 8 1 0 0 0 0 0 0

CheckMate 017 (SQ NSCLC)

1-y PFS = 21%

2-y PFS = 16%

3-y PFS = 12%

1-y PFS = 7% 2-y PFS = NC

3-y PFS = NC

100

80

60

40

20

0

0 6 12 18 24 30 36 42 48 54

Months

Nivolumab (n = 135) Docetaxel (n = 137)

HR (95% CI): 0.63 (0.48, 0.82)

CheckMate 057 (non-SQ NSCLC)

1-y PFS = 19%

2-y PFS = 12%

3-y PFS = 10%

1-y PFS = 10% 2-y PFS = 2%

3-y PFS = <1%

100

80

60

40

20

0 0 6 12 18 24 30 36 42 48 54

Months

Nivolumab (n = 292) Docetaxel (n = 290)

HR (95% CI): 0.89 (0.74, 1.06)

No. of patients at risk Nivolumab

Docetaxel

No. of patients at risk Nivolumab

Docetaxel

3-year PFS rates nivolumab and docetaxel

CheckMate 017: 12% versus not calculable

CheckMate 057 and 10% versus <1%

DOR = duration of response; NE = not estimable

CheckMate 017 (SQ NSCLC) CheckMate 057 (non-SQ NSCLC) Nivolumab

(n = 135)

Docetaxel (n = 137)

Nivolumab (n = 292)

Docetaxel (n = 290)

ORR, % (95% CI) 20 (14, 28) 9 (5, 15) 19 (15, 24) 12 (9, 17)

Median DOR, months (95% CI)

25.2 (9.8, NE)

8.4 (3.6, 14.0)

18.3 (8.4, NE)

5.6 (4.4, 6.9) Response ongoing, n/N (%) 7/27 (26) 0/12 (0) 13/56 (23) 0/36 (0)

Among responders, patients had longer median durations of response with nivolumab

versus docetaxel

Subsequent systemic therapies

aPatients may have received ≥1 subsequent therapy; ^bIn CheckMate 017 and 057, 3 patients in each study received subsequent immunotherapy as part of a combination therapy; ^cIn CheckMate 017 and 057, 40% (2/5 patients) and 20% (3/15 patients) received subsequent immunotherapy as the first therapy after discontinuing docetaxel, respectively; ^dIncludes subsequent nivolumab post- study; ^eIncludes crossover to nivolumab in the extension phase of the study or subsequent nivolumab post-study

CTLA-4 = cytotoxic T-lymphocyte antigen 4; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor

Subsequent therapy

(all randomized patients), n (%)

CheckMate 017 (SQ NSCLC) CheckMate 057 (non-SQ NSCLC) Nivolumab

(n = 135)

Docetaxel (n = 137)

Nivolumab (n = 292)

Docetaxel (n = 290)

Any subsequent systemic therapy

57 (42) 48 (35) 141 (48) 156 (54)

Immunotherapy

7 (5) 11 (8)

10 (3) 32 (11)

Nivolumab 5 (4)

6 (4)

7 (2)

24 (8)

Other anti–PD-(L)1 0 3 (2) 0 4 (1)

Anti–CTLA-4 0 2 (1) 0 3 (1)

Investigational/unspecified 2 (1) 0 3 (1) 1 (<1)

ALK/EGFR inhibitor 9 (7) 9 (7) 40 (14) 68 (23)

VEGF/VEGFR inhibitor 0 0 13 (4) 8 (3)

Investigational agent/other 4 (3) 5 (4) 24 (8) 14 (5)

Chemotherapy 52 (38) 35 (26) 120 (41) 115 (40)

In the nivolumab and docetaxel arms, respectively, 42% and 35% of

patients in CheckMate 017 and 48% and 54% of patients in

CheckMate 057 received other systemic therapy subsequent to

study treatment

Pooled nivolumab (N = 418) Any grade Grade 3−4

Any AE

AE leading to discontinuation

67.7 6.0

10.5 4.1

Most frequent TRAEs,

% Fatigue

Nausea

Decreased appetite Asthenia

Diarrhea Rash Pruritus

Hypothyroidism Arthralgia Vomiting

17.0 11.0 11.0 10.5 8.9 8.1 6.9 6.0 5.7 5.0

1.0 0.5 0.2 0.2 1.0 0.5 0.2 0 0.2

0

(3 years’ minimum follow-up)

Median (range) duration of therapy for patients treated with nivolumab was 2.8 (0–51.8+) months

aIncludes events reported between first nivolumab dose and 30 days after last nivolumab dose (3 mg/kg or 480 mg); ^bThere were no grade 5 TRAEs; ^cReported in ≥5% of patients

Pooled nivolumab (N = 418) Any grade Grade 3−4

Overall, % Skin

Gastrointestinal Endocrine Hepatic Pulmonary Renal

Hypersensitivity/inf usion reaction

37.1 16.3 9.1 8.6 5.7 4.5 2.6 2.4

4.8 1.0 1.2 0 1.0 1.4 0.2 0

(3 years’ minimum follow-up)

aSelect AEs are those with potential immunologic etiology that require frequent monitoring/intervention; ^bIncludes events reported between first nivolumab dose and 30 days after last on-study nivolumab dose (3 mg/kg or 480 mg)

Because no patient remained on docetaxel treatment for >2 years, updated safety data are presented in nivolumab- treated patients only

Between 2 and 3 years’ minimum follow-up:

3 new grade 3–4 TRAEs (arthralgia, joint effusion, interstitial lung disease [select TRAE]) were reported

Authors’ Conclusions

After 3 years’ minimum follow-up in the phase 3 CheckMate 017 and 057 studies:

• Nivolumab continued to demonstrate long-term OS and PFS benefit in patients with advanced SQ and non-SQ NSCLC

• 3-year OS rates with nivolumab were 16% in CheckMate 017 and 18% in CheckMate 057

• In CheckMate 017 and CheckMate 057, 26% and 23% of patients who responded to nivolumab, respectively, had ongoing tumor responses

• No new safety signals were identified for nivolumab and rates of TRAEs

were similar to those seen at 2 years’ minimum follow-up

NSCLC: TARGET THERAPY

PROFILE 1014: Study Design

Solomon BJ, Mok TS, 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/m

+

cisplatin 75 mg/m

or carboplatin AUC 5–6 q3w

for ≤6 cycles (N=171)

Endpoints

● Primary

– PFS (RECIST v1.1, by IRR)

● Secondary – ORR – OS – Safety

– Patient-reported outcomes

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

R A N D O M I Z E

a

ALK status determined centrally using Abbott's Vysis ALK break-apart FISH probe kit;

b

Stratification factors: ECOG PS (0/1 vs 2), Asian vs non-Asian race, and brain metastases (present vs absent);

Assessed by IRR

b

Accrual period: January 2011 − July 2013

Crossover to crizotinib permitted after progression

Median follow up: 46 months

• PROFILE 1014 (Solomon et al NEJM 2014) was published after approximately 17 months of follow- up (data cutoff date 30 Nov 2013).

• Primary efficacy endpoint (superiority of crizotinib versus chemotherapy in terms of progression-free survival by IRR) was met: HR 0.454 (95% CI: 0.346, 0.596) and p-value <0.0001,

• Median PFS was 10.9 and 7.0 months for crizotinib and chemotherapy treatment, respectively

• ORR was significantly higher with crizotinib than with chemotherapy.

• 74% vs 45%, p<0.001

• With only 26% of all-cause deaths at data cutoff, median OS was not reached in either group at the time of first report.

• Here we report OS and safety of an additional 3 years of follow-up (LSLV 30 Nov 2016).

Solomon BJ, Mok TS, et al. N Engl J Med 2014;371:2167−77

• With a median follow-up of approximately 46 months in both arms, this study has reported one of the highest 4 year survival rate to date for any study of TKIs in patients with Stage IV metastatic NSCLC.

• The difference in OS between crizotinib and chemotherapy arm (HR: 0.760 [95% CI:

0.548, 1.053]) did not reach statistical significance.

• After hypothetical adjustment for crossover (84.2% in chemotherapy arm and 19.2% in crizotinib arm), OS in the crizotinib arm could be significantly longer than in the

chemotherapy arm (HR 0.346 [95% bootstrap CI: 0.081, 0.718] log-rank test approach).

• Patients who received crizotinib followed by another ALK-TKI had the longest OS while patients randomized to chemotherapy followed by no ALK-TKI or other treatment had the worst OS.

• No unexpected toxicities were revealed with long-term crizotinib treatment.

Conclusions

ALECTINIB VS CRIZOTINIB IN TREATMENT-NAÏVE ALK+ NSCLC: CNS EFFICACY RESULTS FROM

THE ALEX STUDY

1 Shirish Gadgeel, ² Solange Peters, ³ Tony Mok, ⁴ Alice T. Shaw, ⁵ Dong-Wan Kim,

6 Sai-Hong Ignatius Ou, ⁷ Maurice Pérol, ⁸ Rafal Dziadziuszko, ⁹ Jin Seok Ahn, ¹⁰ Rafael Rosell,

11 Ali Zeaiter, ¹¹ Emmanuel Mitry, ¹¹ Eveline Nueesch, ¹¹ Bogdana Balas, ¹² D. Ross Camidge

1

University of Michigan, Ann Arbor, MI, USA;

Lausanne University Hospital, Lausanne, Switzerland;

State Key Laboratory of South China, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong;

Massachusetts General Hospital, Boston, MA, USA;

Seoul National University Hospital, Seoul, South Korea;

Chao Family Comprehensive Cancer Center, University of California, Irvine School of Medicine, Orange, CA, USA;

Department of Medical Oncology,

Léon Bérard Cancer Center, Lyon, France;

Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland;

Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea;

Catalan Institute of Oncology, Barcelona, Spain;

11

F. Hoffmann-La Roche Ltd, Basel, Switzerland;

University of Colorado, Denver, CO, USA

52

The primary endpoint of the study was met:

HR 0.47 (95% CI 0.34–0.65) P<0.001 Median PFS with alectinib was not reached

compared with 11.1 months with crizotinib

*Isolated asymptomatic CNS progression, treatment until systemic or symptomatic CNS PD allowed

Alectinib 600mg BID (n=152)

Crizotinib 250mg BID (n=151) R

1:1

• Stage IIIB/IV NSCLC

• ALK+ disease according to IHC test

• Treatment naïve

• ECOG PS 0–2

• Brain metastases permitted if asymptomatic (n=303)

Until PD*, toxicity, withdrawal

or death

Subsequent therapy

and survival follow-up

Primary endpoint

Investigator-assessed PFS in the ITT population

Secondary endpoints

Time to CNS progression, CNS ORR, CNS DoR

(CNS endpoints were assessed by IRC) Stratification

factors

ECOG PS (0/1 vs 2); Ethnicity (Asian vs non- Asian); CNS metastases at baseline (presence vs absence)

All patients underwent restaging chest/abdominal CT scans and brain imaging

every 8 weeks

ALEX STUDY DESIGN

• Median duration of follow-up: crizotinib arm 17.6 months (range: 0.3–27.0); alectinib arm 18.6 months (range: 0.5–29.0)

• Primary data cut-off: 9 February 2017

• CNS follow-up was conducted for all patients

• Lesions were documented by computed tomography scans, colour photography and MRI, brain scans, using RECIST v1.1

• Alectinib showed significantly superior CNS activity versus crizotinib in patients with CNS disease both with/without prior CNS RT across multiple CNS endpoints in previously untreated advanced ALK+ NSCLC

• alectinib significantly prolonged PFS in patients with and without CNS disease at baseline (HR 0.40, 95% CI 0.25–0.64; p<0.0001 and HR 0.51, 95% CI 0.33–0.80; p=0.0024, respectively) compared with crizotinib

• alectinib significantly improved intracranial ORR compared with crizotinib, irrespective of RT (alectinib: 85.7% versus crizotinib: 71.4% and alectinib: 78.6% versus crizotinib: 40.0%)

• duration of CNS response with alectinib was longer in all patient subgroups than with crizotinib

• At 12 months, 31.3% of crizotinib vs 4.6% of alectinib patients had CNS metastases at the time of first progression suggesting alectinib is protective against the development of CNS progression

• Overall, these CNS results along with the systemic results consolidate

alectinib as the new standard of care for patients with previously

untreated, advanced ALK+ NSCLC

A special thanks to:

POMPERRA BELLINA CHEBORA ESMO 2017

(in alph. order: A.B., B.D.C., A.F.,T.F., L.P.,D.S., N.S., V.S. ^{ET AL)}

Il Cremonese Jessica

grazie per l’attenzione!