second-line treatment for advanced nsclc · wt 33% mutant 2.4% unknown 64% wt 31.5% mutant 2.9%...

Second-line treatment for advanced NSCLC

Silvia Novello silvia.novello@unito.it

Life was so simple back in 2008

Di Maio M, EJC 2010

In 2017, “second line therapy” is no longer as simple

We must now take into consideration:

1.Tumor histology

2.Molecular phenotype (EGFR, ALK, ROS1, etc), Cappuzzo

3.Frontline chemo components (i.e. bevacizumab)

4.Maintenance therapy (continuation, switch)

5. IO in First Line

6.Others (adequacy of tumor tissue, third party reimbursement,

guidelines, “pathways”, etc)

INDUCTION MAINTENANCE 2 nd LINE 3 rd LINE

Di Maio M, JCO 2009

Clinical Lung Cancer 2014

Second line therapy Outside Clinical Trials (N=464, 86% of pts progressing after first line)

Gridelli C et al, J Cancer Res Clin Oncol. 2014 De Marinis F et al, Clinical Lung Cancer 2014

Y Guidelines [ESMO-AIOM]

Treatment Options Post-platinum Progression: Docetaxel

• Docetaxel was the first treatment to be approved for NSCLC patients with disease progression following first-line chemotherapy1

♦ Patients receiving docetaxel

75 mg/m2 had OS of

7.5 months, compared with

4.6 months for those receiving

♦ Docetaxel-treated patients had

a significantly higher 1-year

survival rate compared with

patients receiving vinorelbine

or ifosfamide (32% vs. 19%;

p=.025)3

1. Sanofi Aventis. Taxotere (docetaxel) prescribing information. Nov 2014

2. Shepherd FA et al. J Clin Oncol 2000;18:2095-103

3. Fossella FV et al. J Clin Oncol 2000;18:2354-62

0.0 0 6 12 18

Survival (months)

Docetaxel 75 mg/m2 (n=55)

BSC (n=49)

• Pemetrexed was approved for patients progressing after chemotherapy after it demonstrated non-inferiority vs. docetaxel, but with a better toxicity profile1-3

Treatment Options Post-platinum Progression: Pemetrexed in nonsquamous NSCLC

♦ In patients with

nonsquamous histology,

pemetrexed treatment

resulted in a median OS of

9.3 months, compared with

8.0 months for docetaxel4

♦ Pemetrexed is only suitable

for patients with

nonsquamous histology1

The increased use of pemetrexed in first-line treatment means docetaxel remains

an option as subsequent therapy for patients of all histologies

1. Eli Lilly and Company. Alimta (pemetrexed) prescribing information. Sep 2013

2. Hanna N et al. J Clin Oncol 2004;22:1589-97

3. Weiss GJ et al. J Clin Oncol 2006;24:4405-11

Survival (months)

4. Scagliotti G et al. Oncologist 2009;14:253-63

0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

18 24 30

Pemetrexed

0.78 (95% CI 0.61 ─1.00) Adjusted HR

Docetaxel

Treatment Options Post-platinum Progression: Erlotinib

• The EGFR TKI erlotinib is approved for use in unselected patients with disease progression after first-line chemotherapy1

1. Astellas Pharma and Genentech. Tarceva (erlotinib) prescribing information. June 2015

2. Garassino MC et al. Lancet Oncol 2013;14:981-8

3. NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer, V.6.2015

4. Gregorc V et al. Lancet Oncol 2014;15:713-21

♦ However, erlotinib was inferior

to docetaxel for OS and PFS

in patients without an EGFR

mutation; other options may

be preferred in this setting2,3

♦ Erlotinib is not recommended

for patients with a ‘poor’

classification following

proteomic testing in patients

with WT or unknown EGFR

status3,4

Cox model adjusted HR 0.73 (95% CI 0.53-1.00)

Erlotinib

Docetaxel

ival (%

0 2 4 6 8 10 12 14 16 18 20

Survival (months)

01.07 PROSE Secondary Endpoint Analysis Vanesa Gregorc, MD

*PCR amplification/Sanger sequencing of common mutations

VS-G 96 (72%)

VS-P 38 (28%)

Chemotherapy (129) Erlotinib (134)

VS-G 88 (68%)

VS-P 41 (32%)

3 major protocol violations 19 never received therapy

285 patients randomized 263 included for primary analysis

PROSE Patient Flow

The patient population was 72% male, 63% adenocarcinoma, 14% never smokers, 52% ECOG PS 0, and 41% ECOG PS 1, and was well balanced between arms. Third-line treatment at progression:

– CT arm: 41% overall (48% VS-G and 27% VS-P) – ERL arm: 52% overall (56% VS-G and 39% VS-P)

SQUAMOUS and NON-SQUAMOUS Carcinoma:

rooms for improvements

SQUAMOUS and NON-SQUAMOUS

HYPERPLASIA DYSPLASIA CARCINOMA INVASIVE

CARCINOMA

Gene Methylation Mutations Translocations

Promotion of

survival signals and evasion of apoptosis

Tissue invasion and metastasis

Limitless potential for replication

Vascular recruitment

and endothelial cell growth

Cellular proliferation through independent growth signaling

Adapted from Weinberg RA. Sci Am. 1996;275:62-70.

Bronchial Epithelium

Air Space

- Stage IV NSCLC after

one platinum- based chemo +/-

maintenance

- Prior Bev allowed - All histologies

- PS 0 or 1

Treatment until disease progression

or unacceptable toxicity

Ramucirumab 10 mg/kg +

Docetaxel 75 mg/m2 q3wks N=628

Placebo +

Docetaxel 75 mg/m2 q3wks N=625

R A N D O M I Z E

Stratification factors:

• ECOG PS 0 vs 1

• Gender

• Prior maintenance

• East-Asia vs. ROW

Primary endpoint: Overall Survival Secondary endpoints: PFS, ORR, safety, patient-reported outcomes

Median (95% CI) Censoring Rate

RAM+DOC

RAM+DOC vs PL+DOC:

10.5 (9.5-11.2) 31.8% PL+DOC 9.1 (8.4-10.0) 27.0%

Stratified HR (95% CI) = 0.886 (0.75-0.98) Stratified log-rank P = .023

RAM+DOC

PL+DOC

Number at risk

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

Survival Time (months)

RAM+DOC

PL+DOC

Censored

Median (95% CI) Censoring Rate

RAM+DOC vs PL+DOC:

4.5 (4.2-5.4) 11.1%

3.0 (2.8-3.9) 6.7%

Stratified HR (95% CI) = 0.76 (0.68-0.86)

Stratified log-rank P = 0.0001

RAM+DOC

PL+DOC

ssessm

RAM+DOC PL+DOC

Number at risk

RAM+DOC

PL+DOC Censored

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

383 301

204 172

120 95

Survival Time (months)

628 625

Responsea, n

Ramucirumab +

Docetaxel

(n=628)

Placebo +

Docetaxel

(n=625) p value

CR 3 (0.5) 2 (0.3)

PR 141 (22.5) 83 (13.3)

SD 258 (41.1) 244 (39.0)

PD 128 (20.4) 206 (33.0)

Unknown 98 (15.6) 90 (14.4)

(95% CI)

144 (22.9)

(19.7-26.4)

85 (13.6)

(11.0-16.5) <.001

(95% CI)

402 (64.0)

(60.1-67.8)

329 (52.6)

(48.6-56.6) <.001

♦ Ramucirumab improved ORR and DCR in nonsquamous and squamous histologies

♦ QoL was

measured using

LCSS and ASBI

♦ A similar increase

in symptom

burden was

observed in both

treatment arms

♦ Addition of

ramucirumab had

no detrimental

effect on QoL

Ramucirumab Placebo

* * * * * * * * * * * * * * * * * *

* * * * * *

0 3 6 7 8 … 10 9 5 2 30-day

follow-up

484 353 233 178 167 111 127 261 422 296 326 366 491 300 196 144 120 86 102 217 433 305 266 367 n =

* * * * * * * * * * * * * * * * * *

* * * * * *

0 3 6 7 8 … 10 9 5 2 30-day

follow-up

493 358 240 181 171 112 129 270 457 300 338 375 501 306 199 149 125 87 102 218 443 311 274 372 n =

Randomized (ITT) Population N=1253

PL+DOC (N=625)

Excluded (n=572)

Screened (N=1825)

RAM+DOC (N=627)*

Patients not receiving treatment

Reasons for discontinuation (N=613) PD 341 Adverse event 94 Subject decision 90 Investigator decision 37 Death due to adverse events 30 Death from study disease 12 Other 9 On treatment at data cutoff N=11

RAM+DOC (N=628)

PL+DOC (N=618)*

Patients not receiving

treatment (n=4)

*Three PL+DOC arm patients were inadvertently treated with RAM and are therefore considered part of the RAM+DOC arm for the safety analyses, but the PL+DOC arm for the ITT efficacy analysis.

Safety Population N=1245

REVEL: Patient Disposition

wt 33% mutant 2.4% unknown 64%

wt 31.5% mutant 2.9% unknown 65%

Reasons for discontinuation (N=611) PD 429 Adverse event 55 Subject decision 53 Investigator decision 19 Death due to adverse events 31 Death from study disease 14 Other 10 On treatment at data cutoff N=10

Forest plot

SC10.04: Second-Line Therapy and Beyond in Squamous Cell NSCLC - Silvia Novello

Pembrolizumab - OS by PD-L1 expression - Keynote001

Garon E et al, NEJM 2015

14.9% second line pts

<1% 1-49% ≥50%

SC10.04: Second-Line Therapy and Beyond in Squamous Cell NSCLC - Silvia Novello Herbst R et al, The Lancet 2016

Pembrolizumab – OS&PFS by PD-L1 expression – Keynote010

OS most impressive in ≥50%, but superior with Pembrolizumab in all groups

PFS benefit was superior in ≥50%,

but not significant for either Pembrolizumab dose in ≥1%

HR 0.53 HR 0.76

Keynote 010: OS by by Subgroups

Pembrolizumab

R Herbst et al., Lancet 2016

Forest plot

Primary analysis from OAK, a randomized Phase 3 study comparing atezolizumab with docetaxel in 2L/3L NSCLC

• Primary endpoints (first 850 enrolled patients): – OS in the ITT population

– OS in patients with ≥1% PD-L1 expression

• Secondary endpoints: ORR, PFS, DoR,

safety

F. Barlesi, et al. ESMO 2016. Abstract LBA44_PR

• One of the largest studies that tested the role of an anti PDL-1 Mab in the setting of 2/3L NSCLC

Atezolizumab 1200 mg IV q3w

PD or loss of clinical

benefit

Docetaxel 75 mg/m2 q3w

Locally advanced or metastatic NSCLC

• 1–2 prior lines of chemotherapy, including ≥1 platinum based

• Tumor specimen available

• Any PD-L1 status

N=1,225 enrolled

No Cross-Over

Stratification factors • PD-L1 expression

• Histology

• Prior chemotherapy regimens

Primary analysis from OAK, a randomized Phase 3 study comparing atezolizumab with docetaxel in 2L/3L NSCLC

Characteristics Atezolizuma

b n = 425

Docetaxel n = 425

Median age, y 63 64

≥65 y 45% 49%

Male 61% 61%

Nonsquamous 74% 74%

Squamous 26% 26%

ECOG PS, 0/1 37%/64% 38%/62%

No. of prior therapies, 1/2

75%/25% 75%/25%

History of tobacco use

Never 20% 17%

Current/previous

14% / 66% 16% / 67%

Known EGFR status, %

Mutant/WT 10% / 75% 10% / 73%

Atezolizumab Docetaxel

No. at risk Atezolizumab 42

74 54 41 28 15 4 1

Docetaxel 425

98 90 70 51 37 28 16 6 3

Median 9.6 mo

(95% CI, 8.6, 11.2)

Median 13.8 mo (95% CI, 11.8, 15.7)

Months

HR, 0.73a (95% CI, 0.62, 0.87) P=0.0003 Minimum follow-up = 19 months

15 6 12 0

21 24 27

Overall survival, ITT (n = 850)

aStratified HR; bUnstratified HR; cP values for descriptive purpose only. TC, tumor cells; IC, tumor-infiltrating immune cells; OS, overall survival. Barlesi et al, Atezolizumab Phase III OAK Study.

Overall survival, PD-L1 expression OS, PD-L1 expression on ≥ 50% TC or ≥ 10% IC

TC3 or IC3; 16% of patients OS, PD-L1 expression on ≥ 1% TC or IC TC1/2/3 or IC1/2/3; 55% of patients

Months

HR, 0.74a (95% CI, 0.58, 0.93) P=0.0102

Minimum follow-up = 19 months

Median 10.3 mo (95% CI, 8.8, 12.0)

Median 15.7 mo (95% CI, 12.6, 18.0)

15 6 12 0

21 24 27

No. at risk Atezolizumab

98 88 71 47 37 28 19 10 3 1

Docetaxel 222

96 89 81 74 72 65 62 59 55 51 41 28 18 15 8 3 1

Atezolizumab Docetaxel

Months

HR, 0.41b (95% CI, 0.27, 0.64) P<0.0001c

Minimum follow-up = 19 months

Median 8.9 mo (95% CI, 5.6, 11.6) Median 20.5 mo

(95% CI, 17.5, NE)

15 6 12 0

21 24 27

No. at risk Atezolizumab

72 69 65 63 61 59 58 55 51 50 49 47 46 46 44 43 43 42 39 34 28 19 16 11 8 6 2

Docetaxel 65 59 57 51 45 40 36 32 32 28 25 24 20 15 14 14 14 13 11 11 9 7 4 3 2

SQUAMOUS Carcinoma: rooms for improvements

Previous ESMO Guidelines

In studies of nivolumab, a history of smoking in patients with NSCLC was associated with improved clinical response and PFS

HR = hazard ratio; mPFS = median progression-free survival; ORR = objective response rate; PFS = progression-free survival. Hellmann MD, et al. Poster presented at ESMO 2014 (asbtr. 1229PD).

Smoking status and response to immunotherapy in NSCLC

Variable ORR, % (n/N)

[95% CI] P-value

Smoking exposure

≤5 pack-yrs 0 (0/14) [0, 23]

>5 pack-yrs 30 (20/66)

[20, 43]

14 3 1 1 1 1

75 28 16 12 7 1

≤5 pack-yrs smokers

>5 pack-yrs smokers

0 6 12 18 24 30 Months Since Treatment Initiation

≤5 pack-yrs smokers (mPFS 1.7 months)

>5 pack-yrs smokers (mPFS 2.2 months) HR (95% CI) = 0.41 (0.22, 0.74), P = 0.003

PFS by smoking exposure

Campbell JD et al, Nat Genet 2016

CheckMate 017 (NCT01642004) - Study Design

• DBL: December 15, 2014

• At time of DBL, 199 deaths (of 272 randomized pts) were reported (86% of 231 deaths required for final analysis)

• The boundary for declaring superiority for OS at the pre-planned interim analysis was P <0.03

• Stage IIIb/IV SQ

• 1 prior platinum

doublet-based

chemotherapy

• ECOG PS 0–1

• N = 272

Endpoints

• Primary: OS

• Secondary:

• Investigator-assessed ORR

• Investigator-assessed PFS

• Correlation between PD-L1

expression and efficacy

(ORR, OS, PFS),

• Quality of life (LCSS)

3 mg/kg IV

Q2W, until PD or

unacceptable toxicity

n = 135

75 mg/m2 IV

Q3W, until PD or

unacceptable toxicity

n = 137

DBL, data base lock; ECOG PS = Eastern Cooperative Oncology Group performance status; IV = intravenous; LCSS = lung cancer symptom scale; PD = progressive disease; PD-L1 =

programmed cell death ligand 1; SQ = squamous; Q2W = every 2 weeks; Q3W = every 3 weeks

Brahamer J et al, NEJM 2015

Reckamp K et al. , WCLC 2015 ORAL 02.01

Checkmate 017: Updated follow-up

Reckamp K et al. , WCLC 2015 ORAL 02.01

Checkmate 017: Updated follow-up

PD-L1 expression

Patients, n Unstratified

HR(95% Cl)

NIVO DOC

1% 63 56 0.69 (0.45, 1.05)

<1% 54 52 0.58 (0.37, 0.92)

5% 42 39 0.53 (0.31, 0.89)

<5% 75 69 0.70 (0.47, 1.02)

10% 36 33 0.50 (0.28, 0.89)

<10% 81 75 0.70 (0.48, 1.01)

Not quantifiable at baseline 18 29 0.39 (0.19, 0.82)

1% 63 56 0.67 (0.44, 1.01)

<1% 54 52 0.66 (0.43, 1.00)

5% 42 39 0.54 (0.32, 0.90)

<5% 75 69 0.75 (0.52, 1.08)

10% 36 33 0.58 (0.33, 1.02)

<10% 81 75 0.70 (0.49, 0.99)

Not quantifiable at baseline 18 29 0.45 (0.23, 0.89)

OS and PFS Hazard Ratios by PD-L1 Status

NIVO DOC Spigel DR et al, ASCO 2015

Forest plot

Is there a room for targeted therapies (WITHOUT target)

in SQUAMOUS carcinoma

Lux Lung 8: Study design

†Dose escalation to 50 mg and dose reduction to 30 or 20 mg permitted ‡Dose reduction to 100 or 50 mg permitted

§Tumor assessment at baseline, Weeks 8, 12, 16; every 8 weeks thereafter.

1. American Joint Committee on Cancer staging manual 7th edition

Key secondary Endpoint:

Overall Survival

Other secondary Endpoints: ORR, DCR,

tumor shrinkage, PRO, safety

Stratified by East Asian vs. Non-East Asian

Afatinib 40 mg† QD

Erlotinib 150 mg‡ QD

SCC of the lung (Stage IIIB/IV)1

Progressed after ≥4 cycles of a first-line platinum doublet

ECOG PS 0–1

Adequate organ function

Primary Endpoint:

PFS by

Independent Review§

Soria JC et al, ASCO 2015

LUX LUNG 8: Safety

Goss GD IASLC Geneva 2015; Soria JC et al, ASCO 2015

Afatinib (N=392)

Erlotinib (N=395)

AE category, % All Grade 3 Grade 4 All Grade 3 Grade 4

Total with related AEs 93 25 1 81 16 1 Diarrhea 70 10 1 33 2 <1 Rash/acne* 67 6 0 67 10 0

Stomatitis* 29 4 0 9 0 0

Fatigue* 15 2 0 12 2 0 Nausea 13 1 0 7 1 0 Decreased appetite 13 1 0 10 1 0 Paronychia* 11 1 0 4 <1 0 Dry skin 9 1 0 10 0 0 Pruritus 8 <1 0 12 0 0 Vomiting 8 1 0 3 1 0

Dehydration 4 1 1 1 1 0

Events, % Afatinib (n=392)

Erlotinib (n=395)

Any AE 99.5 97.5

Drug-related AEs 93.4 81.3

AEs leading to dose reduction 26.5 14.2

AEs leading to discontinuations 20.2 17.0

CTCAE grade 3 or higher 57.1 57.4

Serious AEs 44.1 44.1

Drug-related fatal AEs 1.5§ 1.3¶

Soria JC et al, Lancet Oncol 2015

LUX LUNG 8: Efficacy

Forest plot

For Patients and Caregivers

-A 60-page booklet in English, designed as an information guide for patients with SqCLC -The most frequent key questions from a patient with SqCLC

ADENOCarcinoma (“non-squamous”): rooms for improvements

ADENOCarcinoma

LUME-Lung 1 Study Design

Nintedanib 200mg BID p.o., D2–21,

+ Docetaxel 75mg/m2 IV, D1,

21-day cycles (n=655)

Placebo BID p.o., D2–21,

+ Docetaxel 75mg/m2 IV, D1,

21-day cycles (n=659)

N=1314

Stratification: ECOG PS (0 vs 1)

Prior bevacizumab (yes vs no)

Histology (squamous vs non-

squamous)

Brain metastases (yes vs no)

Stage IIIB/IV

or recurrent

NSCLC patients

after 1st line

chemotherapy

(all histologies)

Number of docetaxel cycles not restricted

Monotherapy allowed after ≥4 cycles of combination therapy

Primary end point: PFS

Next analysis step only allowed if PFS confirmed

with all PFS events at time point of OS analysis

RECK LBA8011, ASCO 2013

Reck M et al, Lancet Oncol 2014

LUME1: PFS

TOTAL population

ADENOCARCINOMA

SQUAMOUS CARCINOMA

LUME1: OS

Adenocarcinoma <9mo

ADENOCARCINOMA

Total population

LUME1: Safety

Forest plot

PRETREATED III/IV PS0-1

NIVO 292 PTS

DOC 290 PTS

RR(%) Median (mos) 1-yr (%)

12 9.4 39

NIVOLUMAB NON SQ CHECK-MATE 057

p= 0.0015 HR 0.73

• Stage IIIB/IV NON-SQUAMOUS

• 1 prior platinum doublet

• ECOG PS 0–1

• Pre-treatment (archival or recent)

tumor samples required for PD-L1

analysis

• Prior maintenance therapy allowed

• Prior TKI therapy allowed for known

ALK translocation or EGFR mutation

N = 582

Nivolumab 3 mg/kg IV Q2W

until PD or unacceptable toxicity

n = 292

Docetaxel 75 mg/m2 IV Q3W

until PD or unacceptable toxicity

n = 290

• Primary Endpoint – OS

• Additional Endpoints – ORRb

– PFSb

– Safety – Efficacy by tumor PD-L1 expression – Quality of life (LCSS)

Patients stratified by prior maintenance therapy

and line of therapy (second- vs third-line)

CheckMate 057: Non Squamous pts

mize 1

Borghaei h et al, NEJM 2015 Sep 27

Take Home Messages

• Chemotherapy is still present in second line NSCLC advanced patients

• Antiangiogenic copound found a second youth in second line

• Immunotherapy plays a relevant role in this setting….at least until it will move to first line

• Today even more than yesterday is crucial to design a treatment algorithm for these patients not to waste therapeutic approaches

second-line treatment for advanced nsclc · wt 33% mutant 2.4% unknown 64% wt 31.5% mutant 2.9%...

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