Gemelli ART - Session 8...ORR, % 61 71 (including 2 CRs) Disease-control rate, % -- 92 at 6 wks...

Session 8

Special focus on hormon, target and immunotherapies

Take home messages

Lung Cancer Remains a Major Global Health Burden

§  One of the most common cancers and leading cause of cancer deaths in US and worldwide[1,2]

–  New cases, 2017 (estimated): global, 1.8 million (ITALY 40.000)

–  Deaths, 2017 (estimated): US, 155,870; global, 1.6 million

§  ~ 80% to 85% of cases are NSCLC (~ 184,000)

–  Stage IV at diagnosis: ~ 57%

–  Represented by multiple disease subtypes

§  Standard of care for stage IV NSCLC: systemic therapy

§  GLOBOCAN Cancer Fact Sheets. 2012. 2. Siegel RL, et al. CA Cancer J Clin. 2016;66:7-30. §  American Cancer Society. Non-small-cell Lung Cancer. 4. SEER Cancer Statistics Review,

1975-2002. 5. Li T, et al. J Clin Oncol. 2013;31:1039-1049.

Therapeutic Decision Making

Histo-typing Geno-typing (Predictive Biomarkers)

These factors are interlinked and not independent

Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Therapeutic Decision Making for Advanced NSCLC

“Immunopheno-typing” (Predictive

Biomarkers?)

Clinico-typing

Treating Stage IV NSCLC

NSCLC M+ NOT ONCOGENE ADDICTED

NSCLC M+ NOT ONCOGENE ADDICTED

NSCLC M+ ONCOGENE ADDICTED

§  EGFR (18,19,20,21) §  ALK §  ROS1, BRAF, Others

PD-L1 (TPS) ≥50%

•  PD-L1 (TPS) <50% •  PD-L1 NEGATIVE •  Controindications

to immunotherapy

NSCLC M+ ONCOGENE ADDICTED

§  EGFR (18,19,20,21) §  ALK §  ROS1, BRAF, Others

LiT,etal.JClinOncol.2013;31:1039-1049.

NSCLCasonedisease

Histology-BasedSubtyping

Squamous34%

Other11%

Adenoca55%

Adenocarcinoma

SquamousCellCancer

ALKHER2BRAFPIK3CAAKT1MAP2K1NRASROS1RETEGFRKRASUnknown

EGFRvIIIPI3KCAEGFRDDR2FGFR1AmpUnknown

First-targetedtxALKEGFR

25-30 %

EGFR Mutations: Context

§  Found in 10% to 30% of NSCLC pts

§  More common in never-smokers, adenocarcinomas, females, Asians[1,2]

§  Predominantly located in EGFR exons 18, 19, 21

–  ~ 85% of EGFR mutations are either deletions in exon 19 or a single-point mutation in exon 21 (L858R)

§  Specific EGFR mutation identified is important –  There are sensitive mutations, primary resistance mutations (often exon

20), and acquired resistance mutations (T790M)

•  Pao W, et al. J Clin Oncol. 2005;23:2556-2568. 2. Wu YL, et al. J Thorac Oncol. 2007;2:430-439. •  Gazdar AF. Oncogene. 2009;28:S24-S31.

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

Study Treatment N Median PFS, Mos ORR, % Median OS, Mos

Maemondo[1] Gefitinib vs carboplatin/ paclitaxel 230 10.8 vs 5.4

(P < .001) 74 vs 31 30.5 vs 23.6 (P = .31)

Mitsudomi[2,3] Gefitinib vs cisplatin/docetaxel 172 9.2 vs 6.3

(P < .0001) 62 vs 32 34.8 vs 37.3 (HR: 1.25)

OPTIMAL[4,5] Erlotinib vs carboplatin/gemcitabine 165 13.1 vs 4.6

(P < .0001) 83 vs 36 22.8 vs 27.2 (HR: 1.19)

EURTAC[6] Erlotinib vs platinum-based chemotherapy 173 9.7 vs 5.2

(P < .0001) 58 vs 15 19.3 vs 19.5 (P = .87)

LUX-Lung 3[7,8] Afatinib vs cisplatin/pemetrexed 345 11.1 vs 6.9

(P = .001) 56 vs 23 28.2 vs 28.2 (P = .39)

LUX-Lung 6[8,9] Afatinib vs cisplatin/gemcitabine 364 11.0 vs 5.6

(P < .0001) 67 vs 23 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. Yoshioka H, et al. ASCO 2014. Abstract 8117. 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;16:141-151. 9. Wu YL, et al. Lancet Oncol. 2014;15:213-222.

EGFR TKI: gefitinib, afatinib, erlotinib

19del

L858R

Uncommon Mutations

EGFR TKI: gefitinib, afatinib, erlotinib

EGFR TKI: gefitinib, afatinib, erlotinib 1st Line

NSCLC EGFR M+

60

Phase III WJOG 5108L Study: Erlotinib vs Gefitinib in Previously Treated NSCLC

Urata Y, et al. J Clin Oncol. 2016;[Epub ahead of print].

EGFR Mutation–Positive 100

80

40

20

0 0 48 42 36 30 24 18 12 6

Mos

PFS

(%)

198 203

0 0

3 0

5 1

11 4

17 15

31 38

74 72

143 136

No. at risk Erlotinib Gefitinib

Erlotinib Gefitinib

10.0 (95% CI; 8.5-11.2) 8.3 (95% CI;7.2-9.7)

HR 1.093 (95% CI; 0.879-1.358) P = .424

Median (mos)

LUX-Lung 7 (Phase IIb Study) : PFS With First-line Afatinib vs

Gefitinib in EGFR-Mutated NSCLC

*Estimated using exploratory Kaplan-Meier analyses.

Park K, et al. Lancet Oncol. 2016;17:577-589.

Afatinib (n = 160) Gefitinib (n = 159)

HR: 0.73 (95% CI: 0.57-0.95; P = .017)

Median PFS, Mos (95% CI)

11.0 (10.6-12.9) 10.9 (9.1-11.5)

12-Mo PFS*, % (95% CI)

47.4 (39.2-55.2) 41.3 (33.0-49.5)

24-Mo PFS*, % (95% CI)

17.6 (11.7-24.6) 7.6 (3.5-13.8)

100

80

60

40

20

0 0 6 12 18 24 30 36 42

Mos

Pts

(%)

First-line Dacomitinib vs Gefitinib in EGFR-Mutant Advanced NSCLC: Background §  Dacomitinib: second-generation ErbB family TKI[1]

–  Irreversible inhibitor of EGFR/HER1, HER2, HER4

§  ARCHER 1017: previous single-arm phase II examination of first-line dacomitinib in pts with EGFR-mutant NSCLC[2] –  ORR: 75.6%, median PFS: 18.2 mos

§  ARCHER 1050: current phase III analysis evaluating safety, efficacy of first-line dacomitinib vs gefitinib for pts with advanced NSCLC and an EGFR-activating mutation[3]

1. Engelman JA, et al. Cancer Res. 2007;67:11924-11932. 2. Jänne PA, et al. Lancet Oncol. 2014;15:1433-1441. 3. Mok T, et al. ASCO 2017. Abstract LBA9007.

ARCHER 1050: Study Design

§  Multicenter, randomized, open-label phase III study

§  Primary endpoint: PFS by blinded independent review

§  Secondary endpoints: PFS by investigator assessment, ORR, DoR, TTF, OS, safety, pt-reported outcomes

Treatment-naive pts with advanced NSCLC, EGFR-activating mutation(s),

and ECOG PS 0/1; no CNS metastases or prior TKIs

(N = 452)

Dacomitinib 45 mg PO QD (n = 227)

Gefitinib 250 mg PO QD (n = 225)

Mok T, et al. ASCO 2017. Abstract LBA9007.

Stratified by race (Asian vs non-Asian), EGFR mutation (exon 19 vs 21)

ARCHER 1050: PFS by Independent Review

§  Median follow-up for PFS: 22.1 mos

Outcome Dacomitinib (n = 227)

Gefitinib (n = 225)

Median PFS, mos (95% CI)*

14.7 (11.1-16.6)

9.2 (9.1-11.0)

24-mo PFS, % 30.6 9.6 *HR: 0.59 (95% CI: 0.47-0.74; P < .0001)

Wu, Yi-Long et al. The Lancet Oncology 2017 Sep 25

ARCHER 1050: Adverse Events


AE Occurring in ≥ 15% in Either Arm, %

Dacomitinib (n = 227) Gefitinib (n = 224) Any Gr 1 Gr 2 Gr 3 Any Gr 1 Gr 2 Gr 3

Diarrhea* 87.2 49.8 28.6 8.4 55.8 46.0 8.9 0.9 Paronychia 61.7 20.3 33.9 7.5 20.1 13.4 5.4 1.3 Dermatitis acneiform 48.9 16.3 18.9 13.7 28.6 19.2 9.4 0 Stomatitis 43.6 22.5 17.6 3.5 17.9 14.7 2.7 0.4 Decreased appetite 30.8 17.6 10.1 3.1 24.6 21.4 2.7 0.4 Dry skin 27.8 18.5 7.9 1.3 17.0 15.6 1.3 0 Weight decrease 25.6 13.7 9.7 2.2 16.5 9.8 6.3 0.4 Alopecia 23.3 18.1 4.8 0.4 12.5 11.6 0.9 0 Cough 21.1 17.2 4.0 0 18.8 16.1 2.2 0.4 Pruritis 19.8 11.9 7.5 0.4 13.8 10.7 1.8 1.3 ALT increase 19.4 16.3 2.2 0.9 39.3 20.1 10.7 8.5 *Gr 5 diarrhea, n = 1. Otherwise, no listed AE with severity above grade 3 in either arm.

19del

L858R

Uncommon Mutations

EGFR TKI: DACOMITINIB 1st Line

Non-squamous NSCLC EGFR M+ Where are we going?

Study investigators conclude that dacomitinib represents new option for treatment-naive pts with advanced EGFR-mutant NSCLC


EGFR TKI: afatinib preferred

19del

L858R

Uncommon Mutations

EGFR TKI: afatinib, gefitinib,erlotinib


Progressive disease

1st Line

Non-squamous NSCLC EGFR M+

≃ 10-12 months

Disease Progression on EGFR TKI in NSCLC With EGFR-Sensitizing Mutations

PD: Clinical characteristics

§  Rapid global progression

§  Slow growth globally

§  Growth in several areas, but not all

PD: Molecular characteristics

§  Unknown (other pathways)

§  EGFR T790M (exon 20)

§  MET amplification

§  PIK3CA

Camidge DR, et al. 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%


19del

L858R

Uncommon Mutations



Progressive disease

plasma Cf DNA

T790M- T790M+

Tumor rebiopsy

Third gereration EGFR TKI: Osimertinib

T790M- T790M+

Chemiotherapy doublet

1st Line

2nd Line

3rd Line


Osimertinib (AZD9291): Novel EGFR TKI in EGFR-Mutated NSCLC §  Osimertinib FDA approved (November 2015) 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)

ORR, % 61 71 (including 2 CRs) Disease-control rate, % -- 92 at 6 wks Median PFS, mos Not reached 8.6 Median DoR, mos Not reached 7.8

1. Mitsudomi T, et al. WCLC 2015. Abstract 1406. 2. Yang JC, et al. WCLC 2015. Abstract 943.

AURA3: Osimertinib vs Platinum/Pemetrexed in EGFR T790M–Positive Advanced NSCLC

§  Primary endpoint: PFS (investigator assessed)

§  Additional endpoints: ORR, DoR, DCR, OS, safety

Locally advanced or metastatic NSCLC with

disease progression and EGFR T790M mutation after first-line EGFR TKI therapy; ≤ 1 line of therapy for

advanced NSCLC (N = 419)

Osimertinib 80 mg QD

(n = 279)

Platinum/Pemetrexed Chemotherapy Q3W for up to 6 cycles

(n = 140)

Mok TS, et al. N Engl J Med. 2017;376:629-640. ClinicalTrials.gov. NCT02151981.

AURA3: PFS by Investigator Assessment

Mok TS, et al. N Engl J Med. 2017;376:629-640.

§  Median PFS significantly improved in all evaluated subgroups (age, sex, sensitizing EGFR mutation, CNS disease, and smoking history)

100

80

60

40

20

0

PFS

(%)

Osimertinib Platinum/pemetrexed

0 3 6 9 12 15 18 Mos

Outcome Osimertinib (n = 279)

Plt/pem (n = 140) HR (95% CI)

Median PFS, mos 10.1 4.4 0.30 (0.23-0.41) P < .001 (95% CI) (8.3-12.3) (4.2-5.6)

AURA3: Treatment-Related Adverse Events

N (%), ≥ 10% incidence in either arm

Osimertinib (n = 279) Platinum/Pemetrexed (n = 136) Any Grade Grade ≥ 3 Any grade Grade ≥ 3

Any adverse event 231 (83) 16 (6) 121 (89) 46 (34) Diarrhea 82 (29) 2 (1) 8 (6) 1 (1) Rash 79 (28) 1 (< 1) 6 (4) 0 Paronychia 57 (20) 0 1 (1) 0 Dry skin 52 (19) 0 2 (1) 0 Stomatitis 34 (12) 0 19 (14) 2 (1) Pruritus 30 (11) 0 4 (3) 0 Nausea 21 (8) 0 64 (47) 4 (3) Decreased appetite 20 (7) 1 (< 1) 43 (32) 4 (3) Anemia 9 (3) 1 (< 1) 35 (26) 13 (10) Fatigue 19 (7) 0 32 (24) 1 (1) Neutropenia 15 (5) 0 27 (20) 15 (11) Vomiting 11 (4) 0 25 (18) 3 (2)

Select Adverse Events Interstitial lung disease 9 (3) 1 (< 1) 1 (1) 1 (1) QT prolongation 7 (3) 0 1 (1) 0

Mok TS, et al. N Engl J Med. 2017;376:629-640.


19del

L858R

Uncommon Mutations



Progressive disease

plasma Cf DNA

T790M- T790M+

Tumor rebiopsy

Chemiotherapy doublet Third gereration EGFR TKI: Osimertinib

T790M- T790M+

Chemiotherapy doublet

1st Line

2nd Line

3rd Line


T790M-Negative EGFR TKI-Resistant NSCLC

To date, there are no specific guidelines for the treatment of this subgroup and, outside of clinical trials, platinum-doublet chemotherapy represents the principal treatment option.


“Osimertinib: The Winner Takes It All?”

cit. Tony Mok

First-line Osimertinib vs SoC for EGFR Mutant Advanced NSCLC (FLAURA)

§  Primary endpoint: PFS

§  Secondary endpoints including: ORR, DoR, OS, safety

Ramalingam S, et al. ESMO 2017. Abstract LBA2_PR.

Treatment-naive pts with advanced NSCLC

adenocarcinoma with an EGFR exon 19 or 21 mutation,

WHO PS 0/1, stable CNS mets permitted

(N = 556)

Osimertinib 80 mg PO daily (n = 279)

Erlotinib 150 mg or Gefitinib 250 mg PO daily (n = 277)

Until disease progression or unacceptable

toxicity

EGFR mutation (del19 vs L858R) and race (Asian vs non-Asian)

FLAURA: Survival and Response Outcomes

Outcome Osimertinib (n = 279)

SoC (n = 277)

HR/OR (95% CI) P Value

Median PFS, mos § No CNS mets (n = 440) § With CNS mets (n = 116)

18.9 19.1 15.2

10.2 10.9 9.6

0.46 (0.37-0.57) 0.46 (0.36-0.59) 0.47 (0.30-0.74)

< .0001 <. 0001 .0009

ORR, % § CR § PR

80 3

77

76 1

74

1.28 (0.85-1.93) .2335

Median DoR, mos 17.2 8.5 NR

§  Median OS not reached in either arm

─  Interim analysis at 25% maturity suggests 37% reduced risk of death with osimertinib vs SoC (P = .0068, not significant)


18.9 (15.2, 21.4) 10.2 (9.6, 11.1)

Prob

abilit

y of p

rogr

essio

n-fre

e sur

vival

0.2

0.4

0.6

0.8

0.0

0 3 6 21 24 27 9 12 15 18 Time from randomisation (months) No. at risk

Osimertinib 279 262 233 210 178 139 71 26 4 0 SoC 277 239 197 152 107 78 37 10 2 0

Osimertinib SoC

Prob

abilit

y of o

vera

ll sur

vival

0.2

0.4

0.6

0.8

0.0

0 3 6 9 27

No. at risk

30 12 15 18 21 24 Time from randomisation (months)

Osimertinib 279 276 269 253 243 232 154 87 29 4 0 SoC 277 263 252 237 218 200 126 64 24 1 0

HR 0.63 (95% CI 0.45, 0.88)

p=0.0068ǂ

Median overall survival Osimertinib Not reached

SoC Not reached


PFS OS interim analysis

FLAURA: Survival and Response Outcomes


Osimertinib: Where are we going?

19del

L858R

Uncommon Mutations

EGFR TKI: OSIMERTINIB 1st Line

2nd Line Chemiotherapy doublet

3rd Line Chemiotherapy

Treatment Based on ALK Translocation and ROS1 Fusion

ALK Fusion Gene

Adapted from Soda et al. Nature; 2007.

ALK Fusion Variants

Sasaki, European Journal of Cancer; 2010.

ALK Gene Rearrangements

§  Most common in younger nonsmokers with adenocarcinoma, adenosquamous carcinoma, and rarely SCC

§  Frequency: 4% overall, 33% in EGFR-negative never-smokers

§  Several ALK variants identified in NSCLC; clinical significance of each is unknown

§  Testing

–  Vysis break apart FISH (> 15% cells with split signal in 50 nuclei scored)

–  ALK IHC

§  3 agents now approved for ALK-positive NSCLC (first-line and/or after progression)

Shaw AT, et al. J Clin Oncol. 2009;27:4247-4253. Soda M, et al. Nature. 2007;448:561-566.

PROFILE 1014: First-line Crizotinib vs Pemetrexed/Platinum* in Advanced NSCLC §  Phase III trial (N = 343) ALK-positive pts with nonsquamous NSCLC

and no prior systemic treatment for advanced disease Crizotinib

(n = 172) Chemotherapy

(n = 171)

Median PFS, mos 10.9 7.0

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

P value < .001

ORR, % 74 45

P value < .001

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

*Carboplatin or cisplatin.

100

80

60

40

0

20

0 5 10 15 20 25 30 35

PFS

(%)

172 171

120 105

65 36

38 12

19 2

7 1

1 0

0 0

Crizotinib

Chemotherapy

Mos Pts at Risk, n Crizotinib

Chemotherapy

Crizotinib

NO-squamous NSCLC ALK rearrangement

1st Line

Treating Stage IV NSCLC EML4/ALK +

Crizotinib Resistance

§  L1196M

§  L1152R

§  C1156Y

§  F1174L

Sasaki Clinical Cancer Research. Epub 2011.

ALK Mutations With Reported Clinical Resistance to ALK Inhibitors

ALK Version Crizotinib Ceritinib Alectinib Brigatinib/Lorlatinib Wild-type

T1151TIns X

L1152R X X

C1156Y X

I1171N X X

F1174C X

F1174L X

F1174V X X

L1196M X

G1202R X X X

D1203N X

S1206F X

S1206Y X

G1269A X

Kim D-W, et al. ASCO 2016. Abstract 9008.

Next-Generation ALK Inhibitor CNS Activity

Kim DW, et al. Lancet Oncol. 2016;17:452-463. Mok T, et al. ASCO 2015. Abstract 8059. Felip E, et al. ASCO 2015. Abstract 8060. Shaw AT, et al. Lancet Oncol. 2016;17:234-242. Ou S, et al. J Clin Oncol. 2016;34:661-668. Kim DW, et al. ASCO 2016. Abstract 9007. Solomon BJ, et al. ASCO 2016. Abstract 9009. Reckamp K, et al. ELCC 2017. Abstract 88O.

Bra

in O

RR

(%)

(n = 8) (n = 28) (n = 33) (n = 17) (n = 16) (n = 35) (n = 25) (n = 18) (n = 18)

*No previous ALK inhibitor.

Ceritinib (750 mg/day)

Alectinib (600 mg BID)

Brigatinib (90 or 180 mg QD)

Lorlatinib (Various)

63%*

36% 39.4%

58.8%*

75%

57%

36%

67%

39%

0

10

20

30

40

50

60

70

80

90

100

(n = 13)

69%

Ensartinib (Various)

Crizotinib

Ceritinib or Alectinib

Chemotherapy Doublet

Pemetrexed based preferred


1st Line

2nd Line

3rd Line

Treating Stage IV NSCLC EML4/ALK +

ASCEND-4: First-line Ceritinib vs Pemetrexed/Platinum* in Advanced NSCLC §  Phase III trial (N = 376) ALK-positive pts with nonsquamous

NSCLC and no prior systemic treatment for advanced disease Ceritinib

(n = 189) Chemotherapy

(n = 187)

Median PFS, mos 16.6 8.1

HR (95% CI) 0.55 (0.42-0.73)

P value < .00001

ORR, % 72.5 26.7

Soria JC, et al. Lancet. 2017;389:917-929.

*Carboplatin or cisplatin.

100

80

60

40

0

20

0 2 4 6 8 10 12 14

PFS

(%)

189 187

155 136

139 114

125 82

116 71

105 60

98 53

76 35

Mos Pts at Risk, n Ceritinib

Chemotherapy

16 18 20 22 24 26 28 30 32 34

59 24

43 16

32 11

23 5

16 3

11 1

1 1

1 0

1 0

0 0

Ceritinib

Chemotherapy

CERITINIB

LORLATINIB(GI202R)

ChemotherapyDoublet

Pemetrexedbasedpreferred

NO-squamousNSCLCALKrearrangement

1stLine

2ndLine

3rdLine

Wherearewegoing?

§  Primary endpoint: PFS by independent review facility

§  Secondary endpoint: OS, ORR, PK, QoL, CNS PFS, safety

J-ALEX: Study Design

Alectinib 300 mg twice daily PO

28-day cycle (n = 103)

Crizotinib 250 mg twice daily PO


Stage IIIB/IV or recurrent ALK+ NSCLC

(by IHC/FISH or RT-PCR) ECOG PS ≤ 2

≥ 1 measurable lesion (investigator assessed)

≤ 1 previous chemotherapy Treated/asymptomatic

brain metastasis permitted (N = 207)

Stratified by clinical stage (IIIB/IV vs recurrent), previous chemotherapy,

ECOG PS (≤ 1 vs 2)

1:1

Nokihara H, et al. ASCO 2016. Abstract 9008.

3 preplanned interim analyses

for efficacy: 33%, 50%, 75% of final events (current report: second interim

analysis)


§  Secondary endpoint: HRQoL, ORR, CNS PFS, DoR, OS, safety

ALEX: Study Design

Alectinib 600 mg twice daily PO


Crizotinib 250 mg twice daily PO


Stage IIIB/IV or recurrent ALK+ NSCLC

(by IHC) ECOG PS ≤ 2

No previous systemic therapy for advanced disease

Asymptomatic brain metastasis permitted

(N = 303)

1:1

ClinicalTrials.gov. NCT02075840.

Until PD, unacceptable

toxicity, or withdrawal

ALEX: Survival Outcomes

Peters S, et al. N Engl J Med. 2017;[Epub ahead of print].

Investigator-Assessed PFS

Mos

PFS

(%)

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30

11.1 mos

Alectinib

NR

Crizotinib

IRC-assessed PFS: 25.7 vs 10.4 mos; HR: 0.50 (95% CI: 0.36-0.70; P < .001)

HR: 0.47 (95% CI: 0.34-0.65; P < .001)

Mos

OS

(%)

0

20

40

60

80

100

0 3 6 9 12 15 18 21 24 27 30

HR: 0.76 (95% CI: 0.48-1.20; P = .24)

Alectinib

Crizotinib

OS

ALEX: PFS According to Pt Subgroups (Investigator Assessed)


Subgroup Overall Age, Yrs

< 65 ≥ 65

Sex Female Male

Ethnicity Asian Non-Asian

Smoking status Active smoker Nonsmoker Past smoker

ECOG PS 0 1 2

CNS Mets at baseline Yes No

Prior Brain Radiation Yes No

Events/Pts, n 164/303

125/233 39/70

91/171 73/132

72/138 92/165

12/17

103/190 49/96

44/97

105/186 15/20

78/122 86/181

26/47

138/256

HR (95% CI) .48 (0.35-0.66)

.48 (0.34-0.70) .45 (0.24-0.87)

.39 (0.25-0.60) .61 (0.38-0.98)

.46 (0.28-0.75) .49 (0.32-0.75)

1.16 (0.35-3.90) .44 (0.29-0.66) .42 (0.23-0.77)

.40 (0.21-0.77) .48 (0.32-0.71) .74 (0.25-2.15)

.40 (0.25-0.64) .51 (0.33-0.80)

.33 (0.14-0.74) .52 (0.36-0.73)

0.1 1 10

Alectinib better Crizotinib better

ALEX: Time to CNS Progression


CNS Progression, no Previous Systemic PD

Alectinib (n = 152)

Crizotinib (n = 151)

Pts with event, n (%) 18 (12) 68 (45) Cause-specific HR (95% CI) P value

0.16 (0.10-0.28) < .001

Cumulative Incidence of CNS Progression § Competing risk of CNS progression, non-CNS progression, and death based on first event was analyzed

Mos

Cum

ulat

ive

Inci

denc

e (%

)

0

10

20

30

40

50

0 6 12 18 24 30

60 Crizotinib, 12-mo cumulative incidence rate: 41.4% (95% CI: 33.2-49.4)

Alectinib, 12-mo cumulative incidence rate: 9.4% (95% CI: 5.4-14.7)

ALEX: AEs (≥ 10% Difference Between Arms)


Crizotinib Alectinib (n = 152)

Crizotinib (n = 151)

Any Grade Grade 3-5 Any Grade Grade 3-5

Nausea 21 (14) 1 (1) 72 (48) 5 (3)

Diarrhea 18 (12) 0 68 (45) 3 (2)

Vomiting 11 (7) 0 58 (38) 5 (3)

Peripheral edema 26 (17) 0 42 (28) 1 (1)

Dysgeusia 4 (3) 0 29 (19) 0

Increased ALT 23 (15) 7 (5) 45 (30) 22 (15)

Increased AST 21 (14) 8 (5) 37 (25) 16 (11)

Visual impairment 2 (1) 0 18 (12) 0

Increased blood bilirubin 23 (15) 3 (2) 2 (1) 0

Myalgia 24 (16) 0 3 (2) 0

Anemia 30 (20) 7 (5) 7 (5) 1 (1)

Increased weight 15 (10) 1 (1) 0 0

ALECTINIB

BRIGANTINIB? LORLATINIB?

Chemotherapy Doublet

Pemetrexed based preferred


1st Line

2nd Line

3rd Line

Wherearewegoing?

Treatment Algorithm for Advanced NSCLC: Molecular Biomarker Positive

ALK positive

Progression

First line Second line and beyond

EGFR mutation positive

Advanced NSCLC (Molecular Biomarker Positive)

ROS1 positive

Crizotinib

Follow treatment options for adenocarcinoma or squamous cell carcinoma without actionable biomarker

Osimertinib

EGFR T790M mutation negative

Alectinib, brigatinib, or

ceritinib dependent on

previous therapy

Alectinib, ceritinib, or crizotinib

Erlotinib, afatinib, or gefitinib

EGFR T790M mutation positive

BRAF V600E positive

Dabrafenib/ trametinib

NSCLC M+ NON-ONCOGENE ADDICTED

PD-L1 (TPS) ≥50%

25-30%

Ribas A. N Engl J Med. 2012;366:2517-2519.

CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment

CTLA-4 mAbs: Ipilimumab Tremelimumab

PD-1 mAbs: Nivolumab Pembrolizumab PD-L1 mAbs: Atezolizumab Avelumab Durvalumab

Priming phase (lymph node)

Effector phase (peripheral tissue)

T-cell migration

Dendritic cell T-cell

MHC TCR

B7

CD28

CTLA-4

T-cell Cancer cell

MHC TCR

PD-1

PD-L1

T-cell Cancer

cell Dendritic

cell T-cell

Pembrolizumab* (Anti–PD-1)

Nivolumab* (Anti–PD-1)

Atezolizumab (Anti–PD-L1)

Durvalumab (Anti–PD-L1)

Diagnostic partner Dako Dako Ventana Ventana

Clone 22C3[1] 28-8[2] SP142[3] SP263

Machine utilized Link 48 Link 48 BenchMark ULTRA

BenchMark ULTRA

Compartment TC TC TC/IC TC

Variables % of cells % of cells % of cells % of cells

Definition of positive

PD-L1(+): ≥ 50%

PD-L1(+): ≥ 1%

PD-L1(+): TC3/IC3 (≥ 50% / ≥ 10%)

TC2/IC2 (5% - 49% / 5% - 9%)

TC1/IC1 (1% - 4%)

PD-L1(+): ≥ 25%

PD-L1 IHC Assays

*FDA-approved assays.

1. Garon EB, et al. N Engl J Med. 2015;372:2018-2028. 2. Phillips T, et al. Appl Immunohistochem Mol Morphol. 2015;23:541-549. 3. Fehrenbacher L, et al. Lancet. 2016;387:1837-1847.

Tumor mutational burden (TMB)

Tumor infiltrating lymphocyte

?

KEYNOTE-024: Pembrolizumab vs CT as First-line Therapy for Advanced NSCLC §  Open-label phase III trial


§  Secondary and exploratory endpoints: ORR, OS, DoR, and safety

Pts with stage IV NSCLC and ECOG PS 0/1, no previous systemic therapy, no actionable EGFR/ALK mutations,

and PD-L1 TPS ≥ 50%* (N = 305)

Pembrolizumab 200 mg IV Q3W for up to 35 cycles

(n = 154)

Chemotherapy (histology based) for up to 6 cycles

(n = 151)

Stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), and

enrollment region

Until PD (crossover to pembrolizumab allowed)

*≥ 50% tumor cell staining using 22C3 companion diagnostic IHC assay.

Until PD or unacceptable toxicity

Reck M, et al. N Engl J Med. 2016;375:1823-1833.

KEYNOTE-024: ORR and Survival Outcomes

§  ORR: 44.8% (pembrolizumab) vs 27.8% (chemotherapy)

§  FDA approval October 2016 §  Now SoC to test for PD-L1 at initial diagnosis (22c3 assay) §  Approximately 25% to 28% of NSCLC cases have PD-L1 ≥ 50%

100

80

60

40

20

0

OS

Mos

OS

(%)

21 0 3 6 9 12 15

Pembrolizumab Chemotherapy

HR for OS: 0.60 (95% CI: 0.41-0.89; P = .005)

18

PFS

Mos

PFS

(%)

100

80

60

40

20

0 18 0 3 6 9 12 15

HR for PFS: 0.50 (95% CI: 0.37-0.68; P < .001)

6.0 10.3


KEYNOTE-024: Treatment-Related AEs With Incidence ≥ 10%

1/2 Grade

3/4 Pembrolizumab Chemotherapy


Inci

denc

e (%

)

50 45 40 35 30 25 20 15 10

5 0

First-line NSCLC M+

EGFR and ALK wild type

PD-L1 ≥ 50%

Pembrolizumab

Platinum Doublet

Chemotherapy

1st Line

2st Line

3st Line

Optimal duration of immune checkpoint therapy is yet to be defined

Treating Stage IV NSCLC PD-L1 (TPS) >50%

§  Anti-PD-L1 vs CT: Avelumab, Atezolizumab, Durvalumab

§  Dual checkpoint blockade

§  Checkpoint blockade plus chemotherapy and/or radiation

§  Checkpoint blockade plus vaccines

§  Checkpoint blockade plus oncolytic viruses

§  Checkpoint blockade plus HDAC inhibitors (Epacatostat, etc.)

§  Checkpoint blockade plus . . .

Wherearewegoing?

NSCLC M+ NON-ONCOGENE ADDICTED

PD-L1 (TPS) < 50%

PD-L1 NEGATIVE

Controindications to immunotherapy

40/50 %

Treating Stage IV NSCLC: 1st line

Immune Checkpoint Inhibitors in Pretreated Advanced NSCLC

CheckMate 017 CheckMate 057

KEYNOTE-010 OAK

Nonsquamous Stage IIIB/IV

(N = 582)

Nivolumab

Docetaxel

Squamous Stage IIIB/IV

(N = 272)

Nivolumab

Docetaxel

Advanced NSCLC with ≥ 1% PD-L1+

tumor cells (N = 1034)

Pembrolizumab (2 mg/kg)

Docetaxel

Pembrolizumab (10 mg/kg)

Advanced NSCLC (2L/3L)

(N = 1225)

Atezolizumab

Docetaxel

Phase III Studies of Second-line Immunotherapy in NSCLC

1. Brahmer J, et al. N Engl J Med. 2015;373:123-135. 2. Herbst RS, et al. Lancet. 2016;387:1540-1550. 3. Rittmeyer A, et al. Lancet. 2017;389:255-265.

Agent/Phase III Study ISTO

PD-L1

TPS Treatment Arms Median OS, Mos

HR for OS Benefit in SqNSCLC

(95% CI)

Nivo/CheckMate 017[1] Squam Any Nivo vs docetaxel 9.2 vs 6.0 (P < .001) 0.59 (0.44-0.79)

(P < .001)

Nivo/CheckMate 057[1] Nonsquam Any Nivo vs docetaxel

12.2 vs 9.4 (P < .002)

0.73 (0.59 to 0.89)

(P=0.002)

Pembro/KEYNOTE-010[2] NSCLC ≥ 1%

§  Pembro 2 mg/kg vs docetaxel

§  Pembro 10 mg/kg

vs docetaxel

§  PD-L1 ≥ 1%: 10.4 vs 8.5 (P = .0008) §  PD-L1 ≥ 50%: 14.9 vs 8.2 (P = .0002) §  PD-L1 ≥ 1%: 12.7 vs 8.5 (P < .0001)

§  PD-L1 ≥ 50%: 17.3 vs 8.2 (P < .0001)

0.74 (0.50-1.09) (NS)*

Atezo/OAK[3] NSCLC Any Atezo vs docetaxel §  ITT: 13.8 vs 9.6 (P = .0003)

§  PD-L1 ≥ 50%: 15.7 vs 10.3 (P = .0102) 0.73 (0.54-0.98)

(P = .0383)

*For pooled pembrolizumab doses vs docetaxel in total population.

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

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

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

20

40

60

80

100 O

S (%

)

Mos

Ram + doc Pbo + doc Censored

Ram + doc Pbo + doc Ram + doc vs pbo + doc HR: 0.86 (95% CI: 0.75-0.98; P = .023)

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

Median OS, Mos (95% CI)

Ramucirumab in combination with docetaxel is approved for metastatic NSCLC with disease progression on or after platinum-based chemotherapy

LUME-Lung 1 Nintedanib + Docetaxel vs Docetaxel in Pts With PD After

Chemotherapy: OS by Histology

Adenocarcinoma subset

Nintedanib+docetaxel(n=655)

Placebo+docetaxel(n=659)

Median,mo 10.1 9.1

HR(95%CI) 0.94(0.83to1.05)

P .2720

Nintedanib+docetaxel(n=322)

Placebo+docetaxel(n=336)

Median,mo 12.6 10.3

HR(95%CI) 0.83(0.70to0.99)

P .0359

All patients

100

80

60

40

20

0 0 4 8 12 16 20 24 28 32 36

0 4 8 12 16 20 24 28 32 36

Reck M, et al. ASCO 2013.

“Old Agents”

Docetaxel, Pemetrexed*, Erlotinib

New Immunotherapy Agents

Nivolumab, Pembrolizumab (PD-L1>1%),

New Antiangiogenic Agents

Ramucirumab + Docetaxel (only USA) Nindetanib + Docetaxel (only EU)*

* only adenocarcinoma

Selecting Second-Line Therapy

PatientFactors

• PS• Tabagism• Comorbidities• Patientpreference

TreatmentHistory

• First-lineregimen• Durationofresponsetofirst-linetreatment

TumorCharacteristics

• Histology• Molecularprofile

D’Argento E, et al. Curr. Treat. Options in Oncol. (2016)

nonsquamous NSCLC squamous NSCLC

2nd line

1

1

Gemelli ART - Session 8...ORR, % 61 71 (including 2 CRs) Disease-control rate, % -- 92 at 6 wks...

Documents

Transcript of Gemelli ART - Session 8...ORR, % 61 71 (including 2 CRs) Disease-control rate, % -- 92 at 6 wks...