I tumori del polmone wild type

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Novità e Sequenze Terapeutiche del Carcinoma Polmonare

I tumori del Polmone wild-type

Francesco Passiglia

Dipartimento di Oncologia

Università degli Studi di Torino

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Outline

1. Who are ?

2. How long survive ?

3. Current Treatment Algorithm ? 4. Future Treatment Scenario ? 5. IO Combo biomarkers ?

6. Chemo-free Regimens: Myth or Reality ?

• Wild-type advanced NSCLC patients:

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Who are wild-type NSCLC patients ? Current Research Scenario

Lovly C. ASCO 2019

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Slide 5

Capmatinib, Tepotinib (MET exon 14 mut) LOXO-292 (RET inhibitor)

Larotrectinib (NTRK inhibitor)

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Who are wild-type NSCLC patients ?

Current Clinical Scenario

Planchard et al. Ann Oncol 2019

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Who are wild-type NSCLC patients ?

Current Italian Scenario

Passiglia, Novello, et al., JTO in press

(7)

Months

No. at risk Nivolumab Docetaxel

427 427

280 264

205 145

150 84

113 57

84 45

64 26

55 19

54 12 70

34

50 9

30 4

6 0

0 0

OS (%)

80

60

40

20

0 0 100

6 12 18 24 30 36 42 48 54 60 66 72 78

Nivolumab (n = 427)

Docetaxel (n = 427)

Median OS, mo 11.1 8.1

(95% CI) (9.2–13.1) (7.2–9.2) HR (95% CI) 0.68 (0.59–0.78)

48.0%

34.3%

1-year

26.9%

13.5%

2-year

17.1%

8.2%

3-year

14.2%

4.6%

4-year

13.4%

2.6%

5-year

Gettinger WCLC 2019

How long survive wild-type NSCLC patients ?

5-year OS from CheckMate 017/057 Phase 3 Studies

(8)

Pembrolizumab 5-year OS: 23%

Gainor, ASCO 2019, JCO 2019

Pembrolizumab 5-year OS: 29% (PD-L1>50%)

How long survive wild-type NSCLC patients?

5-year OS from KEYNOTE-001

(9)

Current Treatment Algorithm in wild-type NSCLC ? 1st-line treatment options by PD-L1 expression

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No. at risk

Pembrolizumab 154 136 121 112 106 96 89 85 78 73 73 69 66 64 50 24 5 Chemotherapy 151 124 108 88 80 69 61 56 48 46 44 37 35 33 24 14 6

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

0 10 20 30 40 50 60 70 80 90 100

Time, months

Overall Survival, % 51.7%

34.2% 43.7%

24.9% 41.0%

23.5%

Median (95% CI)

26.3 mo (18.3–40.4 mo) 14.2 mo (9.8–18.3 mo)

N

Events, n (%)

HR (95% CI)

Pembrolizumab^a 154 97 (63) 0.65 (0.50–0.86)

P = 0.001^b Chemotherapy 151 113 (75)

64.9% cross-over (ITT)

Reck WCLC 2019

Pembrolizumab standard of care in first-line NSCLC ^PD-L1≥50%

3-year OS from KEYNOTE-024

(11)

Mok, Lancet 2019

Pembrolizumab not superior to Platinum-CT in NSCLC PD-L1<50%

OS from KEYNOTE-042 (PD-L1: 1% - 49%)

HR: 0.92 (95% CI 0.77-1-11)

Median OS (months) (95% CI) 13.4 (10.7 – 18.2)

12.1 (11.0 – 14.0)

(12)

Current Treatment Algorithm in wild-type NSCLC ? 2nd-line treatment options after platinum-CT

(13)

Current Treatment Algorithm in wild-type NSCLC ? PD1/PD-L1 Inhibitors vs Docetaxel in 2nd-line

IO more effective and better tolerated than docetaxel in 2nd line

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Current Treatment Algorithm in wild-type NSCLC ? 2nd-line treatment options after platinum-CT

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Current Treatment Algorithm in wild-type NSCLC ? Nintedanib + docetaxel vs docetaxel in 2nd-line

Reck NEJM 14, Capelletto Lung Cancer 19

Adding Nintedanib to 3w docetaxel

increased OS (and AEs) in adenocarcinoma

Weekly regimen equal effective and better tolerated than 3w docetaxel

LUMELung1 SENECA

(16)

Current Treatment Algorithm in wild-type NSCLC ? Nintedanib + docetaxel after IO ?

Grohé, Future Oncology 19; Corral, Clin. Transl. Oncol 19; Capelletto, WCLC 19 VARGADO

N=12

NPU Program N=11

SENECA subgroup

PR 58%% 36% N.A

SD 25% 46% N.A

PD 17% 18% N.A

DCR 83% 82% N.A

Median PFS 5.5 months 3.2 months 5.8 months

(17)

Gadgeel, ASCO 19; Barlesi, ESMO 18; Cappuzzo, ESMO 18; Socinski, NEJM 18.

Trial Keynote 189

IMPower 132

IMPower 130

IMPower 150

Histology

NON-SQUAMOUS NSCLC

Experimental Arm

Pembrolizumab Platinum Pemetrexed

Atezolizumab Platinum Pemetrexed

Atezolizumab Platinum NabPaclitaxel

Atezolizumab Platinum Paclitaxel

Bevacizumab PD-L1

selection? No No No No

Median OS

(months) 22.0 vs 10.7 18.1 vs 13.6 18.6 vs 13.9 19.2 vs 14.7

OS HR

(95% CI) 0.56 (0.45-0.70) 0.81 (0.64-1.03) 0.79 (0.64-0.98) 0.78 (0.64-0.96)

Future Treatment Scenario in wild-type NSCLC ?

IO + CT superior to Platinum-CT

(18)

IMPower 132

IMPower 130

IMPower 150

Keynote 407

IMPower 131

Histology

NON-SQUAMOUS NSCLC SQUAMOUS NSCLC

Experimental Arm

Bevacizumab

Pembrolizumab Platinum NabPaclitaxel

Atezolizumab Platinum NabPaclitaxel PD-L1

selection? No No No No No No

Median OS

(months) 22.0 vs 10.7 18.1 vs 13.6 18.6 vs 13.9 19.2 vs 14.7 15.9 vs 11.3 14.0 vs 13.9

HR

(95% CI) 0.56 (0.45-0.70) 0.81 (0.64-1.03) 0.79 (0.64-0.98) 0.78 (0.64-0.96) 0.64 (0.49-0.85) 0.88 (0.73-1.05)

Gadgeel, ASCO 19; Barlesi, ESMO 18; Cappuzzo, ESMO 18; Socinski, NEJM 18, Paz-Ares, NEJM 2018; Cappuzzo WCLC 19

Future Treatment Scenario in wild-type NSCLC ?

IO + CT superior to Platinum-CT

(19)

IMPower 132

IMPower 130

IMPower 150

Keynote 407

IMPower 131

Histology

NON-SQUAMOUS NSCLC SQUAMOUS NSCLC

Experimental Arm

Bevacizumab

Atezolizumab Platinum NabPaclitaxel OS HR

(PD-L1>50%) 0.59 (0.39-0.88) N.A 0.84 (0.51-1.39) 0.70 (0.43-1.13) 0.64 (0.37-1.10) 0.48 (0.29-0.81)

OS HR

(PD-L1 1-49%) 0.62 (0.42-0.92) N.A 0.70 (0.45-1.08) 0.80 (0.55-1.15) 0.57 (0.36-0.90) 1.08 (0.81-1.45)

OS HR

(PD-L1<1%) 0.52 (0.36-0.74) N.A 0.81 (0.61-1.08) 0.82 (0.62-1.08) 0.61 (0.38-0.98) 0.87 (0.67-1.13)

Future Treatment Scenario in wild-type NSCLC ? IO + CT vs Platinum-CT by PD-L1 expression

(20)

IMPower 132

IMPower 130

IMPower 150

Keynote 407

IMPower 131

Histology

NON-SQUAMOUS NSCLC SQUAMOUS NSCLC

Experimental Arm

Bevacizumab

Atezolizumab Platinum NabPaclitaxel HR

(PD-L1>50%) 0.59 (0.39-0.88) N.A 0.84 (0.51-1.39) 0.70 (0.43-1.13) 0.64 (0.37-1.10) 0.48 (0.29-0.81)

HR

(PD-L1 1-49%) 0.62 (0.42-0.92) N.A 0.70 (0.45-1.08) 0.80 (0.55-1.15) 0.57 (0.36-0.90) 1.08 (0.81-1.45)

HR

(PD-L1<1%) 0.52 (0.36-0.74) N.A 0.81 (0.61-1.08) 0.82 (0.62-1.08) 0.61 (0.38-0.98) 0.87 (0.67-1.13)

Future Treatment Scenario in wild-type NSCLC ? IO + CT vs Platinum-CT by PD-L1 expression

(21)

PD-L1 < 50%

PD-L1 ≥ 50%

Pembrolizumab IO-CT combo

1st line 2nd line

Platinum-CT

Future Treatment Scenario in wild-type NSCLC ? First-line treatment options by PD-L1 expression

IO-CT combo

Clinical Trials Nintedanib+Doc ?

IO-Rechallenge

?

(22)

IO Combo Biomarkers (TMB)

KEYNOTE-189: IO+CT vs CT by tTMB level

Garassino, WCLC 19

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IO Combo Biomarkers (STK11)

Retrospective cohort study (2407 pts)

STK11m (n=40)

STK11wt (n=230) mOS, months

(IQR)

11.2 (7.3–NA)

17.7 (7.0–30.8) HR (95% CI) 1.4 (0.9–2.3)

p-value 0.1

First-line IO-treated population

0.0 0.2 0.4 0.6 0.8 1.0

0 500 1000 1500

Probability of OSProbability of OS

0.0 0.2 0.4 0.6 0.8 1.0

0 500 1000

STK11m (n=111)

(IQR)

6.3 (2.4–17.2)

12.0 (4.6–25.0) HR (95% CI) 1.6 (1.3–2.0)

p-value 0.0002

Second-line IO-treated population

First-line chemotherapy-treated population

0.0 0.2 0.4 0.6 0.8 1.0

0 500 1000 1500 2000

Probability of OS

STK11m (n=288)

(IQR)

11.2 (4.9–24.6)

17.8 (7.7–37.5) HR (95% CI) 1.4 (1.2–1.6)

p-value <0.0001

Second-line chemotherapy-treated population

0.0 0.2 0.4 0.6 0.8 1.0

0 500 1000 1500 2000

Probability of OS

STK11m (n=83)

(IQR)

11.5 (6.2–25.2)

13.2 (6.0–32.0) HR (95% CI) 1.1 (0.8–1.4)

p-value 0.7

Shire, WCLC 19

STK11 associated to poor OS irrespective of treatment received…is prognostic!

(24)

IO Combo Biomarkers (STK11) Retrospective multicenter study

Lack of PFS/OS benefit from addition of IO to CT in STK11/KEAP MUT NSCLC…

…may be predictive ?

Skoulidis WCLC 19, ASCO 19

STK11^WT;KEAP1^WTand PDL1 TPS ≥1%

STK11^MUT

and/or

KEAP1MU^Tand PDL1 TPS ≥1%

HR 0.36 ( 95% CI 0.2-0.65)

P=0.0008, log-rank test HR 0.99 ( 95% CI 0.59-1.69)

P=0.84, log-rank test

STK11^MUT

and/or

KEAP1MU^T

(25)

N = 1189

<1% PD-L1 expression

N = 550

Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W

n = 396

Histology-based chemotherapy^b n = 397

Nivolumab 240 mg Q2W n = 396

Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W

n = 187

Histology-based chemotherapy^b n = 186

Nivolumab 360 mg Q3W + histology-based chemotherapy^b

n = 177

R 1:1:1

Key Eligibility Criteria

• Stage IV or recurrent NSCLC

• No prior systemic therapy

• No known sensitizing EGFR/ALK alterations

• ECOG PS 0–1

Stratified by SQ vs NSQ

R 1:1:1

≥1% PD-L1 expression

Nivolumab + ipilimumab n = 396

Chemotherapy^b n = 397

Patients for PD-L1 co-primary analysis

Co-primary endpoints: Nivolumab + ipilimumab vs chemotherapy

• PFS in TMB-selected populations OS in PD-L1–selected populations

Nivolumab + ipilimumab n = 139

Chemotherapy^b n = 160

Patients for TMB co-primary analysis^c

Chemo-free regimens in wild-type NSCLC ?

CheckMate 227 Trial Design

(26)

≥1% PD-L1 expression <1% PD-L1 expression

38 20 16 15 10 8 4 1 0

48 30 16 4 1 1 1 0 0

Nivo + ipi (n = 38)

Chemo (n = 48) Median PFS, mo^b 7.7 5.3 HR

95% CI

0.48 0.27, 0.85

Chemotherapy Nivolumab + ipilimumab

Months 0

20 40 60 80 100

0 3 6 9 12 15 18 21 24

1-y PFS = 45%

1-y PFS = 8%

101 65 50 40 26 16 7 2 0

112 73 35 13 6 5 3 0 0

1-y PFS = 42%

1-y PFS = 16%

PFS (%)

Chemotherapy

Nivolumab + ipilimumab

Months 0

20 40 60 80 100

0 3 6 9 12 15 18 21 24

Nivo + ipi (n = 101)

Chemo (n = 112) Median PFS, mo^a 7.1 5.5 HR

95% CI

0.62 0.44, 0.88

Nivo + ipi No. at risk Chemo

Hellmann, NEJM 2018

CheckMate 227: Trial Results

PFS in patients with high TMB (>10 mut/Mb) by PD-L1 expression

October 19, 2018: HR OS in TMB high comparable to TMB low subgroup

July 24, 2019: Nivo+IPI increased OS in PD-L1>1% pts (but also in PD-L1<1%)

(27)

Primary endpoints (PD-L1 TC ≥25%*):

• PFS

^‡

(D+T vs CT)

• OS (D vs CT)

• OS (D+T vs CT)

Key secondary endpoints:

• PFS

^‡

(D vs CT; PD-L1 TC ≥25%*)

• OS (D+T vs CT; PD-L1 TC ≥1%*)

• ORR

^‡

• DoR

• Safety and tolerability Key exploratory endpoints:

• OS by additional PD-L1 TC cutoffs

• OS by blood TMB

R

Durvalumab + tremelimumab (n=372)

D 20 mg/kg q4w until disease progression + T 1 mg/kg q4w for up to 4 doses

Platinum-based chemotherapy (n=372)

• Paclitaxel + carboplatin OR

• Gemcitabine + cisplatin/carboplatin (squamous) OR

• Pemetrexed + cisplatin/carboplatin (non- squamous)^†

for up to 6 cycles

Durvalumab (n=374)

20 mg/kg q4w until disease progression

Stratified by PD-L1 TC (<25% vs

≥25%*) and histology

• Stage IV NSCLC

• All-comers population

(i.e. irrespective of PD-L1 status)

• No sensitising EGFR mutation or ALK rearrangement

• ECOG PS 0/1

• Immunotherapy- and CT-naïve

N=1118 randomised

1:1:1

Chemo-free regimens in wild-type NSCLC ?

Mystic Trial Design

(28)

MYSTIC: Trial Results

OS benefit by blood TMB >20 mut/Mb

Peeters S, AACR 2019

Durva+Treme vs CT: OS HR: 0.49 (0.32-0.74) Durva+Treme vs CT: OS HR: 1.16 (0.93-1.45)

August 21, 2019 NEPTUNE Trial:

Durva+Treme not increased OS in blood TMB>20 mut/Mb

(29)

Conclusions

1. Who are? Heterogeneous and evolving (EGFR/ALK/ROS1/BRAF? WT)

• Wild-type advanced NSCLC patients:

(30)

Conclusions

1. Who are? Heterogeneous and evolving (EGFR/ALK/ROS1/BRAF? WT) 2. How long survive? 1:6 pretreated, 1:3 naive PD-L1≥50% pts alive at 5 years

• Wild-type advanced NSCLC patients:

(31)

Conclusions

1. Who are? Heterogeneous and evolving (EGFR/ALK/ROS1/BRAF? WT) 2. Long-term OS? 1:6 pretreated, 1:3 naive PD-L1≥50% pts alive at 5 years

3. Current treatment? IO single agent standard first-line in NSCLC ^PD-L1≥50%

• Wild-type advanced NSCLC patients:

(32)

Conclusions

1. Who are? Heterogeneous and evolving (EGFR/ALK/ROS1/BRAF? WT) 2. Long-term OS? 1:6 pretreated, 1:3 naive PD-L1≥50% pts alive at 5 years

3. Current treatment? IO single agent standard first-line in NSCLC ^PD-L1≥50%

4. Future scenario? IO + CT potential option regardless of PD-L1

• Wild-type advanced NSCLC patients:

(33)

Conclusions

1. Who are? Heterogeneous and evolving (EGFR/ALK/ROS1/BRAF? WT) 2. Long-term OS? 1:6 pretreated, 1:3 naive PD-L1≥50% pts alive at 5 years

3. Current treatment? IO single agent standard first-line in NSCLC ^PD-L1≥50%

4. Future scenario? IO + CT potential option regardless of PD-L1

5. IO Combo biomarkers? PD-L1 and TMB not predictive; STK11 prognostic and…may be predictive of IO resistance

• Wild-type advanced NSCLC patients:

(34)

I tumori del polmone wild type

Novità e Sequenze Terapeutiche del Carcinoma Polmonare