I tumori del polmone non wild type

(1)

Novità e sequenze terapeutiche del carcinoma polmonare:

I tumori del polmone non wild type

Francesco Grossi

UOC Oncologia Medica

Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico

Milano

SuperNovae in Oncologia Pisa, 20 Settembre 2019

(2)

Agenda

Old targets: EGFR and ALK

New targets in the clinical practice: ROS-1, BRAF, NTRK

New targets for the clinical practice in the near future: MET, RET, KRAS

(3)

Agenda

(4)

PFS and OS in EGFR mutated pts treated with EGFR TKIs inhibitors

Lin JJ, JTO 2016

(5)

Acquired resistance mechanisms with comparator EGFR TKI (129 pts)

Ramalingam SS, ESMO 2018

(6)

Assessment of resistance mechanism and clinical implication in patients with EGFR T790M-positive

and acquired resistance to Osimetinib

Oxnard GR, Jama Oncology 2018

(7)

FLAURA: osimertinib vs gefitinib/erlotinib as first-line in EGFR mutated

Soria JC, NEJM 2018

(8)

Candidate acquired alterations with osimertinib

Ramalingam SS, ESMO 2018

(9)

Chemotherapy plus EGFR-TKI as first- line treatment: study design

Zhang W, WCLC 2019

(10)

Chemotherapy plus EGFR-TKI as first- line treatment: best response

(11)

Chemotherapy plus EGFR-TKI as first- line treatment: OS

(12)

Chemotherapy plus EGFR-TKI as first- line treatment: safety

(13)

. 1^stor 2^ndGeneration

TKI in First Line

3rd generation TKI in 1st Line

Cb-Pem + Gefitinib in 1^stLine

Erlotinib + Ramucirumab

in 1^stLine

3 6 9 12 15 18 21 24 27 30

Pt Chemo

Chemo 1^st/2^ndgeneration TKI Osimertinib

Osimertinib

Carbo-Pem+ Gefitinb

Erlotinib + Ramucirumab

Osimertinib

2LChemo

Chemo Pt Chemo

2L Chemo

Chemo

10 – 14 months If T790M+(50%) 10 months

If T790M - (50%) 5 months

5 months

18.9 months

5 months

16 - 21 months 3 months

19.4 months 5 months

If T790M+(50%) 10 months

If T790M+ (50%) 10 months

If T790M- (50%) 3 months

If T790M- (50%) 5 months

25 – 29 months

24 months

29 – 34 months 19 - 24 months

34 months 24 months Median PFS in

Months MPFS 1+2+3

15- 19 months

Various options in the first-line EGFR mutated patients

(14)

PFS for atezo+bev+CP vs bev+CP in EGFR/ALK+ patients

Kowanetz M, AACR 2018

(15)

Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions

Janne PA, ASCO 2019

(16)

Crizotinib (Xalkori) approved by FDA

Crinò L, ASCO 2011 Kwak EL, NEJM 2010

FDA 26/08/11

(17)

ALEX: alectinib vs crizotinib

Peters S, NEJM 2017

(18)

Resistance to crizotinib and next generation first line ALKi

Gainor JF, Cancer Discovery 2016

(19)

Crizotinib

Camidge R, ASCO 2018

Ceritinib

Brigatinib

Alectinib Lorlatinib

PFS 1 ≈ 11 months

PFS2 = 5,4 months

PFS2 = 8,3 to 9,6 months

PFS2 = 12,9 months

PFS n+2 = 6,9 months

Cumulated PFS = 24-31 months

Alectinib

PFS≈ 34-35 months

Sequencing of ALK inhibitors

(20)

Enrolled patients N=864

Treated with CRZ as first ALK-TKI (CRZ group)

N=535

Treated with ALEC as first ALK-TKI (ALEC group)

N=305 Analysis

N=840

Exclusion N=24

No ALK-TKI therapy during the designated period N=15

Enrollment for other clinical trial N=4 No OS data N=2

Duplicate N=2

Received ceritinib as first ALK-TKI N=1

Treated with ALEC after CRZ (Sequential treatment group)

N=301

Consort diagram

✓ A total of 864 patients with NSCLC harboring ALK rearrangement were enrolled in this research.

✓ Group definition as below: CRZ group, 535 patients received CRZ as first ALK-TKI; ALEC group, 305

patients received ALEC as first ALK- TKI; Sequential treatment group, patients received ALEC after CRZ failure in the CRZ group.

The impact of sequential therapy of crizotinib followed by alectinib: real world data analysis

Watanabe S, WCLC 2019

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0 10 20 30 40 50 60 70 80 90 100

0 50 100 150 200 250 300

0 10 20 30 40 50 60 70 80 90 100

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 84

Patients treated with CRZ followed by ALEC (Sequential treatment group vs ALEC group)

Combined TTF vs. TTF of ALEC.

ALEC group

Sequential treatment group

Comparison of OS between Sequential treatment group and ALEC group.

ALEC group

Sequential

treatment group

(months) (%)

CRZ followed by ALEC

N=282

ALEC N=302

Median, months 34.4 27.27

HR [95%CI] 0.709 [0.559 – 0.899]

p value 0.0045

CRZ followed by ALEC

N=301

ALEC N=305

Median, months 88.44 NR

HR [95%CI] 0.954 [0.689 – 1.319]

p value 0.7758

(mFU, 48.6 mo)

(mFU, 24.8 mo)

(mFU, 48.6 mo)

Watanabe S, WCLC 2019

(22)

Anticipated to open January 2019

(23)

Multiple sequential treatment in ALK pos pts in 2020-22

Ceritinib

1L 2L

Brigatinib Alectinib

Ceritinib Lorlatinib

3L

Lorlatinib Alectinib

Ceritinib Brigatinib

1L PD PD

Crizotinib Alectinib Brigatinib Ceritinib Lorlatinib

PD 4L

CT+I/O

Biopsy Biopsy

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Agenda

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Crizotinib in ROS-1 positive NSCLC: best response and PFS

Shaw AT, NEJM 2014 RR=72%

PFS= 19.2 mos

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BRAF V600E mutation: responses with Dabrafenib +Trametinib

Planchard D, Lancet Oncology 2016

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Efficacy of Larotrectinib in TRK fusion–

positive cancers in adults and children

Drilon A, NEJM 2018

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Larotrectinib is active in TRK fusion lung cancer

Farago AF, WCLC 2019

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Agenda

(30)

Capmatinib in MET ex14-mutated

advanced NSCLC: efficacy data from the phase II GEOMETRY trial (pretrated)

Wolf J, ASCO 2019

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Capmatinib in MET ex14-mutated

advanced NSCLC: efficacy data from the phase II GEOMETRY trial (naive)

Wolf J, ASCO 2019

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Phase II study of tepotinib in NSCLC patients with METex14 mutations

Paik PK, ASCO 2019

(33)

BLU-667 demonstrates substantial antitumor activity in RET fusion+ advanced NSCLC

Gainor JF, ASCO 2019

(34)

LIBRETTO-001: Selpercatinib in RET- altered cancers

Drilon A, WCLC 2019

(35)

Efficacy of Selpercatinib: primary analysis set (n=105)

(36)

Efficacy of Selpercatinib: treatment-naive patients (n=34)

(37)

Durability of Selpercatinib efficacy:

primary analysis set

(38)

Phase 1, Multicenter, Open-label Study – Dose Escalation

AMG 510 First-in-Human Study Design

Key Eligibility

– Locally advanced or metastatic malignancy – Received prior

standard therapies – KRAS G12Cmutation as

assessed by molecular

testing of tumor biopsies – No active brain

metastases Cohort 1

180 mg

Cohort 2 360 mg

Cohort 3 720 mg

Cohort 4 960 mg

– 2–4 patients enrolled in each cohort

– Intra-patient dose escalation allowed – Additional patients

may be added to any dose deemed safe

Safety Follow-up & Long-term Follow-upa

a30 (+7) days after end of treatment for safety follow-up; every 12 weeks for long-term follow-up. PK: pharmacokinetics; PFS: progression-free survival.

– Repeated oral daily dosing with 21-day cycles – Treatment until disease

progression, intolerance, or consent withdrawal – Radiographic scan every

6 weeks

Primary endpoints: dose-limiting toxicities; safety

Key secondary endpoints: PK; objective response rate; duration of response; disease control rate; PFS; duration of stable disease

Screening / Enrollment

Dose Expansion

Expansion dose determined

Screening / Enrollment

Patients with KRAS^G12Cmutant advanced tumors

N = ~20 (max 60)

Safety Follow-up & Long-term Follow-upa

4

AMG 510 a Novel KRAS^G12C inhibitor:

study design

Govindan R, WCLC 2019

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Patient Disposition

N = 4

Discontinued study^b

• None was related to treatment

N = 30

Remained on study N = 34

NSCLC patients enrolled

aThe tumor type of this patient was recorded as SCLC as of the data cutoff and changed to NSCLC by the participating site after cutoff. ^bAs of the data cutoff, in addition to four patients who discontinued study, three patients discontinued treatment due to progressive disease. NSCLC: non-small cell lung cancer; CRC: colorectal cancer; SCLC: small cell lung cancer.

First patient enrolled: 27 August 2018 Data cutoff: 17 July 2019

N = 19, escalation cohort

• 180 mg: N = 3

• 360 mg: N = 2

• 720 mg: N = 6

• 960 mg: N = 8

N = 15, expansion cohort

• 960 mg: N = 15

N = 23, evaluable

• Patients who had the first 6-week scan or early progressive disease

N = 76 Total patients enrolled

• NSCLC, N = 34

• CRC, N = 36

• SCLC, N = 1^a

• Appendiceal cancer, N = 3

• Endometrial cancer, N = 1

• Small bowel cancer, N = 1

Overall Trial Accrual

5

AMG 510: patient disposition

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Patient Incidence of Treatment-Related Adverse Events (AEs)

All Treatment-Related AEs

Any Grade N = 34, n (%)

Grade 3 N = 34, n

(%) Any treatment-related

AEs 12 (35.3) 3 (8.8)

Diarrhea 4 (11.8) 2 (5.9)

Nausea 2 (5.9) 0 (0)

Dry mouth 1 (2.9) 0 (0)

Vomiting 1 (2.9) 0 (0)

ALT increased 2 (5.9) 0 (0)

AST increased 2 (5.9) 0 (0)

Blood alkaline phosphate

increased 1 (2.9) 0 (0)

Lymphocyte count

decreased 1 (2.9) 0 (0)

White blood cell count

decreased 1 (2.9) 0 (0)

ALT: alanine aminotransferase; AST: aspartate aminotransferase; AE: adverse event.

All Treatment- Related AEs

Any Grade N = 34, n

(%)

Grade 3 N = 34, n (%)

Decreased

appetite 1 (2.9) 0 (0)

Hyperkalemia 1 (2.9) 0 (0)

Hypokalemia 1 (2.9) 0 (0)

Anemia 1 (2.9) 1 (2.9)

Leukopenia 1 (2.9) 0 (0)

Dysgeusia 1 (2.9) 0 (0)

Neuropathy

peripheral 1 (2.9) 0 (0)

Proteinuria 1 (2.9) 0 (0)

Cont.

• 12 of 34 patients (35.3%) reported treatment-related AEs; most were grade 1 or 2

• 3 of 34 patients (8.8%) reported two grade 3 treatment-related AEs:

diarrhea and anemia

• There were no grade 4 or higher treatment-related AEs.

8

AMG 510: patient incidence of treatment- related adverse events (AEs)

(41)

960 mg 720 mg

360 mg 180 mg

Planned dose:

% Change From Baseline in Sum of Longest Diameter

Evaluable NSCLC Patients With Available Post-baseline Tumor Data, (N = 22)^a

Best Tumor Response and Change in Tumor Burden From Baseline

Efficacy outcomes

All evaluable patients

N = 23

Evaluable patients treated with 960mg

N = 13 Best overall response

Partial response – n (%) Stable disease – n (%) Progressive disease– n (%)

11 (48) 11 (48) 1 (4)^a

7 (54) 6 (46) 0 (0)

Objective response rate – % 48 54

Disease control rate^b– % 96 100

aOne patient discontinued study due to PD prior to the 1^stassessment, and the post-baseline tumor burden data are missing. ^bPR or SD at week 6. ^cPatient had complete response to the target lesions. Evaluable patients: patients who had the first 6-week scan or early PD; NSCLC: non-small cell lung cancer; PR: partial response; SD: stable disease; PD: progressive disease.

SD SD SD SD^# SD^#

SD^# SD^# SD^# SD^# SD^# SD^#

PR PR^# PR^#* _PR^# _PR#

PR* _PR

PR^#* PR^#*

PR^#

PR^#*^c

–100 –80 –60 –40 –20 0 20 40 60 80 100

10

# Study ongoing

* Confirmed response

AMG 510: best tumor response and change in tumor burden from baseline

(42)

Unclear how thresholds established for success?

A1: FGFR2/3mut B1: TSC1/2mut B2S: LKB1mut/del

C1: CDKN2Aloss SCC C2: CDKN2Aloss NonSCC C3: CDK4amp

C4: CCND1amp

C5: LKB1mut/delorTSC1/2mut C6: KRASmut

D1: METamp D2: ROS1fusion D3: METexon14skip E1: NF1mut SCC E2: NF1mut NonSCC E3: NRASmut F1: PIK3CAmut SCC F2: PIK3CAamp SCC F3: PIK3CA/PTEN NonSCC F4: PTEN SCC

G1: EGFRmut + T790Mmut H1: RET rearrangements NA1: Non-actionable

A: AZD4547 (FGFR inhibitor)

B: Vistusertib (MTORC1/2 inhibitor)

C: Palbociclib (CDK4/6 inhibitor)

D:Crizotinib (ALK inhibitor)

E: Selumetinib (MEK inhibitor) + Docetaxel

F: Capivasertib (AKT inhibitor)

G: Osimertinib (EGFRT790M inhibitor) H: Sitravatinib (VEGF inhibitor) NA: Durvalumab (PDL1 inhibitor) B2D: LKB1mut/del+KRASmut

Arms Primary outcomes: targets Objective Response (OR) Durable Clinical Benefit (DCB) Progression-Free Survival (PFS) A,B,D,F,G,H OR rate>30% or DCB rate>30%

E OR rate>40% or DCB rate>40%

C Median PFS time>3 months

First results from an umbrella phase II trial in advanced NSCLC

Middleton J, WCLC 2019

(43)

RTK arms had some success

A1: FGFR mutation; G1:EGFR T790M mutation;

D1: MET amplification; D2:ROS1 gene fusions; D3:MET exon 14 skipping

OR Rate

Middleton J, WCLC 2019

(44)

Next Generation Sequencing (NGS) in NSCLC

(45)

The cancer treatment in the future

“Here’s my sequence …”

New Yorker 2004

today

(46)

Take home messages

No news for EGFR and ALK inhibitors sequence.

ROS-1, BRAF and NTRK treatment is clinical practice.

RET, MET and exon 20 insertion of EGFR are new

targets for new agents that demonstrated better results compared to previous agents used against these

targets.

K-RAS could be for the first time a target for new agents.

(47)

Grazie per l’attenzione!

francesco.grossi@policlinico.mi.it