I nuovi target: ROS1, MEK, NTRK

1

New targets: ROS1, NTRK, MEK

Angelo Delmonte

Responsabile SSD Oncologia Toracica Responsabile Unità Clinica di Studi di Fase 1

IRST-IRCCS

Driver Mutations

NTRK 1%

ROS1 FUSION PROTEIN INTRACELLULAR PATHWAYS

Crizotinib in ROS1+ NSCLC: PFS data

First line drugs under development

• Lorlatinib: ALK ROS1

• Repotrectinib: ROS1, ALK, TRK

• Entrectinib: ALK, ROS1, TRK

Repotrectinib (Phase 1) Lorlatinib (Phase 2 EXP 6)

Novel 1

line ROS1 inhibitors

(44-97)

Entrectinib in ROS1+ NSCLC 1

line: Integrated Analysis

Doebele RC, et al. WCLC 2018. Abstract OA02.01. ClinicalTrials.gov. NCT02568267.

Drilon A, et al. Cancer Discov. 2017;7:400-409.

• Primary endpoints: ORR, DoR

• Secondary endpoints: PFS, OS, intracranial ORR and DoR, safety/tolerability

Efficacy population:

ROS1+ NSCLC with no prior ROS1

inhibitor (n = 53)

Safety population:

Entrectinib-treated ROS1+, all tumor

types and gene rearrangements

(n = 355)

STARTRK-2

Multicenter, global basket phase II study; 600 mg QD, 28-day cycle (n = 37 with NSCLC)

ALKA-372-001

Phase I dose escalation (n = 9 with NSCLC)

STARTRK-1

Phase I dose escalation

(n = 7 with NSCLC)

Doebele RC, et al. WCLC 2018. Abstract OA02.01

Entrectinib in ROS1+ NSCLC: Integrated Analysis

Median DOR 24.6 mo (11.4-34.8)

Acquired Resistance Mechanisms

On target Off target

Available data with ROS1 inhibitors in crizotinib refractory ROS1 NSCLC

Repotrectinib (Phase 1) Lorlatinib (Phase 2 EXP 6)

Novel ROS1 inhibitors after TKI treament

TRK signaling pathway

TRK Inhibitors Under Development

ORR 75% (95% CI, 61 to 85) Grade 3-4 AE 5%

Entrectinib Safety Profile

MEK IN THE RAF INTRACELLULAR PATHWAYS

Leonetti, Cancer Treat Rev 2018

EGFR, MET, Other

PFS in KRASm population OS in KRASm poulation

mORR 33% mDOR 9.9 mo

SAE 42%; most frequent G3: asthenia 5%, cutaneous squamous cell carcinoma 12%, basal-cell carcinoma 5%

Study Results D in 2° line D+T in 2° line D+T in 1° line ORR 33% (23-45%) 63.2% (49.3-75.6%) 64% (46-79%) PFS (mo) 5.5 (3.4-7.3) 9.7 (6.9-19.6) 10.9 (7.0-16.6) DoR (mo) 9.6 (5.4-15.2) 9.0 (6.9-18.3) 10.4 (8.3-17.9) OS (mo) 12.7 (7.3-16.3) 18.2 (14.3- NE) 24.6 (12.3-NE)

Addition of Trametinib (T) to Dabrafenib (D) in V600E positive NSCLC

Planchard et al. Lancet Oncol 2016; 17: 642 Planchard et al. Lancet Oncol 2016; 17: 984 Planchard et al. Lancet Oncol 2017; 18: 1307 Khunger et al. Ther Adv in Resp Dis 2018; 12: 1

EMA APPROVAL FOR FIRST LINE

Conclusions

• Even if rare, alterations of ROS1, TRK and MEK pathways ecompasses 32.2% of NSCLCs

• ROS1 rearrangement and V600E BRAF mutation are

mandatory to test given that approved therapies are available

• Therapeutic startegies for TRK alterations are under

evaluation but they will be available very soon