Larotrectinib for treating NTRK fusion-positive solid tumours
New targets: ROS1, NTRK, MEK - AIOM
Transcript of New targets: ROS1, NTRK, MEK - AIOM
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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 1st line ROS1 inhibitors
(44-97)
Entrectinib in ROS1+ NSCLC 1st 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