57y 👩🏽 short of breath
PMH: GERD
🚬3pk/yr smoking hx, quit 25yrs prior
🩻CT: bilat 🫁 nodules
🔬bx: adenocarcinoma, PDL1 85%
🧲MRI brain: 5 mets, each < 3mm
Asymptomatic
Stage IV NSCLC adenocarcinoma
🔬Liquid bx: EGFR L858R
Next?
👩🏽 🤝👩🏻⚕️#SharedDecision
🟢 Start osimertinib
🗓️ 3 week visit to check on toxicities of therapy
🧐Which is FALSE about osimertinib
🎯Osimertinib - Anti-EGFR
❌No stopping PPI
✨OCEAN: CNS ORR >70%
📚jto.org
✨FLAURA: 91% CNS ORR
AEs:
👺Any Grade rash
🚽diarrhea 58%
📚@plummer_ruth @JhanelleGray @jsoriamd @reungwetwattana
ascopubs.org
CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer
Purpose We report CNS efficacy of osimertinib versus standard epidermal growth factor receptor (EGFR...
A Phase II Study of Osimertinib for Radiotherapy-Naive Central Nervous System Metastasis From NSCLC: Results for the T790M Cohort of the OCEAN Study (LOGIK1603/WJOG9116L)
Osimertinib has been reported to be effective against central nervous system (CNS) metastasis from a...
Back to the case🔎
🗓️ 2 years on osimertinib
🙏🏼 Initial partial response
🫁 Multifocal disease growth in the lung
🤨 What’s your next step?
👩🏼🏫Mini-Tweetorial 1👩🏻🏫
🔬What to biopsy?
@NCCN: tissue &/or liquid
📚nccn.org
🥇Tissue gold standard
Recurrent/resistant dz:
🔬Redo tissue AND plasma
BUT
💦liquid sometimes faster
‼️Make sure enough tissue‼️
📚nature.com
👩🏼🏫Mini Tweetorial 2👩🏻🏫
📌Which TKI is best for EGFR mutant NSCLC?
✨FLAURA
📍1st trial comparing 2 EGFR TKIs
📍Prior trials compared TKIs to chemo
📍556 pts
📍Osimertinib (3rd gen) vs earlier gen EGFR TKIs (gefitinib/erlotinib)
📚nejm.org
👩🏼🏫Mini Tweetorial 3👩🏻🏫
📌Osimertinib
🔹Irreversible
🔸blocks EGFR-activating & T790M resistance mutations
✨FLAURA: mPFS= 18.9 mos vs 10.2 mos with earlier TKIs
🔹ORR similar
🔸mDOR= 17.2 mos vs 8.5 mos with earlier TKIs
🔹CNS penetration
⬇️serious AEs
👩🏼🏫Mini Tweetorial 4👩🏻🏫
📌Osimertinib
👎🏽resistance will occur
EGFR dependent
OR
EGFR independent:
➡️HER2 amplification
➡️MET amplification
➡️MAPK/PI3K activation
➡️Novel fusions
➡️Transformation (SCLC, SCC)
📚nature.com
👩🏼🏫Mini Tweetorial 5👩🏻🏫
📌Osi
📍resistance & losing T790M
✨ AURA3: ctDNA/T790M mut NSCLC
🔹~50% LOST T790M mutation at time of progress
📍T790M loss
✅Early resistance
✅MET Amp, KRAS mut, fusions, & small cell transformation
📚link.springer.com
👩🏼🏫Mini Tweetorial 6
📌Osi
📍resistance & EGFR muts
✨AURA3: tertiary EGFR mut in ~20%/T790M maintained
Common:
🔹C797S (Ex 20) ~10-26% resist to 2L
🔹Position re other EGFR muts
➡️Can re-try 1st + 3rd gen TKI combos
📚@elisagiovan nature.com
👩🏼🏫Mini Tweetorial 7👩🏻🏫
📌Osimertinib
📍Combo Tx: earlier gen TKIs + Osi
🔹Common target (EGFR) method of resistance fueling a lot of drug development & trials
📚classic.clinicaltrials.gov
📚classic.clinicaltrials.gov
📚nature.com
(SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC - Full Text View - ClinicalTrials.gov
(SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC - Full Text View.
(HARMONY) Study of BLU-701 in EGFR-mutant NSCLC - Full Text View - ClinicalTrials.gov
(HARMONY) Study of BLU-701 in EGFR-mutant NSCLC - Full Text View.
👩🏼🏫Mini Tweetorial 8
📍New tx after resistance
💊Amivantamab – Bispecific Ab (EGFR, MET) ➡️anti-tumor effect
Initially in:
Exon 20 +, Pre-Treated
ORR ~40% #WCLC20 mDOR 11.1 mos
AEs:
💉infusion rxn
👺rash
💅paronychia
🚽diarrhea
@Jbauml #ASCO21 Ami v RWD
👩🏼🏫Mini Tweetorial 9👩🏻🏫
✨CHRYSALIS: Ami + Lazertinib (3rd gen TKI)
🧪NGS does NOT predict response
BUT
🧪MET IHC may predict!
📚@AlexSpiraMDPhD @oncoOuLungCA @MNagasaka #ASCO21
👩🏼🏫Mini Tweetorial 10👩🏻🏫
✨CHRYSALIS 2
📍Osi ➡️ Chemo ➡️ Ami + Laz
📍ORR 36%, median duration of response nr at 8 months
📍Prelim CNS activity
📚ascopubs.org
👩🏼🏫Mini Tweetorial 11👩🏻🏫
📌Novel directions
🎯HER3 targeted Abs
🫧HER3 expressed on cell surface in NSCLC (≤ 75%)
🔹Patritumab deruxtecan (HER3-Dxd): antibody-drug conjugate (ADC)
🫧Chemo (topo II inhibitor) to cells with HER3
📚ncbi.nlm.nih.gov
👩🏼🏫Mini Tweetorial 12👩🏻🏫
📌HER3-Dxd
Ongoing trials
📍EGFR-mutated, Osi-resistant NSCLC
Prelim Data
📍RR 39% in 44 pts who received Osimertinib prior
✨U3-1402
📚clinicaltrials.gov
🤨Response across mechanisms?
🤔Active regardless of HER3 IHC express?
Back to our case🔎
💦Liquid biopsy
🧪NGS did not identify resistance mechanism
🔬Tissue bx
❌No SCLC transformation
🧪NGS neg for resistance mechanism
🐟FISH pos for MET amp
🟢Start osimertinib + capmatinib 200mg bid
**Note - Off label use**
MET resistance = MET overexpression, amp, mut, fusion
🥇Gold Standard Dx:
🔬Tissue Bx detection: FISH🐟 (30%) > Liq bx 💦 (15%)
MET Amp a/w poor prognosis
BUT
🎯We have targeted agents now!
📌Level of MET Expression
📍METi (Tepotinib) + EGFR (Gefitinib) vs plat-doublet chemo
❌No gross improvement in mPFS
BUT
⬆️MET IHC & MET gene amp: ⬆️Higher ORR & mPFS, tx length
📍Low accrual > trial termination
✨INSIGHT
📚ncbi.nlm.nih.gov
Prospective Trials
✨INSIGHT-2
📚tinyurl.com
🎯EGFR & MET combination
📍Osi + Tepotinib (initial results)
📍MET Amp
📍ORR > 50% at 9 mos
AEs
⬇️dose in ~20%
👍🏽No new AE
✨TATTON
📚classic.clinicaltrials.gov
✨SAVANNAH
📚classic.clinicaltrials.gov
ESMO Congress | OncologyPRO
OncologyPRO is the home of ESMO’s educational & scientific resources, with exclusive content for ESM...
AZD9291 in Combination With Ascending Doses of Novel Therapeutics - Full Text View - ClinicalTrials.gov
AZD9291 in Combination With Ascending Doses of Novel Therapeutics - Full Text View.
Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib - Full Text View - ClinicalTrials.gov
Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib - Full Text View.
Back to our patient
🗓️3 Month
🩻Scan
🫁Decrease size of lung nodules
Toxicities
👩🏽 Patient ⬇️ reduces dose of MET TKI due to edema
🙏🏼feels well 🎉
🔥Bonus🔥
🎯If no targetable alteration then use chemotherapy +/- continue osimertinib
🧠Get brain MRI at time of disease progression for new baseline
🧲Especially if stopping osimertinib ➡️ MRI brain surveillance q6Month
👉🏽#CME Eval 🔗 integrityce.com
🤔@MMarmarelis @norataranto taught us Tx after progression on Osimertinib, test your 🧠
🧐What Tx?
57yo 👩🏼🦳
Asx Stage IV NSCLC adenocarcinoma
EGFR L858R
5 🧠 mets <3mm
PD-L1 85%
👉🏽 Free CME 🔗 integrityce.com
👉🏽#CME Eval 🔗 integrityce.com
🧐 What treatment next?
57yo 👩🏼🦱
EGFR L858R NSCLC adenocarcinoma
🗓️2 years osimertinib
🫁Progress in lung
🔬Tissue re-biopsy
MET amp
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