Chinmay Jani: Let’s explore EGFR Exon 20 Insertion NSCLC with a twist of Miami flair!

Chinmay Jani, Clinical Fellow, Hematology & Oncology at University of Miami, made the following post on X:

“Join us on a journey from the vibrant streets of Miami to the turquoise waters of the Caribbean at our Tumor Board Tuesday.

Let’s explore EGFR Exon 20 Insertion NSCLC with a twist of Miami flair!

Our case begins:

50F African American never smoker presents w/ SOB and a pleural effusion in 2022
PET CT shows pleural based RLL mass and mediastinal adenopathy
Lung biopsy consistent with adenocarcinoma of lung (Stage IV M1a)

What is your next step?

• Chemo-immunotherapy
• Wait for NGS and PDL1
• PCR testing for EGFR/ALK
• Immunotherapy alone

Biomarker Results: PDL1 negative, EGFR Exon 20 insertion p.D770, BRCA2

Treatment: 1L:Carboplatin/Pemetrexed/Pembrolizumab → 5 mos maintenance pemetrexed/pembrolizumab w/ progression of peritoneal mets

What is your next step?

• Switch to Osimertinib
• Start Amivantamab
• Explore Clinical Trial Op
• Docetaxel +!ramucirumab

Mini Tweetorial 1

EGFR 20Ins
3rd most common EGFR mut (~ 1-2% of adenoCa)
More common in young
Most are a 1-4 AA ins in the loop after the C-helix, similar to HER2 Ex20ins

Mini Tweetorial 2
Testing for EGFR Mutation

Tumor NGS

Hot spot testing & PCR can miss Exon20Ins in 40% of pts

NGS-based testing preferred
Liquid biopsies can detect EGFR20ins

Viteri et al, Mol Oncol. 2023

Mini Tweetorial 3
EGFR Ex20ins↔️typical EGFR mut
ORR w/1st, 2nd, & 3rd-gen EGFR TKI d/t steric hindrance at the TKI-binding site

Response to IO 1st Line
93% progression or death
75% death
5yr OS 8% vs 19% for typical EGFR mut
mTP 3.7 vs 5.8mos

Stay on-board as we explore new therapies for EGFR 20ins

EGFR20ins treatment breakthroughs and Miami’s Skyline both .

2004: EGFR20ins described
2018: Osimertinib negative case report
2021: 2L Mobocertinib & Ami FDA approvals
2024: 1L Amivantamab approval

Low Jl, et al. Ther Adv Med Oncol, 2023

Mini Tweetorial 4

Mechanism of Amivantamab
Blocks EGFR and MET downstream signaling
Antibody-dependent cellular cytotoxicity and trogocytosis

Mini Tweetorial 5
Chrysalis 2nd line approved May 2021

Amivantamab-vmjw: EGFR-MET bispecific Ab

JCO2021. Park et al.

Amivantamab after plat-based chemo in pts with EGFR Exon20ins muts
ORR: 40%
mDOR: 11.1 mo
mPFS: 8.3 mo

After CHRYSALLIS came PAPILLON

Mini Tweetorial 6
Papillon 1st line amivantamab+chemo March 2024

Amivantamab-vmjw + Carbo/pem
https://nejm.org/doi/full/10.1056/NEJMoa2306441

New SOC for 1st line EGFR20ins
ORR: 73% vs 43% (chemo)
PFS 11.4 mo vs 6.7 mo; HR 0.40
mDoR: 9.7mo vs 4.4 mo

Mini Tweetorial 6
EXCLAIM
Response to mobocertinib in EGFR ex20 post plat doublet (PPP cohort) accelerated FDA approval in 2021 (now withdrawn)

ORR: 28%
median DOR: 17.5 mo
median PFS: 7.3 mo

Survey says: You spoke too fast
→ Mobocertinib accelerates approval withdrawn after Phase3 study did not meet primary endpoint.

Back to our case
Patient receives amivantamab in second-line setting develops infusion reaction during treatment

Mini Tweetorial 7
AE Mgmt: Infusion-related reaction with Amivantamab
Symp: Dyspnea, flushing, chills, nausea (mostly grade 1-2; grade 3 <2%)
Median time to IRR onset: 44 min, with 94% occurring on cycle 1 D1 and 4% on Cycle 2 D1
Less w chemo

Mini Tweetorial 8
AE Management: Infusion-related reaction (IRR) with Amivantamab:
Mitigation: Hold infusion and reinitiate at reduced dose. Prophylactic steroids, analgesics, and antihistamines.
Less in combination with chemotherapy (Papillon)

Back to our case
Patient was rechallenged with implementation of IRR mitigation strategies.
She did well but develops worsening rash, hyperpigmentation and mild shortness of breath

EFGR-related Rash (86%) Paronychia (45%) Stomatitis (24%)

Mini Tweetorial 9
AE Mgmt: Skin Tox w/Amivantamab
Rash: Topical steroids, doxy, limit , early refer to derm
Other: Paronychia, stomatitis
Prophylactic Abx can rash: COCOON COCOON Ph2 trial looking at Prophylactic Mgmt. Passaro et al.

Back to our case

Rash improved after starting steroids and antibiotics. She also had a dose reduction but after three more cycles reports new shortness of breath.

Think of Pneumonitis/ILD

Mini Tweetorial 10
AE Mgmt: Pneumonitis
2.6% of patients permanent

ILD-like AEs class effect of EGFR Tx
ILD: 0.9%
Pneumonitis: 3.5%

Management:
Discontinue Amivantamab
Steroids
Supportive care
Ohmori et al. Int J Mol Sci 2021

Back to our case

Treatment paused for one cycle. As symptoms improved, Amivantamab reintroduced at a lower dose without complications. Patient tolerating treatment well.

Future emerging EGFR exon 20 insertion therapies to watch out for:
Sumvazertinib
Zipalertinib / CLN-081
BLU-451
BAY2927088
Fomonertinib
Exciting developments in EGFR Ex20Ins treatment!”

Source: Chinmay Jani/X
.