Understanding, preventing, and delaying EGFR resistance in the era of osimertinib

Lyudmila Bazhenova, MDProfessor of Clinical Medicine

Lung Cancer Disease Team LeaderDirector, Hematology Oncology training program.

• Advisory board: Genentech, Beyondsping pharma, G1 therapeutics, Astra Zeneca, BI, Bayer, Takeda, Blueprint

• Research support: Beyondspring pharmaceuticals

• Stock: epic sciences

• Speaker bureau: none

Disclosures ( past 12 months)

• Discuss management of resistance to 3rd generation EGFR TKI

• On target and off target resistance

• Difference in resistance patterns when osimertinib is used as 1st line vs 2 line.

• Small cell transformation

• Lack of clear benefit with immunotherapy in this population.

Objectives

Osimertinib in first line and second line settings2st line AURA 3 trial. ( T790M +) Improved PFS compared to platinum doublet

1st line FLAURA trial. Improved PFS and OS compared to erlotinib or gefitinib

Three distinct clinical progression patterns

Gandara et all Clinical lung Cancer 2013

• CNS only progression• Consensus on management - do radiation

unless there is availability of therapy with proven CNS efficacy

• Osimertinib for T790M positive EGFR mt secondary resistant patient.

• eCNS progression• Slow asymptomatic diffuse progression

• Could continue TKI• Oligoprogressive disease

• Local therapy for progressive site• Diffuse systemic symptomatic progression

• Change systemic therapy

Case for radiation of oligoprogressive diseaseStudy design Study population TKI Local

therapy N mPFS2

months ( 95% CI)

mOS months ( 95% CI)

Weickhardt Retrospective EGFR mt ALK mt ≤4 sites of eCNS progressionCNS progression without LMC

E, Cr XRT or surgery

15 ALK10 EGFR

All 6.2CNS 7.1eCNS 4.2

NR

Yu Post hoc analysis of prospectively collected cohort.

EGFR mt E, G Surgery, RFA, XRT

18 10 5Y OS 40%

Gan Retrospective ALK mt Cr XRT 33 5.5 2Y P\OS 57

E erlotinib, G gefitinib, Cr-crizotinib • All single arm trials

Weickhardt, JTO, 2012; Yu JTO 2013; GAN Int J radiat Oncol Biol Phys 2014

Case for continuation of EGFR TKI. ASPIRATION trial

• Several retrospective studies showed that patients can continue on EGFR TKI post radiographic progression for 3-6 months

• ASPIRATION is the only prospective study looking at post PD continuation of EGFR TKI• Patients with EGFR sensitizing mutations were allowed to continue on EGFR TKI post

RECIST progression• Decision to continue was made by a treating physician with some guidelines described

in the protocol.• 53% of patients met those criteria

PFS1 = 11.0 month

PFS2 = 14.1 monthTime off erlotinib

Goto et al, ESMO open 2017Park et al. JAMA oncology 2016

RECISTPD

Understanding molecular basis for osimertinibresistance

Osimertinib post 1st and 2nd gen TKIOsimertinib as a first line therapy

Will resistance be different?

Two main categories of acquired resistance

On target resistance

• Additional genetic alterations in the primary oncogenic target that enable continued downstream signaling• Secondary point mutations

and/or gene amplification of the target

Off target resistance

• Upregulation of bypass signaling pathways—commonly through activation of alternative receptor tyrosine kinases ( bypass tracks)• Changes in tumor histology (i.e.,

lineage changes); • Increased growth factor

production; • Overexpression of drug efflux

pumps

Resistance post 1st line osimertinib

Ramalingam. ESMO 2018

• Inhibits covalent binding of afatinib or osimertinib to EGFR protein mediating resistance to 2nd and 3rd

generation EGFR inhibitors

• 1st generation inhibitors ( erlotinib and gefitnib) are not affected due to different binding site.

• in case of T790M positive patient, C797S can happen on the same allele ( cis) or different allele ( trans)

• EGFR/T790M/C797S in trans are sensitive to 1st + 3rd

gen EGFR TKI

• EGFR/T790M/C797S in cis ( triple mutants) are resistant to 1st+3rd generation EGFR TKI combinations.

12

C797S mutation

Thress, Nature Medicine 2015Neiderst, CCR 2015

Lack of activity of AZD 9291 ( osimertinib) in Ba/F3 cells harboring C797S and T79M in cis

2nd line osimertinib.

13

Resistance to 3rd generation EGFR inhibitors in 1st vs 2nd line setting

Native EGFR mutation Resistance to 1st line osimertinib Resistance to 2st line osimertinib

Neiderst, CCR 2015

C797S can develop after 1st line osimertinib

Those cells should are sensitive to monotherapy 1st generation EGFR inhibitors as T790M is not present

Proposed Management of C779S/T790M mutations

Niederst, CCR 2015

Resistance post 2nd line osimertinib ( failed EGFR TKI with T790M mutation)

• After 2nd line osimertinib patients can be separated into two groups

• Loss of T790M ( 50-60% of patients)

• Maintained T790M

• Patients who lose T790M have shorter PFS

16

T790M loss vs. persistence

Oxnard JAMA oncology 2018Le, clinical Cancer Research 2018

Papadimitrakopoulou, ESMO 2018

C797S only happened in patients with preserved T790M

Leonetti et al. BJC (2019)

Comparing resistance mechanisms post 1st vs 2nd line osimertinib

What do we know about treating other acquired abnormalities

19

Ahn MJ et al, WCLC, 2017

Ahn MJ et al, WCLC, 2017

JNJ 61186372 (JNJ 372)

U3-1402

A word about Small cell transformation

• Histologic transformation of EGFR mutant adenocarcinoma to SCLC has been identified as one of the mechanisms of resistance to EGFR TKI

• Those patients have an aggressive clinical course and should be treated with SCLC appropriate chemotherapy

• The transformed SCLC is not a de novo tumor but rather originates from adenocarcinoma as they retain the original EGFR mutation.

• Biallelic inactivation of both RB1 and TP53 increased the risk of SCLC transformation 43 times (relative risk, 42.8; 95% CI, 5.88 to 311).

• Some evidence that clonal diversion to SCLC is an early event..

Small cell transformation

Lee,et all JCO 2017

Ongoing ORCHARD trial

Lack of benefit with monotherapy PD-(L1) inhibitors

2nd line checkpoint inhibitor monotherapy studies

Lee, JAMA Oncology 2018

Key IO clinical trials that excluded EGFR mt patient

• KN 024. treatment naïve, PD-L1 high, randomized between pembrolizumab and platinum doublet

• KN 042, treatment naïve, PD-L1 >1%, randomized between pembrolizumab and platinum doublet

• KN 21G, treatment naïve, PD-L1 any, randomized between platinum double and platinum doublet + pembrolizumab

• KN 189, treatment naïve, PD-L1 any, randomized between platinum double and platinum doublet + pembrolizumab

• CM 026, treatment naïve, PD-L1 > 5%, randomized between nivolumab and chemotherapy

• CM 227, treatment naïve, PD-L1 unselected

IMPOWER 150

IMPOWER 150 Overall survival

IMPOWER 150

• At the time of progression on EGFR TKI patients should undergo molecular testing to select next therapy.

• Blood based testing could be considered if tissue biopsy is not possible

• Be aware that blood based testing does not evaluate for small cell transformation

• Small cell transformation is more likely in patients deficient in p53 and RB1

• Post osimertinib progression

• Limited clinical trial data on therapy based on resistance mechanism

• C797S mutation might be sensitive to 1st generation EGFR inhibitors

• in second line sensitivity is limited to patients with C797S in trans with T790M

• new compounds like JNJ 372 and

Summary