Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC

Journal Pre-proof Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC Iosune Baraibar, Laura Mezquita, Ignacio Gil-Bazo, David Planchard

PII:

S1040-8428(20)30044-5

DOI:

https://doi.org/10.1016/j.critrevonc.2020.102906

Reference:

ONCH 102906

To appear in:

Critical Reviews in Oncology / Hematology

Received Date:

6 December 2019

Revised Date:

6 February 2020

Accepted Date:

7 February 2020

Please cite this article as: Baraibar I, Mezquita L, Gil-Bazo I, Planchard D, Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC, Critical Reviews in Oncology / Hematology (2020), doi: https://doi.org/10.1016/j.critrevonc.2020.102906

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier.

Type of article: Review

Title: Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC

Authors:

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Iosune Baraibar1,2, Laura Mezquita3, Ignacio Gil-Bazo1,2,4,5, David Planchard3

1 Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain

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2 Program of Solid Tumors, Center for Applied Medical Research, University of Navarra,

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Pamplona, Spain

3 Medical Oncology Department, Gustave Roussy, France

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4 IdiSNA, Navarra Institute for Health Research, Pamplona, Spain

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5 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

Corresponding

author:

David Planchard, MD, PhD

Head of Thoracic Oncology Group, Medical Oncology Department, Gustave Roussy, 114

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Rue Edouard Vaillant, Villejuif 94805, France david.planchard@ gustaveroussy.fr

Highlights: 1

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EGFR and HER2 exon 20 mutations are intrinsically resistant to available EGFR tyrosine kinase inhibitors and anti-HER2 agents in metastatic NSCLC.

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Novel drugs that overcome steric resistance have been tested in clinical trials in this population, showing promising results.

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These advances may revolutionize the therapeutic landscape of this particular

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oncogene-driven NSCLC subtype.

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Abstract: Approximately 4% of epidermal growth factor receptor (EGFR)−mutated non-small cell lung cancer (NSCLC) present EGFR exon 20 in-frame insertions, accounting for 0.3%-3.7% of NSCLC. In addition, 2%- 4% of patients with NSCLC harbor human epidermal growth factor receptor 2 gene (HER2) mutations, being the 90% of them exon 20 insertions. These mutations confer intrinsic resistance to available EGFR tyrosine kinase inhibitors (TKIs) and anti-HER2 treatments, as they result in steric hindrance of the drug-binding pocket. Therefore, no targeted therapies have been approved for NSCLC patients with EGFR or HER2 exon 20- activating mutations to date and remain an unmet clinical need. Promising efforts to novel treatment development have been made. Early data provide encouraging activity of novel drugs targeting EGFR and HER2 mutations in metastatic NSCLC. In this review we will summarize all the data reported to date about these driver molecular alterations and potential targeted therapies.

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Keywords: Non-small cell lung carcinoma; EGFR; HER2; exon 20; targeted therapy

1

Introduction

Primary lung cancer is the leading cause of cancer-related mortality (Bray et al. 2018). 2

Non-small cell lung cancer (NSCLC) accounts for up to 80% of all primary lung cancer cases (Molina et al. 2008). Science-based precision medicine for clinical management of advanced NSCLC has come from the hand of the discovery of somatic driver molecular alterations and the better understanding of the tumor ability to escape the immune response that have led to the approval of targeted therapies and immunotherapy, respectively (Planchard et al. 2018). Molecularly driven therapy for advanced NSCLC has been approved against the

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epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1,

combined therapy inhibiting V-raf murine sarcoma viral oncogene homolog B (BRAF) and Mitogen-Activated Protein Kinases/Extracellular Signal-Regulated Kinases (MEK)

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and the agnostic indication recently approved targeting neurotropic tropomyosin receptor

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kinases (NTRK1-3) gene fusions, according to therapy-predictive biomarker testing. However, targeted therapy for other actionable oncogenic drivers, such as Kristen Rat

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Sarcoma viral oncogene (KRAS), human epidermal growth factor receptor 2 (HER2), mesenchymal epithelial transition oncogene (MET) and rearranged during transfection

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oncogene (RET) is not currently approved and, outside large molecular panels, testing is not routinely indicated (Kalemkerian et al. 2018). Despite effectiveness of EGFR inhibitors in EGFR-mutated advanced NSCLC that present single point mutation Leu858Arg (L858R) in exon 21 or variable deletions in

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exon 19 (del19), not all activating EGFR alterations present inherent sensitivity to EGFR inhibitors (Gazdar 2009; Kobayashi and Mitsudomi 2016). Poor response rates to first and second-generation EGFR inhibitors have been reported in NSCLC patients with EGFR exon 20 mutations and, thus, targeted therapy is not currently recommended in this context (Arcila et al. 2013). HER2 alterations comprise exon 20 mutations, transmembrane domain mutations, amplification and protein overexpression 3

(Arcila et al. 2012). Mutations in exon 20 tend to be mutually exclusive to other oncogenic drivers and are analogous to EGFR exon 20 mutations.

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To date, no effective treatment has been approved against these molecular targets. Nonetheless, a great effort has been made in the preclinical field to give insight into the

mechanisms underlying the primary resistance to drugs. The development of novel drugs

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to circumvent the resistance to current standard of care for EGFR-mutated advanced

NSCLC and also to limit the adverse events that may arise from the inhibition of the wild-

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type protein are crucial. These new treatment strategies are currently being tested in

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clinical trials.

We review the data reported about these driver molecular alterations and potential

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targeted therapies. The most relevant clinical data are summarized in Tables 1 and 2.

4

Poziotinib

Irreversible TKI inhibitor, targeting EGFR and HER2

TKI-naïve EGFRmutant advanced NSCLC

600 (EGFR exon 20 insertion =23)

EGFR exon 20 insertions =2 (8.7%)

Retrospective cohort

EGFR exon 20 insertionadvanced NSCLC

17

1 (6%)

Phase II

Korean population with EGFR exon 20 insertionadvanced NSCLC, previously treated with standard chemotherapy Pretreated EGFRand HER2-mutant advanced NSCLC

15

Single-center phase II

Most common toxicities

SAEs (grade 35)

EGFR exon 20 insertion =9.2 (4.114.2) N/A

N/A

N/A

N/A

(Yang 2015)

N/A

N/A

N/A

(van Veggel et al. 2018)

3.5 (1.6-NR)

NR

N/A

Nausea (20%), vomiting (20%), anemia (13.3%)

N/A

(Kim 2019)

3.7 (2.3-5.4)

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Reference et

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EGFR exon 20-mutated cohort =24 (55%)

EGFR exon 20-mutated cohort =5.5 (5.2-NR)

N/A

N/A

Both cohorts: diarrhea (69.8%), oral mucositis (69.8%), paronychia (60.3%)

Both cohorts: skin rash (34.9%), diarrhea (17.5%), paronychia (9.5%)

(Heymach et al. 2018)

Recruiting

N/A

N/A

N/A

N/A

N/A

N/A

NCT03318939

57 (EGFR exon 20 insertions =39, HER2 exon 20 mutations =13)

EGFR exon 20 insertions cohort =7 (39%)

N/A

N/A

N/A

Diarrhea (79%), hyporexia (21%), dry skin (21%)

Diarrhea (6%), nausea (6%), vomiting (6%)

(Neal 2018)

Phase I/II (expansion cohort)

28

12 (42.8%)

7.3 (N/A)

N/A

N/A

First-in-human phase I, dose escalation

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EGFR/HER2 TKI

All grade AEs (%)

EGFR exon 20-mutated cohort =50, HER2 exon 20-mutant cohort =12

Multicentric phase II

TAK-788

0 (0%)

Median OS [95% CI]

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Pooled analysis (LUX-Lung 2 LUX-Lung 3 and LUX-Lung 6)

Median PFS, in months [95% CI] EGFR exon 20 insertions =2.7 (1.84.2)

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N

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Osimertinib

Secondgeneration TKI, targeting EGFR, HER2 and HER4 Third generation EGFR TKI

Population

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Afatinib

Study

ORR n (%)

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Drug

Mechanism of action

Previously treated or treatment naïve, EGFRand HER2-mutant advanced NSCLC Refractory advanced NSCLC with EGFR/HER2activating mutations

Diarrhea (26%), hypokalemia

5

et

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21

Phase II

EGFR exon 20 insertions or HER2-mutant advanced NSCLC EGFR exon 20 insertionsadvanced NSCLC Third generationrelapsed EGFR mutant or EGFR exon 20 insertionadvanced NSCLC

Recruiting

Pretreated NSCLC harboring EGFR exon 20 insertions

EGFR inhibitor

Phase I/IIa

JNJ-61186372

Bispecific antiEGFR and anticMet receptor antibody

Phase I

Luminespib

Hsp90 inhibitor

Phase II

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TAS6417

0 (0%)

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EGFR-mutant NSCLC, previously treated with EGFR TKI and lacking T790M mutation

N/A

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Phase II

Diarrhea (85%), rash (43%), nausea (41%)

(7%), (7%)

nausea

(Riely et al. 2019; Janne et al. 2019)

N/A

N/A

N/A

N/A

(Liu et al. 2016)

N/A

N/A

N/A

N/A

N/A

N/A

NCT03805841

Recruiting

N/A

N/A

N/A

N/A

N/A

N/A

(Piotrowska al. 2019)

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88 (EGFR exon 20 insertions =20)

25 (28.4%) (EGFR exon 20 insertions =6 (30%))

N/A

N/A

N/A

Rash (59%), infusion related reaction (58%), paronychia (28%)

Dyspnea (6%), pneumonia (3%)

(Haura 2019)

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29

5 (17%)

2.8

9.9 (4.9–

N/A

Diarrhea (83%), ocular toxicity (76%), fatigue (45%)

Hypertension (10%), hypophosphate mia (7%), ocular toxicity (3%)

(Piotrowska al. 2018)

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Irreversible EGFR/HER2 inhibitor under low oxygen conditions

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Tarloxotinib

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Refractory EGFR mutant-advanced NSCLC

5.6)

(1.4–

19.5)

Table 1. Clinical trials related with EGFR exon 20 mutations in NSCLC ORR: overall response rate, PFS: progression free survival, OS: overall survival, TKI: tyrosine kinase inhibitor, SAE: serious adverse event, NR: not reached, N/A: not applicable

6

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ADC

HER2 exon 20 insertionadvanced NSCLC

101 (trastuzumabbased combination and TDM1=58)

Phase II

Previously treated HER2-altered NSCLC HER2-mutant advanced NSCLC

10 (HER2 exon 20 insertions =5) 18 (HER2 exon 20 mutations =11)

ADC

Phase I

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Trastuzumabderuxtecan

Multicenter phase II

All grade AEs (%)

Most common toxicities

SAEs (grade 35)

Reference

13.3 (8.115)

N/A

N/A

N/A

(Mazières et al. 2016)

0%

5.2 (1.4-6.3)

N/A

N/A

N/A

Pneumonitis (10%)

(Kinoshita et al. 2018)

8 (44%) (HER2 exon 20 mutations = 6 (54.5%))

5.0 9.0)

(3.0–

N/A

N/A

Hepatotoxicity (44%), thrombocytopen ia (33), fatigue (33%)

Anemia (6%)

(Li et al. 2018)

15 (HER2 exon 20 mutations =7)

1 (6.7%) (HER2 exon 20 mutations = 1 (14.3%))

2.0 4.0)

(1.4–

10.9 (4.4– 12.0)

N/A

N/A

(Hotta 2018)

Advanced breast cancer, gastric cancer, and other HER2expressing/mutated solid tumors, including NSCLC

NSCLC cohort= 18 (HER2 exon 20 mutations =8)

10 (58.8%) (HER2 exon 20 mutations = 6 (75%))

14.1 14.1)

(0.9-

N/A

N/A

Nausea (50%), hyporexia (50%), alopecia (50%)

Thrombocytope nia (40%), hepatotoxicity 3 (40%), acute renal failure 1 (7%) Neutropenia (11.1%), pneumonitis (5.6%), nausea (5.6%)

HER2overexpressing or -mutated advanced NSCLC

Enrolling

N/A

N/A

N/A

N/A

N/A

N/A

(Planchard et al. 2019)

Pretreated HER2positive NSCLC

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Phase II

29 (50.9%)

Median OS [95% CI]

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Retrospective cohort

Single- center phase II

ORR n (%)

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N

Median PFS, in months [95% CI] 4.8 (3.4-6.5)

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Trastuzumabemtansine

Humanized monoclonal antibody targeting HER2

Population

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Trastuzumab

Study

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Drug

Mechanism of action

et

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(Tsurutani et al. 2018)

8

Retrospective cohort

HER2-mutant advanced NSCLC

27 (HER2 exon 20 insertion =23)

Phase II

Previously treated HER2 exon 20mutant advanced NSCLC

13

Neratinib + temsirolimus

Secondgeneration TKI, targeting EGFR, HER2 and HER4 Secondgeneration EGFR TKI, targeting HER2, HER4 TKI + mTOR inhibitor

2 (18.2%)

3.9 (N/A)

N/A

N/A

N/A

N/A

(Mazières et al. 2016)

7 (N/A)

N/A

N/A

N/A

(Lai et al. 2019)

3 (13%) (EGFR exon 20 mutations =3)

N/A

1 (7.7%)

15.9 weeks (6.0–35.4)

56 weeks (16.3–NR)

100%

Rash, diarrhea, vomiting

Dyspnea (15.3%), acute renal injury (7.6%), mucositis (7.6%)

(Dziadziuszko et al. 2019)

Diarrhea (35.7%), skin disorders (28.5%), stomatitis/muco sitis/mouth ulceration (14.2%) Diarrhea (90%), dermatitis (73%), fatigue (53%)

N/A

(Peters 2018)

Diarrhea (23%), mucosal inflammation (7%), vomiting (7%) Vomiting (21%), diarrhea (14%), dyspnea (14%)

(Kris 2015)

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(Besse 2014)

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Diarrhea (14%), stomatitis (7%)

(Gandhi et al. 2017)

28

3 (19%)

N/A

N/A

N/A

HER2-mutant or amplified advanced NSCLC

30 (HER2 exon 20 mutations =26)

HER2-mutant cohort: 3 (11.5)

HER2mutant cohort: 3 (2– 4)

HER2mutant cohort: 9 (7–21)

N/A

Phase II

HER2-mutant advanced NSCLC

27 (neratinib + temsirolimus =14)

3 (21%)

4.0 (2.9 9.8)

N/A

100%

Diarrhea (100%), constipation (57%), vomiting (57%)

Phase II expansion cohort

HER2-mutant advanced NSCLC

7 (16.2%)

4.1 (2.9-5.6)

15.8 (10.819.5)

N/A

Diarrhea (86%), stomatitis (49%)

Phase II

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Dacomitinib

Heavily pretreated HER2-mutant NSCLC

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Retrospective cohort

(afatinib

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101 =9)

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HER2 exon 20 insertionadvanced NSCLC

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Retrospective cohort

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Secondgeneration TKI, targeting EGFR, HER2 and HER4

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Afatinib

62 (neratinib + temsirolimus =43)

9

et

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Single-center phase II

Pretreated EGFRand HER2-mutant advanced NSCLC

EGFR exon 20-mutated cohort =50

24 (55%)

5.5 (5.2-NR)

N/A

N/A

Both cohorts: diarrhea (69.8%), oral mucositis (69.8%), paronychia (60.3%)

N/A

100%

Rash (100%), diarrhea (86%), oral mucositis (77%)

N/A

N/A

N/A

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Irreversible TKI inhibitor, targeting EGFR and HER2

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Poziotinib

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5.6 (N/A)

EGFR/HER2 TKI

First-in-human phase I, dose escalation

Pyrotinib

Irreversible panHER TKI, targeting EGFR, HER2 and HER4

Single-center phase II

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TAK-788

Previously treated or treatment naïve, EGFRand HER2-mutant advanced NSCLC Refractory advanced NSCLC with EGFR/HER2activating mutations

Multicentric phase II

Recruiting

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Multicentric phase II

Pretreated HER2 exon 20-mutated advanced NSCLC

Pretreated HER2 exon 20-mutated advanced NSCLC

6 (50%)

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HER2 exon 20-mutant cohort =12

N/A

Skin rash (34.9%), diarrhea (17.5%), paronychia (9.5%) Rash (58%), diarrhea (17%), nausea (8%)

(Heymach et al. 2018)

(Robichaux al. 2019)

et

N/A

N/A

NCT03318939

57 (EGFR exon 20 insertions =39, HER2 exon 20 mutations =13) 15

EGFR exon 20 insertions cohort =7 (39%)

N/A

N/A

N/A

Diarrhea (79%), hyporexia (21%), dry skin (21%)

Diarrhea (6%), nausea (6%), vomiting (6%)

(Neal 2018)

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8 (53.3%)

6.4 (1.6011.20)

12.9 (2.0523.75)

60%

Diarrhea (27%), hypocalcemia (27%), anemia (27%)

None

(Wang 2019)

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60

31.7%

6.8 8.3)

N/A

N/A

N/A

Diarrhea (20%)

(Gao et al. 2019)

(4.1-

10

Phase II

EGFR exon 20 insertions or HER2-mutant NSCLC

Recruiting

TAS6417

EGFR inhibitor

Phase I/IIa

EGFR exon 20 insertionsadvanced NSCLC

Recruiting

N/A

N/A

N/A

N/A

N/A

N/A

(NCT03805841

N/A

N/A

N/A

N/A

(Piotrowska al. 2019)

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Irreversible EGFR/HER2 inhibitor under low oxygen conditions

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Tarloxotinib

N/A

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N/A

Table 2. Clinical trials related with HER2 exon 20 mutations in NSCLC

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ORR: overall response rate, PFS: progression free survival, OS: overall survival, TKI: tyrosine kinase inhibitor, ADC: antibody drug conjugate,

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SAE: serious adverse event, NR: not reached, N/A: not applicable

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1. EGFR and HER2

ErBb is a family of membrane receptors with tyrosine kinase activity that include ErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4). They form homodimers or heterodimers with each others and bind to extracellular ligands, resulting in phosphorylation of tyrosine kinase intracellular domain and ATP binding to the kinase pocket. Subsequent activation of the downstream pathway mediates proliferation and

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regulates apoptosis (Tao and Maruyama 2008; Sharma et al. 2007).

2.1 EGFR gene and protein in NSCLC

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EGFR gene, also called HER1 or ERBB1, is located in 7p11.2 and encodes a transmembrane receptor protein. Activating EGFR mutations are present in 15% of

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patients with lung adenocarcinoma in the United States and Europe, and up to 40% in

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Asia (Rosell et al. 2009; Yatabe et al. 2015). Although not exclusive, they are more frequent in never-smoker or light-smoker female patients with lung adenocarcinoma. The discovery of EGFR gene mutations in NSCLC was initially reported in 2004 and

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defined a molecular subgroup of cancer patients with specific sensitivity to target therapy with EGFR tyrosine kinase inhibitors (TKIs) (Lynch et al. 2004; Planchard et al. 2018). When EGFR is mutated, activation of EGFR signaling pathway occurs even in the

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absence of ligand and promotes downstream pro-survival and anti-apoptotic signals such as phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and extracellular signal– regulated kinase (ERK)/mitogen-activated protein kinase (MAPK). EGFR inhibitors block the ATP-binding site of the tyrosine kinase intracellular domain and, as a consequence, prevent the phosphotransfer reaction that triggers downstream signaling pathways.

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EGFR mutations can be found in several hotspots between exons 18 and 21. Exon 19 deletion and L858R point mutation in exon 21 are the most common type of mutations and respond to first, second and third-generation EGFR TKIs (H. Shigematsu et al. 2005). All other mutations excluding the aforementioned, mainly in exon 20, are defined as uncommon mutations. In NSCLC, low frequency mutations of the EGFR gene are associated with primary drug resistance to available EGFR TKIs, although some mutations affecting exon 18 present sensitivity to TKIs (Kobayashi and Mitsudomi 2016;

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Yang et al. 2015)

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2.2 HER2 gene and protein in NSCLC

HER2 gene, also called ERBB2, is located in 17q12 and encodes a transmembrane

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receptor protein. HER2 does not have a ligand and it forms heterodimers with other

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members of the ERBB family to activate the signaling pathway and exert its functions concerning cellular proliferation, differentiation, migration, and apoptosis (Graus-Porta, Beerli, and Hynes 1995).

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Dysregulation of HER2 in advanced NSCLC can be caused by mutations, amplification and protein overexpression (Arcila et al. 2012). HER2 amplification and mutations have been reported in 2-3% and 2-4% of patients with NSCLC, respectively. HER2 mutations

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tend to be mutually exclusive with other oncogenic driver mutations and 80-90% of them are located in exon 20 (Pillai et al. 2017; Yoshizawa et al. 2014; Hisayuki Shigematsu et al. 2005). HER2 kinase domain mutations were also reported in 2004 for the first time and, in parallel with EGFR mutations, are more frequent in women and never smoker patients with a diagnosis of lung adenocarcinoma (Stephens et al. 2004).

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Despite the efficacy of anti-HER2 agents in breast and gastric cancer, clinical trials with HER2-targeted agents have yielded disappointing results in patients with NSCLC harboring HER2 exon 20 mutations and no specific therapy against HER2 has been approved to date in this setting (Oh and Bang 2019).

2.3 EGFR/HER2 exon 20 mutations and primary resistance to currently approved

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anti-EGFR and anti-HER2 agents

Approximately 4% of EGFR-mutated NSCLC present exon 20 in-frame insertions, accounting for 0.3%–3.7% of NSCLC (Oxnard et al. 2013). As previously mentioned,

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exon 20 mutations represent 90% of NSCLC HER2 mutations.

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EGFR and HER2 exon 20 principally consist of two regions (figure 1): the α-C helix (from residue 762 to 766 in EGFR and from 770 to 774 in HER2) and the loop following

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the α-C helix (from residue 767 to 774 in EGFR and from 775 to 783 in HER2) (Yasuda et al. 2013; S. E. Wang et al. 2006). The C-helix of the protein acts as regulator element

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that determines the activation status of EGFR and HER2 by rotating from an outward (inactive conformation) to an inward position (active conformation) (Zhang et al. 2006). Upon ligation, the C-lobe of one kinase domain binds the N-lobe of the other one,

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conforming an asymmetric dimer and pushing the C-helix into the inner, active position.

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Figure 1. EGFR and Her2 genes. Exons 18-22 encode the tyrosine kinase domain.

Approximately 4% EGFR−mutated NSCLC present EGFR exon 20 in-frame insertions,

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accounting for 0.3%–3.7% of NSCLC, and 2%–4% of patients with NSCLC harbor HER2 mutations, being the 90% exon 20 insertions. Mutations in exon 20 occur within the C-

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terminal end of the ⍺-C helix or, more frequently, in the loop that follows.

EGFR exon 20 mutations comprise point mutations, such as S768I, or insertions. Exon 20 insertions are based on a combination of in-frame insertions and/or duplications of 3

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to 21 base pairs (bp), 90% clustered after the C-helix of the tyrosine kinase domain between codons 768-774 (Yasuda et al. 2013). When exon 20 insertions, located at the C-terminal end of the C-helix or in the loop following, occur, the C-helix is pushed into a permanent active conformation as result of the insertion (figure 2) (Eck and Yun 2010). Besides, exon 20 insertions do not affect the ATP-binding pocket and, in contrast to common mutations, do not increase the affinity for EGFR TKIs. This lack of drug affinity could be caused by steric hindrance secondary to a prominent shift of the C-helix and 15

phosphate-binding loop of EGFR into the drug-binding pocket (Robichaux et al. 2018). Taken together, this may explain the disappointing results of first-generation EGFR TKIs

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and anti-HER2 therapy in this scenario (Naidoo et al. 2015; Kinoshita et al. 2018).

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Figure 2. EGFR and HER2 activation in wild-type and mutant proteins. Upon ligand binding to the extracellular domain of the receptor, EGFR and HER2 conform asymmetric dimers, in which the C-lobe of one kinase domain binds to the N-lobe of the other one (not shown in the figure). The C-helix acts as regulator element that dictates

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the activation status of EGFR and HER2 by rotating from an outward/inactive conformation (a) to an inward position/active conformation (b) after ligand-induced dimerization. When an insertion in exon 20 occurs, the C-helix is pushed from the Cterminal side into a permanent active conformation as a result of the insertion (c). In case of a deletion in exon 19, the C-helix is pulled from the N-terminal side into the active position (d). 16

Location of insertion may also have an impact in 3-dimensional structure of EGFR and drug affinity (Arcila et al. 2013). Stabilized and rigid active conformation of EGFR exon 20 insertion D770insNPG observed by crystallography might induce resistance to firstgeneration TKIs in the insertions after residue 764, whilst insertions before residue 764

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do not present this effect (Robichaux et al. 2018). In fact, response to first-generation EGFR TKIs in patients harboring EGFR exon 20 insertion A763-Y764insFQEA have been reported (Arcila et al. 2013; Voon et al. 2013).

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HER2 exon 20 mutations comprise point mutations, such as L755S and G776C, or, more

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frequently, insertions. Similarly to EGFR exon 20 insertions, the vast majority of insertions ranges from 3 to 12 bp and are located in the most proximal region of the exon,

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between codons 775 and 881. The most prevalent insertion is p.A775_G776insYVMA in which the insertion of 12bp results in the duplication of aminoacids YVMA at codon 775

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(Ou et al. 2019).

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3 Target therapy against EGFR and HER2 exon 20 mutations

3.1 Tyrosine kinase inhibitors

3.1.1 Second-generation EGFR TKIs

Second generation EGFR inhibitors differ from first generation TKIs by irreversible binding to EGFR and by also binding HER2. Three drugs have been developed so far

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(afatinib, dacomitinib and neratinib). Clinical activity of irreversible EGFR TKIs in patients with NSCLC harboring EGFR and HER2 exon 20 mutations have been studied,

yielding disappointing results. These results may be explained because dose-limiting toxicity of second-generation TKIs results in clinically achievable plasma concentrations

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that are below the inhibitory concentrations of exon 20 insertions (Yasuda et al. 2013).

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A pooled analysis combining the results of the phase II Lux-Lung 2 and phase III LuxLung 3 and 6 that tested afatinib in a TKI-naïve population with advanced NSCLC

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showed that, of 600 patients receiving afatinib, 75 harbored uncommon EGFR mutations and 23 of them presented EGFR exon 20 insertion mutations (11 patients in Lux-Lung 2,

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6 in Lux-Lung 3 and 6 in Lux-Lung 6) (Yang et al. 2015). Durable responses with median PFS similar to common EGFR mutations were observed in a subset of patients with metastatic NSCLC harboring uncommon non-resistant EGFR mutations, such as S768I, L861Q, and/or G719X (ORR 71.1%, IC 95% 54.1 – 84.6, duration of response 11.1

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months, 95% IC 4.1 – 15.2), leading the FDA to broaden the indication of frontline afatinib for patients with metastatic NSCLC harboring non-resistant EGFR mutations. However, response to afatinib was poor in the cohort with EGFR exon 20 insertion mutations, in which only 2 patients responded to afatinib (ORR 8.7%, IC 95% 1.1 – 28) and mPFS was 2.7 months (IC 95% 1.8 – 4.2).

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Afatinib in patients with NSCLC harboring HER2 exon 20 mutations has provided similar results. The retrospective study EUHER2 cohort assessed the effectiveness of 101 patients with advanced HER2-mutated NSCLC that received chemotherapy and HER2targeted drugs (Mazières et al. 2016). Sixty-five patients received anti-HER2 drugs and 11 of them were treated with afatinib. Response rate and median PFS for afatinib were 18.2% and 3.9 months, respectively. Afatinib also showed modest clinical activity in a recently published retrospective multicenter study (Lai et al. 2019). Twenty-seven

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patients were included, with an ORR of 13%, median duration of response of 6 months and median OS from the start of afatinib of 7 months. However, sensitivity to second-

generation inhibitors may differ depending on the type of exon 20 insertion, as the

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presence of the HER2 insertion A775_G776insYVMA has been identified to confer potential clinical sensitivity to afatinib (Dziadziuszko et al. 2019; Lai et al. 2019; Peters

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et al. 2018).

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Heterogeneity in clinical responses to dacomitinib in patients with EGFR or HER2 exon 20 mutations according to the specific type of mutation has also been observed. In the

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phase I clinical trial testing dacomitinib, only one of 6 patients harboring EGFR exon 20 insertion mutations presented partial response to treatment, whose tumor harbored a D770delinsGY mutation (Jänne et al. 2011). In a prespecified cohort of a phase II testing dacomitinib in 30 previously treated patients harboring HER2 mutations or

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amplifications, 3 of 26 patients with HER2-mutant NSCLC, achieved a partial response (Kris et al. 2015). The analysis of the type of mutations revealed that the responding patients’ tumor harbored a P780_Y781insGSP or a M774delinsWLV mutation, while no responses were observed in patients with A775_G776insYVMA HER2 mutation. In a posterior in vitro assay, engineered Ba/F3 and NIH-3T3 cells harboring a range of EGFR and HER2 exon 20 insertions were treated with dacomitinib, neratinib and afatinib 19

(Kosaka et al. 2017). Only those EGFR-mutated cells that presented a glycine at position 770 and those HER2-mutated cells with the insertions P780_Y781insGSP or M774delinsWLV were sensitive to dacomitinib, corroborating the previous clinical data. The in vitro inhibitory concentration for D770delinsGY mutation was below the achievable plasma concentration.

The second-generation TKI neratinib showed limited clinical activity in a phase II clinical

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trial in NSCLC patients with classical EGFR-mutations, potentially due to dose-limiting diarrhea (Sequist et al. 2010). Currently, it is not being further tested in this setting. However, preclinical combination of neratinib with the mTOR inhibitor has demonstrated

efficacy in HER2-mutated lung cancer cells (Perera et al. 2009). Thus, the synergistic

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efficacy of the combined blockade has been tested in a phase II clinical trial in patients

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with advanced NSCLC with HER2 mutations (Besse et al. 2014). Twenty-seven patients were recruited and 3 of 14 patients (21%) that received the combined blockade had a

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response, so the study expanded to 39 patients in the combined treatment arm. In the expansion cohort, the dual inhibition obtained an ORR of 14%, a median PFS of 4.0

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months (95% CI 2.9–5.4) and a median OS of 15.1 months (95% CI 0.8−17.7) (Gandhi et al. 2017).

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3.1.2 Third-generation EGFR TKIs

Third-generation TKIs osimertinib and rociletinib covalently and irreversibly bind to the C797 cysteine residue of EGFR and restore sensibility of EGFR L858R or del19 mutant when secondary mutation T790M arises. Besides, frontline osimertinib has demonstrated

20

clinically and statistically significant improved PFS and OS over first-generation TKIs (Soria et al. 2018; Ramalingam et al. 2019).

Efficacy of osimertinib in the context of EGFR exon 20 mutations remains unclear. Preclinical experiments revealed in vitro activity (Robichaux et al. 2018; Lee et al. 2019) and tumor growth inhibition in murine models using patient-derived xenografts (PDX) was achieved (Floc’h et al. 2018).

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However, osimertinib has shown limited clinical activity in this setting. Response rate in a cohort of 17 patients with advanced NSCLC harboring EGFR exon 20 insertions was as low as 6%, median PFS was 3.7 months (95% CI 2.3-5.4) and disease control rate

-p

(DCR) at 5 months was 35% (van Veggel et al. 2018). Similar results have been recently

reported from a phase II clinical trial testing osimertinib in a Korean population (T M

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Kim et al. 2019). Of 15 patients with previously treated NSCLC with EGFR exon 20

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insertions, none responded to the treatment. Median PFS was 3.5 months (95% CI 1.6-

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not reached) and DCR at 6 months was 31.1%.

3.1.3 Poziotinib

Poziotinib, previously known as HM781-36B, is a covalent, irreversible and potent

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inhibitor of EGFR and HER2 exon 20 insertions (Cha et al. 2012). Similar to afatinib, poziotinib is a flexible quinazoline derivative, but it presents smaller size and increased halogenation and has greater flexibility. 3D modeling predicts that these structural advantages allow poziotinib to stepside the steric changes produced by exon 20 insertions and to bind more tightly in the drug-binding pocket (Robichaux et al. 2018).

21

In vitro assays using engineered Ba/F3 cells bearing exon 20 insertions demonstrated that poziotinib effectively inhibited growth of cells with EGFR or HER2 exon 20 mutations (Robichaux et al. 2018; Koga et al. 2018). In this cell line, inhibition of growth proliferation has shown to be more potent with poziotinib than with other TKIs. Besides, this novel drug presents selectivity for EGFR exon 20 insertions over T790M mutation. However, therapeutic window may be narrow, as poziotinib also exerts in vitro activity in wild-type EGFR. These results were mirrored in in vivo assays using murine models,

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in which poziotinib was effective in genetically engineered mouse models (GEMM) and PDX of NSCLC driven by EGFR and HER2 exon 20 insertions. Compared to afatinib or vehicle group, poziotinib induced significant tumor volume reduction and durable

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regressions without signs of progression at 12 weeks were observed in GEMM.

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Poziotinib has been subsequently tested in clinical trials with encouraging results. A firstin-human phase I trial examined the safety and maximum tolerated dose (MTD) of

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poziotinib in patients with genetically unselected advanced solid tumors including NSCLC with two different schedules: continuous daily dosing and on intermittent basis

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(14-day on and 7-day off) (Tae Min Kim et al. 2018). A MTD of 18 mg and 24 mg/day were determined respectively for each cohort, with a recommended phase II dose (RD) of 16 mg. Treatment was well tolerated, being diarrhea, skin rash, stomatitis, pruritus and anorexia the most common drug-related adverse events. Eight of 51 patients in the daily

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dosing cohort and 4 of 20 patients included in the intermittent dosing cohort experienced partial response, supporting further clinical development of poziotinib. However, a phase II clinical trial in an EGFR-mutant NSCLC population with acquired resistance to firstgeneration TKIs testing poziotinib at a dose of 16 mg in a 28-day cycle schedule yielded disappointing results, with an ORR of 8% (95% CI, 2-21) and a PFS of 2.7 months (95% CI, 1.8-3.7) (Han et al. 2017), which might be explained by poziotinib poor selectivity 22

for T790M mutation and resistance to PIK3CA mutation. These results are in stark contrast with the early results of a single center phase II trial in a selected population of metastatic heavily pretreated NSCLC harboring EGFR and HER2 exon 20 insertions or point mutations (Heymach et al. 2018; Robichaux et al. 2019). Both cohorts presented significant activity, with responses lasting above a year and a PFS of 5.5 months for the EGFR exon 20 mutant group and a PFS of 5.6 months for the HER2 exon 20 mutant group. Confirmed ORR was 43% and 42% respectively. Toxicity profile was similar in

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both cohorts, grading 3-4 in 79% of the patients (skin rash 34.9%, diarrhea 17.5% and paronychia 9.5%) and requiring dose reduction in 60% of them. A confirmatory multicentric phase II study is currently being conducted, including treatment-naïve

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patients (NCT03318939).

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Mechanisms of acquired resistance to poziotinib are under investigation as well. In preclinical studies with Ba/F3 cells harboring exon 20 mutations, poziotinib was not

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active in case of arising C805S mutation in HER2, if secondary C797S or T790M mutations in EGFR were present or in case of epithelial-to-mesenquimal transition,

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postulating them as possible mechanisms of acquired resistance to poziotinib, as it occurs with third-generation TKIs (Koga et al. 2018; Robichaux et al. 2018; Suda et al. 2019). A comparison of matched samples collected from poziotinib-responding patients enrolled in the aforementioned phase II clinical trial collected before treatment initiation and after

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progression showed that activation of MAPK/PI3K pathway, EGFR, MET and CDK6 amplification, T790M mutation and other EGFR kinase domain point mutations may act as poziotinib-resistance drivers (Elamin et al. 2019).

3.1.4 TAK-788 23

TAK-788, formerly known as AP32788, is a next-generation tyrosine kinase inhibitor that irreversibly binds to EGFR via covalent modification of Cys797 residue in the EGFR active site.

Inhibitory profile of this novel drug has been studied in Ba/F3 cells expressing wild-type and mutant variants of EGFR and HER2, showing that TAK-788 inhibits EGFR and HER2 exon 20 mutations with selectivity over the wild-type protein (Gonzalvez et al.

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2016). Therefore, efficacious levels of exposure without limiting side effects secondary to inhibition of wild-type EGFR could be reached in patients. Tumor regression and

inhibition of EGFR signaling was observed in mice models using PDX harboring EGFR

exon 20 insertions and in tumor-bearing mice with Ba/F3 cells containing HER2 exon 20

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insertions that received the drug orally.

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Based on the promising data from preclinical studies, a phase I/II, open-label, multicenter

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trial (NCT02716116) tested TAK-788 in patients harboring EGFR/HER2 exon 20 mutations (Neal et al. 2018). Fifty-seven patients were enrolled in the escalation cohort. Recommended dose was determined to be 160 mg and toxicity profile was consistent

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with other TKIs. Phase II is currently recruiting to evaluate efficacy of TAK-788 in patients with NSCLC harboring EGFR and HER2 exon 20 mutations with or without CNS disease. Preliminary results from the phase II expansion cohort for EGFR exon 20

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mutations have been recently presented (Janne et al. 2019; Riely et al. 2019). Twelve of 28 patients experimented partial response and disease control was achieved in 86%. Similar to other TKIs, most common adverse events were diarrhea (85%), rash (36%), nausea (43%), vomiting (29%), decreased appetite (25%), and stomatitis (18%). The activity of TAK-788 is now being globally investigated in the EXCLAIM extension,

24

along with survival and quality of life, in 91 previously treated patients with locally advanced or metastatic NSCLC carrying EGFR exon 20 insertions.

3.1.5 Pyrotinib

The 3-cyanoquinoline derivative pyrotinib is an oral, irreversible pan-HER TKI against

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EGFR, HER2 and HER4 (Y. Wang et al. 2019; X. Li et al. 2017). The first-in-human, open-label phase I study with this drug was conducted in patients with metastatic HER2positive breast cancer (Ma et al. 2017), in whom pyrotinib at a daily dose of 400 mg

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obtained promising results.

In the HER2 exon 20-mutated NSCLC setting, in vitro cell proliferation assays in patient-

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derived organoids harboring HER2 exon 20 mutations using in vivo plasma

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concentrations of pyrotinib and afatinib according to those obtained in previous phase I clinical trials (Ma et al. 2017; Yap et al. 2010) showed that cell growth inhibition was more potent with the novel drug than with afatinib (Y. Wang et al. 2019). In vivo

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experiments using PDX murine models corroborated efficacy of pyrotinib in comparison with other drugs with activity against HER2, such as afatinib or T-DM1, and immunohistochemistry staining of tumor tissue after treatment with pyrotinib showed that

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HER2 downstream signaling pathway was blocked (Y. Wang et al. 2019).

A single-center phase II clinical study in pretreated HER2 exon 20-mutated advanced NSCLC patients provided promising results (Y. Wang et al. 2019). Eight (53.3%) and 3 (20.0%) of 15 evaluable patients presented partial response and stable disease, respectively, showing a median PFS of 6.4 months (95% CI 1.60- 11.20). Results from a multicenter phase II clinical trial in a similar target population including 60 subjects have 25

been recently reported (Gao et al. 2019), confirming the previous results. Overall response rate was 31.7%, reaching a PFS of 6.8 months (95% CI 4.1 - 8.3). Pyrotinib presented a safe toxicity profile, being diarrhea the most frequent treatment-related grade adverse event (20%).

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3.1.6 Tarloxotinib

The hypoxia-activated prodrug (HAP) tarloxotinib bromide has also been studied as a

potential treatment against tumors harboring EGFR exon 20 mutations. This prodrug

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releases an irreversible EGFR/HER2 inhibitor when low oxygen conditions occur.

In lung cancer, oxygen deprivation in tumor cells promotes genomic instability, enhanced

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aggressiveness and increased metastatic potential (Phillips et al. 2005). It also confers

et al. 2018).

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treatment resistance and poor survival (Murakami et al. 2014; Minakata et al. 2012; Lu

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A phase II clinical trial tested tarloxotinib in metastatic EGFR-mutant NSCLC patients who had progressed to frontline EGFR inhibitors and who lacked T790M resistance mutation (Liu et al. 2016). Unfortunately, it did not translate into patient benefit as none of the 21 patients enrolled responded to therapy and a premature trial termination was

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decided.

However, a recent in vivo study using a murine model with xenografts of NSCLC cell lines harboring endogenous EGFR exon 20 insertions revealed a significant tumor regression with tarloxotinib, while no response was observed under afatinib (EstradaBernal et al. 2018). These preliminary results suggest that tarloxotinib could be useful in

26

a molecularly selected population with NSCLC bearing EGFR exon 20 insertions and a phase II is currently recruiting NSCLC patients harboring EGFR exon 20 insertions or HER2-activating mutations (NCT03805841).

T790M and C797S have been identified as mechanisms of acquired resistance to tarloxotinib in Ba/F3 cells containing EGFR exon 20 insertions that were treated with Nethyl-nitrosurea mutagenesis agent, being the type of resistance mutation dependent on

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the original subtype of exon 20 insertion mutation (Suda et al. 2019). However, whether these alterations arise or not in patients after receiving tarloxotinib has not been

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demonstrated yet.

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3.1.7 TAS6417

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TAS6417, also named CLN-081, is a novel small molecule that inhibits EGFR by covalent modification of the cysteine residue at position 797 in the ATP-binding site of

2018).

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mutated EGFR that harbors an in-frame insertion mutation in the exon 20 (Hasako et al.

In vitro cell proliferation experiments in genetically engineered cells and cell lines established from lung cancer patients harboring EGFR exon 20 mutations or exon 19

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mutations and cells harboring KRAS mutations revealed that TAS6417 inhibits cell proliferation by inhibition of the EGFR downstream pathway and induces apoptosis via caspase activation in EGFR-mutated cells with selectivity over EGFR wild-type cells, but had no effect in EGFR-independent proliferation cells (Hasako et al. 2018; Udagawa et al. 2019). TAS6417 presents a higher selectivity index compared to poziotinib in a wide

27

range of exon 20 mutations, represented as the ratio wild-type EGFR/mutated-EGFR. Thus, it is a more selective inhibitor and presents a wider therapeutic window.

In vivo efficacy was observed in EGFR exon 20 insertion-driven tumor murine preclinical models, in which TAS6417 induced persistent tumor regression and a prolonged survival. Treatment with TAS6417 resulted in inhibition of the PI3K/Akt pathway, as measured by pAKT, and the RAS/MAPK pathway, as measured by pERK, in mice harboring EGFR

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exon 20 mutations, but not in those EGFR wild-type.

However, clinical trials testing TAS6417 in patients with NSCLC have not been performed yet, so its real clinical significacy in this scenario remains unknown. A phase

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I/IIa clinical trial in patients with NSCLC harboring EGFR exon 20 insertion mutations to determine the MTD and RP2D and to assess preliminary efficacy is expected to initiate

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3.2 Antibody therapy

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recruitment soon (Piotrowska et al. 2019).

3.2.1 Trastuzumab

Trastuzumab is a monoclonal IgG1 humanized murine antibody that binds to the HER2

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receptor at a single extracellular domain. It exerts antibody-dependent cellular cytotoxicity, blocks HER2 dimerization,

promotes receptor internalization and/or

degradation and inhibits the PI3K/AKT signaling pathway (Klapper et al. 2000). Regimens with trastuzumab are standard of care for HER2-positive breast and gastric cancer, and it is being tested for other HER2-positive histologies, including colorectal, biliary tract, lung and bladder tumors (Oh and Bang 2019).

28

Efficacy of trastuzumab in patients with NSCLC was reported in the retrospective EUHER2 cohort (Mazières et al. 2016), including the seminal case of a patient with NSCLC harboring HER2 exon 20 and EGFR exon 21 co-mutations that responded to a combination of trastuzumab and paclitaxel (Cappuzzo, Bemis, and Varella-Garcia 2006). However, trastuzumab did not induce response in a phase II clinical trial in pretreated

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patients with NSCLC harboring HER2 alterations (Kinoshita et al. 2018).

3.2.2 JNJ-61186372

JNJ-61186372 (JNJ-372) is a bispecific antibody that simultaneously targets the EGF and

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cMet receptors. It blocks ligand-induced phosphorylation of EGFR and cMet and inhibits

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pERK and pAKT. Additionally, it induces receptor degradation and mediates antibodydependent cellular toxicity through Fc-dependent effector mechanisms (Moores et al.

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2016).

Preclinical in vivo and in vitro activity of this novel drug in NSCLC supported the

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initiation of a clinical trial (Moores et al. 2016). Clinical activity in patients with advanced NSCLC was assessed in a phase I study, in which 25 of 88 patients with evaluable disease experienced partial response and 6 of 20 patients harboring EGFR exon 20 mutations

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presented partial response (Haura et al. 2019).

Based on the activity observed in patients with NSCLC harboring EGFR exon 20 mutations, preclinical studies for a better understanding of the mechanism underlying in this particular context have been performed (Yun et al. 2019). Preclinical experiments on Ba/F3 cell lines containing EGFR exon 20 mutations demonstrated that JNJ-61186372

29

inhibited cell proliferation through a decrease in EGF and cMet receptors expression and in pERK, pAkt and p-S6, as wells as upregulation of caspase-mediated apoptosis.

3.3 Antibody-drug conjugates

3.3.1 Trastuzumab emtansine

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Trastuzumab emtansine, also known as T-DM1, is an antibody-drug conjugate that consists of the humanized monoclonal antibody trastuzumab linked to the cytotoxic microtubule agent DM1. T-DM1 carries an average of 3.5 molecules of DM1 per

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antibody. The ADC binds to the surface receptor HER2 and enters in the cell via receptor-

moiety (Lewis Phillips et al. 2008).

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mediated endocytosis. DM1 is released after proteolytic degradation of the antibody

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The efficacy of T-DM1 has been evaluated in the HER2 exon 20-mutated NSCLC scenario. In a phase II clinical trial testing T-DM1 in HER2-mutated NSCLC, 6 of 11

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patients with HER2 exon 20-mutated NSCLC had a response (B. T. Li et al. 2018). However, limited activity was observed in another phase II trial that enrolled 15 patients, whom 7 presented HER2 exon 20 mutations, and the study had to be curtailed (Hotta et al. 2018). A recent preclinical study using NSCLC PDX model indicates that the

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sensibility of HER2-mutated cells to T-DM1 may improve after an augmentation in cellsurface expression and a decreasement in ubiquitination of mutant HER2 induced by lowdose poziotinib treatment (Robichaux et al. 2019).

3.3.2 DS-8201a 30

Trastuzumab deruxtecan (DS-8201a) is an investigational ADC targeting HER2 that comprises a humanized anti-HER2 antibody bound to a novel topoisomerase I inhibitor named exatecan derivative (DX-8951 derivative, DXd) by a peptide that is cleaved enzymatically (Y. Ogitani et al. 2016).

The humanized monoclonal IgG1 antibody presents the same amino acid sequence as trastuzumab and it retains its functions of ADCC and inhibition of cell proliferation via

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downregulation of phosphorylated Akt despite the conjugation. The peptide linker is stable in plasma and the release rate of DXd from DS-8201a has been demonstrated to be as low as 2.1% after 21 days of incubation (Y. Ogitani et al. 2016). It is cleaved

enzymatically selectively in tumor cells by lysosomal cathepsins B and L, that are

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upregulated in malignant cells, upon ligation of DS-8201a to HER2 receptors and

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internalization. Then, DXd is released. Its mechanism of action differs from other ADC, which most commonly carry tubulin polymerization inhibitors, such as T-DM1 or SGN-

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35 (brentuximab vedotin). In contrast, the campothecin derivative DXd induces doublestrand DNA breaks and apoptosis after binding to and stabilization of topoisomerase I-

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DNA cleavable complexes (Pommier 2006). Each antibody of DS-8201a is conjugated with 8 molecules of DXd. This drug:antibody ratio (DAR) of 8 is higher than for other ADC (DAR for T-DM1 is 3.5 DM1 molecules per antibody), and it improves its efficacy as it may enable the drug delivery even when HER2 expression is low (Y. Ogitani et al.

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2016). Moreover, the released payload exhibits a bystander killing effect due to its high membrane permeability, which allows it to diffuse across the cell membrane of antigenpositive cells to the neighboring HER2-negative cells (Yusuke Ogitani et al. 2016). In coculture experiments with HER2-positive KPL-4 cells and HER2-negative MDA-MB-468 cells, DS-8201a killed both cells lines, while anti-HER2-DXd with low permeability and T-DM1 did not. Interestingly, in cell-free inhibition assays, DXd inhibited cell 31

proliferation ten times more potently than the active metabolite of the topoisomerase I inhibitor irinotecan, but had a short in vivo half-life, which could lead to an acceptable toxicity profile (Y. Ogitani et al. 2016). These results were confirmed in vivo using xenograft models. Furthermore, DS-8201a has been reported to exert antitumor immune effects, as it induced an increase in the tumor-infiltrating dendritic cells and CD8+ T cells in vivo and the rejection of rechallenged tumor cells by adaptive immune cell was observed in immunocompetent mice models after being cured (Iwata et al. 2018).

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Altogether, DS-8201a design improves the characteristics of prior ADC. On the basis of the aforementioned preclinical data, a first-in-human clinical trial in patients with breast and gastric or gastro-oesophageal tumors regardless of HER2

-p

expression was initiated to select the RD for expansion and to evaluate the safety profile

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and activity of DS-8201a (Doi et al. 2017). No dose-limiting toxicities were reported and the MTD was not reached. Doses of 5.4 or 6.4 mg/kg were used for the expansion phase

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in HER2+ tumors, showing promising antitumor activity (ORR of 59.5% and 49.3% for the cohorts of breast cancer and the gastric/gastro-oesophageal cancer, respectively) and

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a manageable toxicity profile (Shitara et al. 2019; Tamura et al. 2019). The phase I expansion cohort also enrolled patients with NSCLC that expressed HER2 or harbored HER2 mutations, including those affecting exon 20, and yielded promising results (Tsurutani et al. 2018). In this cohort, median duration of treatment was 5.5 months (range

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0.69 – 14.19 months) and it was well tolerated, being the most frequent adverse events of low grade gastrointestinal and hematologic toxicities. However, cases of interstitial lung disease/pneumonitis, including leading to fatal events, have been reported in patients under treatment with DS-8201a (Powell et al. 2019) and a deep understanding of this drug-related toxicity is needed to characterize risk factors and to optimize prevention and management. 32

A multicenter phase II clinical trial is currently recruiting subjects with over-expressing (cohort 1) or mutated (cohort 2) HER2 advanced NSCLC, including exon 20 mutations (Planchard et al. 2019).

3.4 Other mechanisms of action

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3.4.1 Luminespib

Luminespib, formerly known as AUY922, is a drug under clinical development that targets the heat shock protein 90 (Hsp90). The Hsp90 chaperone complex protects cellular

-p

proteins, such as several families of hormone receptors, transcription factors and kinases,

from being degraded by the ubiquitin-proteasome system (Pratt 1998). Hsp90 presents as

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a homodimer with an amino-terminal domain that contains an ATP-binding pocket. The

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client protein binds to the co-chaperones Hsp70 and Hsp40 and then loads onto the middle domain. Subsequently, binding of ATP facilitates a conformational change that stabilizes and activates client proteins. Posterior hydrolysis of ATP to ADP provides the release of

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the client protein that can be destructed ty the proteasome through a process of ubiquitination (Ali et al. 2006; Donnelly and Blagg 2008; Prodromou and Pearl 2003).

Tumor cells often use this machinery to prevent mutated and overexpressed oncoproteins

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from misfolding and get degraded (Trepel et al. 2010). In lung cancer, cells harboring EGFR mutations, including exon 20 mutations, are known to use this strategy, leading to a dependence on Hsp90 for viability (Shimamura and Shapiro 2008; Shimamura et al. 2005; Jorge et al. 2018). Therefore, pharmacological inhibition of Hsp90 may lead to protein destabilization and degradation through the proteosome in EGFR-mutant cells.

33

Luminespib is the Hsp90 inhibitor at furthest in clinical development so far for EGFR exon 20 mutations. This investigational non-geldanamycin Hsp90 inhibitor interacts with the ATP-binding pocket, preventing ATP binding. Thus, the chaperone cycle stops and the client proteins degradate. The first-in-human phase 1 dose-escalation study, conducted in patients with advanced solid tumors, demonstrated acceptable tolerability at the recommended dose of 70 mg/m2 (Sessa et al. 2013). In a phase II clinical trial across different molecularly-defined NSCLC subtypes, an ORR of 17.1% was observed in

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EGFR-mutant patients, including patients harboring exon 19 deletions and exon 20 insertions, and in patients with acquired T790M mutations (Felip et al. 2018).

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Based on the preclinical and clinical activity observed among patients with EGFR exon 20 insertion tumors, a phase II clinical trial of luminespib in patients with NSCLC

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harboring EGFR exon 20 insertions was conducted (Piotrowska et al. 2018). Of 29 patients enrolled, 5 experimented partial response. However, median PFS and OS were

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modest (2.9 and 13 months, respectively). Similar to previous reports, diarrhea, ocular toxicity and fatigue were the most common adverse events. Reversible visual disorders

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caused by luminespib could be explained by direct damage of the retinal pigment epithelial cells and adjacent photoreceptors due to Hsp90 inhibition (Munk et al. 2014).

Preclinical data addressing the sensitivity of HER2 exon 20 mutations to Hsp90 inhibitors

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in tumor cell lines has also been reported (Xu et al. 2007), although no clinical activity has been reported yet.

4 Conclusions

34

The therapeutic landscape of NSCLC harboring EGFR and HER2 mutations is rapidly evolving. Although EGFR and HER2 exon 20 mutations in advanced NSCLC confer resistance to currently approved targeted therapy, a deeper molecular knowledge of these mutations has led to the development of novel drugs with the ability to circumvent primary resistance to molecularly driven therapy. These preclinical and clinical advances may revolutionize the current therapeutic management algorithm of this particular oncogene-driven type of NSCLC as early data provide encouraging activity of novel

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drugs that may finally join the cancer armamentarium to fight against disease in this subgroup of patients.

However, size and location of EGFR and HER2 exon 20 insertions differ, conforming a

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heterogenous molecular subgroup of tumors that may present differences in response. In

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addition, the safety profile caused by the inhibition of wild-type proteins and the acquirement of potential mechanisms of resistance are major concerns. Further steps are

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needed to achieve a better understanding of the mechanisms of primary and acquired resistance and the different sensibility to drugs according to the particular type of

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mutations.

Results of ongoing clinical trials concerning efficacy and toxicity profile in this selected population will allow to confirm or not their entrance into the era of molecularly driven

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therapy in the near future.

Conflict of interest statement: Iosune Baraibar: Honoraria: Sanofi. Travel, Accomodations, Expenses: Amgen.

35

Laura Mezquita: Sponsored Research: Bristol-Myers Squibb, Boehringer Ingelheim. Consulting, advisory role: Roche Diagnostics, Takeda. Lectures and educational activities: Bristol-Myers Squibb, Tecnofarma, Roche. Travel, Accommodations, Expenses: Roche. Mentorship program with key opinion leaders: funded by AstraZeneca Ignacio Gil-Bazo: Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Guardant Health, Merck Sharp and Dohme, Roche. Honoraria: AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme.

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Travel, Accommodations, Expenses: AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Roche.

David Planchard: Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers

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Pfizer, prIME Oncology, Peer CME, Roche

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Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis,

Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli

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Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche Clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli

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Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo

Travel, Accommodations, Expenses: AstraZeneca, Roche, Novartis, prIME Oncology,

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Pfizer

Acknowledgement:

We should be thankful for all the patients and clinical investigators who were involved in the studies selected for this review. 36

5 References Ali, Maruf M U, S Mark Roe, Cara K Vaughan, Phillipe Meyer, Barry Panaretou, Peter W Piper, Chrisostomos Prodromou, and Laurence H Pearl. 2006. “Crystal Structure of an Hsp90-Nucleotide-P23/Sba1 Closed Chaperone Complex.” Nature 440 (7087): 1013–17. https://doi.org/10.1038/nature04716.

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Arcila, M. E., J. E. Chaft, K. Nafa, S. Roy-Chowdhuri, C. Lau, M. Zaidinski, P. K. Paik, M. F. Zakowski, M. G. Kris, and M. Ladanyi. 2012. “Prevalence, Clinicopathologic Associations, and Molecular Spectrum of ERBB2 (HER2) Tyrosine Kinase

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Mutations in Lung Adenocarcinomas.” Clinical Cancer Research 18 (18): 4910–18. https://doi.org/10.1158/1078-0432.CCR-12-0912.

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