EGFRHERNCT07303218
The HER Project: HRD in EGFR-mutated NSCLC
An observational study of EGFR and Non Small Cell Lung Cancer, run by IRCCS San Raffaele at 1 site in Italy.
Trial summary
This observational retrospective-prospective study aims to evaluate the prevalence of homologous recombination deficiency (HRD) in metastatic EGFR mutated NSCLC and to assess its correlation with clinical and molecular features. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- EGFR, Non Small Cell Lung Cancer, Homologous Recombination Deficiency
- How many people
- 100 participants
- Where
- 1 siteItaly
- Study dates
- 1 Dec 2025to 31 Dec 2032
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Adult patients (≥18 years) with metastatic EGFR-mutated NSCLC eligible for treatment with EGFR-TKI according to standard clinical practice, with available tumor tissue suitable for HRD testing
Who may be able to join
- Participant is willing and able to give informed consent for participation in the study. However, since a part of the study is retrospective and, considering the large sample sizes required and considering that the disease involved in this study affects elderly subjects with co-morbidities and presents a significant mortality rate based on the stage of the disease, deceased and untraceable patients will also be included.
- Age ≥18 years old
- Have a metastatic histologically confirmed NSCLC
- Presence of EGFR common mutations (i.e. ex19del and L858R)
- Have sufficient biological material to assess genomic profiling with AmoyDx Focus panel or similar
- Clinical data available
Who cannot join
- Insufficient baseline tumour tissue (unsuitable for HRD scoring)
- Presence of EGFR uncommon mutations (i.e. ex20ins)
- Known presence of co-occurring uncommon EGFRm, ALK, ROS1, or other main oncogenic drivers.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The HER Project: Homologous Recombination Deficiency in EGFR-Mutated NSCLC, a Retrospective and Prospective Translational Single-center Study
This observational retrospective-prospective study aims to evaluate the prevalence of homologous recombination deficiency (HRD) in metastatic EGFR mutated NSCLC and to assess its correlation with clinical and molecular features. Based on the hypothesis that HRD identifies a distinct EGFRm subgroup with prognostic value and a potential sensitivity to PARP inhibitor-based strategies, translational analysis will be performed with multiple pre-clinical models, ranging from human cancer cells to murine models.
Read the detailed description
Introduction
Lung cancer is the most common diagnosed cancer, with almost 2.5 million new cases per year, and the leading cause of cancer-related death (18.7%), according to GLOBOCAN (2022). Non-small cell lung cancer (NSCLC) is the most prevalent subtype, accounting for 85% of lung cancers. Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor that regulates survival, proliferation and differentiation in mammalian cells. EGFR mutations occur in around 30% of patients affected by NSCLC, representing the second most frequent targetable oncogenic driver in NSCLC.
The treatment landscape for metastatic EGFR-mutated (EGFRm) NSCLC has significantly evolved since the introduction of 1st generation tyrosine kinase inhibitors (TKIs) in 2010. While osimertinib (a 3rd generation TKI) is currently the standard first-line treatment worldwide in the advanced setting, emerging combination strategies, such as osimertinib plus chemotherapy (FLAURA2 trial) or lazertinib plus amivantamab (MARIPOSA trial), improved progression-free survival (PFS) and overall survival (OS) compared to TKI alone. However, these drug combinations often cause increased treatment-related toxicities, impacting both patients' quality of life and healthcare costs. For this reason, it becomes crucial to identify predictive biomarkers to guide patient selection for combination therapies. For example, post-hoc analyses of FLAURA2 were conducted on poor-risk populations, such as EGFRm patients with high tumour burden or TP53 co-mutations. Despite better outcomes of chemotherapy plus osimertinib across all patient subgroups, only 1 out of 4 patients had baseline tissue samples available for wider genome sequencing. Therefore, understanding the role of co-alterations in EGFRm tumours remains to be explored, particularly those associated with shorter OS and/or more aggressive clinical presentations.
Targeting HRD pathway with PARP-inhibitors in Non-small cell lung cancer
Homologous recombination deficiency (HRD) is a condition linked to an impaired DNA repair mechanism that contributes to genomic instability in several cancers, including NSCLC. PARP-inhibitors (PARPi), drugs targeting a key protein involved in DNA repair, are already available in clinical practice for the treatment of other HRD-positive subgroups of solid tumours (e.g. breast, ovarian, prostate cancer). In NSCLC, however, their clinical benefit remains unclear. Previous studies evaluating PARPi in NSCLC, including combinations with chemotherapy or immunotherapy, have shown modest or non-significant improvements in PFS and OS. However, a significant limitation of these studies is the lack of HRD status assessment, which may have diluted the expected benefits in HRD-positive patients.
Interestingly, emerging evidence suggests that a higher Genomic Scarring Score (GSS), a surrogate for HRD, may predict PARPi sensitivity better than the traditional assessment of the mutational status of homologous recombination repair (HRR) genes. In this study, the administration of PARPi significantly delayed tumour growth in patient-derived xenograft (PDXs) with high GSS, half of which carried pathogenic/likely pathogenic somatic HRR mutations. Importantly, favourable responses to the PARPi-olaparib were observed regardless of HRR gene mutation status, underscoring the potential of GSS as a robust biomarker to more effectively select patients for PARPi-based therapies.
HRD in EGFR mutated NSCLC
In a Chinese cohort of HRD-positive NSCLC, EGFR-mutated tumours are associated with poor TKI response, which might be explained by gene amplifications like MET, a common resistance mechanism that can be promoted by HRD. Studies also showed the co-occurrence of biallelic TP53 mutations and high HRD score in poor-risk EGFRm NSCLC, suggesting a link between this tumour genotype and TKI-resistance. In preclinical models of NSCLC, osimertinib-resistant EGFRm cell lines exhibited sensitivity to olaparib, leading to increased DNA damage and cell death via a pro-oxidant state. Moreover, combining osimertinib with a PARPi in vivo significantly improved tumour regression compared to osimertinib alone. Altogether, these findings lead to hypothesize that the HRD positive score/GSS may define a patient subgroup that could benefit from PARPi-based combination therapy.
Clinical trials evaluating EGFR-TKIs with PARPi failed to achieve their primary endpoint of PFS, possibly due to a lack of patient selection based on HRD score or other molecular criteria. However, subsequent analyses of the GOAL trial found a stronger synergy between gefitinib (a 1st generation TKI) and olaparib in tumours with higher BRCA1 expression, supporting a predictive role for targeting DNA damage repair pathways. In operable NSCLCs, the percentage of HRD positive tumours is ~20-30%, suggesting that the acquisition of HRD status could be an early event. Importantly, a similar incidence was observed in a Chinese cohort of any-stage EGFRm or ALK-rearranged NSCLC patients in which the cases with high HRD score are ~33% of the total. The sensitivity of EGFRm tumours to platinum-based doublets, which is a known characteristic of HRD-positive tumours, and a larger compendium evidence of chromosomal instability further support exploring the role of HRD in EGFR-mutated lung cancer, paving the way for new targeted therapeutic approaches.
The HER Project
With the HER project, we will investigate the role of HRD and genomic instability (GSS) in EGFRm NSCLC by i) defining the fraction of metastatic EGFRm tumours with HRD positive score, ii) correlating HRD score with patient outcomes, and iii) assessing the synergic efficacy of EGFR-TKIs plus PARPi based on the HRD score in different preclinical settings, ranging from cell lines to a murine model of spontaneous EGFRm lung cancer. We expect that this drug combination will be effective in a specific subset of EGFR tumors. However, even if we won't observe any relevant findings by targeting this pathway, our work will increase our knowledge about DNA damage repair and drug resistance in EGFRm tumours.
- Being tested
- No Intervention: Observational Cohort
- Keywords
- EGFR, Non small cell lung cancer, NSCLC, Homologous Recombination Deficiency, HRD, PARP Inhibitors, cell lines, organoids, Osimertinib, Olaparib, Genomic Scarring Score, TP53
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
No Intervention: Observational CohortOther
Observational study only; participants receive standard-of-care treatments not assigned by the study
| Study group | Role | What they receive |
|---|---|---|
| Retrospective Cohort | Patients with metastatic EGFR-mutated NSCLC diagnosed and treated between January 2020 and September 2025, with tumour tissue available for HRD analysis. Receives: Other: No Intervention: Observational Cohort | |
| Prospective Cohort | Patients with newly diagnosed metastatic EGFR-mutated NSCLC, with baseline tumour tissue available for HRD testing and prospectively collected clinical follow-up. Receives: Other: No Intervention: Observational Cohort |
What is being measured
The primary outcome is the main question the study is designed to answer.
Prevalence of HRD in metastatic EGFRm NSCLC
Proportion of EGFRm NSCLC with an HRD positive score evaluated by AmoyDx HRD Panel or similar (GSS ≥ 50).
Measured: Baseline (T0), on diagnostic tumour sample
Secondary outcomes (1)
Correlation between HRD status and clinical outcomes and molecular features
Assessment of the association between HRD status (positive vs negative) and:
- Clinical outcomes including progression-free survival (PFS), defined as time from initiation of first line treatment to evidence of progressive disease, and overall survival (OS), defined as time from initiation of first line treatment to death.
- Baseline clinical characteristics
- Baseline molecular features including EGFR mutation type, variant allele frequency (VAF) and other co-occurring molecular alterations
Measured: Up to 3 years of follow-up for PFS/OS; baseline for clinical and molecular characteristics.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Dec 2025
- Study start1 Dec 2025
- Primary completion31 Dec 2029 (estimated)
- Study completion31 Dec 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for EGFRStudies of the same condition, open and under way.
- More trials run by IRCCS San RaffaeleThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Other
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- IRCCS San Raffaele
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Francesca Rita Ogliari, IRCCS San Raffaele
- Investigators
- Francesca Rita Ogliari, Medical Doctor, Principal investigator, IRCCS Ospedale San Raffaele
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07303218
- Sponsor's protocol ID
- The HER Project
- Acronym
- HER
- Status last verified
- Dec 2025
- First submitted
- 11 Dec 2025
- Last updated
- 31 Dec 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Drews RM, Hernando B, Tarabichi M, Haase K, Lesluyes T, Smith PS, Morrill Gavarro L, Couturier DL, Liu L, Schneider M, Brenton JD, Van Loo P, Macintyre G, Markowetz F. A pan-cancer compendium of chromosomal instability. Nature. 2022 Jun;606(7916):976-983. doi: 10.1038/s41586-022-04789-9. Epub 2022 Jun 15.
PubMed 35705807Fang S, Wang Z, Guo J, Liu J, Li C, Liu L, Shi H, Liu L, Li H, Xie C, Zhang X, Sun W, Li M. Correlation between EGFR mutation status and response to first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer. Onco Targets Ther. 2014 Jul 1;7:1185-93. doi: 10.2147/OTT.S63665. eCollection 2014.
PubMed 25061320Klinakis, A. et al. 1277P HRD status of patients with early stage non-small cell lung cancer. Annals of Oncology 34, S737-S738 (2023)
Karachaliou N, Arrieta O, Gimenez-Capitan A, Aldeguer E, Drozdowskyj A, Chaib I, Reguart N, Garcia-Campelo R, Chen JH, Molina-Vila MA, Rosell R; Spanish Lung Cancer Group (SLCG). BRCA1 Expression and Outcome in Patients With EGFR-Mutant NSCLC Treated With Gefitinib Alone or in Combination With Olaparib. JTO Clin Res Rep. 2020 Oct 23;2(3):100113. doi: 10.1016/j.jtocrr.2020.100113. eCollection 2021 Mar.
PubMed 34589994Garcia-Campelo R, Arrieta O, Massuti B, Rodriguez-Abreu D, Granados ALO, Majem M, Vicente D, Lianes P, Bosch-Barrera J, Insa A, Domine M, Reguart N, Guirado M, Sala MA, Vazquez-Estevez S, Caro RB, Drozdowskyj A, Verdu A, Karachaliou N, Molina-Vila MA, Rosell R; Spanish Lung Cancer Group (SLCG). Combination of gefitinib and olaparib versus gefitinib alone in EGFR mutant non-small-cell lung cancer (NSCLC): A multicenter, randomized phase II study (GOAL). Lung Cancer. 2020 Dec;150:62-69. doi: 10.1016/j.lungcan.2020.09.018. Epub 2020 Oct 3.
PubMed 33070053Marcar L, Bardhan K, Gheorghiu L, Dinkelborg P, Pfaffle H, Liu Q, Wang M, Piotrowska Z, Sequist LV, Borgmann K, Settleman JE, Engelman JA, Hata AN, Willers H. Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity. Cell Rep. 2019 Jun 18;27(12):3422-3432.e4. doi: 10.1016/j.celrep.2019.05.058.
PubMed 31216465Feng J, Lan Y, Liu F, Yuan Y, Ge J, Wei S, Luo H, Li J, Luo T, Bian X. Combination of genomic instability score and TP53 status for prognosis prediction in lung adenocarcinoma. NPJ Precis Oncol. 2023 Oct 31;7(1):110. doi: 10.1038/s41698-023-00465-x.
PubMed 37907595Fischer A, Bankel L, Hiltbrunner S, Rechsteiner M, Ruschoff JH, Rushing EJ, Britschgi C, Curioni-Fontecedro A. Mutational Landscape and Expression of PD-L1 in Patients with Non-Small Cell Lung Cancer Harboring Genomic Alterations of the MET gene. Target Oncol. 2022 Nov;17(6):683-694. doi: 10.1007/s11523-022-00918-6. Epub 2022 Sep 22.
PubMed 36136211Wang Y, Ma Y, He L, Du J, Li X, Jiao P, Wu X, Xu X, Zhou W, Yang L, Di J, Zhu C, Xu L, Sun T, Li L, Liu D, Wang Z. Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population: An integrated genomic and transcriptional analysis. Chin J Cancer Res. 2024 Jun 30;36(3):282-297. doi: 10.21147/j.issn.1000-9604.2024.03.05.
PubMed 38988485Tsilingiri K, Chalari A, Christopoulou G, Voutsina A, Constantoulakis P, Potaris Kappa, Vamvakaris I, Hatzidaki D, Zachou G, Vatsellas G, Georgoulias V, Kotsakis A, Klinakis A. Genomic scarring score predicts the response to PARP inhibitors in non-small cell lung cancer. NPJ Precis Oncol. 2024 Dec 26;8(1):291. doi: 10.1038/s41698-024-00777-6.
PubMed 39725687Clarke JM, Patel JD, Robert F, Kio EA, Thara E, Ross Camidge D, Dunbar M, Nuthalapati S, Dinh MH, Bach BA. Veliparib and nivolumab in combination with platinum doublet chemotherapy in patients with metastatic or advanced non-small cell lung cancer: A phase 1 dose escalation study. Lung Cancer. 2021 Nov;161:180-188. doi: 10.1016/j.lungcan.2021.09.004. Epub 2021 Sep 17.
PubMed 34607210Ahn MJ, Bondarenko I, Kalinka E, Cho BC, Sugawara S, Galffy G, Shim BY, Kislov N, Nagarkar R, Demedts I, Gans SJM, Mendoza Oliva D, Stewart R, Lai Z, Mann H, Shi X, Hussein M. Durvalumab in Combination With Olaparib Versus Durvalumab Alone as Maintenance Therapy in Metastatic NSCLC: The Phase 2 ORION Study. J Thorac Oncol. 2023 Nov;18(11):1594-1606. doi: 10.1016/j.jtho.2023.06.013. Epub 2023 Jun 29.
PubMed 37390980Ramalingam SS, Thara E, Awad MM, Dowlati A, Haque B, Stinchcombe TE, Dy GK, Spigel DR, Lu S, Iyer Singh N, Tang Y, Teslenko I, Iannotti N. JASPER: Phase 2 trial of first-line niraparib plus pembrolizumab in patients with advanced non-small cell lung cancer. Cancer. 2022 Jan 1;128(1):65-74. doi: 10.1002/cncr.33885. Epub 2021 Sep 3.
PubMed 34478166Hochmair M, Schenker M, Cobo Dols M, Kim TM, Ozyilkan O, Smagina M, Leonova V, Kato T, Fedenko A, De Angelis F, Rittmeyer A, Gray JE, Greystoke A, Aggarwal H, Huang Q, Zhao B, Lara-Guerra H, Nadal E. Pembrolizumab With or Without Maintenance Olaparib for Metastatic Squamous NSCLC That Responded to First-Line Pembrolizumab Plus Chemotherapy. J Thorac Oncol. 2025 Feb;20(2):203-218. doi: 10.1016/j.jtho.2024.10.012. Epub 2024 Oct 28.
PubMed 39477187Fennell DA, Porter C, Lester J, Danson S, Blackhall F, Nicolson M, Nixon L, Gardner G, White A, Griffiths G, Casbard A. Olaparib maintenance versus placebo monotherapy in patients with advanced non-small cell lung cancer (PIN): A multicentre, randomised, controlled, phase 2 trial. EClinicalMedicine. 2022 Aug 11;52:101595. doi: 10.1016/j.eclinm.2022.101595. eCollection 2022 Oct.
PubMed 35990583
Study at a glance
From the registry record, last updated by the sponsor on 31 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The HER Project: Homologous Recombination Deficiency in EGFR-Mutated NSCLC, a Retrospective and Prospective Translational Single-center Study
- ClinicalTrials.gov ID
- NCT07303218
- Acronym / sponsor ID
- HER / The HER Project
- Keywords
- EGFR, Non small cell lung cancer, NSCLC, Homologous Recombination Deficiency, HRD, PARP Inhibitors, cell lines, organoids
- Study type
- Observational
- Recruitment status
- Active, not recruiting
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- IRCCS San RaffaeleUniversity, hospital or other
- Study start
- 1 Dec 2025 (actual)
- Primary completion
- 31 Dec 2029 (estimated)
- Study completion
- 31 Dec 2032 (estimated)
- First posted
- 24 Dec 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This observational retrospective-prospective study aims to evaluate the prevalence of homologous recombination deficiency (HRD) in metastatic EGFR mutated NSCLC and to assess its correlation with clinical and molecular features. Based on the hypothesis that HRD identifies a distinct EGFRm subgroup with prognostic value and a potential sensitivity to PARP inhibitor-based strategies, translational analysis will be performed with multiple pre-clinical models, ranging from human cancer cells to murine models.
Detailed description
Introduction
Lung cancer is the most common diagnosed cancer, with almost 2.5 million new cases per year, and the leading cause of cancer-related death (18.7%), according to GLOBOCAN (2022). Non-small cell lung cancer (NSCLC) is the most prevalent subtype, accounting for 85% of lung cancers. Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor that regulates survival, proliferation and differentiation in mammalian cells. EGFR mutations occur in around 30% of patients affected by NSCLC, representing the second most frequent targetable oncogenic driver in NSCLC.
The treatment landscape for metastatic EGFR-mutated (EGFRm) NSCLC has significantly evolved since the introduction of 1st generation tyrosine kinase inhibitors (TKIs) in 2010. While osimertinib (a 3rd generation TKI) is currently the standard first-line treatment worldwide in the advanced setting, emerging combination strategies, such as osimertinib plus chemotherapy (FLAURA2 trial) or lazertinib plus amivantamab (MARIPOSA trial), improved progression-free survival (PFS) and overall survival (OS) compared to TKI alone. However, these drug combinations often cause increased treatment-related toxicities, impacting both patients' quality of life and healthcare costs. For this reason, it becomes crucial to identify predictive biomarkers to guide patient selection for combination therapies. For example, post-hoc analyses of FLAURA2 were conducted on poor-risk populations, such as EGFRm patients with high tumour burden or TP53 co-mutations. Despite better outcomes of chemotherapy plus osimertinib across all patient subgroups, only 1 out of 4 patients had baseline tissue samples available for wider genome sequencing. Therefore, understanding the role of co-alterations in EGFRm tumours remains to be explored, particularly those associated with shorter OS and/or more aggressive clinical presentations.
Targeting HRD pathway with PARP-inhibitors in Non-small cell lung cancer
Homologous recombination deficiency (HRD) is a condition linked to an impaired DNA repair mechanism that contributes to genomic instability in several cancers, including NSCLC. PARP-inhibitors (PARPi), drugs targeting a key protein involved in DNA repair, are already available in clinical practice for the treatment of other HRD-positive subgroups of solid tumours (e.g. breast, ovarian, prostate cancer). In NSCLC, however, their clinical benefit remains unclear. Previous studies evaluating PARPi in NSCLC, including combinations with chemotherapy or immunotherapy, have shown modest or non-significant improvements in PFS and OS. However, a significant limitation of these studies is the lack of HRD status assessment, which may have diluted the expected benefits in HRD-positive patients.
Interestingly, emerging evidence suggests that a higher Genomic Scarring Score (GSS), a surrogate for HRD, may predict PARPi sensitivity better than the traditional assessment of the mutational status of homologous recombination repair (HRR) genes. In this study, the administration of PARPi significantly delayed tumour growth in patient-derived xenograft (PDXs) with high GSS, half of which carried pathogenic/likely pathogenic somatic HRR mutations. Importantly, favourable responses to the PARPi-olaparib were observed regardless of HRR gene mutation status, underscoring the potential of GSS as a robust biomarker to more effectively select patients for PARPi-based therapies.
HRD in EGFR mutated NSCLC
In a Chinese cohort of HRD-positive NSCLC, EGFR-mutated tumours are associated with poor TKI response, which might be explained by gene amplifications like MET, a common resistance mechanism that can be promoted by HRD. Studies also showed the co-occurrence of biallelic TP53 mutations and high HRD score in poor-risk EGFRm NSCLC, suggesting a link between this tumour genotype and TKI-resistance. In preclinical models of NSCLC, osimertinib-resistant EGFRm cell lines exhibited sensitivity to olaparib, leading to increased DNA damage and cell death via a pro-oxidant state. Moreover, combining osimertinib with a PARPi in vivo significantly improved tumour regression compared to osimertinib alone. Altogether, these findings lead to hypothesize that the HRD positive score/GSS may define a patient subgroup that could benefit from PARPi-based combination therapy.
Clinical trials evaluating EGFR-TKIs with PARPi failed to achieve their primary endpoint of PFS, possibly due to a lack of patient selection based on HRD score or other molecular criteria. However, subsequent analyses of the GOAL trial found a stronger synergy between gefitinib (a 1st generation TKI) and olaparib in tumours with higher BRCA1 expression, supporting a predictive role for targeting DNA damage repair pathways. In operable NSCLCs, the percentage of HRD positive tumours is ~20-30%, suggesting that the acquisition of HRD status could be an early event. Importantly, a similar incidence was observed in a Chinese cohort of any-stage EGFRm or ALK-rearranged NSCLC patients in which the cases with high HRD score are ~33% of the total. The sensitivity of EGFRm tumours to platinum-based doublets, which is a known characteristic of HRD-positive tumours, and a larger compendium evidence of chromosomal instability further support exploring the role of HRD in EGFR-mutated lung cancer, paving the way for new targeted therapeutic approaches.
The HER Project
With the HER project, we will investigate the role of HRD and genomic instability (GSS) in EGFRm NSCLC by i) defining the fraction of metastatic EGFRm tumours with HRD positive score, ii) correlating HRD score with patient outcomes, and iii) assessing the synergic efficacy of EGFR-TKIs plus PARPi based on the HRD score in different preclinical settings, ranging from cell lines to a murine model of spontaneous EGFRm lung cancer. We expect that this drug combination will be effective in a specific subset of EGFR tumors. However, even if we won't observe any relevant findings by targeting this pathway, our work will increase our knowledge about DNA damage repair and drug resistance in EGFRm tumours.
Study design
- Observational model
- Cohort
- Time perspective
- Other
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Retrospective Cohort | – | Other: No Intervention: Observational CohortPatients with metastatic EGFR-mutated NSCLC diagnosed and treated between January 2020 and September 2025, with tumour tissue available for HRD analysis. |
| Prospective Cohort | – | Other: No Intervention: Observational CohortPatients with newly diagnosed metastatic EGFR-mutated NSCLC, with baseline tumour tissue available for HRD testing and prospectively collected clinical follow-up. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Adult patients (≥18 years) with metastatic EGFR-mutated NSCLC eligible for treatment with EGFR-TKI according to standard clinical practice, with available tumor tissue suitable for HRD testing
Key inclusion criteria (6 listed)
- Participant is willing and able to give informed consent for participation in the study. However, since a part of the study is retrospective and, considering the large sample sizes required and considering that the disease involved in this study affects elderly subjects with co-morbidities and presents a significant mortality rate based on the stage of the disease, deceased and untraceable patients will also be included.
- Age ≥18 years old
- Have a metastatic histologically confirmed NSCLC
- Presence of EGFR common mutations (i.e. ex19del and L858R)
- Have sufficient biological material to assess genomic profiling with AmoyDx Focus panel or similar
Key exclusion criteria (3 listed)
- Insufficient baseline tumour tissue (unsuitable for HRD scoring)
- Presence of EGFR uncommon mutations (i.e. ex20ins)
- Known presence of co-occurring uncommon EGFRm, ALK, ROS1, or other main oncogenic drivers.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| No Intervention: Observational CohortObservational study only; participants receive standard-of-care treatments not assigned by the study | Other | Prospective Cohort, Retrospective Cohort |
Primary outcome
Prevalence of HRD in metastatic EGFRm NSCLC
Time frame: Baseline (T0), on diagnostic tumour sample
Proportion of EGFRm NSCLC with an HRD positive score evaluated by AmoyDx HRD Panel or similar (GSS ≥ 50).
1 secondary outcome
Correlation between HRD status and clinical outcomes and molecular features
Time frame: Up to 3 years of follow-up for PFS/OS; baseline for clinical and molecular characteristics.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Dec 2025.
- Background: PubMed 35705807Drews RM, Hernando B, Tarabichi M, Haase K, Lesluyes T, Smith PS, Morrill Gavarro L, Couturier DL, Liu L, Schneider M, Brenton JD, Van Loo P, Macintyre G, Markowetz F. A pan-cancer compendium of chromosomal instability. Nature. 2022 Jun;606(7916):976-983. doi: 10.1038/s41586-022-04789-9. Epub 2022 Jun 15.
- Background: PubMed 25061320Fang S, Wang Z, Guo J, Liu J, Li C, Liu L, Shi H, Liu L, Li H, Xie C, Zhang X, Sun W, Li M. Correlation between EGFR mutation status and response to first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer. Onco Targets Ther. 2014 Jul 1;7:1185-93. doi: 10.2147/OTT.S63665. eCollection 2014.
- BackgroundKlinakis, A. et al. 1277P HRD status of patients with early stage non-small cell lung cancer. Annals of Oncology 34, S737-S738 (2023)
- Background: PubMed 34589994Karachaliou N, Arrieta O, Gimenez-Capitan A, Aldeguer E, Drozdowskyj A, Chaib I, Reguart N, Garcia-Campelo R, Chen JH, Molina-Vila MA, Rosell R; Spanish Lung Cancer Group (SLCG). BRCA1 Expression and Outcome in Patients With EGFR-Mutant NSCLC Treated With Gefitinib Alone or in Combination With Olaparib. JTO Clin Res Rep. 2020 Oct 23;2(3):100113. doi: 10.1016/j.jtocrr.2020.100113. eCollection 2021 Mar.
- Background: PubMed 33070053Garcia-Campelo R, Arrieta O, Massuti B, Rodriguez-Abreu D, Granados ALO, Majem M, Vicente D, Lianes P, Bosch-Barrera J, Insa A, Domine M, Reguart N, Guirado M, Sala MA, Vazquez-Estevez S, Caro RB, Drozdowskyj A, Verdu A, Karachaliou N, Molina-Vila MA, Rosell R; Spanish Lung Cancer Group (SLCG). Combination of gefitinib and olaparib versus gefitinib alone in EGFR mutant non-small-cell lung cancer (NSCLC): A multicenter, randomized phase II study (GOAL). Lung Cancer. 2020 Dec;150:62-69. doi: 10.1016/j.lungcan.2020.09.018. Epub 2020 Oct 3.
- Background: PubMed 31216465Marcar L, Bardhan K, Gheorghiu L, Dinkelborg P, Pfaffle H, Liu Q, Wang M, Piotrowska Z, Sequist LV, Borgmann K, Settleman JE, Engelman JA, Hata AN, Willers H. Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity. Cell Rep. 2019 Jun 18;27(12):3422-3432.e4. doi: 10.1016/j.celrep.2019.05.058.
- Background: PubMed 37907595Feng J, Lan Y, Liu F, Yuan Y, Ge J, Wei S, Luo H, Li J, Luo T, Bian X. Combination of genomic instability score and TP53 status for prognosis prediction in lung adenocarcinoma. NPJ Precis Oncol. 2023 Oct 31;7(1):110. doi: 10.1038/s41698-023-00465-x.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Francesca Rita Ogliari, Medical Doctor principal investigator
IRCCS Ospedale San Raffaele
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of EGFR and Non Small Cell Lung Cancer, run by IRCCS San Raffaele at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 31 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Prevalence of HRD in metastatic EGFRm NSCLC (time frame: Baseline (T0), on diagnostic tumour sample). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07303218, which also lists 26 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Dec 2025.