Edited by: Yusuke Okuma, National Cancer Center Hospital, Japan
Reviewed by: Alberto Pavan, Azienda ULSS 3 Serenissima, Italy
Jan Von Der Thüsen, Erasmus Medical Center, Netherlands
*Correspondence: Myriam Mirza,
†These authors have contributed equally to this work
‡Steering committee members (study supervisors)
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Osimertinib is recommended by major guidelines for use in the adjuvant setting in patients with EGFR mutation-positive NSCLC following the significant improvement in disease-free survival observed in the Phase III ADAURA trials. Due to limited real-world data in the adjuvant setting, little guidance exists on how to approach potential recurrences either during or after the completion of the treatment. This study aimed to reach a broad consensus on key treatment decision criteria in the events of recurrence.
To reach a broad consensus, a modified Delphi panel study was conducted consisting of two rounds of surveys, followed by two consensus meetings and a final offline review of key statements. An international panel of experts in the field of NSCLC (n=12) was used to provide clinical insights regarding patient management at various stages of NSCLC disease including patient monitoring, diagnostics, and treatment approach for specific recurrence scenarios. This study tested recurrences occurring 1) within or outside the central nervous system (CNS), 2) during or after the adjuvant-osimertinib regimen in NSCLC disease which is 3) amenable or not amenable to local consolidative therapy.
Panellists agreed on various aspects of patient monitoring and diagnostics including the use of standard techniques (e.g., CT, MRI) and tumour biomarker assessment using tissue and liquid biopsies. Consensus was reached on 6 statements describing treatment considerations for the specific NSCLC recurrence scenarios. Panellists agreed on the value of osimertinib as a monotherapy or as part of the overall treatment strategy within the probed recurrence scenarios and acknowledged that more clinical evidence is required before precise recommendations for specific patient populations can be made.
This study provides a qualitative expert opinion framework for clinicians to consider within their treatment decision-making when faced with recurrence during or after adjuvant-osimertinib treatment.
A significant number of NSCLC patients harbor
Most recently, published data on overall survival (OS) in the overall population (patients with stage IB to IIIA disease) report an OS HR of 0.49 (95% CI 0.34 to 0.70; p < 0.0001) with a 5-year OS rate of 88% with osimertinib vs 78% with placebo. In stage II–IIIA disease, OS HR was reported to be 0.49 (95% CI 0.33 to 0.73; p=0.0001) and the 5-year OS rate was 85% with osimertinib vs 73% with placebo. The median OS was not reached in either population or treatment group (
While adjuvant-osimertinib demonstrated an unprecedented patient benefit in terms of OS improvements, there is a need to understand better the optimal management of patients who show tumor recurrence either during or after the completion of the adjuvant-osimertinib regimen. Given the anticipated emergence of a patient population with disease relapse following adjuvant osimertinib treatment, and the absence of real-world data or trial data, creating formal guidelines on how to approach and manage recurrent patients either during or after completion of adjuvant-osimertinib is not yet possible. The knowledge gap regarding the appropriate approach for patient monitoring, diagnostics, and treatment sequencing decisions in cases of various recurrence scenarios can be bridged via clinical consensus studies. Recent consensus studies echoed the need for further clinical trial data to create formal guidelines (
The study utilized a modified Delphi method which included two rounds of surveys, followed by two consensus meetings and a final offline review by an expert panel. The key topics addressed in this study are listed in
Key topics addressed in this study
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
The table displays the key topics related to disease recurrence events during or after adjuvant osimertinib treatment for EGFRm NSCLC.
iiClinical considerations of treatment sequencing decisions and potential geographic differences in the recommended treatment sequencing were also captured.
iiiLocal consolidative therapy includes surgery, ablation (percutaneous/endoscopic ablations including thermal/cryo ablation), radiotherapy, conformal radiotherapy, or stereotactic body radiation therapy (SBRT).
In this study, an international panel of experts was recruited with significant expertise in NSCLC as well as patient management with
The steering committee consisted of two medical oncologists and one thoracic surgeon from different geographies (Asia, Europe, and the USA) to ensure geographic as well as different clinical expertise were incorporated in the development of materials.
Both surveys were composed of a series of open and close ended question and shared via email. All materials tested in the study were co-developed and reviewed by the steering committee. In Survey 1, panelists were presented with six hypothetical patient case studies representing distinct real-world
Survey 1 and Survey 2 outcomes – Major insights with an overall panellists’ agreement.
| Survey 1 and 2 Outcomes | |||
|---|---|---|---|
| Key topic | Insights | Agreement reached | |
|
|
1 | Patients monitoring during or after ADAURA regimen is conducted using CT scan and brain MRI in line with local guidelines. | Survey 1 |
| 2 | Additional patient monitoring techniques like MRD and blood tests (e.g., Carcinoembryonic antigen assay) can be used as add-on techniques but caution is recommended as currently there is no clinically validated MRD assay | Survey 2 | |
| 3 | Tissue biopsy is performed for histological and molecular analysis to look for actionable targets (e.g., EGFR, PDL-1, others) in all feasible cases | Survey 1 | |
| 4 | Liquid biopsies are performed when tissue biopsy is difficult or as a second diagnostic method. Factors such as patient or doctor preference for non-invasive procedure also influence the decision to perform liquid biopsies but they have secondary priority | Survey 2 | |
| 5 | NGS or other molecular analysis procedures are always performed if progression is observed | Survey 2 | |
| 6 | In case of recurrence, osimertinib is used during the entire diagnostic workup and up until a new treatment regimen is decided |
Survey 2 | |
|
|
7 | Treatment for oligometastatic distant recurrence includes local consolidative therapies – surgery, percutaneous/endoscopic ablations including thermal/cryo ablation, radiotherapy, conformal radiotherapy, or stereotactic body radiation therapy (SBRT) | Survey 1 |
| 8 | Treatment strategies for CNS recurrence include combination of local consolidative therapies (surgery or radiotherapy) with systemic therapies |
Survey 1 | |
| 9 | In case of recurrence during the adjuvant osimertinib regimen that is amenable to local consolidative therapy, local consolidative therapy is performed in parallel to continuation of adjuvant osimertinib use, if possible | Survey 2 | |
| 10 | In case of recurrence after the adjuvant osimertinib regimen is completed, local consolidative therapy is performed in parallel to rechallenge with osimertinib, if possible | Survey 2 | |
|
|
11 | Treatment approach for disseminated distant recurrence involves systemic therapies based on the newly obtained histology. |
Survey 1 |
| 12 | In case of ex-CNS or CNS recurrence during the adjuvant osimertinib regimen and local consolidative therapy is not an option, systemic therapy based on the re-biopsy result is recommended with potential to include osimertinib depending on patient case | Survey 2 | |
| 13 | In case of recurrence ex-CNS and/or CNS after completion of adjuvant osimertinib regimen, therapeutic approach will be based on re-biopsy results and in conjunction with the MDT with potential to include osimertinib depending on patient case | Survey 2 | |
Combination treatment approach with osimertinib and immunotherapy was flagged as unsuitable by KEEs and additional caution was recommended in case of sequential use.
Two virtual consensus meetings were held where a final set of statements were discussed and amended live during the meeting. The level of consensus on the amended statements was probed through anonymous polls. The statement modification process was iterated until an overall clinical consensus (≥80% panelist agreement) was achieved for all six statements (see
Final consensus statements with an overall panelist agreement.
| Recurrence scenarios | Final Consensus Statement | Panelist Agreement | |
|---|---|---|---|
|
|
1 | If a patient experiences an ex-CNS or CNS recurrence amenable to local consolidative therapy during the adjuvant-osimertinib regimen, in absence of existing evidence, I would use the adjuvant-osimertinib regimen in parallel with local consolidative therapy, considering the risk of toxicities, site of recurrence, method of local consolidative therapy and after discussion with the MDT |
|
| 2 | If a patient experiences an ex-CNS or CNS recurrence amenable to local consolidative therapy after completion of the adjuvant-osimertinib regimen, I would consider rechallenging with osimertinib as an option after local consolidative therapy, after discussion with MDT |
|
|
|
|
3 | If a patient experiences CNS-only recurrence not amenable to local consolidative therapy during the adjuvant-osimertinib regimen, I would consider continuing with osimertinib as a part of the overall treatment strategy when a patient has asymptomatic progression, if fits with the best clinical practice |
|
| 4 | In the absence of randomized evidence, if a patient experiences ex-CNS recurrence not amenable to local consolidative therapy during the adjuvant-osimertinib regimen, I would consider continuation with osimertinib as a part of the overall treatment strategy if a patient has asymptomatic progression and if fits with the current guideline recommendations |
|
|
|
|
5 | If a patient experiences an ex-CNS and/or CNS recurrence after completion of the adjuvant-osimertinib regimen, and local consolidative therapy is not an option, I would rechallenge with monotherapy osimertinib or osimertinib as a part of the overall treatment strategy irrespective of when the recurrence happens after treatment completion, if fits with the best clinical practice and is supported by re-biopsy in all feasible cases |
|
|
|
6 | If a patient experiences an ex-CNS and/or CNS recurrence during or after the completion of the adjuvant-osimertinib regimen and I choose to continue with osimertinib as part of the overall treatment strategy, I would continue the osimertinib therapy until the clinical situation mandates a change or stop in therapy |
|
Closed statements were ranked on the Likert scale of 1 to 9, where 1 equals “strongly disagree with the statement,” and 9 equals “strongly agree with the statement,”. Likert scale rating of 7 or higher for a given statement from a minimum of 80% of panelists was defined as a threshold for a consensus on the statement. In contrast, a rating of 3 or lower for a given statement from a minimum of 80% of panelists indicated consensus had been reached of disagreement with the statement.
To limit bias, all surveys were conducted anonymously, and identity of experts was revealed only during the consensus meetings. Furthermore, results from rating exercises were provided as median scores and anonymous votes were held to finalize the consensus statements. In addition, offline review of the final statements was conducted individually without revealing the level of agreement from other panelists.
An independent third-party vendor, Charles River Associates (CRA) designed the survey, moderated the consensus meetings, analyzed the data and supported the manuscript development. The sponsor of the study (AstraZeneca Ltd.) did not participate in consensus meetings.
Surveys 1 and 2 were used to gather a greater understanding of the factors influencing treatment sequencing within the adjuvant-osimertinib setting, including recurrence type and timing. A summary of the key insights gathered from Surveys 1 and 2 is shown in
In Survey 1, six distinct hypothetical NSCLC patient case studies were used to understand how panelists approach management of different patient types and understand the potential differences under varying recurrence scenarios. Patients within the case studies had varying
Overall, panelists agreed that all the hypothetical patient cases are representative of real-world profiles and the use of adjuvant-osimertinib in these hypothetical patient cases is approved under the ADAURA label. Panelists also agreed on the monitoring and diagnostic approaches laid out, albeit frequency of monitoring and how molecular analysis is conducted remained unclear. Moreover, although some panelists mentioned the use of monitoring techniques such as minimal residual disease (MRD) tests and blood tests (e.g., CEA - carcinoembryonic antigen), it was unclear if these techniques would be used for all patients or in specific circumstances. Finally, there was a lack of agreement on the value of liquid biopsy within the diagnostic process. Overall, despite no diagnostic procedural differences between oligometastatic and disseminated recurrences being reported there remained a lack of clarity as to whether adjuvant-osimertinib regimen should be continued during diagnostic workup and up until a new treatment strategy is confirmed.
Panelists agreed on treatment approaches for local and distant oligometastatic CNS/ex-CNS recurrence as well as disseminated CNS/ex-CNS recurrence. However, treatment sequencing decision for both ex-CNS and CNS recurrences and the associated driving factors were unclear. No consensus was observed on how patients treated with the preferred initial treatment (e.g., ablative therapy) are therapeutically followed up and to what extent osimertinib would be considered a therapeutic option.
Gaps identified in Survey 1 were explored in Survey 2, where agreement was reached on all outstanding aspects of diagnosis and monitoring. Panelists were presented with different scenarios to better understand the treatment sequencing drivers and how adjuvant-osimertinib would be considered in the overall treatment strategy. These scenarios focused on understanding the impact of recurrence location (CNS versus ex-CNS), amenability to local consolidative therapy, timing (during or after adjuvant-osimertinib regimen) as well as time points (3, 6, 18 months after initiation of adjuvant-osimertinib versus 3, 12 and 36 months after completion with adjuvant-osimertinib regimen).
While panelists agreed that continuing with adjuvant-osimertinib is clinically suitable during the diagnostic process and can be considered within treatment decision-making in the described CNS/ex-CNS recurrence scenarios, how its use would be decided remained unclear. Furthermore, there was no consensus on how long treatment with osimertinib would continue within recurrence scenarios and what considerations would influence this decision. Finally, some panelists suggested temporarily pausing the adjuvant-osimertinib regimen upon recurrence and resuming after ablative therapy, but the recommended pause duration and its applicability to all ablative therapy procedures are not clear. For recurrences after completing the adjuvant-osimertinib regimen, a combination of ablative therapy and osimertinib rechallenge was proposed, but it remains unclear whether the rechallenge would be performed alongside ablative therapy or after its completion.
Gaps in key treatment decision factors and the value of osimertinib across tested recurrence scenarios were addressed during 2 virtual consensus meetings, where experts amended wording of original proposed statements in line with best clinical practice and experience given limited randomized evidence. A summary of the statements that reached a consensus is shown in
A lack of clinical guidance on how to treat recurrences during or after the completion of the adjuvant-osimertinib regimen has been raised in recent publications (
Our study approach enables experts to share their own opinions based on clinical experience, and, where relevant, knowledge of the ADAURA phase 3 data, with the aim of fostering the integration of these viewpoints. Overall, our research shows a high consensus regarding patient considerations and approaches to various recurrence scenarios. Statements and considerations that garnered consensus can serve as valuable guidance in clinical practice when combined with a tailored patient approach and recommendations from multidisciplinary teams.
Our results show that the decision to use adjuvant-osimertinib is not driven by patient’s gender, ethnicity, age, smoking or alcohol use status, or previous treatment experience with adjuvant-chemotherapy. However, the decision to use adjuvant-osimertinib might change if a patient has poor PS score (PS >1), has high comorbidities or is likely to be less compliant with the dosing regimen.
Furthermore, patients receiving adjuvant-osimertinib should be monitored using local guidelines which broadly align with international guidelines such as ESMO (
In our study, tissue biopsy is recommended in all feasible cases in case of progression to assess the suitability of different treatment options based on tumor biomarker/mutation profile. The diagnostic result from liquid biopsy was highlighted to be less sensitive and contingent on site and burden of the recurrence (
Across all tested scenarios, treatment decisions are taken on a patient-by-patient basis and taking input from the multi-disciplinary team (MDT), aligning with major guidelines (
Pattern and location – Number of lesions, size and location determine if the recurrence is oligometastatic and amenable to local consolidative therapy or disseminated and requires treatment with a systemic therapy. Furthermore, limited metastases which may include lesions in contralateral lung, lymph node, CNS or other organs could be managed with a combination of local consolidative therapy and a systemic therapy. Panelists did not rule out the treatment value of osimertinib in various recurrence scenarios solely based on pattern and location.
Timing of recurrence – whether and when recurrence occurs during or after the adjuvant-osimertinib regimen can indicate if the recurrent lesion is sensitive or resistant to osimertinib in addition to genetic profiling. Recurrence during the adjuvant-osimertinib regimen (especially ex-CNS) might be a sign of acquired resistance to osimertinib, while recurrence after the completion of the regimen might indicate a disease flare post-treatment cessation.
Molecular characterization of the recurrence – Confirming molecular histology or biomarker profile informs the presence of any actionable target and is necessary when considering further treatment with osimertinib.
It is important to note here that while panelists acknowledge osimertinib to be a valuable treatment option for patients with complex clinical presentations, including the emergence of distinct resistance mechanisms (e.g., MET amplification, PIK3CA mutation, BRAF mutation) and/or progression to acquire other genetic alterations (e.g., ALK mutation), these specific recurrence scenarios were not explored in this study.
For ex-CNS or CNS recurrences which occur during the adjuvant-osimertinib regimen and are amenable to local consolidative therapy (surgery, ablation, or radiotherapy), the panel recommended to continue adjuvant-osimertinib treatment along with local consolidative therapy if found clinically suitable (
However, in the absence of safety data in combining local consolidative therapy with osimertinib treatment, recommendations on pausing or continuing with osimertinib during ablative or surgical procedures could not be reached and instead in the absence of treatment guidelines, the decision to pause osimertinib should be based on treatment experience from the metastatic setting, i.e., considering the extent of recurrence including location, size and number of the lesions (note that the treatment guidelines for metastatic settings are also not yet established). Additionally, caution was recommended when patients are given other drugs (e.g., prophylactic antibiotics before local consolidative therapy) that could show drug-drug interactions with osimertinib.
While the place of osimertinib within the treatment strategy is dependent on multiple factors (see Section 4.2), the treatment value of rechallenging with osimertinib was thought to increase as duration between time to recurrence and completion of the adjuvant-osimertinib regimen increases. However, no consensus was achieved on the minimum recurrence free time (3, 12 or 36 months) to consider osimertinib for rechallenge.
In cases of post-adjuvant osimertinib regimen recurrence scenarios that are amenable to local consolidative therapy and rechallenging with osimertinib is suitable, the consensus is to rechallenge with osimertinib after the completion of the local consolidative therapy (
In case of post-adjuvant osimertinib regimen recurrence scenarios that are not amenable to local consolidative therapy, rechallenge with osimertinib may be of high clinical value and should therefore be considered either as osimertinib monotherapy or as a part of treatment strategy involving other therapies (
Our study found that ex-CNS recurrence in the first 6 months is an indication of treatment failure of adjuvant-osimertinib, requiring change of treatment to either chemotherapy, other targeted therapies, or a combination of both. However, for later recurrences, continuation of osimertinib as a part of a broad treatment strategy could be potentially valuable (
For CNS-only recurrences, the consensus is that continuation of osimertinib as a part of a broad treatment strategy could be an effective treatment option (
In cases where osimertinib was considered as a treatment option within the recurrence scenarios, the consensus was that treatment would continue until disease progression or toxicities were observed, or patient quality of life deteriorated. For a low progression risk patient (e.g., indolent oligometastatic progression), the duration of osimertinib treatment should be limited and a decision to stop treatment should be taken after monitoring the efficacy and patient’s health profile and considering the safety and tolerance profile of osimertinib and patient wishes (
Outcomes from the phase 3 ADAURA trial show significant improvements in DFS and OS for EGFR-mutated NSCLC patients with stage IB to IIIA disease. Nonetheless, patterns of recurrence were reported within the osimertinib group, although lower compared with placebo (
The original contributions presented in the study are included in the article/
MM: Conceptualization, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing. AS: Conceptualization, Formal Analysis, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing. CM: Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing – review & editing. NL: Writing – review & editing. CN: Writing – review & editing. DP: Writing – review & editing. SP: Writing – review & editing. JR: Writing – review & editing. ES: Writing – review & editing. RS: Writing – review & editing. MT: Writing – review & editing. FY: Writing – review & editing. BS: Supervision, Writing – review & editing. CG: Supervision, Writing – review & editing. Y-LW: Supervision, Writing – review & editing.
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by AstraZeneca, Cambridge, UK. An independent third party, Charles River Associates (CRA), designed the study, moderated the consensus meeting, and supported manuscript development.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.
NL reports research funding from Amgen, AstraZeneca Canada, Bayer, EMD Serono, Guardant Health, Lilly, MSD, MSD Oncology, Roche Canada, and Takeda; travel and accommodation support from Merck Sharp & Dohme. CN reports advisor to Medtronic, Johnson & Johnson; speaker fees from AstraZeneca, Merck Sharp & Dohme, Roche, Medtronic, Johnson & Johnson. DP reports being an advisor to AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, Roche, Janssen, and Abbvie; honoraria from AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck, Novartis, Pfizer, Roche, Janssen, and Abbvie; travel and accommodation grants from AstraZeneca, Roche, Novartis, and Pfizer; and conducting clinical trials research as principal or co-investigator institutional financial interests for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Abbvie, and Janssen. SP reports consultancy to Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, EQRx, GlaxoSmithKline, Guardant Health, Janssen, Lilly, Merck KGaA, MSD, Novartis, Pfizer, Roche, Sanofi, Seattle Genetics, Takeda, and Turning Point Therapeutics. JR reports being an advisor to AbbVie, Amgen, AstraZeneca, BioAtla, BMS, Daichi-Sankyo, G1 Therapeutics, Genentech, Gritstone Bio, Guardant, Janssen, Lilly, Jazz, Summit Therapeutics Takeda; speaker fees from AstraZeneca; institutional research funding from BioAtla, AbbVie, AstraZeneca, Blueprint, RedCloud, Loxo Oncology, Daiichi Sankyo, Enliven, ORIC, and Summit. ES reports being an advisor to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Lilly, Merck KGaA, MSD Oncology, Novartis, Roche/Genentech, Seagen, and Takeda; honoraria from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo/Astra Zeneca, and Merck KGaA; research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Roche/Genentech. RS reports being an advisor to Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Janssen, Lily, Merck, Merck Serono, Novartis, Pfizer, Puma, Roche, Taiho, Takeda, Thermo Fisher, Yuhan and has received research grants from AstraZeneca and Boehringer Ingelheim. MT reports being an advisor to AstraZeneca Japan, Chugai Pharma, Lilly Japan, MSD, Novartis and MiREXS; honoraria from AstraZeneca Japan, Bristol-Myers Squibb Japan, Chugai Pharma, Johnson & Johnson, Lilly Japan, Medtronic, MSD K.K, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, and Teijin Pharma; research funding from AstraZeneca Japan, Boehringer Ingelheim KK, Bristol-Myers Squibb KK, Merck, Ono Pharmaceutical, BMG Incorporated, and MiREXS. FY reports speaker fees from MSD, Pfizer, Roche, AstraZeneca, and Bristol-Myers Squibb. BS reports wife’s employment with PPD and Xalud Therapeutics; leadership at Verrica Pharmaceuticals; stock and other ownership interests in Pfizer, PPD, and Xalud Therapeutics; personal honoraria from AstraZeneca, Bristol Myers Squibb, Genentech, and Pfizer; consulting or advisor role at AstraZeneca, Gala Therapeutics, Medtronic, Arcus Biosciences, and Pfizer; research funding from Bristol Myers Squibb Foundation; patents, royalties, and other intellectual property related with a therapeutic antibody targeting ART1, an extracellular mono-ADP ribosyltransferase, for the treatment of cancer patent application filed; other relationship with Lung Cancer Research Foundation and Lungevity. CG reports being an advisor to AstraZeneca, Boehringer Ingelheim, and MSD Oncology; honoraria from AstraZeneca, Boehringer Ingelheim, Lilly, MSD Oncology, Novartis, Roche, and Takeda; research funding from AstraZeneca; travel and accommodation support from Boehringer Ingelheim, Bristol-Myers Squibb, and Roche. Y-LW reports being an advisor to AstraZeneca, Boehringer Ingelheim, Roche, and Takeda; honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/China, Hengrui Pharmaceutical, Lilly, MSD Oncology, Pfizer, and Roche; research funding from Boehringer Ingelheim, Pfizer, and Roche.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
The Supplementary Material for this article can be found online at:
CNS, central nervous system; CT, computerized tomography; DFS, disease-free survival; EGFRm, Epidermal growth factor receptor mutation; HR, hazard ratio; HRQoL, Health-related quality of life; MDT, multi-disciplinary team; MRD, minimal residual disease; MRI, magnetic resonance imaging; NGS, next-generation sequencing); OS, overall survival; PET, positron emission tomography; SBRT, stereotactic body radiation therapy; SRS, stereotactic radiosurgery; TKI, tyrosine kinase inhibitor; NSCLC,non-small-cell lung cancer; WBRT, whole-brain radiotherapy.