Introduction Limited clinical studies have been conducted on rare solid tumours, and there are few guidelines on the diagnosis and treatment, including experiences with targeted therapy and immunotherapy, of rare solid tumours in China, resulting in limited treatment options and poor outcomes. This study first proposes a definition of rare tumours and is designed to test the preliminary efficacy of targeted and immunotherapy drugs for the treatment of rare tumours.
Methods and analysis This is a phase II, open-label, non-randomised, multiarm, single-centre clinical trial in patients with advanced rare solid tumours who failed standard treatment; the study aims to evaluate the safety and efficacy of targeted drugs in patients with advanced rare solid tumours with corresponding actionable alterations, as well as the safety and efficacy of immune checkpoint (programmed death receptor inhibitor 1, PD-1) inhibitors in patients with advanced rare solid tumours without actionable alterations. Patients with advanced rare tumours who fail standardised treatment and carry actionable alterations (Epidermal growth factor receptor (EGFR) mutations, ALK gene fusions, ROS-1 gene fusions, C-MET gene amplifications/mutations, BRAF mutations, CDKN2A mutations, BRCA1/2 mutations, HER-2 mutations/overexpressions/amplifications or C-KIT mutations) will be enrolled in the targeted therapy arm and be given the corresponding targeted drugs. Patients without actionable alterations will be enrolled in the PD-1 inhibitor arm and be treated with sintilimab. After the patients treated with vemurafenib, niraparib and palbociclib acquire resistance, they will receive combination treatment with sintilimab or atezolizumab. With the use of Simon’s two-stage Minimax design, and the sample size was estimated to be 770. The primary endpoint of this study is the objective response rate. The secondary endpoints are progression-free survival in the targeted treatment group and single-agent immunotherapy group; the duration of response in the targeted therapy and single-agent immunotherapy groups; durable clinical benefit in the single-agent immunotherapy group; and the incidence of adverse events.
Ethics and dissemination Ethics approval was obtained from the Chinese Academy of Medical Sciences (ID: 20/132-2328). The results from this study will be actively disseminated through manuscript publications and conference presentations.
Trial registration numbers NCT04423185; ChiCTR2000039310.
- cancer genetics
- clinical trials
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Strengths and limitations of this study
This is the first well-designed PLATFORM study to comprehensively evaluate the efficacy of multiple targeted therapy and immunotherapy drugs in the treatment of rare tumours.
This study innovatively brings the definition of primary and acquired resistance into targeted therapy and immunotherapy in rare tumours.
A novel strategy of targeted therapies combined with immunotherapy after the development of acquired resistance to original targeted drugs is introduced.
Through the current study, a ‘PLATFORM’ will be built for novel agents or products to be investigated and submitted for ‘fast-track’ approval for the treatment of rare tumours.
The limitation of this trial might be the comparatively small sample size of the single-agent targeted treatment subgroup, and there is heterogeneity among different subtypes of rare tumours regarding prognosis and responses to the investigated drugs.
Genotyping-guided precision targeted therapy and immune checkpoint inhibitors have brought significant treatment efficacy and improved survival for patients with metastatic solid tumours such as non-small-cell lung cancer (NSCLC) and melanoma. However, limited studies have been conducted on rare solid tumours, and there is a shortage of diagnostic and treatment guidelines, clinical trials and experiences with targeted therapy and immunotherapy for rare solid tumours in China, resulting in limited treatment options as well as relatively poorer outcomes compared with most common cancers.1
Since 2017, three drugs have been approved by the Food and Drug Administration (FDA) based on small-sample molecular-guided pan-tumour phase II clinical trials for the treatment of advanced pansolid tumours with specific molecular alterations: pembrolizumab (programmed death receptor inhibitor 1 (PD-1) blockade on solid tumours PD-L1 expression positive), larotrectinib (solid tumours with Neurotrophic tyrosine receptor kinase (NTRK) fusions) and entrectinib (solid tumours with NTRK fusions).2 3 All of these drugs have substantially improved the treatment efficacy, including the objective response rate (ORR) and progression-free survival (PFS), in patients with corresponding actionable alterations. This led the current study to pursue efficacious treatment of rare tumours or common tumours with rare genetic alterations and obtain rapid approval by the government.
A type of study design known as pragmatic clinical trials (PCTs) overcomes the limitations of tumour types and solves the problem of difficulty in recruiting subjects for randomised clinical trials (RCTs). The PCT modality is well suited for clinical investigation of rare tumours. It combines the advantages of basket studies and umbrella studies for clinical trial investigations on rare tumours, which could help to improve the efficiency and solve the problems of clinical research on rare tumours. Therefore, it is important to conduct a real-world study based on molecular genotyping for rare tumours.
Evidence for this study
This study first proposes a definition of rare solid tumours
Based on the definition of rare tumours by the European Society for Medical Oncology (ESMO) and National Cancer Institute/WHO in the USA, combined with data from the National Cancer Registry Office of the National Cancer Center of China comprising the annual incidence of tumours and the characteristics of the patient population in China, this study first proposes a definition of rare tumours. We consulted the National Cancer Registry of the National Cancer Center and generated an estimation of the incidence of tumours in mainland China. Tumour types were classified according to the International Classification of Diseases (ICD), and we comprehensively synthesised the epidemiology data and availability of standard treatment as well as opinions of experts from the National Cancer Centre. We then defined rare tumours according to the following standards:
According to the statistics from the National Cancer Registry, a tumour with an annual incidence (classified by system, table 1) that is lower than 2.5 per 100 000 people, including advanced or metastatic malignant tumours with the following ICD codes: C3, C7, C8, C17, C23, C24, C26, C30, C31, C33, C37, C38, C39, C40, C41, C44, C45, C48, C49, C51, C52, C55, C57, C58, C60, C62, C63, C68, C69, C65, C70, C71, C72, C74, C75.
If the incidence of a tumour (classified by systems) was higher than 2.5 per 100 000 people (ICD code: C15, C16, C18, C20, C22, C25, C34, C47, C50, C54, C56, C61, C64, C67), pathological subtypes of the tumour with an incidence of less than 2.5 per 100 000 people were included in this study, according to the WHO pathological classification of rare tumours from the ESMO and the latest pathological classification of MSK OncoTree (http://oncotree.mskcc.org/) in 2020.
Primary unknown malignant tumours (ICD code: C76, C77, C80).
The above definitions and the list of rare tumours were formulated according to the current epidemiological situation and the diagnosis and treatment of malignant tumours in China and the world. They will be further clarified and improved during the course of clinical study.
The shortage of diagnostic and treatment guidelines for rare solid tumours
According to the above definition and the tumour incidence rate of the Cancer Registration Office of the National Cancer Centre and combined with ESMO and OncoTree’s latest pathological classification in 2020, the final list of rare tumours in China is shown in table 1, including the first pathological subtype (by location), the second pathological subtype and the third pathological subtype. There were 133 s pathological subtypes and 316 specific third pathological subtypes. Through the search of international and domestic guidelines, there are only 65 tumour types with a first-line recommended treatment in the National Comprehensive Cancer Network (NCCN) guidelines. Twenty-five pathological subtypes had second-line recommended treatments, and nine had third-line recommended treatments. It is notable that there are only six rare tumours with a first-line recommendation in the Chinese Society of Clinical Oncology (CSCO) guidelines (pulmonary sarcomatoid carcinoma; pleural lung blastoma, recommended according to the treatment of NSCLC; breast salivary gland malignant tumours, recommended according to the treatment of breast cancer; soft tissue Ewing’s sarcoma and soft-tissue sarcoma), seven rare tumours with second-line recommended regimens, and only two rare tumours with third-line recommended treatment (pulmonary sarcomatoid carcinoma and pleural blastoma, also according to the treatment recommendation of NSCLC). In addition, there are six rare tumours that have recommendations for targeted therapy and five rare tumours that have recommendations for immunotherapy in the CSCO guidelines. Immunotherapy is approved for only two types of rare tumours, lung sarcomatoid carcinoma and pleural blastoma, in light of treatment recommendations for NSCLC.
High incidence of actionable gene alterations in rare tumours
Based on the analysis of results from next-generation sequencing (NGS) of genomic variations in 4901 patients with rare tumours in the international cBioPortal database, the mutation rate of therapeutic targets (ALK fusion, BRAF mutation, BRCA1/2 mutation, CDKN2A deletion, EGFR mutation, FGFR1/2/3 fusion/amplification, MET amplification, KIT mutation, NTRK fusion, RET fusion and ROS-1 fusion, etc) in 63 pathological subtypes is 20.40% (1000/4901). Additionally, the results from NGS testing of rare tumour samples (including 67 subtypes) in the Chinese patient population showed that the rate of actionable gene alterations (as defined above) was 53.43% (701/1312). Thus, the incidence of mutations in targeted genes included in this study (EGFR, ALK, BRAF, BRCA1/2, C-MET, ROS-1, C-KIT, CDKN2A) in the Chinese population is three times higher than the incidence rate in the world population according to cBioPortal. The incidence of actionable gene alterations covered by the current protocol was 32.4% among the 63 pathological subtypes, which suggests that studying these mutations in rare tumours in the Chinese patient population might help greatly improve patient outcomes.4
Limited exploration of targeted therapy of rare solid tumours with promising efficacy
Of the 133 s pathological subtypes of rare solid tumours, clinical investigations of targeted therapy cover only 11.9% (16/135) of rare solid tumours (except for all solid tumours similar to MSI-H/dMMR approved for treatment with pembrolizumab). However, notably, the ORR and disease control rate (DCR) of targeted therapy are superior to those of standard treatment in rare tumours with actionable alterations.
For example, among dermatofibrosarcoma patients with KIT mutations, the ORR of nilotinib (a TKI) was 26.2% (n=11/42; 95% CI 13.9% to 42.0%), and the median response duration time for patients with partial responses was 7.1 months.5 The DCR of erlotinib (an EGFR tyrosine kinase inhibitor (TKI)) treatment in vulvar malignant tumours was 67.5%; however, molecular screening for EGFR mutations was not performed before treatment.6 The FDA granted fast-track approval to infigratinib, a novel small-molecule inhibitor of FGFR 1–3, in January 2020 for the first-line treatment of cholangiocarcinoma with FGFR fusion or translocation. The ORR of infigratinib for the treatment of cholangiocarcinoma with FGFR2 fusion/translocation is 39.3%, the DCR is 83.6%, the median PFS is 6.8 months and the median overall survival (OS) is 12.5 months.7 Additionally, pemigatinib, an oral small-molecule inhibitor of FGFR 1, 2, and 3, achieved a 40% ORR, 9.2-month PFS and 15.8-month OS8 in a study of patients with gallbladder cancer. Limited data on targeted therapies in other rare tumours are available. Taken together, these results suggest that molecularly targeted therapy is a promising treatment strategy for rare tumours, and further investigation is warranted.
No indications for PD-1 inhibitors have been approved regarding rare tumours in China
Of the 135 rare solid tumours of the second pathological subtype, the study of immunotherapy covers only less than 12.6% (17/135) (pembrolizumab has been approved for all solid tumours with MSI-H/dMMR regardless of tumour type). Although some initial response has been observed, Libtayo (PD-1, cemiplimab-rwlc) has been indicated only for the treatment of skin squamous cell carcinoma.9
Several smaller studies investigating the use of immunotherapy in rare cancers have shown promising results. Among malignant tumours of the skin, only Merkel cell carcinoma has been recommended as an indication for first-line immune checkpoint inhibitor treatment according to the NCCN guidelines. The ORR of PD-1 monotherapy for the treatment of Merkel cell carcinoma is 56%–68%, and the ORR is 67%10 when combined with the use of platinum-containing chemotherapy. However, only avelumab has been approved for Merkel cell by the FDA to date. Studies investigating the use of cemiplimab (a PD-1 inhibitor) in third-line or later-line therapy for the treatment of skin squamous cell carcinoma suggest that the ORR is 47.2%.11 Cemiplimab has now been indicated for use in this setting by the FDA. The ORR of pembrolizumab monotherapy for the treatment of cholangiocarcinoma is 17.4%,12 the ORR of lovastinib combined with a PD-1 inhibitor is 21.4%, and the DCR is 93%.13 The ORR of SHR-1210 combined with GEMOX is 54%, and the DCR is 100%,14 both of which were determined in small-sample studies. The ORR of pembrolizumab monotherapy in patients with MSI-H/dMMR gallbladder cancer is 40%, and the 3-month PFS rate is 78%2 In patients with duodenal adenocarcinoma, the ORR of pembrolizumab as a single-agent second-line treatment is 40%.2 In thymic malignancies, pembrolizumab had a complete remission (CR) rate of 3% in second-line and third-line treatment, a partial remission (PR) rate of 20%, a median PFS of 4.2 months (95% CI 2.9 to 10.3) and a median OS of 24.9 months (15.5–NR).11 Pembrolizumab has been recommended as second-line therapy for the treatment of malignant mesothelioma, with an ORR of 20% (95% CI 6.8 to 40.7), a 12-month PFS rate of 20.8% (7.6–38.5) and a 12-month OS rate of 62.6% (40.4–78.5).14 And lately it was reported that nivolumab plus ipilimumab improved the median OS with 18.1 months (95% CI 16.8 to 21.4), compared with 14.1 months (95% CI 12.4 to 16.2) in the chemotherapy arm (HR 0.74; 96.6% CI 0.60 to 0.91; p=0.0020) in unresectable malignant pleural mesothelioma, with non-epithelioid patients deriving most benefit (OS median, 18.1 vs chemotherapy 8.8 months; HR 0.46; 95% CI 0.31 to 0.68).15 Taken together, these studies suggest that immunotherapy is a promising treatment strategy for rare tumours. However, few of the above treatment strategies/regimens/modalities have been approved by the FDA or the National Medicine Products Administration. The exploration of immunotherapy in other rare tumours is extremely limited, and some of these studies are presented as case reports.
Definition of primary and secondary drug resistance in targeted therapy
TKIs targeting EGFR driver gene mutations, such as gefitinib, erlotinib, osimertinib and dacomitinib, currently play a leading role in precision medicine. Experiences from this field have provided direction for other targeted treatments, such as the concept of primary resistance and secondary resistance and the concept of slow progression and rapid progression. Resistance to EGFR-TKIs is currently subdivided into two categories: primary resistance and secondary resistance. Primary resistance to EGFR-TKIs is currently outlined as follows: patients have disease progression at the first response evaluation after receiving a single EGFR-TKI treatment, or patients achieve PR/CR/SD, but it does not last over 6 months. Secondary resistance is defined as follows: (1) patient achieves a PR/CR (response evaluation criteria in solid tumours, RECIST V.1.1) after single-agent EGFR-TKI treatment, (2) achieves a significant and long-lasting clinical benefit (stable disease ≥6 months), (c3) within 30 days after disease progression and (4) with no other treatment used after disease progression.12
In this study, the above criteria were used to define primary drug resistance and secondary drug resistance in the targeted therapy group. If a patient develops primary drug resistance, it suggests that the mutated gene is not a driver for that particular tumour, and they will be permitted to cross over to the immunotherapy group.
The current investigator-initiated study evaluated the efficacy and safety of targeted therapies and PD-1 inhibitors in the treatment of metastatic malignant solid rare tumours. At the same time, we also evaluated the driver gene status and resistance patterns of rare tumours with corresponding postprogression strategies.
Methods and analysis
This study is a phase II, open-label, non-randomised, multiarm, single-centre clinical study in patients with advanced rare solid tumours who have or have not previously received standard treatment. Detailed measures of this study are demonstrated in figure 1.
To evaluate the safety and efficacy of drugs that have been approved by the Chinese Center for Drug Evaluation (CDE) for the treatment of rare tumours with specific indications:
These drugs have been approved by the CDE for targeting specific tumour-driving gene alterations in patients with advanced rare solid tumours with the corresponding actionable alterations.
To evaluate the safety and efficacy of immune checkpoint inhibitors (PD-1 antibodies) in patients with advanced rare solid tumours without actionable alterations.
To evaluate the ORR of targeted therapeutic drugs in the treatment of advanced rare solid tumours with actionable alterations, DCRs, the duration of response (DoR), OS and PFS will be determined.
To evaluate the ORR of immune checkpoint inhibitors in the treatment of advanced rare solid tumours without actionable alterations, the DCR, DoR, OS and PFS will be determined.
To evaluate the PFS of the combined therapy with PD-1 inhibitor after the secondary resistance to single targeted agent, to see whether the combination with immunotherapy is able to reverse the resistance.
To evaluate the improvement of disease-related symptoms and quality of life (QoL).
To evaluate the adverse events (AEs) due to the study treatment regimens.
To explore biomarkers related to targeted therapy and immunotherapy based on the detection of the genome, transcriptome and proteome of tumour tissue specimens and peripheral blood samples.
To evaluate the combination of spatiotemporal-specific therapeutic biomarkers of immunotherapy based on the identification and analysis of important components of the dynamic, stereoscopic and multispatial immune microenvironment.
To develop diagnostic kits or detection technologies.
Study timetable and site
The programme commenced in September 2020, and accrual is planned to be completed in September 2022. The recruitment site is the Cancer Hospital of the Chinese Academy of Medical Sciences.
Patients with advanced or metastatic rare solid tumours who fail standard treatment or have no standard treatment are the target population. Additional eligibility criteria are listed in table 2. Specific criteria for each subprotocol are outlined in online supplemental table S1). Eligibility assessments and informed consent will be obtained before recruitment.
The sample size of each treatment group used in this study possesses great likelihood to determine whether the study drug has antitumour activity in statistics and the clinic. Designed for a single-centre multiarm study, the main purpose of this study is to evaluate the ORR of each group of patients with advanced rare tumours. The Simon two-stage minimax design will be applied, and the primary endpoint is the ORR evaluated by a BICR. On the basis of the research results of historical research data, only when the lower limit of the 95% CI of the ORR obtained by each group using the accurate method is greater than 5% can it be judged as valid. Assuming that the ORR of targeted therapy/immunotherapy for advanced rare tumours is 25%, the control type I error is 0.05, the power is 80%, the overall mutation rate is 30%, and the expulsion rate is 10%.
Adopting Simon’s two-stage minimax design, in the first stage of clinical research, 12 subjects will be observed. If the number of patients with a CR and a PR is less than 1, the trial will be terminated; otherwise, the group will continue to expand to 16 subjects. Therefore, in the first stage, there will be 12*13/(1%–10%)=173 patients in the targeted treatment group and 405 patients in the immunotherapy group, for a total of 578 patients in the first stage. If all of these patients enter the second stage, there will be 16*13/(1%–10%)=231 patients in the final targeted treatment group and 539 patients in the immunotherapy group, for a total of 770 patients. The sample size of the study will be adjusted according to the interim analysis.
After disease progression, the patients will be followed for survival every 6 weeks (±7 days). Data collection will end at the time of final OS analysis.
Patients will be separated into two treatment subgroups according to the results of genetic testing, and two types of treatments will be used differently for the two groups in this study.
After gene detection, after failure to standardised treatment, patients with advanced rare tumours who carry the actionable alterations (EGFR mutation (exon 19 deletion mutation, L858R replacement mutation or T790M mutation), ALK gene fusion, Ros-1 gene fusion, MET gene amplification or mutation, BRAF mutation (V600), BRCA1/2 mutation, HER-2 positive (mutation or overexpression or amplification), c-kit mutation, CDK4 amplification or CDKN2A mutation) will be separated into 13 study groups in which the corresponding target drugs (almonertinib, dacomitinib, alectinib, crizotinib, vemurafenib, niraparib, pyrotinib, imatinib, palbociclib) will be administered. The details of usage, dose adjustment principles and precautions of the abovementioned drugs will follow the individual drug instructions. Information on all AEs/serious AEs (SAEs) due to these drugs used in the treatment of advanced rare solid tumours will be collected as safety analysis data. After the subjects are enrolled in the corresponding targeted treatment groups, they will be treated according to the dose specified in the instructions until disease progression or intolerable side effects occur.
Subjects with primary resistance to the single-agent targeted treatment group will be transferred to the single-agent immunotherapy group. The subjects in the almonertinib, dacomitinib, alectinib, crizotinib, pyrotinib and imatinib treatment group will be transferred out of the group if they develop secondary resistance. The subjects with secondary resistance in the vemurafenib, niraparib and palbociclib group will be treated with a combination of immune checkpoint inhibitors. The usages and dosages of the drug, the principles of dose adjustment and precautions will be conducted with reference to the drug instructions and the relevant early clinical research data. The specific and detailed targeted therapy drug plan is illustrated in figure 2.
After failure of all the standardised treatment with approved drugs in China, patients with advanced rare tumours baring no actionable gene alterations after NGS testing will be treated with (PD-1 monoclonal antibody). The usages and dosages of the drug, the principles of dosage adjustment and precautions will be conducted with reference to the drug instructions. Concurrently, all the safety data for AEs/SAEs in late rare solid tumours will be recorded and analysed. PD-1 antibody treatment will be administered according to the dosage specified in the instructions until the disease progresses or intolerable side effects occur.
The primary endpoint is defined as follows:
The clinical activity of treatments according to the ORR. The ORR in the targeted therapy group and immunotherapy group will be assessed by a BICR and an investigator according to RECIST V.1.1 and iRECIST, respectively.
The secondary endpoints are defined as follows:
PFS in the targeted treatment group, as assessed by a BICR and an investigator.
PFS (RECIST V.1.1) and iPFS (iRECIST) in the single-agent immunotherapy group, as assessed by a BICR and an investigator.
A BICR and an investigator evaluated PFS2 of combined targeted agents with PD-1 therapy in the niraparib, palbociclib and vemurafenib groups, evaluated after primary resistance.
A 6-month iPFS rate of PD-1 monotherapy, as assessed by a BICR and an investigator.
The DoR in the targeted and single-agent immunotherapy groups, as assessed by an investigator.
The DCR of the single-agent targeted and immunotherapy groups, as assessed by an investigator.
The rate of durable clinical benefit in the single-agent immunotherapy group at different enrollment stages.
A 1-year OS rate (1-year OS rate) in the single-agent targeted and immunotherapy groups.
OS in the single-agent targeted and immunotherapy groups.
The incidence of AEs in subjects (evaluated from the first study treatment administration to the 30th day and from 90 days after treatment with immunosuppressive drug regimens to approximately 5 years after the last treatment).
The efficacy evaluation criteria of the target group and immunotherapy group will be evaluated according to RECIST V.1.1 and iRECIST separately. Changes in vital signs, physical examination results and laboratory results before, during and after treatment will be recorded.
Exploratory endpoints are defined as follows:
The relationship between actionable alterations and the efficacy of each targeted drug (ORR, PFS, DoR).
The relationship between the expression of Programmed death-ligand 1 (PD-L1) (tumour and mesenchymal cells) and the tumour mutation burden within the immune microenvironment and its heterogeneous and dynamic changes and immunotherapy efficacy (ORR, PFS, DoR and OS) in the immunotherapy group.
Clinical data will be collected for all patients, including those not eligible for participation in a clinical trial substudy. All patients will be followed up every 4–9 weeks, depending on the substudy regimen, for 48 weeks and every 12 weeks beyond 48 weeks after entry into the molecular profiling phase to determine survival and disease status and whether they received matched molecular therapy on the basis of tumour profiling.
Patients enrolled in a substudy will be followed up every 4 weeks until progression or until the end of treatment and for at least 30 days after the end of treatment or 90 days after immunotherapy. After the end of treatment, patients will be followed up every 8 weeks until death or lost to follow-up. The date of death will be ascertained in medical records and appropriate registries.
Additional measures related to the assessment of clinical or biological activity of the study treatment collected as secondary outcomes will include associations of response, tolerability or resistance with biomarkers. The precise nature of any additional data to be collected will be specified in each subprotocol.
Health-related quality of life. Health-related quality of life will be measured by performance status assessments and with the The European Organization for Research and Treatment of Cancer, Quality of Life C30 (EORTC QLQ-C30) questionnaire16 during the treatment phase. Validated patient-reported outcomes for assessing the patient’s knowledge, values, attitudes, coping strategies, and decisional and psychosocial outcomes will be collected during the consent to molecular profiling, immediately after the return of profiling results and 2 months later. At these assessment points, patients will be invited to participate in an audiotaped interview to answer these questions.
Patient and public involvement statement
This PLATFORM study overcomes the limitations of tumour types and solves the problem of difficulty in recruiting subjects for RCTs and was designed for clinical investigation of rare tumours aim to help improve the efficiency and solve the problems of clinical research on rare tumours. No patients were involved in the design of this study. No patients were involved in the recruitment to and conduct of the study. Results of the study will be disseminated to patients after publication in peer-review journal. This is not an RCT.
Ethics and dissemination
The framework protocol and each substudy addendum have been reviewed in full and approved by the Cancer Hospital, Chinese Academy of Medical Sciences Ethics Committee (reference, 20/132–2328). The results from this study will be actively disseminated through manuscript publications and conference presentations.
SW, H-YH, DW and HF contributed equally.
Contributors NL led the clinical implementation of the framework and main study as well as substudy protocols. SW contributed to the trial and protocol design. H-YH performed the statistical analysis, calculated the sample size and revised the protocol. DW and HF contributed to building the electric data collection system and protocol revision. JY contributed to the description of actionable alterations and the identification of genetic testing methods. YB, YY, YF, NJ, CS, AY, QF, SX, YN, WZ, CW, XJ, YG, QT, HW, YW and YT offered quality assessments of archival material and revised the protocol. All the authors involved in the manuscript writing and reviewed every version of the submitted protocol.
Funding Chinese Academy of Medical Sciences; grant number 2019XK320068. Chinese Academy of Medical Sciences; grant number (2020-I2M-2-007).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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