UpSwinG: Real World Study on TKI Activity in Uncommon Mutations and Sequencing Giotrif®
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All trials for Non-squamous, Non-Small Cell Lung Cancer All trials of Afatinib (Gi(l)otrif®) All trials of Erlotinib (Tarceva®)
-Summary
Non-interventional, multi-country, multi-centre cohort study based on existing data from medical records (paper or electronic) or electronic health records of patients with advanced NSCLC harbouring EGFR mutations and treated with an EGFR-TKI
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+Arms and interventions
| Arm | Type | Interventions | Description |
|---|
| Uncommon EGFR mutation cohort | | Drug: Afatinib (Gi(l)otrif®); Drug: Erlotinib (Tarceva®); Drug: Gefitinib (IRESSA®); Drug: Osimertinib (Tagrisso®) | This arm included patients with Non-Small Cell Lung Cancer (NSCLC) carrying uncommon mutations in the epidermal growth factor receptor (EGFR) who were treated with the following Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) as first or second-line therapy:
* Afatinib (Gi(l)otrif®):50mg or 40mg or 30mg or 20mg tablet once daily as indicated in the approved labels of afatinib (Gi(l)otrif®).
* Erlotinib (Tarceva®): 25mg or 100mg or 150mg tablet once daily as indicated in the approved labels of erlotinib (Tarceva®).
* Gefitinib (IRESSA®): 250mg tablet once daily as indicated in the approved labels of gefitinib (IRESSA®).
* Osimertinib (Tagrisso®): 80 mg or 40 mg tablets once daily as indicated in the approved labels of osimertinib).
In the first- or second-line with a threshold of start of treatment of at least 12 months respectively prior to data entry. |
| Sequencing cohort | | Drug: Afatinib (Gi(l)otrif®); Drug: Osimertinib (Tagrisso®) | This arm included Non-Small Cell Lung Cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation positive who received the following treatment sequence:
\- Afatinib (Gi(l)otrif®): 50mg or 40mg or 30mg or 20mg tablet once daily as indicated in the approved labels of afatinib (Gi(l)otrif®) as first line therapy, in the case the T790M resistance mutation was developed (second line therapy) the patients received osimertinib (Tagrisso®): 80 mg or 40 mg tablets once daily as indicated in the approved labels of osimertinib; the threshold of start of osimertinib at least 10 months prior to data entry. |
- Afatinib (Gi(l)otrif®) (Drug): Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) as first or second-line therapy.
- Erlotinib (Tarceva®) (Drug): Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) as first or second-line therapy.
- Gefitinib (IRESSA®) (Drug): Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) as first or second-line therapy.
- Osimertinib (Tagrisso®) (Drug): Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) as first or second-line therapy.
- Afatinib (Gi(l)otrif®) (Drug): As first line therapy.
- Osimertinib (Tagrisso®) (Drug): In the case the T790M resistance mutation was developed (second line therapy).
+Outcome measures
Primary outcomes
- Time on Treatment With Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) [Up to 13 years for Uncommon EGFR mutation cohort and up to 6 years for the Sequencing Cohort.]: Uncommon Mutation Cohort: Time on treatment with EGFR-TKI assessed as the time from start of EGFR-TKI treatment until the end of treatment or death by any cause is reported.
Common mutation cohort: Time on treatment with EGFR-TKI assessed as the time from start of afatinib (Gi(l)otrif®) as first-line treatment until the end of the second line treatment (the last dose of osimertinib) or death date by any cause.
Time on treatment was analysed using Kaplan-Meier method, and the median was tabulated along with two-sided 95% confidence interval using the Greenwood's variance estimate.
Secondary outcomes
- Uncommon Epidermal Growth Factor Receptor (EGFR) Mutation Cohort: Overall Response Rate to Index Line Treatment [Up to 13 years.]: Overall response rate (ORR) using RECIST criteria as assessed by investigator. ORR to index line Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) treatment is reported (ORR is defined as number of patients with complete or partial response evaluated by Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1)).
(Per RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR).
- Sequencing Cohort: Overall Response Rate to First Line Afatinib [Up to 6 years.]: Overall response rate (ORR) using RECIST criteria as assessed by investigator. Overall response rate to first line afatinib treatment for the Common Epidermal Growth Factor Receptor (EGFR) mutation cohort is reported. (ORR is defined as number of patients with complete or partial response evaluated by Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1)).
(Per RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR).
- Sequencing Cohort: Overall Response Rate to Second-line Treatment Osimertinib [Up to 6 years.]: Overall response rate (ORR) using RECIST criteria as assessed by investigator. Overall response rate to second-line treatment (Osimertinib) is reported. (ORR is defined as number of patients with complete or partial response evaluated by Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1)).
(Per RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR).
- Overall Survival [Up to 13 years for Uncommon EGFR mutation cohort and up to 6 years for the Sequencing Cohort.]: Uncommon Mutation Cohort: Overall survival since index line treatment start of Tyrosine Kinase Inhibitor (TKI) medication administered per generation until death date by any cause or the end of index line is reported. Sequencing cohort: Overall survival for since first-line afatinib treatment start until death date by any cause or the end of index line. Kaplan-Meier estimates of quartiles of time to death were computed (with their 95% Confidence Intervals, using Greenwood's variance estimate.
- Number of Participants for Each Type of Biological Samples Used for Mutation Detection at First Line Treatment Start [At first-line treatment start (i.e. between 2007 and 2019 for the Uncommon Epidermal Growth Factor Receptor (EGFR) mutation cohort and between 2014 and 2018 for Sequencing Cohort).]: Number of participants for each type of biological samples used for mutation detection at first line treatment start is reported.
The reported types of biological samples are:
* Tissue, histological sample (solid biopsy);
* Cytological sample;
* Blood (liquid biopsy);
* Other and
* Unknown.
- Number of Participants for Each Category of Methodology Used for Mutational Testing at First Line Treatment Start [At first-line treatment start (i.e. between 2007 and 2019 for the Uncommon Epidermal Growth Factor Receptor (EGFR) mutation cohort and between 2014 and 2018 for the Sequencing Cohort).]: Number of participants for each type of methodologies used for mutational testing is reported.
The reported types of methodology are:
* Amplification Refractory Mutation System (ARMS);
* Polymerase Chain reactions (PCR)-based techniques;
* Sequencing;
* Next-Generation Sequencing (NGS);
* Other;
* Unknown.
- Uncommon Mutation Cohort: Time on Treatment Until Failure of Second-line (TTF2) [From start of first-line treatment to stop of second-line or death by any cause, up to 13 years.]: Time on treatment until failure of second-line (TTF2), defined as time elapsed from start of first-line treatment (regardless the type of treatment) to stop of second-line (regardless of the type of treatment) or death by any cause is reported. Kaplan-Meier estimates of quartiles of time to second-line treatment failure were computed (with their 95% Confidence Intervals, using Greenwood's variance estimate).
- Number of Participants for Each Type of Biological Samples Used for Mutation Detection at Second Line Treatment Start [At second-line treatment start (i.e. between 2007 and 16-Jul-2020 for "Uncommon EGFR mutation cohort" and between 2014 and 23-Oct-2020 for the "Sequencing Cohort]: Number of participants for each type of biological samples used for mutation detection at second line treatment start is reported.
The reported types of biological samples are:
* Tissue, Histological sample (solid biopsy);
* Cytological sample;
* Blood (liquid biopsy);
* Not applicable-Clinical evaluation;
* Other;
* Unknown. Not applicable - Clinical evaluation: The uncommon Epidermal Growth Factor Receptor (EGFR) mutational status had become available after Progression on conventional second-line therapy. Erlotinib was given as state of the art second-line therapy in 2014, and an EGFR mutation was clinically suspected due to the Long-Lasting response. However, due to the unavailability of tumor tissue, this could be proven only after liquid biopsy had subsequently become available at the center in 2016.
For the Sequencing cohort second-line treatment start is initiated by the beginning of the therapy with Osimertinib.
- Number of Participants for Each Type of Biological Samples Used for Mutation Detection at Second Line Treatment Stop/End of Observation [At second-line treatment start (i.e. between 2007 and 16-Jul-2020 for Uncommon Epidermal Growth Factor Receptor (EGFR) mutation cohort and between 2014 and 23-Oct-2020 for the Sequencing Cohort).]: Number of participants for each type of biological samples used for mutation detection at second line treatment stop/end of observation is reported.
The reported categories of biological samples are:
* Tissue, Histological sample (solid biopsy);
* Cytological sample;
* Blood (liquid biopsy);
* Other.
- Uncommon Cohort: Number of Participants for Each Type of Biological Samples Used for Mutation Detection at Index Therapy Start [Up to 13 years.]: Number of participants for each type of biological samples used for mutation detection at index therapy start (index therapy refers to therapy switch from first-line chemotherapy to second-line Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) therapy (index line)) is reported.
The reported categories of biological samples are:
* Tissue, Histological sample (solid biopsy);
* Cytological sample;
* Blood (liquid biopsy);
* Other and
* Unknown.
- Number of Participants for Each Type of Methodology Used for Mutational Testing at Second-line Treatment Start [At second-line treatment start (i.e. between 2007 and 16-Jul-2020 for Uncommon Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR) mutation cohort and between 2014 and 23-Oct-2020 for the Sequencing Cohort).]: Number of participants for each type of methodology used for mutational testing at second-line treatment start is reported.
The reported types of methodologies are:
* Amplification Refractory Mutation System (ARMS);
* Polymerase Chain Reaction (PCR)-based techniques;
* Sequencing;
* Next-Generation Sequencing (NGS);
* Other;
* Unknown/Not applicable- Clinical evaluation.
- Number of Participants for Each Type of Methodology Used for Mutational Testing at Second-line Treatment Stop/End of Observation [At second-line treatment stop/end of observation (i.e. between 2007 and 16-Jul-2020 for Uncommon Epidermal Growth Factor Receptor (EGFR) mutation cohort and between 2014 and 23-Oct-2020 for the Sequencing Cohort).]: Number of participants for each type of methodology used for mutational testing is reported.
The reported types of methodologies are:
* Polymerase Chain Reaction (PCR)-based techniques;
* Next-Generation Sequencing (NGS);
* Unknown.
- Uncommon Mutation Cohort: Number of Participants for Each Type of Methodology Used for Mutation Detection at Index Therapy Start [Up to 13 years.]: Number of participants for each type of methodology used for mutation detection at index therapy start is reported. Index therapy refers to therapy switch from first-line chemotherapy to second-line Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) therapy (index line).
The reported categories of methodology are:
* Amplification Refractory Mutation System (ARMS),
* Polymerase chain reaction based techniques (PCR-based techniques),
* Sequencing,
* Next-Generation Sequencing (NGS),
* Unknown.
- Uncommon Mutation Cohort: Number of Participants for Each Type of Methodology Used for Mutation Detection at Start of First-line Chemotherapy Before Index Line [At start of first-line chemotherapy before index line (i.e. between 2007 and 2019).]: Number of participants for each type of methodology used for mutation detection at start of first-line chemotherapy before index line is reported.
The reported types of methodologies are:
* PCR-based techniques;
* Sequencing;
* Next-Generation Sequencing (NGS);
* Unknown.
Index therapy refers to therapy switch from first-line chemotherapy to second-line Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) therapy (index line).
- Uncommon Mutation Cohort: Number of Participants for Each Type of Biological Samples Used for Mutation Detection at Start of First-line Chemotherapy Before Index Line [At start of first-line chemotherapy before index line (i.e. between 2007 and 2019).]: Number of participants for each type of biological samples used for mutation detection at start of first-line chemotherapy before index line is reported. Index therapy refers to therapy switch from first-line chemotherapy to second-line Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) therapy (index line).
The reported types of biological samples are:
* Tissue, Histological sample (solid biopsy);
* Cytological sample, Blood (liquid biopsy).
+Eligibility
Sex: All, ages: 18 Years to any
Inclusion Criteria:
1. Adult patients
2. Diagnosed with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFRTKI) naive advanced EGFR mutated non-small cell lung cancer (NSCLC),
3. treated for Epidermal Growth Factor Receptor (EGFR) mutated NSCLC within regular clinical practice.
4. Informed and privacy consent signature must be obtained depending on local regulations.
More specific inclusion criteria for each cohort are the following:
Uncommon mutation cohort:
5. Patients harbouring uncommon or compound EGFR mutations
6. Patients who started with either afatinib (Gi(l)otrif®), gefitinib (Iressa®), erlotinib (Tarceva®), or osimertinib (Tagrisso®) in the first- or second-line setting within regular clinical practice
7. Patients must have started EGFR-TKI treatment at least 12 months prior to data entry.
Sequencing cohort:
5\. Patients with common EGFR mutations (Del19, L858R) 6. Patients were treated with afatinib (Gi(l)otrif®) in the first-line setting and for acquired T790M mutation with osimertinib in the second line; 7. Patients must have started osimertinib treatment at least 10 months prior to data entry.
Patients treated with osimertinib within an early access program/ compassionate use program (EAP/CUP) are allowed
Exclusion Criteria:
1. Patients treated for EGFR mutated NSCLC within a clinical trial or participated in GioTag study.
2. Patients with active brain metastases at start of EGFR-TKI therapy (independent of treatment line)
3. For uncommon mutation cohort: Patients treated with osimertinib with no further uncommon mutation than acquired T790M Further exclusion criteria apply
+Posted results
Participant flow
| Milestone | Uncommon EGFR Mutation Cohort | Sequencing Cohort |
|---|
| Started | 255 | 207 |
| Eligible patients | 246 | 191 |
| Completed | 246 | 191 |
| Not completed | 9 | 16 |
Outcome results
- Time on Treatment With Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) (Primary), Median, Months: Uncommon EGFR Mutation Cohort 9.89 (7.75 to 11.56); Sequencing Cohort 27.7 (23.95 to 30.23)
- Uncommon Epidermal Growth Factor Receptor (EGFR) Mutation Cohort: Overall Response Rate to Index Line Treatment (Secondary), Count of participants, Participants: Uncommon EGFR Mutation Cohort 96
- Sequencing Cohort: Overall Response Rate to First Line Afatinib (Secondary), Count of participants, Participants: Sequencing Cohort 131
- Sequencing Cohort: Overall Response Rate to Second-line Treatment Osimertinib (Secondary), Count of participants, Participants: Sequencing Cohort 75
- Overall Survival (Secondary), Median, Months: Uncommon EGFR Mutation Cohort 24.44 (20.24 to 28.16); Sequencing Cohort 36.50 (32.85 to 41.76)
- Number of Participants for Each Type of Biological Samples Used for Mutation Detection at First Line Treatment Start (Secondary), Count of participants, Participants: Uncommon EGFR Mutation Cohort 212; Sequencing Cohort 160
- Number of Participants for Each Category of Methodology Used for Mutational Testing at First Line Treatment Start (Secondary), Count of participants, Participants: Uncommon EGFR Mutation Cohort 4; Sequencing Cohort 4
- Uncommon Mutation Cohort: Time on Treatment Until Failure of Second-line (TTF2) (Secondary), Median, Months: Uncommon EGFR Mutation Cohort 14.46 (13.24 to 18.00)
- Number of Participants for Each Type of Biological Samples Used for Mutation Detection at Second Line Treatment Start (Secondary), Count of participants, Participants: Uncommon EGFR Mutation Cohort 22; Sequencing Cohort 93
- Number of Participants for Each Type of Biological Samples Used for Mutation Detection at Second Line Treatment Stop/End of Observation (Secondary), Count of participants, Participants: Uncommon EGFR Mutation Cohort 5; Sequencing Cohort 9
- Uncommon Cohort: Number of Participants for Each Type of Biological Samples Used for Mutation Detection at Index Therapy Start (Secondary), Count of participants, Participants: Uncommon EGFR Mutation Cohort 199
- Number of Participants for Each Type of Methodology Used for Mutational Testing at Second-line Treatment Start (Secondary), Count of participants, Participants: Uncommon EGFR Mutation Cohort 23; Sequencing Cohort 121
- Number of Participants for Each Type of Methodology Used for Mutational Testing at Second-line Treatment Stop/End of Observation (Secondary), Count of participants, Participants: Uncommon EGFR Mutation Cohort 7; Sequencing Cohort 11
- Uncommon Mutation Cohort: Number of Participants for Each Type of Methodology Used for Mutation Detection at Index Therapy Start (Secondary), Count of participants, Participants: Uncommon EGFR Mutation Cohort 4
- Uncommon Mutation Cohort: Number of Participants for Each Type of Methodology Used for Mutation Detection at Start of First-line Chemotherapy Before Index Line (Secondary), Count of participants, Participants: Uncommon EGFR Mutation Cohort 9
- Uncommon Mutation Cohort: Number of Participants for Each Type of Biological Samples Used for Mutation Detection at Start of First-line Chemotherapy Before Index Line (Secondary), Count of participants, Participants: Uncommon EGFR Mutation Cohort 13
Adverse events
Time frame: From the start of the first-line treatment between 2007 and 2019, until Database Lock in 2021. Up to 14 years.
| Arm | Deaths | Serious adverse events | Other adverse events |
|---|
| Sequencing Cohort | 0/44 (0.0%) | 12/44 (27.3%) | 41/44 (93.2%) |
| Uncommon EGFR Mutation Cohort | 0/35 (0.0%) | 6/35 (17.1%) | 30/35 (85.7%) |
Serious adverse events by term
| Term | Organ system | Sequencing Cohort | Uncommon EGFR Mutation Cohort |
|---|
| Diarrhoea | Gastrointestinal disorders | 1/44 | 0/35 |
| Disease progression | General disorders | 1/44 | 0/35 |
| Neutropenic sepsis | Infections and infestations | 1/44 | 0/35 |
| Blood creatine phosphokinase increased | Investigations | 0/44 | 1/35 |
| Decreased appetite | Metabolism and nutrition disorders | 0/44 | 1/35 |
| Malignant neoplasm progression | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 10/44 | 3/35 |
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | 0/44 | 1/35 |
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | 0/44 | 1/35 |
Other adverse events by term
| Term | Organ system | Sequencing Cohort | Uncommon EGFR Mutation Cohort |
|---|
| Diarrhoea | Gastrointestinal disorders | 34/44 | 24/35 |
| Stomatitis | Gastrointestinal disorders | 13/44 | 12/35 |
| Paronychia | Infections and infestations | 17/44 | 12/35 |
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | 6/44 | 12/35 |
| Dry skin | Skin and subcutaneous tissue disorders | 4/44 | 2/35 |
| Rash | Skin and subcutaneous tissue disorders | 19/44 | 7/35 |
| Nausea | Gastrointestinal disorders | 3/44 | 0/35 |
| Inflammation | General disorders | 3/44 | 0/35 |
| Mucosal inflammation | General disorders | 3/44 | 0/35 |
| Oedema peripheral | General disorders | 0/44 | 3/35 |
| Decreased appetite | Metabolism and nutrition disorders | 1/44 | 2/35 |
| Dermatitis | Skin and subcutaneous tissue disorders | 3/44 | 1/35 |
| Nail fold inflammation | Skin and subcutaneous tissue disorders | 0/44 | 2/35 |
| Pruritus | Skin and subcutaneous tissue disorders | 0/44 | 2/35 |
Limitations and caveats: As in all studies based on secondary use of data, the risk of missing data shall be taken into consideration. Stratified analyses include no formal testing for statistical significance since such analyses have a descriptive exploratory purpose. In fact, no a priori hypotheses were defined. Patient's duration of observation was different for each subject without specific censoring rules by protocol, and there were no limitations on time periods for starting treatments by protocol.
+Locations (1)
| Facility | City | Country | Status |
|---|
| Royal Marsden Hospital | London | United Kingdom | |
+Publications
- Results publication: Popat S, Hsia TC, Hung JY, Jung HA, Shih JY, Park CK, Lee SH, Okamoto T, Ahn HK, Lee YC, Sato Y, Lee SS, Mascaux C, Daoud H, Marten A, Miura S. Tyrosine Kinase Inhibitor Activity in Patients with NSCLC Harboring Uncommon EGFR Mutations: A Retrospective International Cohort Study (UpSwinG). Oncologist. 2022 Apr 5;27(4):255-265. doi: 10.1093/oncolo/oyac022. PMID 35274704
+Study documents