Trial Outcomes & Findings for Osimertinib Treatment on EGFR T790M Plasma Positive NSCLC Patients (APPLE) (NCT NCT02856893)

Last Updated: 2025-10-31

Results Overview

The primary endpoint is defined as the proportion of patients at 18 months who are alive and did not experience an event for PFS by RECIST 1.1 while receiving osimertinib (PFS-OSI). Specifically, it relates to progression of disease according to RECIST 1.1 or death after switching to osimertinib in arms "Gefitinib till + blood test/progression then Osimertinib" and "Gefitinib till progression then Osimertinib". It is formally assessed in these two arms, whilst only provided as a reference for the "Osimertinib till progression" arm, in which progression of disease or death is measured from baseline considering that patients start with osimertinib.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE2

Target enrollment

156 participants

Primary outcome timeframe

18 months after randomization

Results posted on

2025-10-31

Participant Flow

After registration was completed, eligible patients were randomized within 4 weeks.

The patients were first registered (step 1) to the trial by authorized sites. The site immediately sent the blood samples for circulating free DNA EGFR T790M (cfDNA T790M) testing to the central lab. Once the sample was assessed (step 2), the site was notified whether they could proceed to patient randomization. Patients were then randomized (step 3) after verification of all eligibility criteria.

Participant milestones

Participant milestones
Measure	Osimertinib Till Progression Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily until progression	Gefitinib Till + Blood Test/Progression Then Osimertinib Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") or RECIST progression followed by Osimertinib until second PD according to RECIST 1.1 Gefitinib: Gefitinib 250mg daily until progression Osimertinib: Osimertinib 80 mg daily until second progression Note: Osimertinib 60 or 40 mg only upon first progression until second PD	Gefitinib Till Progression Then Osimertinib Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until second PD according to RECIST 1.1 Gefitinib: Gefitinib 250mg daily until progression Osimertinib: Osimertinib 80 mg daily until progression Note: Osimertinib 60 or 40 mg only upon first progression until second PD
Overall Study STARTED	53	52	51
Overall Study COMPLETED	20	33	27
Overall Study NOT COMPLETED	33	19	24

Reasons for withdrawal

Reasons for withdrawal
Measure	Osimertinib Till Progression Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily until progression	Gefitinib Till + Blood Test/Progression Then Osimertinib Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") or RECIST progression followed by Osimertinib until second PD according to RECIST 1.1 Gefitinib: Gefitinib 250mg daily until progression Osimertinib: Osimertinib 80 mg daily until second progression Note: Osimertinib 60 or 40 mg only upon first progression until second PD	Gefitinib Till Progression Then Osimertinib Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until second PD according to RECIST 1.1 Gefitinib: Gefitinib 250mg daily until progression Osimertinib: Osimertinib 80 mg daily until progression Note: Osimertinib 60 or 40 mg only upon first progression until second PD
Overall Study Lack of Efficacy	27	15	19
Overall Study Death	1	0	0
Overall Study Adverse Event	2	0	0
Overall Study Physician Decision	0	2	3
Overall Study Withdrawal by Subject	1	1	0
Overall Study Other reasons	2	1	2

Baseline Characteristics

Osimertinib Treatment on EGFR T790M Plasma Positive NSCLC Patients (APPLE)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Osimertinib Till Progression n=53 Participants Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 60 or 40 mg daily until progression	Gefitinib Till + Blood Test/Progression Than Osimertinib n=52 Participants Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1 Osimertinib: Osimertinib 60 or 40 mg daily until progression Gefitinib: Gefitinib 250mg daily until progression	Gefitinib Till Progression Than Osimertinib n=51 Participants Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 60 or 40 mg daily until progression Gefitinib: Gefitinib 250mg daily until progression	Total n=156 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	21 Participants n=5 Participants	20 Participants n=7 Participants	31 Participants n=5 Participants	72 Participants n=4 Participants
Age, Categorical >=65 years	32 Participants n=5 Participants	32 Participants n=7 Participants	20 Participants n=5 Participants	84 Participants n=4 Participants
Age, Continuous	68 years n=5 Participants	69 years n=7 Participants	61 years n=5 Participants	66 years n=4 Participants
Sex: Female, Male Female	30 Participants n=5 Participants	39 Participants n=7 Participants	33 Participants n=5 Participants	102 Participants n=4 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	13 Participants n=7 Participants	18 Participants n=5 Participants	54 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) White	40 Participants n=5 Participants	42 Participants n=7 Participants	38 Participants n=5 Participants	120 Participants n=4 Participants
Race (NIH/OMB) More than one race	6 Participants n=5 Participants	5 Participants n=7 Participants	5 Participants n=5 Participants	16 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants	15 Participants n=4 Participants
Region of Enrollment Poland	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
Region of Enrollment Slovenia	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants	2 participants n=4 Participants
Region of Enrollment France	22 participants n=5 Participants	20 participants n=7 Participants	21 participants n=5 Participants	63 participants n=4 Participants
Region of Enrollment Jordan	5 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants	15 participants n=4 Participants
Region of Enrollment Spain	25 participants n=5 Participants	28 participants n=7 Participants	21 participants n=5 Participants	74 participants n=4 Participants
Region of Enrollment Belgium	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants
EGFR mutation Del19	35 Participants n=5 Participants	33 Participants n=7 Participants	33 Participants n=5 Participants	101 Participants n=4 Participants
EGFR mutation L858R	18 Participants n=5 Participants	19 Participants n=7 Participants	18 Participants n=5 Participants	55 Participants n=4 Participants
Presence of brain metastases Yes	10 Participants n=5 Participants	16 Participants n=7 Participants	14 Participants n=5 Participants	40 Participants n=4 Participants
Presence of brain metastases No	43 Participants n=5 Participants	36 Participants n=7 Participants	37 Participants n=5 Participants	116 Participants n=4 Participants
WHO Performance Status 0	21 Participants n=5 Participants	23 Participants n=7 Participants	26 Participants n=5 Participants	70 Participants n=4 Participants
WHO Performance Status 1	30 Participants n=5 Participants	28 Participants n=7 Participants	22 Participants n=5 Participants	80 Participants n=4 Participants
WHO Performance Status 2	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	6 Participants n=4 Participants

PRIMARY outcome

Timeframe: 18 months after randomization

Population: Per-protocol population defined as patients who have started their study treatment and satisfying all eligibility criteria as per medical review

Outcome measures

Outcome measures
Measure	Osimertinib Till Progression n=45 Participants Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression	Gefitinib Till + Blood Test/Progression Than Osimertinib n=47 Participants Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) mg daily until progression Gefitinib: Gefitinib 250mg daily until progression	Gefitinib Till Progression Than Osimertinib n=44 Participants Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression Gefitinib: Gefitinib 250mg daily until progression
PFS Rate at 18 Months	51.1 Percentage of participants Interval 40.2 to 61.0	67.2 Percentage of participants Interval 56.4 to 75.9	53.5 Percentage of participants Interval 42.3 to 63.5

SECONDARY outcome

Timeframe: From randomization till the date of progression on osimertinib or death, an average of 2 years.

Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review.

For patients in arm "Osimertinib till progression", progression Free Survival "while receiving osimertinib" (PFS-OSI) is defined as the time interval between the date of randomization and the date of disease progression according to the RECIST 1.1 or death whichever comes first. For patients in arm "Gefitinib till + blood test/progression than Osimertinib" and "Gefitinib till progression than Osimertinib "switching to osimertinib, PFS-OSI is defined as the time interval between the date of randomization and the date of disease progression or death "after switching to osimertinib" whichever comes first. For patients in those two arms who do not start osimertinib for any reason, PFS-OSI is defined as the time interval between the date of randomization and the date of first disease progression according to the RECIST 1.1 or death whichever comes first. The median will be calculated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Osimertinib Till Progression n=45 Participants Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression	Gefitinib Till + Blood Test/Progression Than Osimertinib n=47 Participants Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) mg daily until progression Gefitinib: Gefitinib 250mg daily until progression	Gefitinib Till Progression Than Osimertinib n=44 Participants Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression Gefitinib: Gefitinib 250mg daily until progression
PFS While Receiving Osimertinib by RECIST Criteria 1.1	19.48 months Interval 14.42 to 26.97	21.98 months Interval 18.56 to upper limit for the confidence interval around the median was not reached due to an insufficient number of participants with event	20.17 months Interval 14.62 to 34.99

SECONDARY outcome

Timeframe: From randomization till the date of positive cfDNA T790M status or death, on average 2 years.

Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review.

The proportion of patients receiving osimertinib based on the determination of cfDNA T790M is the number of patients receiving at least 1 dose of osimertinib based on the determination of cfDNA T790M (positive mutation). This endpoint is only defined and applicable for the "Gefitinib till + blood test/progression than Osimertinib" arm. The 95% confidence intervals will be calculated using the exact binomial method.

Outcome measures

Outcome measures
Measure	Osimertinib Till Progression n=47 Participants Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression	Gefitinib Till + Blood Test/Progression Than Osimertinib Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) mg daily until progression Gefitinib: Gefitinib 250mg daily until progression	Gefitinib Till Progression Than Osimertinib Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression Gefitinib: Gefitinib 250mg daily until progression
Proportion of Patients Receiving Osimertinib Based on the Determination of cfDNA T790M Mutation Positive	0.170 proportion of participants Interval 0.076 to 0.308	—	—

SECONDARY outcome

Timeframe: From randomization till the date of progression on osimertinib or death, on average 2 years.

Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review. Only patients who started osimertinib are included in this analysis.

Time to progression on osimertinib is defined as the time interval between the date receiving osimertinib and the date of disease progression. Death is not counted as an event. If the event has not been observed or if the patient dies before the analysis cut-off date, then the patient is censored at the date of the last disease assessment or the date of death prior the cut-off date. Patients not receiving osimertinib are excluded for this endpoint. The nature of this endpoint is different in Arm "Osimertinib till progression" (first line progression) compared to the other two arms (second line progression).

Outcome measures

Outcome measures
Measure	Osimertinib Till Progression n=45 Participants Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression	Gefitinib Till + Blood Test/Progression Than Osimertinib n=31 Participants Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) mg daily until progression Gefitinib: Gefitinib 250mg daily until progression	Gefitinib Till Progression Than Osimertinib n=34 Participants Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression Gefitinib: Gefitinib 250mg daily until progression
Time to Progression on Osimertinib	19.48 Time in months Interval 14.42 to 32.53	10.81 Time in months Interval 8.15 to 15.57	7.39 Time in months Interval 5.32 to 11.63

SECONDARY outcome

Timeframe: Time from randomization until end of osimeritinib treatment, or death, on average 2 years.

Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review. Patients not receiving Osimertinib will not be included in the osimertinib analysis.

Overall response rate (ORR) to osimertinib is defined as the proportion of patients achieving complete response (CR) or partial response (PR) during osimertinib treatment. The analysis of overall response rate (ORR) on osimertinib was performed on the per-protocol population. Patients not receiving Osimertinib will not be included in the osimertinib analysis.

Outcome measures

Outcome measures
Measure	Osimertinib Till Progression n=45 Participants Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression	Gefitinib Till + Blood Test/Progression Than Osimertinib n=32 Participants Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) mg daily until progression Gefitinib: Gefitinib 250mg daily until progression	Gefitinib Till Progression Than Osimertinib n=34 Participants Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression Gefitinib: Gefitinib 250mg daily until progression
Overall Response Rate (ORR) to Osimertinib	0.889 proportion of patients Interval 0.759 to 0.963	0.656 proportion of patients Interval 0.468 to 0.814	0.588 proportion of patients Interval 0.407 to 0.754

SECONDARY outcome

Timeframe: From randomization till the date of end of protocol treatment

Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review.

treatment duration is measured from randomization till the last day of treatment administration. For patients in arm "Osimertinib till progression" this corresponds to the whole osimertinib treatment duration, and for patients in the other two arms, to the whole gefitinib and osimertinib treatment duration. Patients for whom no end of treatment form has been collected, are known be alive and have not started any off protocol treatment prior to clinical cut off date will be considered as still on treatment and censored in this analysis.

Outcome measures

Outcome measures
Measure	Osimertinib Till Progression n=45 Participants Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression	Gefitinib Till + Blood Test/Progression Than Osimertinib n=47 Participants Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) mg daily until progression Gefitinib: Gefitinib 250mg daily until progression	Gefitinib Till Progression Than Osimertinib n=44 Participants Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression Gefitinib: Gefitinib 250mg daily until progression
Treatment Duration	24.4 Months Interval 16.6 to 28.0	21.6 Months Interval 14.7 to 25.6	16.2 Months Interval 12.0 to 27.2

SECONDARY outcome

Timeframe: From randomization till the date of death

Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review.

Overall survival (OS) is defined as the time interval between the date of randomization and the date of death from any cause. Patients still alive at the analysis cut-off date are censored at the last date known to be alive (before the cut-off date). The median will be calculated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Osimertinib Till Progression n=45 Participants Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression	Gefitinib Till + Blood Test/Progression Than Osimertinib n=47 Participants Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) mg daily until progression Gefitinib: Gefitinib 250mg daily until progression	Gefitinib Till Progression Than Osimertinib n=44 Participants Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression Gefitinib: Gefitinib 250mg daily until progression
Overall Survival (OS)	NA Months Interval 28.4 to Median and upper limit could not be determined due to an insufficient number of participants with events	NA Months Interval 26.4 to Median and upper limit could not be determined due to an insufficient number of participants with events	42.84 Months Interval 27.01 to upper limit could not be determined due to an insufficient number of participants with events

SECONDARY outcome

Timeframe: From randomization till the date of progression in the brain

Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review.

Brain progression free survival is defined as the time interval between the randomization and the date of brain progression (progression within target lesions in the brain, unequivocal progression in non-target lesions in the brain, or appearance of new lesions in the brain) or death whichever comes first. CT scan will be used to evaluate new or recurrence progression in the brain. If the event has not been observed or if the patient dies or has PD that hampered further assessment/evaluation of brain progression, then the patient is censored at the date of the last follow up examination. The medians have been estimated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Osimertinib Till Progression n=45 Participants Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression	Gefitinib Till + Blood Test/Progression Than Osimertinib n=47 Participants Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) mg daily until progression Gefitinib: Gefitinib 250mg daily until progression	Gefitinib Till Progression Than Osimertinib n=44 Participants Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression Gefitinib: Gefitinib 250mg daily until progression
Brain Progression Free Survival (BPFS)	34.30 Months Interval 25.0 to Upper limit could not be determined due to an insufficient number of participants with events	24.44 Months Interval 17.87 to 28.58	21.39 Months Interval 14.49 to 42.84

SECONDARY outcome

Timeframe: From randomization till the date of second progression on second line treatment

Population: Per-protocol population defined as patients who started treatment and satisfied all eligibility criteria as per medical review.

In the "Osimertinib till progression" arm, PFS-2 is calculated as the time between randomization and the second PD by RECIST 1.1 or death, irrespective of treatment(s) received. In the other two arms, PFS-2 is calculated as the time between randomization and the second PD by RECIST 1.1 or death after switching to osimertinib, the first PD being PD by RECIST 1.1 or by positive cfDNA T790M status. For patients unable to start osimertinib, PFS-2 is calculated as the time between randomization and the second PD by RECIST 1.1 on any subsequent off protocol anticancer treatment line. If no PFS-2 event has been observed prior to the analysis cut-off date, then the patient is censored at the date of the last disease assessment before the cut-off date.

Outcome measures

Outcome measures
Measure	Osimertinib Till Progression n=45 Participants Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression	Gefitinib Till + Blood Test/Progression Than Osimertinib n=47 Participants Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) mg daily until progression Gefitinib: Gefitinib 250mg daily until progression	Gefitinib Till Progression Than Osimertinib n=44 Participants Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 80 mg daily (QD) until progression Gefitinib: Gefitinib 250mg daily until progression
PFS-2	25.76 Months Interval 21.78 to Upper limit could not be determined due to an insufficient number of participants with events	21.98 Months Interval 18.56 to Upper limit could not be determined due to an insufficient number of participants with events	20.27 Months Interval 14.82 to 34.99

Adverse Events

Osimertinib Till Progression

Serious events: 9 serious events

Other events: 52 other events

Deaths: 19 deaths

Gefitinib Till + Blood Test/Progression Than Osimertinib

Serious events: 6 serious events

Other events: 51 other events

Deaths: 20 deaths

Gefitinib Till Progression Than Osimertinib

Serious events: 13 serious events

Other events: 50 other events

Deaths: 18 deaths

Serious adverse events

Other adverse events

Additional Information

Yassin Pretzenbacher

EORTC

Phone: +32 2 774 1365

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results. There are no timeline for this review.
Publication restrictions are in place

Restriction type: OTHER

Measure	Osimertinib Till Progression n=53 participants at risk Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 60 or 40 mg daily until progression	Gefitinib Till + Blood Test/Progression Than Osimertinib n=52 participants at risk Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1 Osimertinib: Osimertinib 60 or 40 mg daily until progression Gefitinib: Gefitinib 250mg daily until progression	Gefitinib Till Progression Than Osimertinib n=51 participants at risk Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1 Osimertinib: Osimertinib 60 or 40 mg daily until progression Gefitinib: Gefitinib 250mg daily until progression
Respiratory, thoracic and mediastinal disorders ACUTE RESPIRATORY INSUFFICIENCY	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	2.0% 1/51 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.
Renal and urinary disorders BILATERAL RENAL INFARCTS	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	2.0% 1/51 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.
Infections and infestations COVID-19	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	3.9% 2/51 • Number of events 2 • Adverse events were collected during a 3 year and 9 months period.
Metabolism and nutrition disorders DECREASE ORAL INTAKE	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	1.9% 1/52 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
General disorders DETERIORATION OF HEALTH STATUS	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	2.0% 1/51 • Number of events 3 • Adverse events were collected during a 3 year and 9 months period.
Gastrointestinal disorders DYSPHAGIA	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	1.9% 1/52 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Infections and infestations INFECTED SKIN ULCER IN THE RIGHT LEG	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	1.9% 1/52 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Nervous system disorders LOSS OF CONSCIOUSNESS	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	2.0% 1/51 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.
Musculoskeletal and connective tissue disorders LUMBAR SPINAL STENOSIS	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	1.9% 1/52 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Infections and infestations LUNG INFECTION (PNEUMONIA)	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	2.0% 1/51 • Number of events 2 • Adverse events were collected during a 3 year and 9 months period.
Gastrointestinal disorders ORAL MUCOSITIS	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	1.9% 1/52 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Respiratory, thoracic and mediastinal disorders PNEUMONITIS	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	2.0% 1/51 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.
Blood and lymphatic system disorders SPLENIC INFARCT	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	2.0% 1/51 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.
Infections and infestations UROSEPSIS	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	1.9% 1/52 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) INTRAEPITHELIAL CECAL ADENOCARCINOMA	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	2.0% 1/51 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.
Infections and infestations PULMONARY INFECTION (PNEUMOCOCCAL PNEUMONIA)	1.9% 1/53 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Infections and infestations ACUTE GASTROENTERITIS	1.9% 1/53 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Infections and infestations DIVERTICULITIS	1.9% 1/53 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Respiratory, thoracic and mediastinal disorders DYSPNEA	3.8% 2/53 • Number of events 2 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
General disorders GAIT DISTURBANCE	1.9% 1/53 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Injury, poisoning and procedural complications HIP FRACTURE	1.9% 1/53 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) LEPTOMENINGEAL CARCINOMATOSIS	1.9% 1/53 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
General disorders MULTIORGAN FAIL	1.9% 1/53 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Renal and urinary disorders RENAL INSUFFICIENCY	1.9% 1/53 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Cardiac disorders SEGMENTAL KINETIC DISORDERS OF THE LEFT VENTRICULE	1.9% 1/53 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Infections and infestations SEPTIC SHOCK (URINARY INFECTION)	1.9% 1/53 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Infections and infestations SEVERE SEPSIS	1.9% 1/53 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Infections and infestations URINARY TRACT INFECTION	1.9% 1/53 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Infections and infestations SEPTIC SHOCK	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	1.9% 1/52 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Respiratory, thoracic and mediastinal disorders RIGHT PLEURAL SPILL	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	1.9% 1/52 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/51 • Adverse events were collected during a 3 year and 9 months period.
Respiratory, thoracic and mediastinal disorders RESPIRATORY DISTRESS SYNDROME	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	2.0% 1/51 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.
Nervous system disorders NEUROLOGICAL TROUBLES	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	2.0% 1/51 • Number of events 2 • Adverse events were collected during a 3 year and 9 months period.
Nervous system disorders DECREASE LEVEL OF CONSCIOUSNESS	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	2.0% 1/51 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.
Infections and infestations SEPSIS	0.00% 0/53 • Adverse events were collected during a 3 year and 9 months period.	0.00% 0/52 • Adverse events were collected during a 3 year and 9 months period.	2.0% 1/51 • Number of events 1 • Adverse events were collected during a 3 year and 9 months period.