-Revision of background information to include recent published data on palbociclib and fulvestrant on the treatment of ER+/HER2- metastatic breast cancer patients. -Revision of statistical assumptions leading to: • Modification of statistical assumptions regarding expected median PFS and Hazard Ratio for control vs. interventional arm. • Modification of primary variable from Progression free Survival at 1 year (1y-PFS) to overall PFS. • Change in sample size from 304 patients to 486 as result of updating the assumptions for its calculation. -Switch of analysis of primary end-point from superiority only to non-inferiority analyses, if the superiority criteria cannot be met. -Re-definition of interim analysis. Interim analysis was initially planned to occur after half of all expected patients have completed one-year follow-up period or have discontinued. Re-defined interim analysis will occur at 22 months after 35% of the total PFS events (89 events) have been observed. -Addition of new secondary end-points: Duration of Response and time to response. -Update on the definition of End of Study, EoS will occur one year after randomization of the last patient or when trial efficacy decision criteria are met, whichever is earlier. -Extend the justification of translational sub-studies analysis in the statistical section. -Addition of patient derived xenograft (PDX) models as potential studies to be performed from tumor samples obtained form patients enrolled in the study.

-Inclusion criteria # 7 is modified to no longer limit the time to take biopsy sample within 60 days prior to patient entry in the study. The limitation for accepting a tumor sample as valid is restricted to the absence of systemic treatment for advanced or metastatic non-small cell lung cancer between tumor sample collection to study start. -Exclusion criteria #8 to modify that the corrected QT value > 470 msec, it calculated based on ECG data at rest removing the requirement for triplicate ECGs -Exclusion criteria #14 modified to remove restriction for anticoagulant therapy. -Exclusion criteria #16 and #17 modified to add radiation therapy as exclusionary anti- cancer treatments within 6 months prior to study start. -Primary End-Point is modified removing the requirement for confirmation of response -Evaluations and procedures of the study. Clarification on the expected parameters to be included in the Hemogram, Biochemistry and coagulation lab results. -It has also been specified that the radiological assessments with CT, PET-CT or MRI should include at least thorax and abdomen. -Clarification on the definition of end of study (EoS). EoS should occur at the latest 78 weeks after the first dose administered to last patient included in the study. -Clarification of the patient treatment period: Patient treatment should continue up to progression disease, death, unacceptable toxicities or until the end of study. -Modification on the follow-up period until interim analysis. -Minimum follow-up period to conduct interim analysis has been corrected from 42 to 24 weeks according to primary end-point and time frequency for tumor assessments defined in the study protocol. -Removal of multivariate analysis of baseline data vs safety data. -Update estimated recruitment period from 10 months to 26 months. -Clarification on the definitions of population analysis

The Adverse Events listing has been updated with the following information: addition in the rare section (less than 0,1%, less than 1 in 1000 cases) the following adverse event: Blisters formation or severe skin peeling (suggests a Stevens-Johnson Syndrome).