Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC

This is a Phase Ib, open label, non-randomized dose escalation study of EGF816 in combination
with ribociclib, trametinib, or LXH254, followed by dose expansion of EGF816 in combination
with ribociclib, trametinib, LXH254, INC280, or gefitinib in adult patients with advanced
EGFR-mutant NSCLC.

During the dose escalation part, patients will be assigned to the addition of trametinib,
ribociclib, or LXH254 to EGF816.

Following determination of the recommended dose for the combination of EGF816 + trametinib,
EGF816 + ribociclib, and EGF816 + LXH254, patients may be enrolled to the dose expansion arms
of each of these combinations. Patients may also be assigned to EGF816 + INC280 or EGF816 +
gefitinib in dose expansion.

Efficacy assessments will be performed at baseline and every 2 cycles during treatment.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed locally advanced (stage
IIIB) or metastatic (stage IV) EGFR mutant (ex19del, L858R) NSCLC.

- Requirements of EGFR mutation status and prior lines of treatment:

- Treatment naive patients, who have locally advanced or metastatic NSCLC with EGFR
sensitizing mutation (e.g., L858R and/or ex19del), have not received any systemic
antineoplastic therapy for advanced NSCLC and are eligible to receive EGFR TKI
treatment. Patients with EGFR exon 20 insertion/duplication are not eligible. Note:
patients who have received only one cycle of chemotherapy in the advanced setting are
allowed.

- Patients who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation
AND an acquired T790M mutation (e.g., L858R and/or ex19del, T790M+) following
progression on prior treatment with a 1st-generation EGFR TKI or 2nd-generation EGFR
TKI. These patients may not have received more than 4 prior lines of antineoplastic
therapy in the advanced setting, including EGFR TKI, and may not have received any
agent targeting EGFR T790M mutation (i.e., 3rd-generation EGFR TKI).

- Patients who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation
and a "de novo" T790M mutation (i.e., no prior treatment with any agent known to
inhibit EGFR including EGFR TKI). These patients may not have received more than 3
prior lines of antineoplastic therapy in the advanced setting, and may not have
received any prior 3rd generation EGFR TKI.

- Patients must have a site of disease amenable to biopsy, and be a candidate for tumor
biopsy according to the treating institution's guidelines. Patients must be willing to
undergo a new tumor biopsy during therapy on this study, and at screening if an
archival tumor sample obtained since the diagnosis of advanced disease (1L patients)
or since last treatment failure (2L+ patients) is not available.

Exclusion Criteria:

- Patients with a history or presence of interstitial lung disease or interstitial
pneumonitis, including clinically significant radiation pneumonitis.

- Patients with unstable brain metastases.

- Patients with a history of another malignancy.

- Patients with a known history of human immunodeficiency virus (HIV) seropositivity.

- Patients with clinically significant, uncontrolled heart disease.

- Patients participating in additional parallel investigational drug or medical device
studies.

- Prior therapies:

- Patients who have been treated with EGFR TKI in the adjuvant setting within 6 months,
unless acquired EGFR T790M is present in a tumor or blood sample obtained since the
discontinuation of the EGFR TKI.

- Patients who have been treated with prior EGFR TKI targeting T790M (3rd generation).

- Patients who have been treated with systemic anti-neoplastic therapy within:

- 2 weeks for fluoropyrimidine monotherapy

- 6 weeks for nitrosoureas and mitomycin

- 4 weeks or ≤ 5 half-lives (whichever is shorter) for biological therapy
(including monoclonal antibodies) and continuous or intermittent small molecule
therapeutics or any other investigational agent