A Study to Evaluate the Impact of Management Strategies on Gastrointestinal-Related Adverse Events in Participants With Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations Receiving TAK-788

A Randomized Open-label Phase 2 Multicenter Study to Evaluate the Impact of Management Strategies on Gastrointestinal-Related Adverse Events in Patients With Non-Small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations Receiving TAK-788

The purpose of the study is to characterize the incidence and severity of TAK-788-associated diarrhea in previously treated participants with locally advanced or metastatic non-small-cell lung cancer (NSCLC) whose tumors harbor EGFR exon 20 insertion mutations treated with TAK-788 when administered with or without intensive loperamide prophylaxis.

The drug being tested in this study is called TAK-788. TAK-788 administered with or without antidiarrheal prophylaxis is being tested to evaluate the impact of management strategies on gastrointestinal-related adverse events in participants with non-small cell lung cancer harboring EGFR Exon 20 insertion mutations receiving TAK-788.

The study will enroll approximately 90 patients. Participants will be randomly assigned in 1:1 ratio (by chance, like flipping a coin) to one of the two treatment groups-

• Cohort 1
• Cohort 2

All participants will be asked to take TAK-788 capsules with or without a low-fat meal in Cohort 1 and TAK-788 capsule with antidiarrheal prophylaxis and with or without a low-fat meal in Cohort 2.

This is a multi-center trial and will be conducted worldwide. The overall time to participate in this study is approximately 2 years. Participants will make multiple visits to the clinic after receiving their last dose of drug for a follow-up assessment.

Inclusion Criteria:

1. Diagnosed with histologically or cytologically confirmed nonsquamous cell locally advanced (not suitable for definitive therapy) or metastatic non-small-cell lung cancer (NSCLC) (Stage IIIB or IV) NSCLC; and, has received at least 1 prior line of therapy for this disease.

2. A documented epidermal growth factor receptor (EGFR) mutation with in-frame exon 20 insertion, confirmed as follows:

   • For sites located in the United States (US): assessment must be done by a certified laboratory functioning under the guidelines of the Clinical Laboratory Improvements Amendment (CLIA).
   • For site located outside of the US: assessment must be done by an accredited local laboratory.

   Note: A documented EGFR in-frame exon 20 insertion or insertion-duplication includes but is not limited to one of the following:

   • A763_Y764insFQEA,
   • V769_D770insASV (also referred to as ASV duplication)
   • D770_N771insNPG
   • D770_N771insSVD (also referred to as SVD duplication)
   • H773_V774insNPH (also referred to as NPH duplication), or
   • Any other in-frame insertion mutation in the exon 20 [amino acids 739 -823].

   The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations. The reported insertion-duplication can have been detected on either tissue or liquid biopsy using a well-validated test based on either polymerase chain reaction, sequencing or next-generation sequencing (NGS).

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

4. Minimum life expectancy of ≥3 months.

5. All toxicities from prior therapy have been resolved to ≤Grade 1, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 or have resolved to baseline, at the time of first dose of TAK-788.

Exclusion Criteria:

1. Has been diagnosed with another primary malignancy other than NSCLC, except for the following:

   1. Adequately treated non-melanoma skin cancer or cervical cancer in situ.
   2. Definitively treated non-metastatic prostate cancer.
   3. Non-NSCLC primary malignancies that are definitively relapse-free for ≥3 years.

2. Has unstable brain metastases to include previously untreated intracranial central nervous system (CNS) metastases or previously treated intracranial CNS metastases with radiologically documented new or progressing CNS lesions.

   - Brain metastases that are stable do not preclude eligibility if they have been treated with surgery and/or radiation, and have been stable without requiring corticosteroids to control symptoms within 7 days before randomization, and have no evidence of new or enlarging brain metastases.

3. Has a current spinal cord compression (symptomatic or asymptomatic that is detectable by radiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic).

4. Currently has or has had a history of interstitial lung disease, to include radiation or drug related pneumonitis that requires/required steroid treatment.

5. Has an ongoing or active infection, to include but not limited to infections requiring intravenous antibiotics or has a known history of HIV. Testing for HIV is not required in the absence of history.

   Note: Hepatitis B surface antigen-positive participants are allowed to enroll if hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is below 1000 copies/mL in the plasma. Patients who are positive for anti-hepatitis C virus antibody can be enrolled but must not have detectable hepatitis C virus (HCV) RNA in the plasma.

6. Have uncontrolled hypertension. Participants with hypertension should be under treatment on study entry to control blood pressure.

7. A prolonged QTcF interval, or is being treated with medications known to be associated with the development of Torsades de Pointes.

8. Has a GI illness or disorder, including but not limited to a history of GI perforation, that could affect oral absorption of TAK-788.