Business Decision (no safety or efficacy concerns)

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.

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.