Summary

This study is about a medicine called TAK-788, also known as mobocertinib, given to adults
with non-small cell lung cancer. The main aims of this study are to check if there are any
side effects from TAK-788, to learn how TAK-788 is processed by the body, and to determine
the best dose of TAK-788 to treat this condition. Participants will take TAK-788 capsules
with chemotherapy. Participants will continue to take TAK-788 unless they or their doctor
decide they should stop this treatment. Participants will take TAK-788 capsules with or
without chemotherapy under antidiarrhea prevention to determine the safety of TAK-788
treatment. Non-Asian, non-White participants will take TAK-788 to determine the safety and
tolerability of TAK-788 treatment.

Objectives

This phase 1/2 study will evaluate the safety, pharmacokinetics, and anti-tumor activity of
oral EGFR/HER2 Inhibitor TAK-788 in participants with NSCLC and anti-tumor activity of
TAK-788 in participants with solid tumors other than NSCLC with EGFR or HER2 mutations. The
trial will be conducted in three parts: a dose escalation (Part 1), expansion phase (Part 2),
followed by an extension phase (Part 3).

The objectives of the dose escalation phase (Part 1), is to determine the safety profile of
orally administered TAK-788, including the MTD, DLTs, RP2D, pharmacokinetic profile. The
primary goal of the expansion component of the trial is to evaluate the anti-tumor activity
of TAK-788 in seven histologically and molecularly defined cohorts at the RP2D (determined
based on dose escalation phase of the trial).

The seven expansion cohorts will be:

1. NSCLC participants with EGFR exon 20 activating insertions, who have either not received
or not shown an objective response to an EGFR TKI, and who have no active, measurable
CNS metastases;

2. NSCLC participants with HER2 exon 20 activating insertions or point mutations and no
active, measurable CNS metastases;

3. NSCLC participants with EGFR exon 20 activating insertions or HER2 exon 20 activating
insertions or point mutations and active, measurable CNS metastases;

4. NSCLC participants with other targets against which TAK-788 is active (examples include
EGFR exon 19 deletions or exon 21 substitutions [with or without T790M mutations] and
other uncommon EGFR activating mutations), without active CNS metastases;

5. NSCLC participants with EGFR exon 20 activating insertions, who have previously shown an
objective response to an EGFR TKI and subsequently progressed, without active CNS
metastases;

6. NSCLC participants with EGFR exon 20 activating insertions, who have not received prior
systemic anticancer treatment for locally advanced or metastatic disease, without active
CNS metastases; and

7. Participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which
TAK-788 is active, without active CNS metastases.

The extension phase will evaluate efficacy of TAK-788 in participants with locally advanced
or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations and who have been
previously treated. The study enrolled 324 participants.

Eligibility

1. Refractory to standard available therapies. Part 2: Expansion Cohort 1 Specific Inclusion Criteria:
2. Have a documented EGFR in-frame exon 20 insertion by a local test.
3. Previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease.
4. Prior treatment with an EGFR TKI is allowed unless the participants had an objective response and subsequent progression as assessed by the investigator or treating physician. Expansion Cohort 2 Specific Inclusion Criteria:
5. Have one of the following documented by a local test:
6. A HER2 exon 20 insertion;
7. An activating point mutation in HER2.
8. Previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease.
9. With an EGFR exon 20 insertion: Prior treatment with a pan-HER TKI (example, afatinib, neratinib, or dacomitinib) is allowed unless the participants had an objective response and subsequent progression as assessed by the investigator or treating physician. Part 2: Expansion Cohort 3 Specific Inclusion Criteria:
10. Have one of the following documented by a local test:
11. An EGFR exon 20 insertion;
12. A HER2 exon 20 insertion;
13. An activating point mutation in HER2.
14. Previously treated with one or more regimen of systemic therapy for locally advanced or metastatic disease.
15. For participants with an EGFR exon 20 insertion: prior treatment with an EGFR TKI is allowed unless the participants had an objective response and subsequent progression as assessed by the investigator or treating physician.
16. For participants with a HER2 exon 20 insertion or HER2 activating point mutation: prior treatment with a pan-HER TKI (example, afatinib, neratinib, or dacomitinib) is allowed unless the participants had an objective response and subsequent progression as assessed by the investigator or treating physician during treatment with that prior TKI.
17. Have either previously untreated intracranial CNS metastases or previously treated intracranial CNS metastases with radiologically documented new or progressing CNS lesions.
18. Have at least one target (that is, measurable) intracranial CNS lesion (greater than or equal to [ = ]10 millimeter [mm] in longest diameter by contrast enhanced magnetic resonance imaging [MRI]). Part 2: Expansion Cohort 4 Specific Inclusion Criteria:
19. Have one of the following documented by a local test: an activating mutation in EGFR including exon 19 deletions or exon 21 L858R substitution (with or without T790M), or an uncommon activating mutation other than exon 20 insertion including, but not limited to, G719X (where X is any other amino acid), S768I, L861Q, or L861R.
20. Treatment naive for locally advanced or metastatic disease or previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease. Part 2: Expansion Cohort 5 Specific Inclusion Criteria: NSCLC participants with EGFR exon 20 activating insertions, who have previously shown an objective response to an EGFR TKI and subsequently progressed, without active CNS metastases.
21. Have a documented EGFR in-frame exon 20 insertion by a local test.
22. Previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease.
23. Previously showed an objective response to an EGFR TKI, and subsequently progressed as assessed by the investigator or treating physician. Part 2: Expansion Cohort 6 Specific Inclusion Criteria: NSCLC participants with EGFR exon 20 activating insertions, who have not received prior systemic anticancer treatment for locally advanced or metastatic disease, without active CNS metastases.
24. Have a documented EGFR in-frame exon 20 insertion by a local test.
25. No prior systemic treatment for locally advanced or metastatic disease. Part 2: Expansion Cohort 7 Specific Inclusion Criteria: Participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which TAK-788 is active, without active CNS metastases.
26. Have a solid tumor that is not NSCLC, including, but not limited to, bladder/urinary tract cancer, breast cancer, gastric/esophageal cancer, biliary tract cancer, and head and neck cancer.
27. Is refractory to standard therapy.
28. Have EGFR or HER2 mutations, documented by a local test. Part 3: Extension Cohort Specific Inclusion Criteria:
29. Have a documented EGFR in-frame exon 20 insertion by a local test and sufficient tumor tissue available for central analysis.
30. Must have received at least 1 prior line of therapy for locally advanced or metastatic disease and no more than 2 regimens of systemic anticancer chemotherapies for locally advanced or metastatic disease.
31. Prior treatment with an EGFR TKI is allowed unless the participant had an objective response and subsequent progression as assessed by the investigator or treating physician during treatment with that prior TKI.

Treatment Sites in Georgia