This Phase 1b trial is an open label, multi-center study of XMT-1522 administered as an intravenous infusion once every three weeks. The dose escalation part of the study will establish the maximum tolerated dose or recommended Phase 2 dose for in patients with advanced breast cancer and either a HER2 immunohistochemistry (IHC) score of at least 1+ using a validated IHC assay or with evidence of HER2 amplification. Patients with HER2 positive (by IHC or amplification) gastric cancer or nonsmall cell lung cancer may also be eligible for participation in dose escalation. Upon completion of dose escalation, the cohort expansion segment of the study will consist of four parallel cohorts of different patients groups to confirm the maximum tolerated dose or the recommended Phase 2 dose and estimate the objective response in each of the patient populations.

The dose escalation segment of the study utilizes a 3+3 design. Initially, 3 patients will be dosed at each dose level. The first 3-week cycle of treatment constitutes the dose limiting toxicity (DLT) evaluation period. If none of the 3 patients experience a DLT during the evaluation period and the Safety Review Committee agrees this was a reasonably well tolerated dose, 3 patients will be enrolled at the next dose level. However, in the event of 1 DLT, 3 additional patients will be enrolled at the same dose level. Any dose level with 2 or more DLTs will be considered to have exceeded the maximum tolerated dose and subsequent patients will be enrolled at lower dose levels. After the first cycle, patients may continue to receive XMT-1522 until disease progression as long as the drug is well-tolerated and patients continue to derive clinical benefit in the opinion of the Investigator.

After completion of the dose escalation, the expansion segment will enroll the patients with the following kinds of cancer:

• Cohort 1: Advanced breast cancer, HER2 IHC 1+, or HER2 IHC 2+ without HER2 gene amplification
• Cohort 2: Advanced breast cancer, HER2-positive, who have received prior ado-trastuzumab emtansine
• Cohort 3: Advanced gastric cancer, HER2-positive, who have received prior trastuzumab
• Cohort 4: Advanced non-small cell lung cancer, HER2 IHC 2+ or 3+, any HER2 gene amplification or mutation status

Inclusion Criteria:

• Able and willing to give informed consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Measurable disease via RECIST
• Resolution of all toxic side effects from prior oncology treatments
• Adequate organ function as measured by various blood parameters
• Not pregnant or lactating, willing to prevent pregnancy while on study and for 6 months after the last dose of XMT-1522
• Histologically or cytologically confirmed adenocarcinoma of the breast with unresectable locally advanced disease, or metastatic disease and HER2 IHC 1+ or 2+ OR
• Histologically or cytologically confirmed adenocarcinoma of the breast with unresectable locally advanced disease, or metastatic disease and HER2 IHC 3+ or positive for HER2 gene amplification
• Progressed following all standard of care therapies for advanced breast cancer. OR
• Histologically or cytologically confirmed locally advanced or metastatic gastric cancer and HER2 IHC 3+ or positive for HER2 gene amplification OR
• Histologically or cytologically confirmed Stage IIIb or IV non-small cell lung cancer HER2 IHC 2+ or 3+ by local laboratory assessment.

Exclusion Criteria:

• Major surgery, radiation therapy, or systemic anti-cancer therapy within 28 days of starting study treatment.
• Some types of brain metastases
• Peripheral neuropathy of Grade 2 within 3 weeks prior to the first study therapy
• History of exposure to cumulative doxorubicin dose ≥ 360 mg/meter squared. If another anthracycline or more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/meter squared of doxorubicin
• History of clinically significant cardiac dysfunction
• Current known active infection with HIV, hepatitis B virus, or hepatitis C virus
• Current severe, uncontrolled systemic disease
• Severe dyspnea at rest, due to complications of advanced malignancy, or requiring supplementary oxygen therapy.
• History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or other malignancy with a similar expected curative outcome

Patients who participate in the dose escalation segment of the study cannot participate in the expansion segment of the study.