Background: The tolerability and efficacy of targeted therapy in older adults with cancer have not been adequately studied. Neratinib is an oral pan-HER1, HER2, and HER4 tyrosine kinase inhibitor that has been FDA approved for early stage HER 2+ breast cancer. This phase II trial is designed to evaluate the safety of neratinib in older adults (≥60 years) who have HER2 amplified or HER2 mutated metastatic breast cancer (MBC). Methods: Older adults with HER2+ or HER2 mutated MBC with any number of previous lines of therapy received neratinib at 240 mg daily in 28-day cycles. Loperamide was used for diarrhea prophylaxis: 4mg tid x 14 days followed by 4mg bid for days 15-28, and as needed after first cycle. Participants completed a pre-treatment geriatric assessment (GA) including measures of function, comorbidity, cognition, nutrition, and psychosocial status at cycle 1, cycle 4, and end of the study. Relationships between tolerability (dose reductions and number of completed courses) and log₂ risk score were assessed using t-test and linear regression. Response rate (RR), progression free survival (PFS) and overall survival (OS) were evaluated. Results: Twenty-five patients (mean age 68 [60-79]) were enrolled from 12/2016 to 03/2019, and 36% of patients (pts) were >70 years old. Median number of cycles completed was 3 (0-13): 1/25 (4%) pts had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not evaluable for response. PFS was 2.6 months (95% CI [2.56-5.26]). The median OS was 17.4 months (95% CI [10.3, NA]). A total of 9/25 pts (36%) had dose modification. Of these, 3/9 had at least one dose hold, and all 9 had at least one dose reduction (diarrhea, n = 6). 20/25 participants (80%, 95% CI [59%, 93%]) had grade ≥2 toxicities, and 9/25 pts (36%, 95% CI [18%, 57%]) had grade 3 toxicities that were attributable to treatment: diarrhea (n = 5), abdominal pain (n = 2), and vomiting (n = 2). There were no grade 4 or 5 toxicities. Two pts (8%) were hospitalized due to neratinib toxicity, and two pts went off treatment due to toxicity attributed to neratinib (diarrhea and nausea). There was a trend in the difference in toxicity risk scores by whether a participant had a dose reduction (t-test: p-value = 0.054) with participants with higher risk scores being more likely to require a dose reduction; however, toxicity risk score did not predict number of cycles completed based on linear regression (slope = -1.29, se = 1.44, p = .39). Conclusions: Neratinib is safe in older adults with HER2 positive or HER2 mutated MBC. Clinical trial information: NCT02673398.