Treating advanced refractory malignancies remains a major challenge. In some cancers, the combination of immune checkpoint inhibitors (ICI) and chemotherapy has been shown to be superior to chemotherapy alone. We chose to add targeted therapy (TT) to this combination to treat these diseases as the three approaches have convergent efficacy but divergent toxicity. Between 04/2016 and 10/2018, 19 consecutive patients with advanced malignancies were treated with the above combination based on diagnosis, prior therapy, and eligibility for TT. The median patient age was 62 years (range 27-82), and 15 were female. The median Eastern Cooperative Oncology Group performance status was 2 (range 0-4). Tumor types included lung, pancreas, lymphoma, melanoma, cholangiocarcinoma, ureter, cervix, and glioblastoma multiforme. Of the 14 patients who underwent prior therapy, 7 received ICI and 3 received TT. The ICIs used were pembrolizumab, nivolumab, and atezolizumab. Chemotherapy was given in 28-day cycles. Platinum-based combinations were used in 13 patients and taxanes in 10. Four patients were not eligible for TT. Complete responses were achieved in 11 patients (57%) for a median 6+ months (range 1+-15+), and partial responses in 7 (37%) for a median 4 months (1-7). One patient had stable disease. Responses were observed even in patients with intracranial metastases, extensive prior therapy, bulky disease, poor performance, and prior ICI. No unexpected side effects were observed. This personalized combination of ICI, chemotherapy, and TT yielded impressive results in advanced refractory cancer diseases. Further evaluation in properly designed clinical trials is recommended.