The goal of the current study is to determine whether Foundation Medicine's next generation sequencing assay, called FoundationOne, will provide information that allows physicians to make treatment decisions using targeted therapies in clinical trials or FDA approved therapies, including "off-label" agents, that result in superior OS compared to historical outcomes for standard CUP therapy.

Inclusion Criteria:

1. Patients with a histologically or cytologically confirmed diagnosis of metastatic or advanced unresectable cancer of unknown primary including adenocarcinoma, poorly differentiated adenocarcinoma, poorly differentiated carcinoma, or squamous carcinoma.
2. To be categorized as CUP, the following clinical evaluations must have been performed without identification of an anatomic primary site: medical history, physical examination, chemistry profile, blood counts, serum PSA (men), CT scans of chest/abdomen/pelvis, specific evaluation of symptomatic areas.
3. Sufficient Formalin Fixed Paraffin Embedded tissue from cancer of study will allow previously completed profiling panels other than for treatment assignment; however, FoundationOne profiling is required as part of this study. Adequate tumor tissue must remain, in the estimate of the consenting physician, to confirm genomic alterations in enrolled patients. Previous unknown primary available for FoundationOne testing. (Note: This FoundationOne® profiling is also allowed and is not required to be FoundationOne repeated.) (see Appendix A and Appendix B)
4. First and second line patients enrolling in this study must have an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 2. Third line patients enrolling in this study must have an ECOG Performance Status score of 0 to 1 (Appendix C).
5. Patients must have measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Appendix D).
6. Age greater than or equal to 18 years.
7. Patients are considered potential candidates for treatment with targeted therapy.
8. Willingness and ability to comply with study and follow-up procedures.
9. Ability to understand the nature of this study and give written informed consent.
10. The presence of other active cancers is not allowed, unless indolent and not requiring therapy. Patients with early stage cancer who have received definitive local treatment and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e., non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.

Exclusion Criteria:

1. Patients who have received three or more lines of systemic therapy for cancer of unknown primary.

2. Patients who have previously received matched targeted therapy for the same Class 1 alteration (see Table 1) or the same drug.

3. Patients with treatable CUP syndrome, including the following:

   • extragonadal germ cell syndrome
   • neuroendocrine carcinoma
   • adenocarcinoma isolated to axillary lymph nodes (women)
   • peritoneal carcinomatosis (women)
   • squamous cell carcinoma limited to cervical, supraclavicular, or inguinal lymph nodes
   • single resectable metastasis

4. Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 2 weeks prior to study entry and there is no evidence of central nervous system disease progression, mild neurologic symptoms, and no requirement for chronic corticosteroid therapy. Enzyme-inducing anticonvulsants are contraindicated.

5. Pregnant or lactating.

6. Psychological, familial, sociologic, or geographic conditions that do not permit compliance with the protocol.

Newly diagnosed and previously treated patients with CUP.