A Phase II Randomized Study Comparing the Efficacy and Safety of Targeted Therapy or Cancer Immunotherapy Versus Platinum-Based Chemotherapy in Patients With Cancer of Unknown Primary Site

• Alectinib (Drug): Alectinib will be administered orally at the label-recommended dose (600 mg) twice daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
• Vismodegib (Drug): Vismodegib will be administered orally at the label-recommended dose (150 mg) once daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
• Ipatasertib (Drug): Ipatasertib will be administered orally at the label-recommended dose (400 mg) once daily on Days 1-21 of each 28-day Cycle in combination with paclitaxel, and as monotherapy after the final administration of paclitaxel, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
• Olaparib (Drug): Olaparib will be administered orally at the label-recommended dose (400 mg) twice daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
• Erlotinib (Drug): Erlotinib will be administered orally in combination with Bevacizumab at the label recommended dose (150 mg) once daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
• Bevacizumab (Drug): Bevacizumab will be administered intravenously at 15mg/kg every 3 weeks in combination with Erlotinib until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
• Vemurafenib (Drug): Vemurafenib will be administered orally, 960 mg twice daily, in combination with Cobimetinib, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
• Cobimetinib (Drug): Cobimetinib will be administered orally, 60mg once daily, in combination with Vemurafenib, on Days 1-21 of each 28-day Cycle, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
• Trastuzumab Subcutaneous (SC) (Drug): Trastuzumab will be administered subcutaneously, 600 mg every 3 weeks, in combination with Pertuzumab and chemotherapy, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
• Pertuzumab (Drug): Pertuzumab will be initially be administered intravenously, 840 mg, followed by 420 mg every 3 weeks, in combination with Trastuzumab and chemotherapy, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
• Atezolizumab (Drug): Atezolizumab will be administered intravenously at the label-recommended dose (1200 mg), alone or in combination with chemotherapy, every 3 weeks until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
• Carboplatin (Drug): Carboplatin will be administered intravenously at the area under the curve (AUC) dose once every 3 weeks for up to 9 Cycles (Cycle = 21 days) in some combination with the following: Paclitaxel, Gemcitabine, Atezolizumab, Pertuzumab, and Trastuzumab SC.
• Paclitaxel (Drug): Paclitaxel will be administered intravenously, 175 mg/m\^2, once every 3 weeks for up to 9 cycles (Cycle = 21 days) in some combination with the following: Carboplatin, Ipatasertib, Atezolizumab, Pertuzumab, and Trastuzumab SC
• Cisplatin (Drug): Cisplatin will be administered intravenously, 60-75 mg/m\^2, once every three weeks, for up to 9 cycles (Cycle = 21 days) in some combination with the following: Gemcitabine, Paclitaxel, Atezolizumab, Pertuzumab, and Trastuzumab SC.
• Gemcitabine (Drug): Gemcitabine will be administered intravenously, 1000 mg/m\^2, twice every three weeks for up to 9 cycles (Cycle = 21 days) in some combination with the following: Cisplatin, Carboplatin, Atezolizumab, Pertuzumab, and Trastuzumab SC.
• Entrectinib (Drug): Entrectinib will be administered orally at the label-recommended dose (600 mg) once daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
• Ivosidenib (Drug): Ivosidenib will be administered orally at the label-recommended dose (500mg) once daily across a 28-day treatment cycle until loss of clinical benefit or unacceptable toxicity.
• Pemigatinib (Drug): Pemigatinib will be administered orally at the label-recommended dose (13.5mg) once daily across a 21-day treatment cycle until loss of clinical benefit or unacceptable toxicity.

Primary outcomes

• Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) [From randomization to the first occurrence of disease progression or death from any cause, until 330 PFS events were observed (approx. 4.3 years for MGT Cat 1 and 3.4 years for Chemotherapy Cat 1).]: This efficacy objective was to evaluate the efficacy of MGT vs platinum chemotherapy in term of PFS in participants with CUP whose best response to 3 cycles of platinum induction chemotherapy was assessed CR, PR, or SD.

Secondary outcomes

• Overall Survival (OS) [From randomization to death from any cause (approx. 4 years)]
• Objective Response Rate (ORR) [Two consecutive occurrences of complete or partial response >/=4 weeks apart (up to approximately 4 months)]
• Duration of Response (DOR) [From the first documentation of a complete response (CR) or partial response (PR) to disease progression or death from any cause, whichever occurs first (up to approximately 4 years)]
• Disease Control Rate (DCR) [From randomization to death from any cause, through the end of study (approximately 4 years)]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Histologically-confirmed unresectable cancer of unknown primary site (CUP) diagnosed according to criteria defined in the 2015 European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for CUP
* No prior lines of systemic therapy for the treatment of CUP
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Candidate for platinum-based chemotherapy (according to the reference information for the intended chemotherapy)
* At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)
* Formalin-Fixed Paraffin-Embedded (FFPE) tumor tissue sample </= 4 months old that is expected to be sufficient for generation of a comprehensive genomic profile at a central reference pathology laboratory

Exclusion Criteria:

* Squamous cell CUP
* Participants who can be assigned to a specific subset of CUP for which a specific treatment is recommended by the 2015 ESMO Clinical Practice Guidelines for CUP or with a clinical and IHC profile indicative of a specific primary tumor (favorable prognosis CUP subsets): Poorly differentiated carcinoma with midline distribution; women with papillary adenocarcinoma of the peritoneal cavity; women with adenocarcinoma involving only the axillary lymph nodes; squamous cell carcinoma of the cervical lymph nodes; poorly differentiated neuroendocrine tumors; men with blastic bone metastases and elevated prostate-specific antigen (PSA); participants with a single, small, potentially resectable tumor; colon cancer-type CUP, including participants with a CK7 negative, CK20 positive, CDX-2 positive immunohistochemistry profile; CK7-positive, CK20-negative and TTF-1 positive tumors in a context suggestive of lung adenocarcinoma or thyroid cancer; IHC profile definitely indicative of breast cancer OR an IHC profile indicative of breast cancer and either a history of breast cancer or lymph nodes in the drainage areas of the breast; high-grade serious carcinoma histology and elevated CA125 tumor marker and/or a mass in the gynecological tract or any tumor mass or lymph node in the abdominal cavity; IHC profile suggestive of renal cell carcinoma and renal lesions, with a Bosniak classification higher than IIF; IHC profile compatible with cholangiocarcinoma or pancreatobiliary (or upper gastrointestinal carcinoma) AND 1 or 2 liver lesions without extrahepatic disease or with only pulmonary metastases and/or lymph nodes in the drainage areas of the liver
* Known presence of brain or spinal cord metastasis (including metastases that have been irradiated only)
* Histology and immunohistology profiles (per 2015 ESMO guidelines) that are not adenocarcinoma or poorly differentiated carcinoma/adenocarcinoma
* History or known presence of leptomeningeal disease
* Known human immunodeficiency virus (HIV) infection
* Significant cardiovascular disease
* Prior allogeneic stem cell or solid organ transplantation
* Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or for up to 7 months after the final dose of treatment

Participant flow

Outcome results

• Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) (Primary), Median, Months: Molecularly-Guided Therapy (MGT) Category 1 6.14 (4.70 to 6.47); Chemotherapy Category 1 4.40 (4.17 to 6.37) (p 0.0177)
• Overall Survival (OS) (Secondary), Median, Months: Molecularly-Guided Therapy MGT) Category 1 15.18 (13.90 to 18.43); Chemotherapy Category 1 12.78 (9.86 to 15.38)
• Objective Response Rate (ORR) (Secondary), Number, Percentage of participants: Molecularly-Guided Therapy MGT) Category 1 4.9 (2.83 to 7.85); Chemotherapy Category 1 3.6 (1.00 to 9.05)
• Duration of Response (DOR) (Secondary), Median, Months: Molecularly-Guided Therapy MGT) Category 1 16.39 (8.08 to NA); Chemotherapy Category 1 NA (4.14 to NA)
• Disease Control Rate (DCR) (Secondary), Number, Percentage of responders: Molecularly-Guided Therapy MGT) Category 1 64.7 (59.27 to 69.91); Chemotherapy Category 1 60.0 (50.22 to 69.22)

Adverse events

Time frame: Approximately 4.5 years

Serious adverse events by term

97 more terms not shown.

Other adverse events by term

25 more sites not listed.

• Results publication: Kramer A, Bochtler T, Pauli C, Shiu KK, Cook N, Janoski de Menezes J, Pazo-Cid RA, Losa F, Robbrecht DGJ, Tomasek J, Arslan C, Ozguroglu M, Arni P, Bigot F, Kim SY, Naito Y, Italiano A, Chalabi N, Duran-Pacheco G, Ma N, Scarato J, Ross JS, Moch H, Mileshkin L. Molecularly Guided Therapy Versus Continued Chemotherapy in Unfavorable Cancer of Unknown Primary: Updated Efficacy and Safety From the Randomized, Phase II CUPISCO Study. J Clin Oncol. 2026 Sep 3:JCO2502974. doi: 10.1200/JCO-25-02974. Online ahead of print. PMID 42691436
• Results publication: Kramer A, Bochtler T, Pauli C, Shiu KK, Cook N, de Menezes JJ, Pazo-Cid RA, Losa F, Robbrecht DG, Tomasek J, Arslan C, Ozguroglu M, Stahl M, Bigot F, Kim SY, Naito Y, Italiano A, Chalabi N, Duran-Pacheco G, Michaud C, Scarato J, Thomas M, Ross JS, Moch H, Mileshkin L. Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study. Lancet. 2024 Aug 10;404(10452):527-539. doi: 10.1016/S0140-6736(24)00814-6. Epub 2024 Jul 31. PMID 39096924

• Study Protocol and Statistical Analysis Plan (PDF, 2024-03-09)

• Clinical Trials, Study director, Hoffmann-La Roche

NIH grants: 2017