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34 Background: BRAF V600E-mutant metastatic colorectal cancer (mCRC) is associated with a poor prognosis and limited clinical data. Based on results from the BEACON CRC trial, targeted treatment with encorafenib plus cetuximab (E+C) is available as a standard of care for these patients (pts) after prior systemic therapy. Since data from controlled clinical trials are based on a selected patient population, the non-interventional study (NIS) BERING CRC observes a broader patient population in clinical practice. Methods: BERING CRC is the first NIS investigating the use of E+C in clinical practice of BRAF V600E-mutant mCRC treatment after prior systemic therapy in Germany, Austria, and Switzerland. For the present analysis, disease characteristics and treatment data of the initial 81 pts were documented in 44 sites across Germany and Austria between 09/2020 and 04/2022. BERING-CRC is ongoing and aims to enroll up to 300 pts from 126 German, Austrian, and Swiss sites. The study observes pts treated according to the approved respective Summary of Product Characteristics (SmPC). The primary endpoint is the 1-year overall survival rate. Secondary endpoints include efficacy, QoL, and tolerability of E+C. Results: 81 pts were included in this baseline analysis. Median age was 67 years (range 34-88) and 48% were female. 48 pts (59%) were documented with right-sided tumors and for 62% stage IV disease was noted at initial diagnosis. In the metastatic setting, main sites of metastasis were liver, peritoneum, and lung (52%, 32%, and 22% of pts, respectively), with 16% of pts having ≥ 3 sites documented. For 30% of pts, an ECOG performance status (PS) of 0 was documented at baseline assessment (57% ECOG PS 1 or 2). Adjuvant treatment was reported for 22 pts while relapse ≤ 6 months was documented for 10 of them. Consistent with BEACON CRC, adjuvant systemic therapy with relapse within ≤6 months was counted as metastatic 1st line treatment. 91% of pts with adjuvant treatment received chemotherapy alone in this setting. 4 pts (5%) were documented with E+C treatment directly following adjuvant therapy and 55% of all pts with documented first-line treatment (69 pts) received chemotherapy alone (CT), for 35% chemotherapy was combined with targeted therapy (CT+TT), 3% received immunotherapy, and 1% received TT alone. In second-line, 71% of pts with documented treatment received E+C (7% CT, 16% CT+TT). An initial bi-weekly cetuximab dosing was reported for 10% of pts treated with E+C. Conclusions: While the high number of pts with right-sided tumors was in line with previous findings on BRAF V600E-mutant mCRC pts, synchronous metastasis was reported considerably more often in this real-world cohort. As complementation to previous controlled clinical trial data, pts enrolled in BERING-CRC were notably older and presented with higher ECOG PS compared to the pivotal study. Clinical trial information: NCT04673955 .

e15584 Background: BRAF V600E-mutant metastatic colorectal cancer (mCRC) is characterized by a poor prognosis and limited clinical data. Based on results from the phase 3 BEACON CRC trial, targeted treatment with encorafenib plus cetuximab (E+C) represents a newly approved standard of care for these patients (pts) upon systemic therapy. As data from controlled clinical trials are based on a selected patient population, the non-interventional study (NIS) BERING CRC observes a broader patient population under real-world conditions. Methods: BERING CRC is the first NIS to investigate the real-world use of E+C in BRAF V600E-mutant metastatic colorectal cancer upon systemic treatment in Germany, Austria, and Switzerland. For the present baseline analysis, disease characteristics and treatment data of the initial 40 pts were documented prospectively in 27 sites across Germany and Austria between 09/2020 and 08/2021. As BERING-CRC is ongoing, the study aims to enroll up to 500 pts from 96 German, Austrian, and Swiss sites. The study observes pts treated according to the approval as given in the respective Summary of Product Characteristics (SmPC). The primary objective is to analyze the 1-year overall survival rate. Secondary endpoints include efficacy, quality of life and tolerability of E+C. Data are analyzed descriptively using standard summary statistics. Results: 40 pts were included in this baseline analysis. The median age was 68 years (range 34-88) and 38% were female. 26 pts (65%) were documented with right-sided tumors and for 63% stage IV disease was noted at initial diagnosis. In the metastatic setting, the main sites of metastasis were liver, peritoneum, and lung (55%, 40%, 33% of pts, respectively), with 20% of pts having ≥ 3 organs involved. For 38% of pts, an ECOG performance status (PS) of 0 was documented at baseline assessment (60% ECOG PS 1 or 2). Adjuvant treatment was reported for 8 pts and 88% received chemotherapy alone in this setting. 3 pts (8%) were documented with E+C treatment directly following adjuvant therapy and half of all pts with documented first-line treatment received chemotherapy alone (CT), for 42% chemotherapy was combined with targeted therapy (CT+TT). In second-line, 74% of pts with documented treatment received E+C (9% CT, 17% CT+TT). Bi-weekly cetuximab dosing was reported for 11% of pts treated with E+C. Conclusions: While the high number of pts with right-sided tumors was in line with previous findings on BRAF V600E-mutant mCRC pts, considerably more pts were male in this initial real-world cohort and synchronous metastasis was reported markedly more often. As complementation to previous controlled clinical trial data, pts enrolled to date in BERING-CRC were notably older and presented with higher ECOG PS compared to the pivotal study. Clinical trial information: NCT04673955.

Bei einem CUP-Syndrom findet sich kein Primartumor. Deshalb stellt es eine besondere Herausforderung dar. Das Syndrom ist vielgestaltig, zeichnet sich aber durch eine Reihe gemeinsamer biologischer Charakteristika aus. Infolge verbesserter diagnostischer Moglichkeiten lassen sich spezifische Subgruppen differenzieren, die unterschiedlich behandelt werden mussen.

BACKGROUND The objective of this study was to evaluate the efficacy of belinostat, a histone deacetylase inhibitor, when added to paclitaxel/carboplatin in the empiric first-line treatment of patients with carcinoma of unknown primary site (CUP). METHODS In this randomized phase 2 trial, previously untreated patients with CUP were randomized to receive belinostat plus paclitaxel/carboplatin (group A) or paclitaxel/carboplatin alone (group B) repeated every 21 days. Patients were re-evaluated every 2 cycles, and those without disease progression continued treatment for 6 cycles. Patients in group A then continued receiving single-agent belinostat, whereas patients in group B stopped treatment. The primary endpoint was progression-free survival (PFS): The authors postulated that the addition of belinostat would improve PFS from 5 months (expected with paclitaxel/carboplatin) to 8 months. RESULTS In total, 89 patients were randomized (group A, n = 44; group B, n = 45), and the demographics and disease characteristics were balanced between the 2 groups. The addition of belinostat to paclitaxel/carboplatin did not improve PFS (group A, 5.4 months [95% confidence interval, 3.0-6.0 months]; group B, 5.3 months [95% confidence interval, 2.8-6.6 months]; P = .85). Overall survival was 12.4 months for group A versus 9.1 months for group B (P = .20). The response rate favored the belinostat group (45% vs 21%; P = .02). Belinostat resulted in a modest increase in treatment toxicity. CONCLUSIONS The addition of belinostat to paclitaxel/carboplatin did not improve the PFS of patients with CUP who were receiving first-line therapy, although the patients who received belinostat had a higher investigator-assessed response rate. Future trials in CUP should focus on specific subsets, defined either by the predicted tissue of origin or by the identification of targetable molecular abnormalities. Cancer 2015;121:1654–1661. © 2015 American Cancer Society.

Advanced CUP (cancer of unknown primary) as defined by disseminated involvement of several organs is the typical manifestation of the disease, making up 75–85 % of the patients. In a small share, the prognosis is favorable and specific therapeutic options are available (see Chap. 10). Empiric chemotherapy is the standard treatment for the vast majority of patients. A combination of platinum and taxane is the best documented option, yielding a median survival of 8–11 months, a 1-year survival rate of 37–45 %, and a 2-year survival rate of 18–26 %. Gemcitabine and irinotecan also proved to be effective in first-line treatment. Individual patient-specific and prognostic factors have to be considered for the choice of therapy. In many cases, single compound treatment is feasible; in some cases, the therapy should be limited to symptomatic treatment as defined by palliative care. Second-line therapy is not well documented but may be effective in selected patients. New treatment options are expected to result from gene expression profiling and recent developments in immunotherapy (see Chaps. 11 and 12).

The objective of this study was to evaluate the efficacy of belinostat, a histone deacetylase inhibitor, when added to paclitaxel/carboplatin in the empiric first-line treatment of patients with carcinoma of unknown primary site (CUP).In this randomized phase 2 trial, previously untreated patients with CUP were randomized to receive belinostat plus paclitaxel/carboplatin (group A) or paclitaxel/carboplatin alone (group B) repeated every 21 days. Patients were re-evaluated every 2 cycles, and those without disease progression continued treatment for 6 cycles. Patients in group A then continued receiving single-agent belinostat, whereas patients in group B stopped treatment. The primary endpoint was progression-free survival (PFS): The authors postulated that the addition of belinostat would improve PFS from 5 months (expected with paclitaxel/carboplatin) to 8 months.In total, 89 patients were randomized (group A, n = 44; group B, n = 45), and the demographics and disease characteristics were balanced between the 2 groups. The addition of belinostat to paclitaxel/carboplatin did not improve PFS (group A, 5.4 months [95% confidence interval, 3.0-6.0 months]; group B, 5.3 months [95% confidence interval, 2.8-6.6 months]; P = .85). Overall survival was 12.4 months for group A versus 9.1 months for group B (P = .20). The response rate favored the belinostat group (45% vs 21%; P = .02). Belinostat resulted in a modest increase in treatment toxicity.The addition of belinostat to paclitaxel/carboplatin did not improve the PFS of patients with CUP who were receiving first-line therapy, although the patients who received belinostat had a higher investigator-assessed response rate. Future trials in CUP should focus on specific subsets, defined either by the predicted tissue of origin or by the identification of targetable molecular abnormalities.

The term cancer of unknown primary site (CUP) syndrome is used to describe malignancies in which a complete diagnostic work-up detects metastases in the absence of an identifiable primary tumor.Based on a selective literature review, national and international guidelines, and the experience of the "Arbeitskreis CUP-Syndrom der Arbeitsgemeinschaft Internistische Onkologie der Deutschen Krebsgesellschaft" (CUP Syndrome Committee of the Medical Oncology Joint Working Group of the German Cancer Society), developments in the diagnosis and treatment of CUP syndrome are reported.Most patients diagnosed with CUP have an unfavorable prognosis, with a life expectancy of less than 12 months. Nevertheless, it is important to identify subsets of patients in whom specific treatment offers the chance of long-term survival or even full recovery.Only rigorous further development of diagnostic tools and treatment protocols will enable an improvement of the poor prognosis of patients with CUP syndrome. Specific molecular treatment strategies have shown promising results.

Carcinoma of unknown primary (CUP) is an intriguing clinical finding that is defined as biopsy-proven metastasis from a malignancy in the absence of an identifiable primary site after a complete clinical work-up. CUP is a relatively common clinical entity, accounting for approximately 3–5% of all cancer diagnoses, and consists of a heterogeneous group of tumors that have acquired the capacity to metastasize before the development of a clinically evident primary lesion. Notable advances have been made over the past years in the treatment of well-defined clinical subgroups of CUP, such as women with peritoneal carcinomatosis and young adults with poorly differentiated carcinomas of midline distribution, but for the majority of patients, the prognosis still remains poor. In this review, we highlight recent advances in the diagnosis and treatment of patients with CUP syndrome, and emphasize the importance of identifying several favorable subsets of CUP, amenable to specific treatment options. In addition, we will point out novel diagnostic and therapeutic approaches which will hopefully improve both our understanding and the prognosis of this more or less neglected disease.

To the Editor: Profound neutropenia bearing an increased risk of infections represents one of the cardinal problems after myeloablative and high-dose chemotherapy. In two recent reports we showed stable engraftment in patients transplanted with selected allogeneic CD34+ blood cells alone[1][1] or