Determination of PD-L1 Expression in Circulating Tumor Cells of NSCLC Patients and Correlation with Response to PD-1/PD-L1 Inhibitors.

Circulating tumor cells (CTCs) hold great potential to answer key questions of how non-small cell lung cancer (NSCLC) evolves and develops resistance upon anti-PD-1/PD-L1 treatment. Currently, their clinical utility in NSCLC is compromised by a low detection rate with the established, Food and Drug Administration (FDA)-approved, EpCAM-based CellSearch® System. We tested an epitope-independent method (ParsortixTM system) and utilized it to assess PD-L1 expression of CTCs from NSCLC patients. We prospectively collected 127 samples, 97 of which were analyzed with the epitope-independent system in comparison to the CellSearch system. CTCs were determined by immunocytochemistry as intact, nucleated, CD45-, pankeratins (K)+ cells. PD-L1 status of CTCs was evaluated from 89 samples. With the epitope-independent system, ≥1 CTC per blood sample was detected in 59 samples (61%) compared to 31 samples (32%) with the EpCAM-based system. Upon PD-L1 staining, 47% of patients harbored only PD-L1+CTCs, 47% had PD-L1+ and PD-L1-CTCs, and only 7% displayed exclusively PD-L1-CTCs. The percentage of PD-L1+CTCs did not correlate with the percentage of PD-L1+ in biopsies determined by immunohistochemistry (p = 0.179). Upon disease progression, all patients showed an increase in PD-L1+CTCs, while no change or a decrease in PD-L1+CTCs was observed in responding patients (n = 11; p = 0.001). Our data show a considerable heterogeneity in the PD-L1 status of CTCs from NSCLC patients. An increase of PD-L1+CTCs holds potential to predict resistance to PD-1/PD-L1 inhibitors.

Frequency of Circulating Tumor Cells (CTC) in Patients with Brain Metastases: Implications as a Risk Assessment Marker in Oligo-Metastatic Disease.

Forty percent of non-small cell lung cancer (NSCLC) patients develop brain metastases, resulting in a dismal prognosis. However, patients in an oligo-metastatic brain disease setting seem to have better outcomes. Here, we investigate the possibility of using circulating tumor cells (CTCs) as biomarkers to differentiate oligo-metastatic patients for better risk assessment. Using the CellSearch® system, few CTCs were detected among NSCLC patients with brain metastases (n = 52, 12.5% ≥ two and 8.9% ≥ five CTC/7.5 mL blood) and especially oligo-metastatic brain patients (n = 34, 5.9%, and 2.9%). Still, thresholds of both ≥ two and ≥ five CTCs were independent prognostic indicators for shorter overall survival time among all of the NSCLC patients (n = 90, two CTC ≥ HR: 1.629, p = 0.024, 95% CI: 1.137⁻6.465 and five CTC ≥ HR: 2.846, p = 0.0304, CI: 1.104⁻7.339), as well as among patients with brain metastases (two CTC ≥ HR: 4.694, p = 0.004, CI: 1.650⁻13.354, and five CTC ≥ HR: 4.963, p = 0.003, CI: 1.752⁻14.061). Also, oligo-brain NSCLC metastatic patients with CTCs had a very poor prognosis (p = 0.019). Similarly, in other tumor entities, only 9.6% of patients with brain metastases (n = 52) had detectable CTCs. Our data indicate that although patients with brain metastases more seldom harbor CTCs, they are still predictive for overall survival, and CTCs might be a useful biomarker to identify oligo-metastatic NSCLC patients who might benefit from a more intense therapy.

First salvage treatment of germ cell tumor patients with bone metastases: retrospective analysis of a large international database.

PURPOSE: To retrospectively analyze clinical characteristics, prognostic factors, and optimal treatment of patients with bone metastases (BM) of germ cell tumors (GCT) at first relapse. METHODS: One hundred and four GCT patients with BM were identified from the IPFSG database containing 1,594 patients at first relapse. Within this database, all patients experienced unequivocal relapse/progression after cisplatin-based chemotherapy and had received either conventional (CD-CTX) or high-dose chemotherapy (HD-CTX) as first salvage treatment. RESULTS: At relapse, eight patients (8 %) had BM only, concomitant relapse with lung, brain, liver and/or nodal metastases were present in 40 (39 %), 6 (6 %), 27 (26 %), and 69 (66 %) pts, respectively. Patients clustered over all IPFSG subgroups, and the IPFSG score could be confirmed. Salvage treatment was CD-CTX in 35 and HD-CTX in 69 patients. Overall response (CR, PR) rate to salvage chemotherapy was 81 % (HD-CTX) versus 43 % (CD-CTX; p < 0.001). Median follow-up was 14 months (mos; range 1-161). Both, median PFS and OS, were higher after HD-CTX compared to CD-CTX [PFS 9 (95 % CI 6-12) vs. 5 (3-7) mos (p < 0.01); OS 18 (12-24) vs. 13 (8-18) mos (p = 0.078)]. CONCLUSIONS: GCT patients relapsing with BM have a dismal outcome. Retrospectively, first salvage HD-CTX seems to improve treatment response and outcome. Further evaluation of characteristics and treatment of GCT patients with BM is warranted.

First salvage treatment in patients with advanced germ cell cancer after cisplatin-based chemotherapy: analysis of a registry of the German Testicular Cancer Study Group (GTCSG).

PURPOSE: We analyzed prognostic categories at first relapse according to the International Prognostic Factors Study Group (IPFSG) criteria as well as the efficacy of salvage treatment. METHODS: 143 patients with relapsed or refractory germ cell cancer undergoing first salvage treatment with conventional-dose (CD-CX, n = 48) or high-dose chemotherapy with autologous stem cell support (HD-CX, n = 95) contributed by nine centers were retrospectively analyzed. RESULTS: Prognostic subgroups according to IPFSG criteria were: very low risk 13/143, low risk 36/143, intermediate risk 66/143, high risk 22/143, and very high risk 6/143 patients. The IPFSG categories significantly correlated with overall survival (OS) (p = 0.025) after 1st salvage treatment. After a median follow-up of 19 months, 55 % of all patients had relapsed and 33 % had died. For the entire cohort, progression-free survival (PFS) rate after 2 years was 43 %, and OS rate after 5 years was 52 %. Compared to the HD-CX group, vital carcinoma was found more often in secondarily resected lesions following CD-CX (22/29 vs. 22/45; p = 0.021). Second relapse rate was higher with 75 versus 44 %, resulting in a shorter median PFS with 8 versus 42 months (p < 0.001), but this did not translate into different OS (p = 0.931). At subsequent relapses, 26/36 patients received HD-CX as ≥2nd-salvage treatment. CONCLUSION: This analysis confirms the prognostic value of the IPFSG prognostic score. HD-CX seemed superior to CD-CX as first salvage treatment with respect to PFS in this retrospective analysis.

CNS metastases in non-small-cell lung cancer: current role of EGFR-TKI therapy and future perspectives.

A considerable proportion of non-small-cell lung cancer (NSCLC) patients will develop central nervous system (CNS) metastases throughout the course of their disease and these manifestations cause significant morbidity and mortality. Accordingly, novel therapies with high efficacy and low toxicity are needed for NSCLC-related CNS metastases. In NSCLC patients with activating epidermal growth factor receptor gene (EGFR) mutations EGFR-specific tyrosine kinase inhibitors (TKI) represent effective and well tolerated modes of therapy, however, it has been unclear whether these drugs are also able to cross the blood-brain-barrier (BBB) and cause remission of CNS metastases. Recent studies suggest that this might indeed be the case and intracerebral response rates of 70-80% in molecularly selected patients are considerably higher compared to what would be expected for standard approaches like systemic chemotherapy and whole brain radiation therapy. Limitations in the application of EGFR-TKI may arise from genetic heterogeneity between the primary tumor and CNS metastases. Accordingly, the acquisition of repeated biopsies from all relevant metastatic sites, including the CNS, may be necessary to guide therapeutic decisions. However, even in EGFR-wildtype patients EGFR-TKI seem to represent a valuable second line therapy with response rates of about 10%. Application of EGFR-TKI in a "pulsative" pattern may help to overcome insufficient delivery of TKI to the cerebro-spinal fluid and may further increase response rates and time until progression. In the future, combination of EGFR-TKI with radiation or chemotherapy and/or incorporation of next-generation TKI should be evaluated regarding their potential for further optimizing therapy of NSCLC patients with CNS metastases.

Bone metastases in germ cell tumor patients.

PURPOSE: Little data exist on characteristics, treatment, and outcome of patients with bone metastases from germ cell cancer. METHODS: A total of 434 patients with poor prognosis germ cell cancer, who underwent primary high-dose chemotherapy (HD-CTX) within two phase II trials, were retrospectively analyzed. RESULTS: 40 patients (9%) presented with primary bone metastases. Bone metastases were significantly more frequently observed in patients with primary mediastinal tumors, yolk sac tumor histology, and synchronous liver metastases. Overall response rate to HD-CTX was 85%. 20% of patients underwent consolidating radiotherapy, and 10% had resection of bone metastases revealing necrosis in all cases. Progression-free survival rate after primary treatment was 63% and, including salvage treatment after first relapse, overall long-term survival rate was 75%. Four patients (0.9%) relapsed with isolated bone metastases, all with bone metastases at primary diagnosis. None had previously received surgery or radiotherapy and all died within 1 year. 10 patients with primary bone metastases showed recurrences at other localizations. No patient relapsed with bone plus other metastases or with de novo bone metastases. CONCLUSIONS: Bone metastases were associated with a primary mediastinal nonseminoma, yolk sac histology, and liver metastases at first diagnosis. In this cohort of patients receiving HD-CTX as first-line treatment, 63% achieved long-term progression-free survival. Skeletal relapses were rare, but showed dismal outcome.