A prospective observational registry evaluating clinical outcomes of Radium-223 treatment in a nonstudy population.

The ALSYMPCA study established a 3.6 month Overall Survival (OS) benefit in metastatic Castration Resistant Prostate Cancer (mCRPC) patients treated with Radium-223 dichloride (Ra-223) over placebo. Here we report clinical outcomes of Ra-223 treatment in a nonstudy population. In this prospective registry, patients from 20 Dutch hospitals were included prior to Ra-223 treatment. Clinical parameters collected included previous treatments and Adverse Events. Primary outcome was 6 months Symptomatic Skeletal Event (SSE)-free survival, while secondary outcomes included Progression-Free Survival (PFS) and Overall Survival (OS). Of the 305 patients included, 300 were evaluable. The mean age was 73.6 years, 90% had ≥6 bone metastases and 74.1% were pretreated with Docetaxel, 19.5% with Cabazitaxel and 80.5% with Abiraterone and/or Enzalutamide. Of all patients, 96.7% were treated with Ra-223 and received a median of 5 cycles. After a median follow-up of 13.2 months, 6 months SSE-free survival rate was 83%, median PFS was 5.1 months and median OS was 15.2 months. Six months SSE-free survival rate and OS were comparable with those reported in ALSYMPCA. "Previous Cabazitaxel treatment" and "bone-only metastases" were independent predictors of a shorter and longer PFS, respectively, while above-median LDH and "bone-only metastases" were independent predictors of shorter and longer OS, respectively. Toxicity was similar as reported in the ALSYMPCA trial. These results suggest that in a nonstudy population, Ra-223 treatment is well-tolerated, equally effective as in the ALSYMPCA population and that patients not previously treated with Cabazitaxel benefit most from Ra-223.

Comparability of PD-L1 immunohistochemistry assays for non-small-cell lung cancer: a systematic review.

Programmed cell death ligand 1 (PD-L1) immunohistochemistry is used to determine which patients with advanced non-small-cell lung cancer (NSCLC) respond best to treatment with PD-L1 inhibitors. For each inhibitor, a unique immunohistochemical assay was developed. This systematic review gives an up-to-date insight into the comparability of standardised immunohistochemical assays and laboratory-developed tests (LDTs), focusing specifically on tumour cell (TC) staining and scoring. A systematic search was performed identifying publications that assessed interassay, interobserver and/or interlaboratory concordance of PD-L1 assays and LDTs in tissue of NSCLC patients. Of 4294 publications identified through the systematic search, 27 fulfilled the inclusion criteria and were of sufficient methodological quality. Studies assessing interassay concordance found high agreement between assays 22C3, 28-8 and SP263 and properly validated LDTs, and lower concordance for comparisons involving SP142. A decrease in concordance, however, is seen with use of cut-offs, which hampers interchangeability of PD-L1 immunohistochemistry assays and LDTs. Studies assessing interobserver concordance found high agreement for all assays and LDTs, but lower agreement with use of a 1% cut-off. This may be problematic in clinical practice, as discordance between pathologists at this cut-off may result in some patients being denied valuable treatment options. Finally, five studies assessed interlaboratory concordance and found moderate to high agreement levels for various assays and LDTs. However, to assess the actual existence of interlaboratory variation in PD-L1 testing and PD-L1 positivity in clinical practice, studies using real-world clinical pathology data are needed.

Prognostic parameters for response to enzalutamide after docetaxel and abiraterone treatment in metastatic castration-resistant prostate cancer patients; a possible time relation.

BACKGROUND: Abiraterone Acetate (AA) and Enzalutamide (Enz) are effective hormonal treatments in mCRPC patients. Retrospective studies suggested clinical cross-resistance between Enz and AA. However, 12.8-39.1% of patients previously treated with docetaxel (Doc) and AA do respond to Enz. These responders have not been characterized. METHODS: 102 Enz treated mCRPC patients after AA and Doc treatment were included in this study. Differences in patient characteristics and previous treatment outcomes between PSA responders and non-responders on Enz were evaluated. RESULTS: Median Progression-Free Survival was 12.2 weeks (95%CI 11.7-14.3) and Overall Survival 43.5 weeks (95%CI 37.4-61.2). There were 26 (25%) Enz-responders and 76 (75%) non-responders. Significant higher percentages of Gleason scores ≥ 8 and PSA doubling times (PSA-DT) <3 months were found in Enz responders than in non-responders. The interval between end of AA and start of Enz treatment (IAE) for responders was 24.6 weeks (IQR 4.0-48.1) and 8.9 weeks for non-responders (IQR 3.7-25.9) (P = 0.08). In an IAE <40 days subgroup (34 patients), Enz responses were related to AA non-responsiveness, while univariate and logistic regression analysis of baseline criteria of a subgroup of patients with an IAE ≥ 40 (68 patients) revealed significant differences in baseline PSA levels, PSA-DT <3 months, Gleason scores ≥ 8 and IAE's between Enz responders and non-responders. CONCLUSIONS: PSA response to Enz after previous AA and Doc treatment was associated with a longer IAE, a higher Gleason score and a PSA-DT <3 months. Identification of these patients might be of value for sequencing of treatment options.

Enzalutamide as a Fourth- or Fifth-Line Treatment Option for Metastatic Castration-Resistant Prostate Cancer.

OBJECTIVE: To evaluate the efficacy of enzalutamide (Enz) as fourth- or fifth-line treatment in men with metastasized castration-resistant prostate cancer (mCRPC), by analyzing a retrospective cohort of heavily pretreated patients. METHODS: We evaluated toxicity, overall survival (OS), progression-free survival (PFS) and time to prostate-specific antigen (PSA) progression data from 47 CRPC patients treated with fourth- or fifth-line Enz. RESULTS: All patients were treated with docetaxel and abiraterone acetate and 42 patients (89%) with cabazitaxel. The median age of the patients was 69 years (IQR, 63-73.5), 79% had bone metastases, 55% had lymph node metastases, and 17% had visceral metastases. The median duration of Enz treatment was 12.0 weeks (IQR, 8.3-20.4), and 11 patients (23%) responded to Enz (maximum PSA decline ≥50%). In general, Enz was well tolerated, with the most frequently reported adverse events being fatigue and nausea. The median OS was 40.1 weeks (95% CI, 25.4-61.4), the median PFS was 12.1 weeks (95% CI, 9.9-14.0) and the median time to PSA progression was 15.7 weeks (95% CI, 14.0-28.7). CONCLUSIONS: Analysis of this retrospective cohort suggests that Enz is well tolerated and that there is a 23% response rate in heavily pretreated CRPC patients, which is comparable with third-line treatment outcomes.

Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment.

BACKGROUND: Enzalutamide (Enz) and abiraterone acetate (AA) are hormone treatments that have a proven survival advantage in patients with metastatic, castration-resistant prostate cancer who previously received docetaxel (Doc). Recently, limited activity of AA after Enz and of Enz after AA was demonstrated in small cohort studies. Here, the authors present the activity and tolerability of Enz in patients who previously received AA and Doc in the largest cohort to date. METHODS: The efficacy and tolerability of Enz were investigated in men with progressive, metastatic, castrate-resistant prostate cancer who previously received Doc and AA. Toxicity, progression-free survival, time to prostate-specific antigen (PSA) progression, and overall survival were retrospectively evaluated. RESULTS: Sixty-one patients were included in the analysis. The median age was 69 years (interquartile range [IQR], 64-74 years), 57 patients (93%) had an Eastern Cooperative Oncology Group performance status from 0 to 2, 48 patients (79%) had bone metastases, 33 patients (54%) had lymph node metastases, and 13 patients (21%) had visceral metastases. The median duration of Enz treatment was 14.9 weeks (IQR, 11.1-20.0 weeks), and 13 patients (21%) had a maximum PSA decline ≥50%. The median progression-free survival was 12.0 weeks (95% confidence interval [CI], 11.1-16.0 weeks), the median time to PSA progression was 17.4 weeks (95% CI, >16.0 weeks), and the median overall survival was 31.6 weeks (95% CI, >28.7 weeks). Enz was well tolerated, and fatigue and musculoskeletal pain were the most frequent grade ≥2 adverse events. The PSA response to Doc and AA did not predict the PSA response to Enz. CONCLUSIONS: Enz has modest clinical activity in patients with metastatic, castrate-resistant prostate cancer who previously received Doc and AA. PSA response to Doc and AA does not predict for PSA response to ENz.

Prognostic Value of Nivolumab Clearance in Non-Small Cell Lung Cancer Patients for Survival Early in Treatment.

INTRODUCTION: Immune checkpoint inhibitors improved survival of advanced stage non-small cell lung cancer patients, but the overall response rate remains low. A biomarker that identifies non-responders would be helpful to allow treatment decisions. Clearance of immune checkpoint inhibitors is related to treatment response, but its prognostic potential early in treatment remains unknown. Our primary aim was to investigate the prognostic potential of nivolumab clearance for overall survival early in treatment. Our secondary aim was to evaluate the performance of nivolumab clearance as prognostic biomarker. PATIENTS AND METHODS: Individual estimates of nivolumab clearances at first dose, 6 and 12 weeks after treatment initiation were obtained via nonlinear mixed-effects modelling. Prognostic value of nivolumab clearance was estimated using univariate Cox regression at first dose and for the ratios between 6 and 12 weeks to first dose. The performance of nivolumab clearance as biomarker was assessed by calculating sensitivity and specificity. RESULTS: During follow-up of 75 months, 69 patients were included and 865 died. Patients with a nivolumab clearance ≥ 7.3 mL/h at first dose were more likely to die compared to patients with a nivolumab clearance < 7.3 mL/h at first dose (hazard ratio [HR] = 3.55, 955 CI 1.75-7.20). The HRs of dose nivolumab clearance ratios showed similar results with a HR of 3.93 (955 CI 1.66-9.32) for 6 weeks to first-dose clearance ratio at a 0.953 cut-point and a HR of 2.96 (955 CI 1.32-6.64) for 12 weeks to first-dose clearance ratio at a cut-point of 0.814. For nivolumab clearance at all early time points, sensitivity was high (≥ 0.95) but specificity was low (0.11-0.29). CONCLUSION: Nivolumab clearance is indicative of survival early in treatment. Our results encourage to further assess the prognostic potential of immunotherapy clearance.

Chemotherapy for patients with EGFR-mutated NSCLC after progression on EGFR-TKI's: Exploration of efficacy of unselected treatment in a multicenter cohort study.

OBJECTIVES: In patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung (NSCLC) chemotherapy remains standard of care after progression on EGFR-tyrosine kinase inhibitors (TKIs). With the development of anti-angiogenic agents and immune checkpoint inhibitors the landscape of systemic regimens has changed significantly. This cohort study aims to evaluate the efficacy of chemotherapy regimens after progression on EGFR-TKI in a European population. MATERIAL AND METHODS: All consecutive patients treated with chemotherapy after progression on EGFR-TKI for EGFR-mutated NSCLC, were identified in two tertiary centers in the Netherlands. Data on best response, progression free survival (PFS) and overall survival (OS) were extracted from medical records. RESULTS: In total, 171 lines of chemotherapy were identified: platinum/pemetrexed (PP, n = 95), carboplatin/paclitaxel/bevacizumab/atezolizumab (CPBA, n = 32), paclitaxel/bevacizumab (PB, n = 36) and carboplatin/paclitaxel/bevacizumab (CPB, n = 8). Of the 171 lines, 106 were given as first-line after EGFR-TKI. Median PFS did not differ significantly between the first-line regimens (p = 0.50), with the highest PFS in PP (5.2 months [95% CI 4.5-5.9]) and CPBA (5.9 months [95% CI 3.8-80]). The majority of the PB group (n = 32) received this regimen in a second- or later line with a median PFS of 4.9 months (95% CI 3.3-6.6). First-line regimens had a median OS of 15.3 months (95% CI 11.6-18.9) with no significant difference between regimens (p = 0.85). CONCLUSION: After progression on EGFR-TKI, patients with EGFR-mutated NSCLC show substantial benefit on different chemotherapy regimens. In particular, favorable outcomes were seen in patients treated with PP and CPBA as first-line chemotherapy, and PB in further lines of chemotherapy.

Integrated analysis of pain, health-related quality of life, and analgesic use in patients with metastatic castration-resistant prostate cancer treated with Radium-223.

BACKGROUND: Radium-223 (Ra-223), an alpha-emitting radiopharmaceutical, established an improved overall survival and health-related quality of life (HRQoL) in symptomatic metastatic castration-resistant prostate cancer (mCRPC) patients. However, effects on pain were not specifically evaluated. Here we assess integrated HRQoL, pain, and opioid use in a contemporary, more extensively pretreated, symptomatic and asymptomatic mCRPC population. METHODS: mCRPC patients scheduled for Ra-223 treatment were included and analyzed for HRQoL, pain, and opioid use, using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Brief Pain Inventory-Short Form (BPI-SF) questionnaires and recording of opioid use and dosage, respectively. Primary outcome measure was the percentage of patients experiencing a complete pain response (score of 0 on the BPI-SF Worst pain item and no increase in daily use of analgesics). A complete or partial pain response (better BPI-SF score and decrease in opioid use) and a better or no change in HRQoL was evaluated as an integrated overall clinical response (IOCR). Secondary endpoints included the time to pain progression (TPP) and Total FACT-P deterioration (TTFD), defined as time from first Ra-223 treatment to clinical meaningful increase in BPI-SF Worst pain item score and Total FACT-P score, respectively. RESULTS: This registry included 300 patients, of whom 105 (35%) were evaluable for FACT-P and BPI-SF during Ra-223 treatment. Forty-five (43%) patients had pain at baseline (PAB) (BPI-SF Worst pain score 5-10 points) and 60 (57%) had no pain at baseline (no-PAB) (BPI-SF Worst pain score 0-4 points). Complete pain response was achieved in 31.4% of the patients, while 58% had an IOCR. The median TTP and TTFD were 5.6 and 5.7 months, respectively, while the difference between PAB and no-PAB patients was not significant. CONCLUSIONS: In contemporary, extensively pretreated mCRPC patients, Ra-223 treatment induced complete pain responses while integrated analysis of HRQoL, pain response, and opioid use demonstrated that the majority of patients derive clinical benefit.