Victoria Neiman

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

BACKGROUND Nivolumab plus ipilimumab produced objective responses in patients with advanced renal‐cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear‐cell advanced renal‐cell carcinoma. METHODS We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6‐week cycle). The coprimary end points were overall survival (alpha level,0.04), objective response rate (alpha level,0.001), and progression‐free survival (alpha level,0.009) among patients with intermediate or poor prognostic risk. RESULTS A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow‐up of 25.2 months in intermediate‐ and poor‐risk patients, the 18‐month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression‐free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment‐related adverse events occurred in 509 of 547 patients (93%) in the nivolumab‐plus‐ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment‐related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate‐ and poor‐risk patients with previously untreated advanced renal‐cell carcinoma. (Funded by Bristol‐Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749.)

Activity of Cabazitaxel After Docetaxel and Abiraterone Acetate Therapy in Patients With Castration-Resistant Prostate Cancer

BACKGROUND Cabazitaxel and AA have been approved by the US Food and Drug Administration for use after docetaxel in mCRPC. Recently, CAB appeared to be active when given after AA. AA is capable of inducing AR splice variants that confer ligand-independent AR transactivation. Because microtubule-targeting agents impair AR nuclear transport and activity, we raised concerns about CAB efficacy after AA failure in mCRPC. PATIENTS AND METHODS One hundred thirty mCRPC patients received AA after docetaxel treatment in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data using conventional methods. RESULTS Twenty-four patients received a median of 4 (range, 1-13) CAB cycles. Nineteen (79.1%) of them received primary prophylaxis with growth factors. Median patient characteristics were: age 65 (range, 57-85) years; Gleason score: 8 (range, 6-10); and PSA: 128.1 (range, 0.01-1700) ng/mL. A PSA response (≥ 50% decrease from baseline) occurred in 6 (31.5%) of 19 evaluable patients (95% confidence interval [CI], 11.8-54.2%). CAB therapy obtained a partial response in 2 of the 13 (15.3%) evaluable patients (95% CI, 2.9-45.4%). Median survival from initiation of CAB was 8.2 (95% CI, 3.34-13.05) months, from AA 16.1 (95% CI, 11.56-20.64) and from docetaxel 32.0 (95% CI, 11.56-39.69). CONCLUSION A limited number of patients with mCRPC received CAB after docetaxel and AA treatment. In this selected population, CAB was active.

Activity of cabazitaxel following docetaxel and abiraterone acetate in patients with castration-resistant prostate cancer.

186 Background: Cabazitaxel (CAB) and abiraterone-acetate (AA) have been approved after docetaxel in castration resistant prostate cancer (CRPC). Both exhibit hormonal effects. AA depletes androgen in microenvironment; taxanes affect the microtubule-dependent trafficking of the androgen receptor. Recently, clinical cross-resistance has been suggested between AA and taxanes. This prompted evaluation of CAB following docetaxel and AA in CRPC. METHODS Over 13 months until December 2011, 130 CRPC patients received AA after docetaxel in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data (PCWG2/RECIST and NCI toxicity criteria). RESULTS Fourteen (58.3%) received CAB/prednisone at 20 mg/m2 and 10 patients 25 mg/m2, overall a median of 4 (1-13) cycles. Nineteen (79.1%) received primary G-CSF support. Patient characteristics (median, range in parenthesis): Age 65 (57-85) years, Gleason- 8 (6-10), K.S- 80 (50-90) %. Metastatic sites: liver- 5 (20.8%), visceral- 8 (33.3%), osseous- 22 (91.6%), No. sites involved- 2 (1-4). Lab-work: PSA- 128.1 (0.01-1700) ng/ml, PSA Doubling time- 2.16 (0.64-7.41) months, alkaline phosphatase 129 (35-1200) u/L. Castration sensitive period - 16.2 (2.0-92.1) months. Using Cox univariate analysis, only K.S was near-significant for prediction of survival after initiating CAB, p=0.075, OR=0.315, 95% C.I (0.88-1.125). A PSA response of 30%, 95% C.I (11,8-54,2)% was observed after CAB with non progression occurring in 6 (26%) out of 23 evaluable patients, 95% CI (10.2-48.4)%. At analysis 11 patients are alive. Median survival from initiation of CAB was 8.2 (95% C.I 3.34-13.05) months, from AA 16.1 (95 C.I 11.56-20.64) and from docetaxel 32.0 (95% C.I 11.56-39.69). Non-progression with docetaxel (but not AA) was associated with longer survival with CAB, p=0.049, 43.1 v.s 17.4 months. Four (16.6%) patients developed infectious complications, including one death due to septic shock. CONCLUSIONS Limited number of patients with CRPC received CAB following docetaxel and AA. In this selected population CAB was active. Response to prior docetaxel was associated with prolonged survival to CAB therapy.

Decline in pulmonary function in patients with breast cancer receiving dose-dense chemotherapy: a prospective study

BACKGROUND Prompted by complaints of dyspnea in breast cancer patients receiving adjuvant dose-dense chemotherapy (DDC), we sought to evaluate the possible association of DDC with pulmonary dysfunction. PATIENTS AND METHODS A total of 34 consecutive patients receiving adjuvant DDC were enrolled. The chemotherapy regimen consisted of i.v. doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) (AC) every 14 days x4 with growth factor support followed by weekly i.v. paclitaxel 80 mg/m(2) x12. The following parameters were prospectively measured before and after the AC protocol (P1, P2) and at completion of paclitaxel treatment (P3): presence of dyspnea, blood pressure, pulse rate, hemoglobin, erythrocyte sedimentation rate, C-reactive protein level, cardiac ejection fraction, and pulmonary function. Repeated measures analysis was used to evaluate differences among the time points, and paired t-test was used to evaluate differences between consecutive time points. RESULTS Although only five patients (15%) complained of dyspnea, there was a significant decrease in mean carbon monoxide diffusing capacity (DLCO), in all patients from P1 (22.09 ml/min/mmHg) to P3 (15 ml/min/mmHg) and in 29 of 32 patients (90.6%) from P1 to P2 (15.96 ml/min/mmHg) (P<0.001). CONCLUSIONS DDC is associated with a statistical significant reduction in DLCO. Awareness of this potential toxicity may be important in women with preexisting lung disease.

RET Fusion Lung Carcinoma: Response to Therapy and Clinical Features in a Case Series of 14 Patients

Background RET (rearranged during transfection) fusions have been reported in 1% to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B‐RET and CCDC6‐RET fusion genes have been identified in 70% to 90% and 10% to 25% of tumors, respectively. The natural history and management of RET‐rearranged LADC are still being delineated. Materials and Methods We present a series of 14 patients with RET‐rearranged LADC. The response to therapy was assessed by the clinical response and an avatar model in 2 cases. Patients underwent chemotherapy, targeted therapy, and immunotherapy. Results A total of 14 patients (8 women; 10 never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B‐RET and CCDC6‐RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients had an early disseminated manifestation, seven with KIF5B‐RET rearranged tumor. The features of this subset included bilateral miliary lung metastases, bone metastases, and unusual early visceral abdominal involvement. One such patient demonstrated an early and durable complete response to cabozantinib for 7 months. Another 2 patients treated with cabozantinib experienced a partial response, with rapid significant clinical improvement. Four patients with tumors harboring CCDC6‐RET and KIF5B‐RET fusions showed pronounced and durable responses to platinum‐based chemotherapy that lasted for 8 to 15 months. Two patients’ tumors showed programmed cell death ligand 1‐positive staining but did not respond to pembrolizumab. The median overall survival was 22.8 months. Conclusion RET‐rearranged LADC in our series tended to occur as bilateral disease with early visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response. However, further studies are required in this group of patients. Micro‐Abstract Data are increasing regarding RET (rearranged during transfection) fusions in lung cancer. We present our experience with the natural history of this disease and its response to targeted therapy and standard chemotherapy in 14 patients. In our series, RET‐rearranged lung adenocarcinoma had an early disseminated presentation, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response.

Cost Effectiveness of Nivolumab in Advanced Renal Cell Carcinoma

BACKGROUND In recent years, new drugs have been introduced for second-line treatment of advanced renal cell carcinoma (RCC). Nivolumab increases overall survival and is associated with less toxicity compared to everolimus in this setting according to the CheckMate 025 study. However, because of the high cost of nivolumab, there is a need to define its value by considering both efficacy and cost. OBJECTIVE To estimate the cost effectiveness of nivolumab for second-line treatment of advanced RCC from the US payer perspective. DESIGN, SETTING, AND PARTICIPANTS A Markov model was developed to compare the costs and effectiveness of nivolumab with those of everolimus and placebo in second-line treatment of advanced RCC. Health outcomes were measured in life-years (LYs) and quality-adjusted LYs (QALYs). Drug costs were based on 2016 Medicare reimbursement rates. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Model robustness was assessed in univariable and probabilistic sensitivity analyses. We addressed the issue of the extensive duration of immunotherapy treatment among long-term survivors, which may or may not be approved by payers. RESULTS AND LIMITATIONS The total mean cost per patient was

Adjuvant Docetaxel and Cyclophosphamide (DC) with Prophylactic Granulocyte Colony-Stimulating Factor (G-CSF) on Days 8 &12 in Breast Cancer Patients: A Retrospective Analysis

101 070 for nivolumab and

Cost-effectiveness of Pembrolizumab in Second-line Advanced Bladder Cancer

50 935 for everolimus. Nivolumab generated a gain of 0.24 LYs (0.34 QALYs) compared to everolimus. The incremental cost-effectiveness ratio (ICER) for nivolumab was

Rapid Response to Larotrectinib (LOXO-101) in an Adult Chemotherapy-Naive Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6-NTRK3 Fusion

146 532/QALY versus everolimus and

Personalized prostate cancer screening among men with high risk genetic predisposition- study protocol for a prospective cohort study

226 197/QALY versus placebo. Limiting the maximal treatment duration of nivolumab to 2 yr reduced the ICER to