Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma.

BACKGROUND: Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow-up of 5 years. METHODS: Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6-week cycles). Efficacy was assessed in intent-to-treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk/poor-risk, and favorable-risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed. RESULTS: The median follow-up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression-free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent-to-treat patients (N = 550 vs 546). Point estimates for 2-year conditional overall survival beyond the 3-year landmark were higher with NIVO+IPI versus SUN (intent-to-treat patients, 81% vs 72%; intermediate-risk/poor-risk patients, 79% vs 72%; favorable-risk patients, 85% vs 72%). Conditional progression-free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune-mediated adverse event experience, body mass index, and age. CONCLUSIONS: Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow-up for a first-line checkpoint inhibitor-based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.

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 .).

Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial.

BACKGROUND: CheckMate 025 has shown superior efficacy for nivolumab over everolimus in patients with advanced renal cell carcinoma (aRCC) along with improved safety and tolerability. This analysis assesses the long-term clinical benefits of nivolumab versus everolimus. METHODS: The randomized, open-label, phase 3 CheckMate 025 trial (NCT01668784) included patients with clear cell aRCC previously treated with 1 or 2 antiangiogenic regimens. Patients were randomized to nivolumab (3 mg/kg every 2 weeks) or everolimus (10 mg once a day) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The secondary endpoints were the confirmed objective response rate (ORR), progression-free survival (PFS), safety, and health-related quality of life (HRQOL). RESULTS: Eight hundred twenty-one patients were randomized to nivolumab (n = 410) or everolimus (n = 411); 803 patients were treated (406 with nivolumab and 397 with everolimus). With a minimum follow-up of 64 months (median, 72 months), nivolumab maintained an OS benefit in comparison with everolimus (median, 25.8 months [95% CI, 22.2-29.8 months] vs 19.7 months [95% CI, 17.6-22.1 months]; hazard ratio [HR], 0.73; 95% CI, 0.62-0.85) with 5-year OS probabilities of 26% and 18%, respectively. ORR was higher with nivolumab (94 of 410 [23%] vs 17 of 411 [4%]; P < .001). PFS also favored nivolumab (HR, 0.84; 95% CI, 0.72-0.99; P = .0331). The most common treatment-related adverse events of any grade were fatigue (34.7%) and pruritus (15.5%) with nivolumab and fatigue (34.5%) and stomatitis (29.5%) with everolimus. HRQOL improved from baseline with nivolumab but remained the same or deteriorated with everolimus. CONCLUSIONS: The superior efficacy of nivolumab over everolimus is maintained after extended follow-up with no new safety signals, and this supports the long-term benefits of nivolumab monotherapy in patients with previously treated aRCC. LAY SUMMARY: CheckMate 025 compared the effects of nivolumab (a novel immunotherapy) with those of everolimus (an older standard-of-care therapy) for the treatment of advanced kidney cancer in patients who had progressed on antiangiogenic therapy. After 5 years of study, nivolumab continues to be better than everolimus in extending the lives of patients, providing a long-lasting response to treatment, and improving quality of life with a manageable safety profile. The results demonstrate that the clinical benefits of nivolumab versus everolimus in previously treated patients with advanced kidney cancer continue in the long term.

Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.

BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.

Context-dependent scaling of kinematics and energetics during contests and feeding in mantis shrimp.

Measurements of energy use, and its scaling with size, are critical to understanding how organisms accomplish myriad tasks. For example, energy budgets are central to game theory models of assessment during contests and underlie patterns of feeding behavior. Clear tests connecting energy to behavioral theory require measurements of the energy use of single individuals for particular behaviors. Many species of mantis shrimp (Stomatopoda: Crustacea) use elastic energy storage to power high-speed strikes that they deliver to opponents during territorial contests and to hard-shelled prey while feeding. We compared the scaling of strike kinematics and energetics between feeding and contests in the mantis shrimp Neogonodactylus bredini We filmed strikes with high-speed video, measured strike velocity and used a mathematical model to calculate strike energy. During contests, strike velocity did not scale with body size but strike energy scaled positively with size. Conversely, while feeding, strike velocity decreased with increasing size and strike energy did not vary according to body size. Individuals most likely achieved this strike variation through differential compression of their exoskeletal spring prior to the strike. Post hoc analyses found that N. bredini used greater velocity and energy when striking larger opponents, yet variation in prey size was not accompanied by varying strike velocity or energetics. Our estimates of energetics inform prior tests of contest and feeding behavior in this species. More broadly, our findings elucidate the role behavioral context plays in measurements of animal performance.

Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors.

BACKGROUND: Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, flat dosing is expected to shorten preparation time and improve ease of administration. With knowledge of nivolumab safety, efficacy, and pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment of the benefit-risk profile of a 240-mg flat dose relative to the approved 3-mg/kg dose was approached by quantitative clinical pharmacology. PATIENTS AND METHODS: A flat dose of 240 mg was selected based on its equivalence to the 3-mg/kg dose at the median BW of ∼80 kg in patients in the nivolumab program. The benefit-risk profile of nivolumab 240 mg was evaluated by comparing exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC; and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC, and RCC. RESULTS: The median nivolumab exposure and its distribution at 240 mg Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did not demonstrate a clinically meaningful relationship between BW or nivolumab exposure quartiles and frequency or severity of adverse events. The predicted safety and efficacy were similar across nivolumab exposure ranges achieved with 3 mg/kg Q2W or 240 mg Q2W flat dose. CONCLUSION: Based on population pharmacokinetic modeling, established flat exposure-response relationships for efficacy and safety, and clinical safety, the benefit-risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology approach provided evidence for regulatory decision-making on dose modification, obviating the need for an independent clinical study.

Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the CheckMate 025 study.

BACKGROUND: Nivolumab improved overall survival (OS) and objective response rate (ORR) versus everolimus in previously treated patients with advanced renal cell carcinoma in the phase III CheckMate 025 study (minimum follow-up: 14 months). We report efficacy and safety in the global and Japanese populations (minimum follow-up: 26 months). METHODS: Patients were randomized 1:1 to receive nivolumab 3 mg/kg intravenously every 2 weeks or everolimus 10-mg tablet orally once daily. Primary endpoint: OS, key secondary endpoints: ORR, progression-free survival and safety. RESULTS: Of 410 (nivolumab) and 411 (everolimus) patients, 37 (9%) and 26 (6%), respectively, were Japanese. Median OS for the global population was 26.0 months (nivolumab) and 19.7 months (everolimus; hazard ratio 0.73 [95% confidence interval [CI]: 0.61-0.88]; P = 0.0006), with medians not reached for Japanese patients. ORR for the global population was 26% (nivolumab) versus 5% (everolimus; odds ratio 6.13; 95% CI: 3.77-9.95); ORR for Japanese patients: 43% versus 8% (odds ratio 9.14; 95% CI: 1.76-88.33). In Japanese patients, any-grade treatment-related adverse events (AEs) occurred in 78% (Grade 3-4, 19%; most common, anemia [5%]) treated with nivolumab and 100% (Grade 3-4, 58%; most common, hypertriglyceridemia [12%]) treated with everolimus; the most common with nivolumab was diarrhea (19%) and with everolimus was stomatitis (77%). Quality of life was stable in the nivolumab arm. CONCLUSIONS: With >2 years of follow-up, Japanese patients had a higher response rate with nivolumab versus everolimus that was more pronounced yet consistent with the global population, with median OS not reached, and a favorable safety profile.

The comparative hydrodynamics of rapid rotation by predatory appendages.

Countless aquatic animals rotate appendages through the water, yet fluid forces are typically modeled with translational motion. To elucidate the hydrodynamics of rotation, we analyzed the raptorial appendages of mantis shrimp (Stomatopoda) using a combination of flume experiments, mathematical modeling and phylogenetic comparative analyses. We found that computationally efficient blade-element models offered an accurate first-order approximation of drag, when compared with a more elaborate computational fluid-dynamic model. Taking advantage of this efficiency, we compared the hydrodynamics of the raptorial appendage in different species, including a newly measured spearing species, Coronis scolopendra The ultrafast appendages of a smasher species (Odontodactylus scyllarus) were an order of magnitude smaller, yet experienced values of drag-induced torque similar to those of a spearing species (Lysiosquillina maculata). The dactyl, a stabbing segment that can be opened at the distal end of the appendage, generated substantial additional drag in the smasher, but not in the spearer, which uses the segment to capture evasive prey. Phylogenetic comparative analyses revealed that larger mantis shrimp species strike more slowly, regardless of whether they smash or spear their prey. In summary, drag was minimally affected by shape, whereas size, speed and dactyl orientation dominated and differentiated the hydrodynamic forces across species and sizes. This study demonstrates the utility of simple mathematical modeling for comparative analyses and illustrates the multi-faceted consequences of drag during the evolutionary diversification of rotating appendages.

Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. FINDINGS: From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5-12·7) with ipilimumab and 10·0 months (8·3-11·0) with placebo (hazard ratio [HR] 0·85, 0·72-1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1·46 (95% CI 1·10-1·95), for 5-12 months was 0·65 (0·50-0·85), and beyond 12 months was 0·60 (0·43-0·86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. INTERPRETATION: Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. FUNDING: Bristol-Myers Squibb.

Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies.

BACKGROUND: This report provides a survival update at a follow-up of >5 years (5.5-6 years) for patients with advanced melanoma who previously received ipilimumab in phase II clinical trials. Safety and efficacy data following ipilimumab retreatment are also reported. PATIENTS AND METHODS: Patients who previously received ipilimumab 0.3, 3, or 10 mg/kg in one of six phase II trials (CA184-004, CA184-007, CA184-008, CA184-022, MDX010-08, and MDX010-15) were eligible to enroll in the companion study, CA184-025. Upon enrollment, patients initially received ipilimumab retreatment, extended maintenance therapy, or were followed for survival only. Overall survival (OS) rates were evaluated in patients from studies CA184-004, CA184-007, CA184-008, and CA184-022. Safety and best overall response during ipilimumab retreatment at 10 mg/kg were assessed in study CA184-025. RESULTS: Five-year OS rates for previously treated patients who received ipilimumab induction at 0.3, 3, or 10 mg/kg were 12.3%, 12.3%-16.5%, and 15.5%-28.4%, respectively. Five-year OS rates for treatment-naive patients who received ipilimumab induction at 3 or 10 mg/kg were 26.8% and 21.4%-49.5%, respectively. Little to no change in OS was observed from year 5 up to year 6. The objective response rate among retreated patients was 23%. Grade 3/4 immune-related adverse events occurred in 25%, 5.9%, and 13.2% of retreated patients who initially received ipilimumab 0.3, 3, and 10 mg/kg, with the most common being observed in the skin (4.2%, 2.9%, 3.8%) and gastrointestinal tract (12.5%, 2.9%, 3.8%), respectively. CONCLUSIONS: At a follow-up of 5-6 years, ipilimumab continues to demonstrate durable, long-term survival in a proportion of patients with advanced melanoma. In some patients, ipilimumab retreatment can re-establish disease control with a safety profile that is comparable with that observed during ipilimumab induction. Further studies are needed to determine the contribution of ipilimumab retreatment to OS. CLINICALTRIALSGOV: NCT00162123.

Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study.

BACKGROUND: This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy. PATIENTS AND METHODS: In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor response. RESULTS: Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA declines of ≥50% (duration: 3-13+ months), one had complete response (duration: 11.3+ months), and six had stable disease (duration: 2.8-6.1 months). CONCLUSIONS: In mCRPC patients, ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating ipilimumab 10 mg/kg ± radiotherapy are ongoing. ClinicalTrials.gov identifier: NCT00323882.

A randomized, phase II, three-arm study of two schedules of ixabepilone or paclitaxel plus bevacizumab as first-line therapy for metastatic breast cancer.

The aim of this phase II trial was to estimate the objective response rate (ORR) of two different schedules of ixabepilone [weekly or every 3 weeks (Q3W)] combined with bevacizumab, relative to a reference arm of weekly paclitaxel and bevacizumab. Patients with human epidermal growth factor receptor 2-normal, chemotherapy-naïve metastatic breast cancer (MBC) were randomized 3:3:2 to ixabepilone 16 mg/m(2) weekly plus bevacizumab 10 mg/kg Q2W (Arm A: n = 46); ixabepilone 40 mg/m(2) Q3W (reduced to 32 mg/m(2) after four cycles of treatment) plus bevacizumab 15 mg/kg Q3W (Arm B: n = 45); or paclitaxel 90 mg/m(2) weekly plus bevacizumab 10 mg/kg intravenous infusion Q2W (Arm C: n = 32). Of 123 randomized patients, 122 were treated. All were followed for ≥19 months; 5 % of patients remained on study treatment at the time of this analysis. Grade 3 or 4 neutropenia was more common in Arm B (60 %) than Arms A (16 %) or C (22 %); other adverse events were similar. The investigator-assessed ORR was 48, 71, and 63 % for Arms A, B, and C, respectively. Median progression-free survival (randomized patients) was 9.6 months in Arm A, 11.9 months in Arm B, and 13.5 months in Arm C. In conclusion, ixabepilone Q3W plus bevacizumab has clinical activity as first-line therapy for MBC relative to paclitaxel plus bevacizumab, but with significantly greater risk of grade 3 or 4 neutropenia. In addition, these data suggest that weekly dosing of ixabepilone may be less active than Q3W dosing, but with less neutropenia.

Biomarker analysis from CheckMate 214: nivolumab plus ipilimumab versus sunitinib in renal cell carcinoma.

BACKGROUND: The phase 3 CheckMate 214 trial demonstrated higher response rates and improved overall survival with nivolumab plus ipilimumab versus sunitinib in first-line therapy for advanced clear-cell renal cell carcinoma (RCC). An unmet need exists to identify patients with RCC who are most likely to benefit from treatment with nivolumab plus ipilimumab. METHODS: In exploratory analyses, pretreatment levels of programmed death ligand 1 were assessed by immunohistochemistry. Genomic and transcriptomic biomarkers (including tumor mutational burden and gene expression signatures) were also investigated. RESULTS: Biomarkers previously associated with benefit from immune checkpoint inhibitor-containing regimens in RCC were not predictive for survival in patients with RCC treated with nivolumab plus ipilimumab. Analysis of gene expression identified an association between an inflammatory response and progression-free survival with nivolumab plus ipilimumab. CONCLUSIONS: The exploratory analyses reveal relationships between molecular biomarkers and provide supportive data on how the inflammation status of the tumor microenvironment may be important for identifying predictive biomarkers of response and survival with combination immunotherapy in patients with RCC. Further validation may help to provide biomarker-driven precision treatment for patients with RCC.

First-line Nivolumab plus Ipilimumab Versus Sunitinib in Patients Without Nephrectomy and With an Evaluable Primary Renal Tumor in the CheckMate 214 Trial.

We present an exploratory post hoc analysis from the phase 3 CheckMate 214 trial of first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in a subgroup of 108 patients with advanced renal cell carcinoma (aRCC) without prior nephrectomy and with an evaluable primary tumor, a population under-represented in clinical trials. Patients with clear cell aRCC were randomized to NIVO+IPI every 3 wk for four doses followed by NIVO monotherapy, or sunitinib every day for 4 wk (6-wk cycle). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and primary tumor shrinkage were assessed. PFS and ORR were assessed per independent radiology review committee using RECIST version 1.1. With minimum study follow-up of 4 yr for intent-to-treat patients, OS favored NIVO+IPI (n = 53) over sunitinib (n = 55; hazard ratio 0.63, 95% confidence interval 0.40-1.0) among patients without prior nephrectomy. ORR was higher (34% vs 15%; p = 0.0041) and median duration of response was longer with NIVO+IPI versus sunitinib (20.5 vs 14.1 mo); the best overall response was partial response in either arm. A ≥30% reduction in the diameter of intact target renal tumors was achieved in 35% of patients with NIVO+IPI versus 20% with sunitinib. Safety was consistent with the global study population. In conclusion, in patients with aRCC without prior nephrectomy and with an evaluable primary tumor, NIVO+IPI showed survival benefits and renal tumor reduction versus sunitinib. This trial is registered at ClinicalTrials.gov as NCT02231749. PATIENT SUMMARY: In an exploratory analysis of a large global trial (CheckMate 214), we observed positive outcomes (both survival and tumor response to treatment) with nivolumab plus ipilimumab over sunitinib in a subgroup of patients with advanced kidney cancer who did not undergo removal of their primary kidney tumor. This subset of patients represents a population that has not been studied in clinical trials and for whom outcomes with new immunotherapy combination regimens are not yet known. We conclude that treatment with nivolumab plus ipilimumab offers these patients a survival benefit versus sunitinib, consistent with that observed in the overall study, as well as a notable kidney tumor reduction.

Mechanoethology: The Physical Mechanisms of Behavior.

Research that integrates animal behavior theory with mechanics-including biomechanics, physiology, and functional morphology-can reveal how organisms accomplish tasks crucial to their fitness. Despite the insights that can be gained from this interdisciplinary approach, biomechanics commonly neglects a behavioral context and behavioral research generally does not consider mechanics. Here, we aim to encourage the study of "mechanoethology," an area of investigation intended to encompass integrative studies of mechanics and behavior. Using examples from the literature, including papers in this issue, we show how these fields can influence each other in three ways: (1) the energy required to execute behaviors is driven by the kinematics of movement, and mechanistic studies of movement can benefit from consideration of its behavioral context; (2) mechanics sets physical limits on what behaviors organisms execute, while behavior influences ecological and evolutionary limits on mechanical systems; and (3) sensory behavior is underlain by the mechanics of sensory structures, and sensory systems guide whole-organism movement. These core concepts offer a foundation for mechanoethology research. However, future studies focused on merging behavior and mechanics may reveal other ways by which these fields are linked, leading to further insights in integrative organismal biology.

Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma.

PURPOSE: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC. PATIENTS AND METHODS: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics. RESULTS: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3-22.9); n = 65; HR, 0.45 (95% CI, 0.3-0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33-0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged. CONCLUSIONS: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population.See related commentary by Hwang et al., p. 5.

Hydrodynamic sensing does not facilitate active drag reduction in the golden shiner (Notemigonus crysoleucas).

The lateral line system detects water flow, which allows fish to orient their swimming with respect to hydrodynamic cues. However, it is unclear whether this sense plays a role in the control of propulsion. Hydrodynamic theory suggests that fish could reduce drag by coordinating the motion of the head relative to detected flow signals. To test this hypothesis, we performed measurements of undulatory kinematics during steady swimming in the golden shiner (Notemigonus crysoleucas) at three speeds (4.5, 11.0 and 22.0 cm s(-1)). We found that the phase shift between yaw angle and lateral velocity (20.5+/-13.1 deg., N=5) was significantly greater than the theoretical optimum (0 deg.) and the amplitude of these variables created a hydrodynamic index (H=0.05+/-0.03, N=6) that was less than an order of magnitude below the theoretical prediction. Furthermore, we repeated these measurements after pharmacologically ablating the lateral line hair cells and found that drag reduction was not adversely influenced by disabling the lateral line system. Therefore, flow sensing does not facilitate active drag reduction. However, we discovered that ablating the lateral line causes the envelope of lateral displacement to nearly double at the envelope's most narrow point for swimming at 4.5 cm s(-1). Therefore, fish may use hydrodynamic sensing to modulate the lateral amplitude of slow undulatory swimming, which could allow rapid responses to changes in environmental flow.

The Strategy of Predator Evasion in Response to a Visual Looming Stimulus in Zebrafish (Danio rerio).

A diversity of animals survive encounters with predators by escaping from a looming visual stimulus. Despite the importance of this behavior, it is generally unclear how visual cues facilitate a prey's survival from predation. Therefore, the aim of this study was to understand how the visual angle subtended on the eye of the prey by the predator affects the distance of adult zebrafish (Danio rerio) from predators. We performed experiments to measure the threshold visual angle and mathematically modeled the kinematics of predator and prey. We analyzed the responses to the artificial stimulus with a novel approach that calculated relationships between hypothetical values for a threshold-stimulus angle and the latency between stimulus and response. These relationships were verified against the kinematic responses of zebrafish to a live fish predator (Herichthys cyanoguttatus). The predictions of our model suggest that the measured threshold visual angle facilitates escape when the predator's approach is slower than approximately twice the prey's escape speed. These results demonstrate the capacity and limits to how the visual angle provides a prey with the means to escape a predator.

Una diversidad de animales sobrevive a los encuentros con los depredadores al escapar de un inminente estímulo visual. A pesar de la importancia de este comportamiento, generalmente no está claro cómo las señales visuales facilitan la supervivencia de una presa de la depredación. Por lo tanto, el objetivo del presente estudio fue comprender cómo el ángulo visual que el depredador subtiende en el ojo de la presa afecta la distancia del pez cebra adulto (Danio rerio) de los depredadores. Realizamos experimentos para medir el ángulo visual del umbral y modelamos matemáticamente la cinemática del depredador y la presa. Analizamos las respuestas al estímulo artificial con un enfoque novedoso que calculaba las relaciones entre los valores hipotéticos para un ángulo umbral-estímulo y la latencia entre el estímulo y la respuesta. Estas relaciones se verificaron contra las respuestas cinemáticas del pez cebra a un depredador de peces vivos (Herichthys cyanoguttatus). Las predicciones de nuestro modelo sugieren que el ángulo visual del umbral medido facilita el escape cuando el enfoque del depredador es más lento que aproximadamente el doble de la velocidad de escape de la presa. Estos resultados demuestran la capacidad y los límites de cómo el ángulo visual proporciona a una presa los medios para escapar de un depredador.

Efficacy of Nivolumab plus Ipilimumab According to Number of IMDC Risk Factors in CheckMate 214.

In the randomized, open-label, phase 3 CheckMate 214 trial, nivolumab plus ipilimumab (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 wk for four doses, then nivolumab 3 mg/kg every 2 wk) had superior efficacy over sunitinib (50 mg once daily, 4 wk on, 2 wk off) in patients with untreated International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate- or poor-risk advanced renal cell carcinoma; the benefits were sustained through extended follow-up. To better characterize the association between outcomes and IMDC risk in CheckMate 214, we completed a post hoc analysis (n = 1051) of efficacy by the number of IMDC risk factors. The investigator-assessed objective response rate (ORR), overall survival (OS), and investigator-assessed progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors v1.1 were evaluated. ORR with nivolumab plus ipilimumab was consistent across zero to six IMDC risk factors, whereas with sunitinib it decreased with increasing number of risk factors. Benefits of nivolumab plus ipilimumab over sunitinib in terms of ORR (40-44% vs 16-38%), OS (hazard ratio [HR] 0.50-0.72), and PFS (HR 0.44-0.86) were consistently observed in subgroups with one, two, three, or four to six IMDC risk factors (p < 0.05 for treatment × no. of risk factors interaction). These results demonstrate the benefit of first-line nivolumab plus ipilimumab over sunitinib across all intermediate-risk and poor-risk groups, regardless of the number of IMDC risk factors. PATIENT SUMMARY: This report from the CheckMate 214 study describes a consistent efficacy benefit with first-line nivolumab plus ipilimumab over first-line sunitinib in all groups of patients with intermediate-risk or poor-risk advanced renal cell carcinoma, regardless of the number of risk factors they had before starting treatment. We conclude that there is a benefit of first-line treatment with nivolumab plus ipilimumab for all intermediate-risk patients, including those with one or two risk factors, and for all poor-risk patients, independent of the number of risk factors.