Impact of Increasing PD-L1 Levels on Outcomes to PD-1/PD-L1 Inhibition in Patients With NSCLC: A Pooled Analysis of 11 Prospective Clinical Trials.

BACKGROUND: Programmed death ligand 1 (PD-L1) expression is recognized as a key biomarker in the treatment of non-small cell lung cancer (NSCLC) with anti-PD(L)1 inhibitors. Previous work has highlighted that outcomes in patients with NSCLC treated with anti-PD(L)1 inhibitors generally improve with increasing PD-L1 expression. The objectives of these analyses are to quantitate the effect of PD-L1 expression on outcomes, to characterize the potentially nonlinear relationship between PD-L1 expression and outcomes, and to assess potential differences in these relationships across subgroups. PATIENTS AND METHODS: We performed a retrospective, pooled analysis of 11 clinical trials submitted to the US FDA between 2015 and 2022 that included patients with advanced NSCLC treated with anti-programmed death 1 or anti-PD-L1 immune checkpoint inhibitor (ICI) monotherapy in the first-line (1L) or second-line (2L) treatment setting. The clinical outcomes explored were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). RESULTS: The primary analysis population included 3806 patients with advanced NSCLC, of which 2040 were treated in 1L and 1766 in 2L. For patients with a PD-L1 score of 100% in the 1L setting, the hazard ratio versus a patient with 1% PD-L1 was 0.55 (95% CI, 0.43 to 0.70) for OS and 0.50 (95% CI, 0.41 to 0.61) for PFS. For patients with a PD-L1 score of 100% in the 2L setting, the hazard ratio versus a patient with 0% PD-L1 was 0.55 (95% CI, 0.43 to 0.71) for OS and 0.51 (95% CI, 0.41 to 0.63) for PFS. Subgroup analyses suggested that this relationship may vary by subgroup, particularly by region. CONCLUSIONS: These analyses suggest PD-L1 expression has an appreciable impact on clinical outcomes for patients with NSCLC treated with ICI. As the impact of PD-L1 expression on outcomes may vary across regions, it is critical that future trials are multiregional and enroll a diverse patient population.

Accelerating pandemic response with the emergency Omicron RT-PCR test: A comprehensive solution for COVID-19 diagnosis and tracking.

The Omicron variant of concern (VOC) has surged in many countries and replaced the previously reported VOC. To identify different Omicron strains/sublineages on a rapid, convenient, and precise platform, we report a novel multiplex real-time reverse transcriptase polymerase chain reaction (RT-PCR) method in one tube based on the Omicron lineage sequence variants' information. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subvariants were used in a PCR-based assay for rapid identification of Omicron sublineage genotyping in 1000 clinical samples. Several characteristic mutations were analyzed using specific primers and probes for the spike gene, del69-70, and F486V. To distinguish Omicron sublineages (BA.2, BA.4, and BA.5), the NSP1:141-143del in the ORF1a region and D3N mutation in membrane protein occurring outside the spike protein region were analyzed. Results from the real-time PCR assay for one-tube accuracy were compared to those of whole genome sequencing. The developed PCR assay was used to analyze 400 SARS-CoV-2 positive samples. Ten samples determined as BA.4 were positive for NSP1:141-143del, del69-70, and F486V mutations; 160 BA.5 samples were positive for D3N, del69-70, and F486V mutations, and 230 BA.2 samples were without del69-70. Screening these samples allowed the identification of epidemic trends at different time intervals. Our novel one-tube multiplex PCR assay was effective in identifying Omicron sublineages.

Iatrogenic Abdominal Aortic Rupture During Transpedicular Bone Grafting for Thoracolumbar Burst Fractures Successfully Treated by Endovascular Stent Implantation.

PURPOSE: Vascular injury resulting from transpedicular bone grafting in the treatment of thoracolumbar burst fractures has not been reported but can be lethal. The management of patients with iatrogenic aortic injury remains a difficult clinical problem. This study describes a case of iatrogenic abdominal aortic rupture at the level of L2 during transpedicular bone grafting for the first time. CASE REPORT: A 55 year-old male patient suffered from a T12 vertebral body mild compression fracture and an L2 vertebral body burst fracture due to falling. This patient was treated with posterior open reduction and pedicle screw fixation combined with transpedicular bone grafting in the L2 vertebrae using a paravertebral approach. Unfortunately, during transpedicular bone grafting, the abdominal aorta was punctured by the tip of the graft funnel. The use of endovascular stent implantation successfully averted a clinical catastrophe. The patient had a good clinical outcome, and no complications associated with vascular trauma were apparent at a 1-year follow-up examination. CONCLUSION: For the repair of vascular injury caused by transpedicular bone grafting, endovascular techniques can provide a safe, minimally invasive, and effective treatment option. CLINICAL IMPACT: Surgeons should carefully evaluate the specificity of the patient's anatomical structures preoperatively and be more cautious during transpedicular bone grafting in the treatment of thoracolumbar burst fractures.

Time to deterioration of symptoms or function using patient-reported outcomes in cancer trials.

Time-to-event endpoints for patient-reported outcomes, such as time to deterioration of symptoms or function, are frequently used in cancer clinical trials. Although time-to-deterioration endpoints might seem familiar to cancer researchers for being similar to survival or disease-progression endpoints, there are unique considerations associated with their use. The complexity of time-to-deterioration endpoints should be weighed against the information that they add to the tumour, survival, and safety data used to inform the risks and benefits of an investigational drug. Here we use the estimand framework to show how analytical decisions answer different clinical questions of interest, some of which might be uninformative. Challenges including the consideration of intercurrent events, the difficulty in maintaining adequate completion rates, and considerable patient and trial burden from long-term, serial, patient-reported outcome measurements render time to deterioration a problematic approach for widespread use. For trials in which a comparative benefit in symptoms or function is an objective, an analysis at pre-specified relevant timepoints could be a better approach.

Overall survival in patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer treated with a cyclin-dependent kinase 4/6 inhibitor plus fulvestrant: a US Food and Drug Administration pooled analysis.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first-line or second-line treatment of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival in patients in specific clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival results in patients treated with a CDKI and fulvestrant. METHODS: In this exploratory analysis, we pooled individual patient data from three phase 3 randomised trials of CDKI or placebo in combination with fulvestrant in patients with breast cancer submitted to the US Food and Drug Administration and approved before Aug 1, 2020, in support of marketing applications. All analysed patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0-1, had hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, and received at least one dose of CDKI or placebo in combination with fulvestrant. The median overall survival was estimated using Kaplan-Meier methods, and hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression models. Patients were analysed collectively, by number of previous lines of systemic endocrine therapy in any disease setting (first-line or endocrine naive vs second-line and later), and in various clinicopathological subgroups of interest. The estimated median overall survival was not reported by group when the pooled population included patients treated across lines of therapy because of potential patient heterogeneity. All results presented are considered exploratory and hypothesis generating. FINDINGS: Across the three pooled trials, 1960 patients were randomly assigned between Oct 7, 2013, and June 10, 2016 (12 patients were not treated and 1296 [66%] patients were randomly assigned to CDKI and 652 [33%] to placebo). In all treated patients (n=1948), the estimated HR for overall survival was 0·77 (95% CI 0·68-0·88), with a median follow-up of 43·7 months (IQR 37·8-47·7) and deaths in 935 (48%) of the 1948 patients. The difference in estimated median overall survival was 7·1 months, favouring CDKIs. In patients who received CDKIs or placebo in combination with fulvestrant as first-line systemic endocrine therapy (two trials; n=396), the estimated HR for overall survival was 0·74 (95% CI 0·52-1·07), with a median follow-up of 39·4 months (IQR 37·0-42·2). 123 (31%) of these patients died. The difference in estimated median overall survival could not be calculated because median overall survival was not estimable (95% CI 50·9-not estimable) in the CDKI group and was 45·7 months (95% CI 41·7-not estimable) in the placebo group. In patients who received CDKIs or placebo in combination with fulvestrant as second-line or later systemic endocrine therapy (three trials; n=1552), the estimated HR for overall survival was 0·77 (95% CI 0·67-0·89), with a median follow-up of 45·1 months (95% CI 39·2-48·5). 812 (52%) of these patients died. The difference in estimated median overall survival was 7·0 months, favouring CDKIs. INTERPRETATION: The addition of CDKIs to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDKIs plus fulvestrant for the treatment of patients with hormone receptor-positive, HER2-negative, advanced breast cancer. FUNDING: None.

Survival outcomes in older men with non-metastatic castration-resistant prostate cancer treated with androgen receptor inhibitors: a US Food and Drug Administration pooled analysis of patient-level data from three randomised trials.

BACKGROUND: Little is known about the benefit-risk profile of second-generation androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. We aimed to examine the efficacy and safety of second-generation androgen receptor inhibitors in men aged 80 years or older with non-metastatic castration-resistant prostate cancer. METHODS: We searched for all randomised controlled clinical trials evaluating second-generation androgen receptor inhibitors in patients with non-metastatic castration-resistant prostate cancer submitted to the US Food and Drug Administration before Aug 15, 2020, and pooled data from three trials that met the selection criteria. All three trials enrolled patients who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, castration-resistant prostate cancer, prostate-specific antigen (PSA) 2·0 µg/L or greater, PSA doubling time of 10 months or less, and no evidence of distant metastatic disease on conventional imaging per the investigator's assessment at the time of screening. All patients had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell features. All patients who were randomly assigned to androgen receptor inhibitor or placebo groups in these trials were considered assessable and were included in this pooled analysis. We evaluated the effect of age on metastasis-free survival and overall survival across age groups (<80 years vs ≥80 years) in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study treatment. FINDINGS: Between Oct 14, 2013, and March 9, 2018, 4117 patients were assigned to androgen receptor inhibitor (apalutamide, enzalutamide, or daralutamide; n=2694) or placebo (n=1423) across three randomised trials. The median follow-up duration for metastasis-free survival was 18 months (IQR 11-26) and for overall survival was 44 months (32-55). In patients aged 80 years or older (n=1023), the estimated median metastasis-free survival was 40 months (95% CI 36-41) in the androgen receptor inhibitor groups and 22 months (18-29) in the placebo groups (adjusted hazard ratio [HR] 0·37 [95% CI 0·28-0·47]), and the median overall survival was 54 months (50-61) versus 49 months (43-58), respectively (adjusted HR 0·79 [0·64-0·98]). In patients younger than 80 years of age (n=3094), the estimated median metastasis-free survival was 41 months (95% CI 36-not estimable [NE]) in the androgen receptor inhibitor groups and 16 months (15-18) in the placebo groups (adjusted HR 0·31 [95% CI 0·27-0·35]), and the median overall survival was 74 months (74-NE) versus 61 months (56-NE), respectively (adjusted HR 0·69 [0·60-0·80]). In patients aged 80 years or older, grade 3 or worse adverse events were reported in 371 (55%) of 672 patients in the androgen receptor inhibitor groups and 140 (41%) of 344 patients in the placebo groups, compared with 878 (44%) of 2015 patients in the androgen receptor inhibitor groups and 321 (30%) of 1073 patients in the placebo groups among patients younger than 80 years. The most common grade 3-4 adverse events were hypertension (168 [8%] of 2015 patients aged <80 years and 51 [8%] of 672 patients aged ≥80 years in the androgen receptor inhibitor groups vs 53 [5%] of 1073 patients aged <80 years and 22 [6%] of 344 patients aged ≥80 years in the placebo groups) and fracture (61 [3%] and 36 [5%] in the androgen receptor inhibitor groups vs 15 [1%] and 11 [3%] in the placebo groups). INTERPRETATION: The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with non-metastatic castration-resistant prostate cancer might help clinicians to offer individualised treatment to each patient. FUNDING: None.

FDA Approval Summary: Olaparib Monotherapy or in Combination with Bevacizumab for the Maintenance Treatment of Patients with Advanced Ovarian Cancer.

On December 19, 2018, the U.S. Food and Drug Administration (FDA) granted approval to olaparib monotherapy for first-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer and, on May 8, 2020, expanded the indication of olaparib to include its use in combination with bevacizumab for first-line maintenance treatment of homologous recombination deficient (HRD)-positive advanced ovarian cancer. Both these approvals were based on randomized, double-blind, placebo-controlled trials. Approval for olaparib monotherapy was based on the SOLO-1 trial, comparing the efficacy of olaparib versus placebo in patients with BRCAm advanced ovarian, fallopian tube, or primary peritoneal cancer after surgical cytoreduction and first-line platinum-based chemotherapy. Two companion diagnostic (CDx) tests were approved with this indication: BRACAnalysis CDx, for germline BRCA1/2 alterations, and FoundationOne CDx, for BRCA1/2 alterations in tissue specimens. Approval for olaparib in combination with bevacizumab was based on the results of the PAOLA-1 trial that compared olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer after first-line platinum-based chemotherapy and bevacizumab. Myriad myChoice CDx was designated as a companion diagnostic device for use of olaparib plus bevacizumab combination for ovarian cancer associated with HRD-positive status. Both trials demonstrated clinically meaningful improvements in progression-free survival and favorable benefit-risk profiles for the indicated populations. This article summarizes the FDA thought process and data supporting the approval of olaparib as monotherapy and in combination with bevacizumab for maintenance therapy in this setting. IMPLICATIONS FOR PRACTICE: These approvals represent the first poly (ADP-ribose) polymerase inhibitor, alone or in combination with bevacizumab, approved in first-line maintenance treatment of women with advanced ovarian cancer after cytoreductive surgery and chemotherapy. In patients with BRCA-mutated tumors, olaparib monotherapy demonstrated a 70% reduction in the risk of disease progression or death compared with placebo, and olaparib in combination with bevacizumab demonstrated a 67% reduction in the risk of disease progression or death compared with bevacizumab alone in homologous recombination deficient-positive tumors. These approvals represent a major advance for the treatment of women with advanced ovarian cancer who are in complete or partial response after their initial platinum-based chemotherapy.

FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious BRCA-Mutated Metastatic Castrate-Resistant Prostate Cancer.

The U.S. Food and Drug Administration (FDA) granted accelerated approval to rucaparib in May 2020 for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane. This approval was based on data from the ongoing multicenter, open-label single-arm trial TRITON2. The primary endpoint, confirmed objective response rate, in the 62 patients who met the above criteria, was 44% (95% confidence interval [CI]: 31%-57%). The median duration of response was not estimable (95% CI: 6.4 to not estimable). Fifty-six percent of patients had a response duration of >6 months and 15% >12 months. The safety profile of rucaparib was generally consistent with that of the class of poly-(ADP-ribose) polymerase enzyme inhibitors and other trials of rucaparib in the treatment of ovarian cancer. Deaths due to adverse events (AEs) occurred in 1.7% of patients, and 8% discontinued rucaparib because of an AE. Grade 3-4 AEs occurred in 59% of patients. No patients with prostate cancer developed myelodysplastic syndrome or acute myeloid leukemia. The trial TRITON3 in patients with mCRPC is ongoing and is planned to verify the clinical benefit of rucaparib in mCRPC. This article summarizes the FDA thought process and data supporting this accelerated approval. IMPLICATIONS FOR PRACTICE: The accelerated approval of rucaparib for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer who have been treated with androgen receptor-directed therapy and a taxane represents the first approved therapy for this selected patient population. This approval was based on a single-arm trial demonstrating a confirmed objective response rate greater than that of available therapy with a favorable duration of response and an acceptable toxicity profile. The ongoing trial TRITON3 is verifying the clinical benefit of this drug.

Single-stage debridement via autogenous iliac bone graft through the OLIF corridor and lateral fixation in treating spontaneous single-level lumbar pyogenic spondylodiscitis.

BACKGROUND: The aim of the present study was to investigate the efficacy and safety of mini-open oblique debridement and lumbar interbody fusion combined with lateral screw fixation for treating single-level pyogenic spondylodiscitis. METHODS: Twelve patients with single-level lumbar pyogenic spondylodiscitis underwent OLIF combined with lateral screw fixation were analyzed. Patients underwent follow-up for 12 to 24 months. The clinical characteristics, etiological examinations, operative time, intraoperative blood loss, Oswestry Disability Index (ODI), visual analog scale score (VAS), postoperative complications, and the bony fusion rate were recorded. RESULTS: The mean follow-up period of time was 14.8 months. The average operative time and intra-operative blood loss were 129.0 ± 19.76 min and 309.2 ± 92.96 mL, respectively. No severe intra-operative complications were observed during surgery, except in 1 case that develops abdominal pain and distension after surgery, 2 cases that develop left-sided transient thigh pain/numbness and 8 cases that complains of donor site (iliac crest) pain. All of these symptoms disappeared 8 weeks after surgery. Tissue sample cultures were obtained from all patients intraoperatively and four (33.3%) were positive, including 2 with Staphylococcus aureus, 1 with Staphylococcus epidermidis, and 1 with Escherichia coli. During an average of 22.5 ± 2.1 days (range, 14-29 days) after surgery, WBC, CPR, and ESR levels in all patients had returned to normal. All patients were pain free with no recurring infection. Solid bony fusions were observed in all cases within 6 months, including 10 with I grade fusion, 2 with II grade fusion according to the classification suggested by Burkus et al. No fixation failure was observed during follow up and solid bony fusions were observed in all 12 patients at finally follow-up. A significant postoperative increase was also observed in the mean segmental height and lordosis (P < 0.05), followed by a slight decrease of segmental height and lordosis at final follow-up. At the final follow up, the mean VAS (1.5 ± 0.6) and ODI (18.9 ± 7.6) were significantly lower than VAS (8.4 ± 2.7) and ODI (71.2 ± 16.5) before surgery (P < 0.01). CONCLUSION: Single-stage debridement with autogenous iliac bone graft through the OLIF corridor and lateral fixation was a feasible surgical approach in our consecutive 12 cases of pyogenic spondylitis.

Hypermethylation of SHISA3 DNA as a blood-based biomarker for colorectal cancer.

In Taiwan, colorectal cancer (CRC) is the second most common cancer and the cancer with the third highest mortality rate. This may be because of the difficulty of detecting the disease in the early stages, as well as the fact that colonoscopy, a typical method used in screening for CRC, causes discomfort to the recipient and is prone to technical interference. For the earlier detection of CRC, finding an easier screening method with a simpler collection procedure is essential. Thus, in the present study, plasma samples from patients with CRC were analyzed to determine the extent of methylation in SHISA3 DNA. Studies have suggested that SHISA3, a newly identified tumor suppressor, can regulate tumor growth, and that the inactivation of its DNA can be traced to epigenomic alterations in CRC. Another study reported the presence of hypermethylated SHISA3 DNA in CRC biopsy specimens. In the present study, the plasma of 30 patients with CRC and nine healthy controls was collected and analyzed for the concentration of cell-free DNA through bisulfite sequencing. The methylation rates were determined. Our results have shown that an increasing amount of cell-free DNA in the group of CRC patient's plasma compared to the healthy group. Moreover, patients with later stages of CRC had higher concentrations of cell-free DNA. Notably, the methylation rate of SHISA3 was higher in the plasma of the CRC group than in that of the healthy group. The results indicated that the presence of tumor cells does not reduce the degree of SHISA3 DNA in the peripheral blood of patients with CRC. In other words, the hypermethylation of SHISA3, which inactivates the gene, is a potential cause of tumorigenesis. Furthermore, the methylation rate of SHISA3 DNA was higher in the plasma of patients with stage II CRC than in that of those with stage I CRC. In conclusion, the combination of conventional testing and screening for SHISA3 hypermethylation in plasma could improve the rate at which CRC is detected.

Immune Response Evaluation and Treatment with Immune Checkpoint Inhibitors Beyond Clinical Progression: Response Assessments for Cancer Immunotherapy.

PURPOSE OF REVIEW: This review provides a comprehensive assessment of recent literature reports describing atypical response patterns observed with immune checkpoint inhibitors (ICIs), modifications to response evaluation criteria for ICIs, and treatment beyond progression in clinical trials. RECENT FINDINGS: Certain response patterns such as durable response, pseudoprogression, hyperprogression, and dissociated responses can be seen with ICI treatment. These patterns carry differing prognoses and are associated with varied factors. There are multiple modifications of standard Response Evaluation Criteria in Solid Tumors (RECIST) that have been proposed to better characterize immunotherapy response; however, standard RECIST1.1 remains most commonly used in clinical trials. Treatment beyond progression varies in frequency and benefit depending on assessment criteria and cancer type. Future research incorporating modified imaging criteria and biomarker assessments may serve to clarify who will benefit most from treatment beyond progression.

U.S. Food and Drug Administration Benefit-Risk Assessment of Nilotinib Treatment Discontinuation in Patients with Chronic Phase Chronic Myeloid Leukemia in a Sustained Molecular Remission.

On December 22, 2017, the U.S. Food and Drug Administration (FDA) updated the product label for nilotinib to include information for providers on how to discontinue this drug in certain patients. With the updated dosing recommendations, select patients with chronic phase myeloid leukemia (CML) taking nilotinib for 3 years or more and whose leukemia has responded with sustained molecular remission (MR4.5, BCR-ABL transcripts of ≤0.0032%) as determined by a FDA-approved test may be eligible to discontinue nilotinib. The updated dosing regimen was based on the efficacy results from two trials that measured how long patients could stop taking nilotinib without the leukemia returning (treatment-free remission). Trial results demonstrated that, among selected patients who received nilotinib as first-line therapy or after transition from imatinib, approximately 50% continued to be in remission at 96 weeks after stopping therapy. Relapses continued to occur throughout the study, indicating that long-term monitoring is needed for safety and disease monitoring. Discontinuation of treatment was associated with an increased risk of low grade musculoskeletal adverse events, some of which were prolonged. Overall, the results support the approval of updates to the dosing recommendations with regard to treatment discontinuation in selected patients who have received nilotinib for at least 3 years, are in a sustained molecular remission, and who can undergo appropriate monitoring. IMPLICATIONS FOR PRACTICE: The updated dosing information provides eligibility criteria for treatment discontinuation, strict monitoring criteria after nilotinib discontinuation, and guidance for treatment reinitiation in eligible patients with chronic phase myeloid leukemia. About half of appropriately selected patients remained in remission 96 weeks after treatment discontinuation. Patients may experience musculoskeletal pain on withdrawal of treatment, incidence of which appears to decrease over time; however, some patients may have long lasting events. The decision to withdraw or continue treatment with nilotinib should be based on clinical condition and patient preferences.

FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy.

The U.S. Food and Drug Administration (FDA) granted accelerated approval to atezolizumab and pembrolizumab in April and May 2017, respectively, for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. These approvals were based on efficacy and safety data demonstrated in the two single-arm trials, IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). The primary endpoint, confirmed objective response rate, was 23.5% (95% confidence interval [CI]: 16.2%-32.2%) in patients receiving atezolizumab and 28.6% (95% CI: 24.1%-33.5%) in patients receiving pembrolizumab. The median duration of response was not reached in either study and responses were seen regardless of PD-L1 status. The safety profiles of both drugs were generally consistent with approved agents targeting PD-1/PD-L1. Two ongoing trials (IMvigor130 and KEYNOTE-361) are verifying benefit of these drugs. Based on concerning preliminary reports from these trials, FDA revised the indications for both agents in cisplatin-ineligible patients. Both drugs are now indicated for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors/infiltrating immune cells express a high level of PD-L1. The indications for atezolizumab and pembrolizumab in patients who have received prior platinum-based therapy have not been changed. This article summarizes the FDA thought process and data supporting the accelerated approval of both agents and the subsequent revision of the indications. IMPLICATIONS FOR PRACTICE: The accelerated approvals of atezolizumab and pembrolizumab for cisplatin-ineligible patients with advanced urothelial carcinoma represent the first approved therapies for this patient population. These approvals were based on single-arm trials demonstrating reasonable objective response rates and favorable durations of response with an acceptable toxicity profile compared with available non-cisplatin-containing chemotherapy regimens. However, based on concerning preliminary reports from two ongoing phase III trials, the FDA revised the indication for both agents in cisplatin-ineligible patients. Both are now indicated either for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors have high expression of PD-L1.

FDA Approval Summary: Nivolumab in Advanced Renal Cell Carcinoma After Anti-Angiogenic Therapy and Exploratory Predictive Biomarker Analysis.

On November 23, 2015, the U.S. Food and Drug Administration approved nivolumab (OPDIVO, Bristol-Myers Squibb Company) for patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. The approval was based on efficacy and safety data demonstrated in an open-label, randomized study of 821 patients with advanced RCC who progressed after at least one anti-angiogenic therapy. Patients were randomized to nivolumab or everolimus and followed for disease progression. The primary end point was overall survival. Subsequent therapies, including everolimus for patients who developed progressive disease on the nivolumab arm, were allowed, but no cross-over was permitted. The median overall survival was 25.0 months on the nivolumab arm and 19.6 months on everolimus arm (hazard ratio: 0.73; 95% confidence interval: 0.60-0.89). The confirmed response rates were 21.5% versus 3.9%; median durations of response were 23.0 versus 13.7 months, and median times to response were 3.0 versus 3.7 months in the nivolumab and everolimus arms, respectively. A statistically significant improvement in progression-free survival was not observed in this trial. The safety profile of nivolumab in renal cell cancer was similar to that in other disease settings. However, the incidence of immune-mediated nephritis appeared to be higher in patients with RCC. The Oncologist 2017;22:311-317 IMPLICATIONS FOR PRACTICE: The overall benefit/risk profile demonstrated in trial CA209025 supported the approval of nivolumab as an additional treatment option for patients with advanced renal cell carcinoma after anti-angiogenic therapy. The use of nivolumab in patients who had received vascular endothelial growth factor-targeted therapy resulted in a 5.4 month improvement in median overall survival compared with the everolimus arm. This difference is statistically significant and clinically meaningful.

FDA Approval Summary: Atezolizumab for the Treatment of Patients with Progressive Advanced Urothelial Carcinoma after Platinum-Containing Chemotherapy.

Until recently in the United States, no products were approved for second-line treatment of advanced urothelial carcinoma. On May 18, 2016, the U.S. Food and Drug Administration approved atezolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody and represents the first approved product directed against PD-L1. This accelerated approval was based on results of a single-arm trial in 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression after prior platinum-containing chemotherapy. Patients received atezolizumab 1,200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. Key efficacy measures were objective response rate (ORR), as assessed by Independent Review per RECIST 1.1, and duration of response (DoR). With a median follow-up of 14.4 months, confirmed ORR was 14.8% (95% CI: 11.1, 19.3) in all treated patients. Median DoR was not reached and response durations ranged from 2.1+ to 13.8+ months. Of the 46 responders, 37 patients had an ongoing response for ≥ 6 months. The most common adverse reactions (≥20%) were fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation. Infection and immune-related adverse events also occurred, including pneumonitis, hepatitis, colitis, endocrine disorders, and rashes. Overall, the benefit-risk assessment was favorable to support accelerated approval. The observed clinical benefits need to be verified in confirmatory trial(s). IMPLICATIONS FOR PRACTICE: This accelerated approval of atezolizumab for second-line use in advanced urothelial carcinoma provides patients with an effective, novel treatment option for the management of their disease. This represents the first immunotherapy approved in this disease setting.

Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.

BACKGROUND: Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. METHODS: We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response--ypT0 ypN0, ypT0/is ypN0, and ypT0/is--for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. FINDINGS: We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70). INTERPRETATION: Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. FUNDING: US Food and Drug Administration.

U.S. Food and Drug Administration Approval Summary: Ramucirumab for the Treatment of Metastatic Non-Small Cell Lung Cancer Following Disease Progression On or After Platinum-Based Chemotherapy.

UNLABELLED: On December 12, 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for use in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab. This approval was based on an improvement in overall survival (OS) with an acceptable toxicity profile in a randomized, multicenter, double-blinded, placebo-controlled trial of 1,253 patients with metastatic NSCLC previously treated with a platinum-based combination therapy. Patients were randomized 1:1 to receive either ramucirumab in combination with docetaxel or placebo in combination with docetaxel. The primary endpoint was OS. Patients who received ramucirumab in combination with docetaxel had improved OS (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.75, 0.98). Median OS was 10.5 months on the ramucirumab plus docetaxel arm versus 9.1 months on the placebo plus docetaxel arm. The most frequent (≥ 30%) adverse reactions in ramucirumab-treated patients were fatigue, neutropenia, and diarrhea. The most frequent (≥ 5%) grade 3 and 4 adverse reactions in the ramucirumab arm were fatigue, neutropenia, febrile neutropenia, leukopenia, and hypertension. IMPLICATIONS FOR PRACTICE: This report presents key information on the U.S. Food and Drug Administration approval of ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor-2, given in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer whose disease has progressed on or after platinum-based chemotherapy. This report specifically addresses the issues of safety in patients with squamous cell tumors, effect of treatment in elderly patients, and uncertainties regarding effects in patients with tumors harboring epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations.

U.S. Food and Drug Administration Approval Summary: Enzalutamide for the Treatment of Patients With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

The U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm. The overall benefit-risk profile supports the expanded indication for enzalutamide. On September 10, 2014, the U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Enzalutamide was initially approved in 2012 for use in patients with mCRPC who had previously received docetaxel. The current approval was based on the results of a randomized, placebo-controlled, double-blind trial conducted in 1,717 asymptomatic or minimally symptomatic patients with chemotherapy-naïve mCRPC. Patients were assigned to receive either enzalutamide 160 mg or placebo orally once daily. The coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS), which was assessed by independent central radiology review. At the prespecified interim analysis, a statistically significant improvement in OS was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.60-0.84). The median OS was 32.4 and 30.2 months in the enzalutamide and placebo arms, respectively. A statistically significant prolongation of rPFS was observed in patients in the enzalutamide arm (HR, 0.17; 95% CI, 0.14-0.21). In addition, the time to initiation of cytotoxic chemotherapy was prolonged in the enzalutamide arm (HR, 0.35; 95% CI, 0.30-0.40), with median times of 28.0 and 10.8 months in the enzalutamide and placebo arms, respectively. The safety profile was similar to that previously reported for enzalutamide. Adverse reactions of interest included seizure, hypertension, and falls. Enzalutamide should be discontinued if a seizure occurs during treatment. The overall benefit-risk profile supports the expanded indication for enzalutamide.

Repair of massively defected hemi-joints using demineralized osteoarticular allografts with protected cartilage.

Surgical replacement of massively defected joints necessarily relies on osteochondral grafts effective to both of bone and cartilage. Demineralized bone matrix (DBM) retains the osteoconductivity but destroys viable chondrocytes in the cartilage portion essential for successful restoration of defected joints. This study prepared osteochondral grafts of DBM with protected cartilage. Protected cartilage portions was characterized by cellular and molecular biology and the grafts were allogenically used for grafting. Protected cartilage showed similar histomorphological structure and protected proteins estimated by total proteins and cartilage specific proteins as in those of fresh controls when DBMs were generated in bone portions. Such grafts were successfully used for simultaneously repair of bone and cartilage in massively defected osteoarticular joints within 16 weeks post-surgery. These results present an allograft with clinical potential for simultaneous restoration of bone and cartilage in defected joints.

Multiconfigurational actinide nitrides assisted by double Möbius aromaticity.

Understanding the bonding nature between actinides and main-group elements remains a key challenge in actinide chemistry due to the involvement of f orbitals. Herein, we propose a unique "aromaticity-assisted multiconfiguration" (AAM) model to elucidate the bonding nature in actinide nitrides (An2N2, An = Ac, Th, Pa, U). Each planar four-membered An2N2 with equivalent An-N bonds possesses four delocalized π electrons and four delocalized σ electrons, forming a new family of double Möbius aromaticity that contributes to the molecular stability. The unprecedented aromaticity further supports actinide nitrides to exhibit multiconfigurational characters, where the unpaired electrons (2, 4 or 6 in naked Th2N2, Pa2N2 or U2N2, respectively) either are spin-free and localized on metal centres or form metal-ligand bonds. High-level multiconfigurational computations confirm an open-shell singlet ground state for actinide nitrides, with small energy gaps to high spin states. This is consistent with the antiferromagnetic nature observed experimentally in uranium nitrides. The novel AAM bonding model can be authenticated in both experimentally identified compounds containing a U2N2 motif and other theoretically modelled An2N2 clusters and is thus expected to be a general chemical bonding pattern between actinides and main-group elements.