Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600–Mutant Unresectable or Metastatic Melanoma

PURPOSE Preclinical data suggest the combination of an anti–programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600–mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti–programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600–mutant unresectable or metastatic melanoma. METHODS Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600–mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692 ). RESULTS At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm. CONCLUSION The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.

Efficacy and safety of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors in colorectal cancer: a meta-analysis

Aims: To evaluate the efficacy and safety of PD-1/PD-L1 and/or CTLA-4 inhibitors in the treatment of colorectal cancer (CRC) by meta-analysis. Methods: Electronic databases were searched. Eligible studies included investigations of efficacy and safety of anti-PD-1/PD-L1 or anti-CTLA-4 agents in patients with CRC. Corresponding indicators were calculated. Results: A total of 15 articles were included. The pooled objective response rate, overall survival rate, progression-free survival rate and adverse event rate were 33, 56, 46 and 59%, respectively. The objective response rates for CRC with deficient mismatch repair and CRC with proficient mismatch repair were 43 and 3%, respectively, in patients treated with PD-1 inhibitors. Conclusion: The authors' study indicates that PD-1/PD-L1 inhibitors manifest promising clinical responses in the treatment of CRC with deficient mismatch repair with acceptable treatment-related adverse events.

Safety and Efficacy of Transarterial Chemoembolization Combined With Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma

PurposeTo explore the safety and efficacy of transarterial chemoembolization (TACE) in combination with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the treatment of unresectable hepatocellular carcinoma (uHCC).Materials and MethodsFrom August 2019 to July 2020, patients who received TACE combined with ICIs and TKIs were retrospectively analyzed. Treatment-related adverse events (AEs) were recorded. The Kaplan–Meier method was used to estimate time to progression (TTP) and progression-free survival (PFS).ResultsIn total, 31 patients with uHCC were included. Eleven patients were classified as BCLC-C. Nineteen patients had multiple lesions, and the cumulative targeted lesions were 69 mm (range, 21-170 mm) according to mRECIST. Twenty-nine (93%) patients experienced at least one AE during the treatment. Four (12.9%) patients developed AEs of higher grade (grade≥3). The objective response rate (ORR) and disease control rate (DCR) were 64.5% and 77.4%, respectively. The median time to response was 7 weeks (range, 4-30 w), and the duration of response was 17.5 weeks (range, 2-46 w). From the first ICIs, TTP and PFS were 6.5 months (95% CI, 3.5-11) and 8.5 months (95% CI, 3.5-NE), respectively.ConclusionsTACE combined with ICIs and TKIs shows an acceptable safety profile and considerable efficacy in patients with HCC.

Nanoparticle albumin-bound paclitaxel and PD-1 inhibitor (sintilimab) combination therapy for soft tissue sarcoma: a retrospective study

Background There is increasing evidence that combination therapy with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and programmed cell death protein 1 (PD-1) inhibitor is safe and efficacious in treating many types of malignant tumors. However, clinical data demonstrating the effect of this treatment combination for patients with metastatic soft tissue sarcoma (STS) are currently limited. Methods The clinical data of patients with metastatic STS who received nab-paclitaxel plus PD-1 inhibitor (sintilimab) therapy between January 2019 and February 2021 were retrospectively analyzed. The effectiveness and safety of the combined treatment were evaluated in terms of the median progression-free survival (PFS), estimated using the Kaplan–Meier method. The univariate Cox proportional hazards model was used to analyze the relationship between clinicopathological parameters and PFS. All statistical analyses were two-sided; P < 0.05 was considered statistically significant. Results A total of 28 patients treated with nab-paclitaxel plus sintilimab were enrolled in this study. The objective response rate was 25%, the disease control rate was 50%, and the median PFS was 2.25 months (95% CI = 1.8–3.0 months). The most common grade 1 or 2 adverse events (AEs) were alopecia (89.3%; 25/28), leukopenia (25.0%; 7/28), fatigue (21.4%; 6/28), anemia (21.4%; 6/28), and nausea (21.4%; 6/28). The most common grade 3 AEs were neutropenia (10.7%; 3/28) and peripheral neuropathy (10.7%; 3/28). No grade 4 AEs were observed. Among the present study cohort, patients with angiosarcoma (n = 5) had significantly longer PFS (P = 0.012) than patients with other pathological subtypes, including undifferentiated pleomorphic sarcoma (n = 7), epithelioid sarcoma (n = 5), fibrosarcoma (n = 4), synovial sarcoma (n = 3), leiomyosarcoma (n = 2), pleomorphic liposarcoma (n = 1), and rhabdomyosarcoma (n = 1); those who experienced three or more AEs had significantly longer median PFS than those who experienced less than three AEs (P = 0.018). Conclusion Nab-paclitaxel plus PD-1 inhibitor is a promising treatment regimen for advanced STS. Randomized controlled clinical trials are required to further demonstrate its efficacy and optimal application scenario.

Biometrics from a Wearable Device Reveals Temporary Effects of COVID-19 Vaccines on Cardiovascular, Respiratory, and Sleep Physiology

Although vaccines against SARS-CoV-2 have been proven safe and effective, transient side-effects lasting 24-48 hours post-vaccination have been reported. To better understand the subjective and objective response to COVID-19 vaccination, we conducted a retrospective analysis on 69619 subscribers to a wrist-worn biometric device (WHOOP Inc, Boston, MA, USA) who received either the AstraZeneca, Janssen/Johnson & Johnson, Moderna, or Pfizer/BioNTech vaccine. The WHOOP device measures resting heart rate (RHR), heart rate variability (HRV), respiratory rate (RR), and sleep architecture, and these physiological measures were normalized to the same day of the week, one week prior to vaccination. Averaging across vaccines, RHR, RR, and percent sleep derived from light sleep were elevated on the first night following vaccination and returned to baseline within four nights post-vaccination. When statistical differences were observed between doses on the first night post-vaccination, larger deviations in physiological measures were observed following the first dose of AstraZeneca and the second dose of Moderna and Pfizer/BioNTech. When statistical differences were observed between age groups or gender on the first night post-vaccination, larger deviations in physiological measures were observed in younger populations and in females (compared to males). When combining self-reported symptoms (fatigue, muscle aches, headache, chills, or fever) with the objectively measured physiological parameters, we found that self-reporting fever or chills had the strongest association with deviations in physiological measures following vaccination. In summary, these results suggest that COVID-19 vaccines temporarily affect cardiovascular, respiratory, and sleep physiology, and that dose, gender, and age affect the physiological response to vaccination.

Efficacy and Safety of Selumetinib in Pediatric Patients With Neurofibromatosis Type 1: A Systematic Review and Meta-analysis

Background and Objectives:Although the recent approval of selumetinib is expected to transform the management of children with Neurofibromatosis type 1 (NF1), particularly those with symptomatic and inoperable PN, no systematic review has summarized their efficacy and safety based on the latest studies. This study was conducted to systematically evaluate the efficacy and safety of selumetinib in children with NF1Methods:Original articles reporting the efficacy and safety of selumetinib in patients with NF1 were identified in PubMed and EMBASE up to January 28, 2021. The pooled objective response rates (ORRs) and disease control rates (DCRs) were calculated using the DerSimonian–Laird method based on random-effects modeling. The pooled proportion of adverse events (AEs) was also calculated. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation system.Results:Five studies involving 126 patients were included in our analysis. The studies had a very low to moderate quality of the evidence. The pooled ORR was 73.8% (95% CI: 57.3–85.5%), and the DCR was 92.5% (95% CI: 66.5–98.7%). The two most common AEs were diarrhea, which had a pooled rate of 63.8% (95% CI, 52.9–73.4%) and an increase in creatine kinase levels, which had a pooled rate of 63.3% (95% CI, 35.6–84.3%).Discussion:Our results indicate that selumetinib is an effective and safe treatment for pediatric patients with symptomatic, inoperable plexiform neurofibromas. Further larger-scale randomized controlled studies are needed to confirm the long-term outcome of patients treated with this drug.

Quantitative washout in patients with hepatocellular carcinoma undergoing TACE: an imaging biomarker for predicting prognosis?

Background The delayed percentage attenuation ratio (DPAR) was recently identified as a novel predictor of an early complete response in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). In this study, we aimed to validate the role of DPAR as a predictive biomarker for short-, mid-, and long-term outcomes after TACE. Methods We retrospectively reviewed laboratory and imaging data for 103 treatment-naïve patients undergoing initial TACE treatment at our tertiary care center between January 2016 and November 2020. DPAR and other washin and washout indices were quantified in the triphasic computed tomography performed before the initial TACE. The correlation of DPAR and radiologic response was investigated. Furthermore, the influence of DPAR on the 6-, 12-, 18-, and 24-month survival rates and the median overall survival (OS) was compared to other established washout indices and estimates of tumor burden and remnant liver function. Results The DPAR was significantly of the target lesions (TLs) with objective response to TACE after the initial TACE session was significantly higher compared to patients with stable disease (SD) or progressive disease (PD) (125 (IQR 118–134) vs 110 (IQR 103–116), p < 0.001). Furthermore, the DPAR was significantly higher in patients who survived the first 6 months after TACE (122 vs. 115, p = 0.04). In addition, the number of patients with a DPAR > 120 was significantly higher in this group (n = 38 vs. n = 8; p = 0.03). However, no significant differences were observed in the 12-, 18-, and 24-month survival rates after the initial TACE. Regarding the median OS, no significant difference was observed for patients with a high DPAR compared to those with a low DPAR (18.7 months vs. 12.7 months, p = 0.260). Conclusions Our results confirm DPAR as the most relevant washout index for predicting the short-term outcome of patients with HCC undergoing TACE. However, DPAR and the other washout indices were not predictive of mid- and long-term outcomes.

The Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Patients with Hepatocellular Carcinoma Receiving Atezolizumab Plus Bevacizumab

Atezolizumab plus bevacizumab has been approved as the first-line systemic treatment for patients with unresectable hepatocellular carcinoma (uHCC). This study was designed to assess the clinical impact of atezolizumab plus bevacizumab in uHCC patients. A total of 48 uHCC patients receiving atezolizumab plus bevacizumab were identified, including first-line, second-line, third-line, and later-line settings. In these patients, the median progression-free survival (PFS) was 5.0 months, including 5.0 months for the first-line treatment, not reached for the second-line treatment, and 2.5 months for the third line and later line treatment. The objective response rate and disease control rate to atezolizumab plus bevacizumab were 27.1% and 68.8%, respectively. The severity of most adverse events was predominantly grade 1–2, and most patients tolerated the toxicities. The ratios of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte (PLR) were used to predict PFS in these patients. The optimal cutoff values of NLR and PLR were 3 and 230, and NLR and PLR were independent prognostic factors for superior PFS in the univariate and multivariate analyses. Our study confirms the efficacy and safety of atezolizumab plus bevacizumab in uHCC patients in clinical practice and demonstrates the prognostic role of NLR and PLR for PFS in these patients.

Clinical Effectiveness and Safety of Chinese Herbal Medicine Compound Kushen Injection as an Add-On Treatment for Breast Cancer: A Systematic Review and Meta-Analysis

Objective. To systematically evaluate the effect and safety of compound Kushen injection (CKI) as an add-on treatment on the treatment for breast cancer. Methods. We searched eight major electronic databases from their inception to November 1, 2021, for randomized clinical trials (RCTs) comparing CKI plus chemotherapy with chemotherapy alone. Primary outcomes included objective response rate (ORR) and disease control rate (DCR), health-related quality of life (HRQoL), progression-free survival (PFS), and overall survival (OS). Secondary outcomes included adverse drug reactions (ADRs) and tumor marker level. We used Cochrane’s RevMan 5.3 for data analysis. The GRADEpro was used to appraise the certainty of evidence. Trial sequential analysis (TSA) was applied to estimate the required sample size in a meta-analysis and test the robustness of the current results. Results. Thirty RCTs with 2556 participants were totally included. CKI plus chemotherapy showed significant effects in increasing ORR (RR 1.30, 95%CI [1.18, 1.43], I2 = 27%, n = 1694), increasing DCR (RR 1.21, 95%CI [1.15, 1.28], I2 = 16%, n = 1627), increasing HRQol as measured by Karnofsky Performance Scale (KPS) score improvement rate (RR 1.42, 95% CI [1.26, 1.61], I2 = 37%, n = 1172), increasing the PFS (MD 2.24 months, 95%CI [1.26, 3.22], n = 94) and the OS (MD 2.24 months, 95%CI [1.45, 3.43], n = 94), compared to chemotherapy alone. The results showed that CKI plus chemotherapy had a lower risk of ADRs than that of chemotherapy alone group. The certainty of evidence of the included trials was generally low to very low. TSA for ORR and KPS score improvement rate demonstrated that the current results reached a sufficient power regarding both numbers of trials and participants. Conclusions. Low certainty of evidence suggested that the combination of CKI and conventional chemotherapy appeared to improve ORR, DCR, and KPS score in breast cancer patients. Conclusions about PFS and OS could not be drawn due to lack of evidence. Additionally, CKI appeared to relieve the risk of ADRs in patients with breast cancer receiving chemotherapies. However, due to weak evidence, the findings should be further confirmed in large and rigorous trials.

Promising Immunotherapy in Metastatic Testicular Sex Cord Stromal Tumours After First-Line Chemotherapy

BackgroundTesticular sex cord stromal tumours (TSCSTs) are rare, with few studies focusing on the metastatic TSCST prognosis. The value of treatments, including radical orchiectomy (RO) and retroperitoneal lymph node dissection (RPLND), in preventing metastasis is controversial. Additionally, metastatic TSCSTs are resistant to chemotherapy. We aimed to assess the effectiveness and safety of immunotherapy in metastatic TSCSTs after first-line chemotherapy.MethodsWe retrospectively screened patients with testicular tumours undergoing testis surgery between January 2005 and January 2019. Patients with TSCSTs who had undergone testis-sparing surgery (TSS) or RO were identified. The malignant type was defined as metastasis confirmed by pathology. Treatment responses, progression-free survival (PFS), overall survival (OS) and safety were analysed.ResultsAmong the 494 testicular tumour patients who received TSS or RO, 11 (2.2%) patients with histologically proven TSCSTs were identified. At the last follow-up, 7 patients survived without tumours, and 4 patients developed metastasis and received first-line cisplatin-based chemotherapy, with 1 of them achieving an objective response. Their PFS times were 1.5, 2.2, 9.0, and 17.0 months, respectively. Two patients received immune checkpoint inhibitors (ICIs) after developing chemotherapy resistance and achieved a partial response up to the last follow-up; one of them experienced Grade 1 adverse events, and the other experienced Grade 2 adverse events during immunotherapy. The median OS time of the 4 patients with metastatic TSCSTs was 32 months.ConclusionsTSCSTs are rare, and most are benign with a good prognosis. ICIs represent a promising option for improving clinical outcomes in metastatic TSCSTs.