Efficacy and Tolerability of Selective Internal Radiotherapy With Yttrium-90 as Consolidation Treatment After Chemotherapy in Metastatic Colorectal Cancer

BackgroundSelective internal radiotherapy (SIRT) with yttrium-90 (Y-90)-labeled resin microspheres may have a role in consolidating the response to chemotherapy in patients with metastatic colorectal cancer unamenable to resection after assessment of the best response to first-line chemotherapy.Patients and MethodsThis was a retrospective analysis of outcomes in patients who had received SIRT as consolidation therapy after one or more lines of chemotherapy. Eligible patients were 18 years or older, had confirmed colorectal liver metastases, and had disease unsuitable for surgical resection or local ablation with curative intent. The primary endpoint was progression-free survival.ResultsSixty-eight patients with colorectal liver metastases were treated with at least one SIRT procedure after receiving one or more lines of chemotherapy. Median progression-free survival was significantly longer in patients who received SIRT after prior first-line chemotherapy compared to those who received SIRT after two or more lines of chemotherapy (9 vs. 3 months, respectively; hazard ratio = 0.07; 95% confidence interval, 0.02854‒0.2039; P < .001), and in patients with liver-only disease compared to those who had extrahepatic metastases (6.4 vs. 4.1 months, respectively; hazard ratio = 0.57; 95% confidence interval, 0.34-0.95; P = .0318). There were no grade 3 or higher adverse events.ConclusionSIRT represents a valid option for the treatment of colorectal liver metastases. Earlier use of SIRT may provide a greater survival benefit compared to that afforded by the procedure when used in salvage settings.     

Chemotherapy plus Vandetanib or Chemotherapy Alone in Advanced Non-small Cell Lung Cancer: A Meta-analysis of Four Randomised Controlled Trials

AimsMost patients with advanced non-small cell lung cancer (NSCLC) require systemic chemotherapy. Vandetanib, targeting epidermal growth factor receptor and vascular endothelial growth factor receptor signalling in NSCLC, has recently been evaluated in combination chemotherapy in advanced NSCLC. However, the advantage of chemotherapy plus vandetanib over chemotherapy alone in advanced NSCLC remains largely unknown. A meta-analysis of randomised controlled trials was carried out to compare the efficacy and toxicity of chemotherapy plus vandetanib with chemotherapy alone in advanced NSCLC.Materials and methodsThe PubMed database, American Society of Clinical Oncology, European Society for Medical Oncology and the Cochrane Library and references of published trials were searched. Two reviewers independently assessed the quality of the trials. Data were extracted and the overall response rate, pooled progression-free survival, overall survival with 95% confidence intervals and main toxicity were analysed.ResultsFour randomised controlled trials involving 2160 patients with advanced NSCLC were ultimately analysed. Compared with chemotherapy alone, chemotherapy plus vandetanib significantly increased the overall response rate (relative risk = 1.96, 95% confidence interval = 1.53––2.52) and progression-free survival (hazard ratio = 0.79, 95% confidence interval = 0.71–0.87), but there was no significant difference in overall survival (hazard ratio = 0.91, 95% confidence interval = 0.79–1.03). Patients who received chemotherapy plus vandetanib had more rash, diarrhoea, hypertension and QTc prolongation (odds ratio = 2.32, 95% confidence interval = 1.93–2.79; odds ratio = 1.64, 95% confidence interval = 1.37–1.97; odds ratio = 4.08, 95% confidence interval = 2.51–6.01, odds ratio = 17.77, 95% confidence interval = 3.54–61.66, respectively), and less nausea and vomiting (odds ratio = 0.70, 95% confidence interval = 0.58–0.85; odds ratio = 0.69, 95% confidence interval = 0.55–0.86, respectively). The incidences of haemorrhage, fatigue and cough were comparable between the two groups.ConclusionsAlthough similar in overall survival, chemotherapy plus vandetanib showed particular advantages over chemotherapy alone in terms of progression-free survival and overall response rate. The toxicity was comparable between the two groups. Therefore, chemotherapy plus vandetanib might be a safe and valid therapeutic option for advanced NSCLC patients.     

Efficacy and Safety of First-Line Immunotherapy Combinations for Advanced NSCLC: A Systematic Review and Network Meta-Analysis

IntroductionA series of randomized controlled trials have investigated different first-line immunotherapy combinations, but the optimal combination strategy is yet to be established.MethodsWe performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences. We included published and gray sources of randomized clinical trials comparing immunotherapy combinations with other treatments as first-line treatments for patients with advanced NSCLC. This study was registered in the Prospective Register of Systematic Reviews (CRD42020210501) to ensure transparency.ResultsWe analyzed a total of 16 studies involving 8278 patients and including 10 immunotherapy combinations. For patients without programmed death-ligand 1 (PD-L1) selection, pembrolizumab plus chemotherapy was found to be comparable with sintilimab plus chemotherapy in providing the best overall survival (OS) benefit (hazard ratio = 0.96, 95% confidence interval [CI]: 0.72–1.29). Furthermore, atezolizumab plus bevacizumab plus chemotherapy seemed to provide the best progression-free survival (hazard ratio = 0.45, 95% CI: 0.36–0.55) and the best objective response rate (OR = 0.23, 95% CI: 0.12–0.42). Subgroup analysis by PD-L1 suggested that nivolumab plus ipilimumab plus chemotherapy was associated with the best OS in patients with PD-L1 less than 1% and that pembrolizumab plus chemotherapy was associated with the best OS in patients with PD-L1 greater than or equal to 1%. Pembrolizumab and sintilimab were associated with relatively fewer grade greater than or equal to 3 adverse events when compared with other immunotherapies combined with chemotherapy.ConclusionsOur results suggest that antiprogrammed death-1 combinations are associated with potentially higher survival outcomes than anti–PD-L1 combinations with comparable safety profiles. Moreover, pem-chemo and nivo-ipi-chemo seem to be superior first-line immunotherapy combinations for patients with advanced NSCLC with positive and negative PD-L1 expression, respectively. Although atezo-beva-chemo treatment provided the best progression-free survival and objective response rate, the addition of chemotherapy to immunotherapy would increase the toxicity, especially when antiangiogenesis drugs are simultaneously added.     

Association of Carcinoembryonic Antigen Reduction With Progression-free and Overall Survival Improvement in Advanced Non-small-cell Lung Cancer

BackgroundNon-small cell lung cancer elevates serum carcinoembryonic antigen (CEA). CEA determinations are not recommended currently. This study aims to identify the correlation between reducing serum CEA levels with progression-free survival (PFS) and overall survival.MethodsThis study assessed at baseline and in every scheduled visit serum CEA levels throughout first-line therapy. A sensitivity and specificity analysis identified the best cut-off point and correlated it with progression-free survival and overall survival. Multivariate Cox proportional hazard models were conducted.ResultsWe assessed 748 patients with elevated serum CEA levels at diagnosis. A ≥20% decrease from baseline was associated with a 2-fold median survival compared with patients with lower decreases (20.5 months vs 9.1 months; hazard ratio, 0.53; 95% confidence interval, 0.44 to –0.64; P < .001). CEA sensitivity and specificity to predict survival was 79.8% and 59.8%, respectively. A ≥10% decrease in CEA concentrations was associated with longer progression-free survival (7.7 months vs 5.9 months; hazard ratio, 0.71; 95% confidence interval, 0.57 to –0.88; P = .001) in those treated with chemotherapy, and in patients under tyrosine kinase inhibitors (11.9 months vs 7.3 months; hazard ratio, 0.63; 95% confidence interval, 0.47 to –0.83; P = .0001) and a ≥20% decrease.ConclusionIn patients with metastatic non-small cell lung cancer with an elevated baseline CEA level, the percentage decrease of CEA concentrations above the threshold during the first-line therapy was associated with more prolonged survival and progression-free intervals. Serum CEA determinations are a feasible, noninvasive option for monitoring and prognosis.     

Influence of non-measurable disease on progression-free survival in patients with metastatic breast cancer

BackgroundThe presence of non-measurable disease is common in metastatic breast cancer. It is unknown whether treatment effect on progression free survival (PFS) is consistent among patients with measurable and non-measurable disease.MethodsA systematic literature search identified phase III randomized controlled trials (RCTs) in metastatic breast cancer that reported outcomes in patients with non-measurable and measurable disease. Hazard ratios (HRs) and 95% confidence intervals were computed to compare the individual trial treatment effect on PFS in non-measurable versus measurable disease. Analyses were repeated for bone-only compared to non-bone-only disease and based on drug mechanism of action.ResultsAmong 82 RCTs that enrolled patients with non-measurable disease, data were available from 16 trials comprising 8516 patients. Treatment effect on PFS was similar in patients with non-measurable and measurable disease (HR for intra-study comparison = 1.01, p = 0.82). However, compared to non-bone-only disease, a significantly greater effect on PFS was seen in those with bone-only disease (HR 0.83, p = 0.03). Compared to patients with measurable disease, there was a greater effect on PFS in those with non-measurable disease in RCTs of signal transduction inhibitors and endocrine therapy (HR 0.74, p = 0.01) and a lesser effect on PFS in RCTs of antiangiogenic drugs (HR 1.34, p = 0.02). Comparable effect on PFS was shown in RCTs evaluating endocrine therapy (HR 1.13, p = 0.23) and chemotherapy (HR 0.73, p = 0.22).ConclusionsThere is variability in treatment effect on PFS in patients with measurable and non-measurable disease, especially those with bone-only disease. Standardization of PFS determination in these patients is warranted.     

Ribociclib for the treatment of hormone receptor-positive,human epidermal growth factor receptor 2-negative advanced breast cancer

Introduction: The emergence of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors marked a significant advancement in the treatment of advanced breast cancer. Ribociclib is an orally bioavailable, highly selective inhibitor of CDK4/6. In combination with various endocrine therapies, ribociclib has demonstrated clinical activity as a first-line therapy for patients with HR+, HER2? advanced breast cancer, without compromising the favorable toxicity profile associated with endocrine therapy. Thus, ribociclib is now considered a new standard of care for HR+, HER2? advanced breast cancer.

Areas covered: This review provides a concise overview of the preclinical and clinical development of ribociclib, including evidence of its clinical activity and safety profile when combined with endocrine therapy in HR+, HER2? advanced breast cancer.

Expert commentary: CDK4/6 inhibition represents a promising treatment option for patients with HR+ metastatic breast cancer. Ribociclib significantly improved progression-free survival in patients receiving first-line endocrine therapy for HR+, HER2? advanced breast cancer. Planned and ongoing trials investigating ribociclib in combination with other endocrine therapies and in various clinical settings will help to determine the optimal treatment sequence for different patient populations.     

CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC

IntroductionFirst-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC.MethodsThis open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety.ResultsA total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6–19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6–18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67–1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5–8.5) and 3.2 months (95% CI: 2.7–5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52–0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04–2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS.ConclusionsThe addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.     

Real-World Efficacy of First-Line Pembrolizumab in Patients With Advanced or Recurrent Non–Small-Cell Lung Cancer and High PD-L1 Tumor Expression

BackgroundIn clinical trials, first-line treatment with pembrolizumab improved overall survival (OS) in patients with advanced non–small-cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score of ≥ 50%. However, data on the efficacy of this treatment between clinical trials and actual clinical practice are inconsistent.Patients and MethodsNinety-five patients with histologically diagnosed advanced or recurrent NSCLC and a PD-L1 tumor proportion score of ≥ 50% who received pembrolizumab as first-line treatment were consecutively enrolled onto this multicenter retrospective study from February 2017 to December 2018. Clinical data were collected from electronic medical records. We assessed the objective response rate, progression-free survival (PFS), OS, and immune-related adverse events (irAE), and determined their associations with clinical characteristics.ResultsThe objective response rate was 40.0%. The median PFS was 6.1 months, and OS did not reach the median. Multivariate analyses revealed that nonadenocarcinoma histology (hazard ratio, 1.78; 95% confidence interval, 1.05-3.03; P = .015) and ≥ 3 metastatic sites (hazard ratio, 3.97; 95% confidence interval, 1.97-8.01; P < .001) were independently correlated with poor PFS. Patients with irAE and patients without interstitial lung disease had significantly longer PFS (14.0 and 4.9 months, respectively; P = .011) than patients without irAE or patients with interstitial lung disease.ConclusionThe outcome of patients receiving first-line pembrolizumab treatment was worse in those with nonadenocarcinoma and with a large number of metastatic sites. Patients with irAE and without interstitial lung disease had a more favorable outcome.     

Is Axitinib Still a Valid Option for mRCC in the Second-Line Setting? Prognostic Factor Analyses From the AXIS Trial

BackgroundAxitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting.Patients and MethodsAXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors.ResultsOf 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter < 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments.ConclusionIn patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.     

Comparison of treatment-related adverse events of different Cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer: A network meta-analysis

BackgroundPalbociclib, ribociclib and abemaciclib have all been approved in combination with endocrine therapy in hormone-receptor positive, HER2 negative metastatic breast cancer. While the efficacy of these drugs appears similar, differences in safety and tolerability are apparent.MethodsWe searched PubMed and ASCO, ESMO and SABCS proceedings to identify randomized trials of palbociclib, ribociclib and abemaciclib. Data on common and serious adverse events (AE) were extracted for each approved drug. The odds ratio for each AE and the hazard ratio for progression-free survival were calculated relative to endocrine therapy alone. A network meta-analysis was then performed for each endocrine therapy backbone (aromatase inhibitor (AI) or fulvestrant) to compare ribociclib and abemaciclib to palbociclib.Results8 trials were included in the analysis and comprised 2799 patients receiving cyclin-dependent kinase 4/6 inhibitors palbociclib: 873 patients; ribociclib: 1153 patients; abemaciclib: 773 patients. In 5 trials (1524 patients), the endocrine therapy backbone was an AI and in 3 trials (1275 patients) it was fulvestrant. Compared to palbociclib, ribociclib and abemaciclib showed significantly lower grade 3–4 neutropenia, but significantly higher GI toxicity. Treatment discontinuation was higher with abemaciclib than other drugs. Efficacy of the 3 drugs was similar. Compared to palbociclib, for AI backbone, the HR for PFS for ribociclib was 0.98 and for abemaciclib 1.02. For fulvestrant backbone, the HR were 0.88 and 0.93 respectively.ConclusionsPalbociclib, ribociclib and abemaciclib have comparable efficacy, but differences in safety and tolerability. Abemaciclib has worse tolerability with significantly higher treatment discontinuation likely due to GI toxicity.     

Combining Src inhibitors and aromatase inhibitors: A novel strategy for overcoming endocrine resistance and bone loss

Aromatase inhibitors have largely replaced tamoxifen as the first-line treatment for postmenopausal women with metastatic, hormone receptor-positive (HR+) breast cancer. However, many patients develop clinical resistance with prolonged treatment, and oestrogen deprivation following aromatase inhibition can result in loss of bone mineral density. Furthermore, most patients with metastatic breast cancer develop bone metastases, and the resulting adverse skeletal-related events are a significant cause of patient morbidity. Src, a non-receptor tyrosine kinase, is a component of signalling pathways that regulate breast cancer cell proliferation, invasion and metastasis as well as osteoclast-mediated bone turnover. Preclinical evidence also suggests a role for Src in acquired endocrine resistance. As such, Src inhibition represents a logical strategy for the treatment of metastatic breast cancer. In vitro, combination therapy with Src inhibitors and endocrine agents, including aromatase inhibitors, has been shown to inhibit the proliferation and metastasis of both endocrine-responsive and endocrine-resistant breast cancer cell lines more effectively than either of the therapy alone. Src inhibition has also been shown to suppress osteoclast formation and activity. Combination therapy with aromatase inhibitors and Src inhibitors therefore represents a novel approach through which the development of both acquired resistance and bone pathology could be delayed. Data from clinical trials utilising such combinations will reveal if this strategy has the potential to improve patient outcomes.     

The next era of treatment for hormone receptor-positive,HER2-negative advanced breast cancer: Triplet combination-based endocrine therapies

Until recently, the standard of care for hormone receptor-positive (HR+) breast cancer was single-agent endocrine therapy, which aims to prevent estrogen receptor signaling. This therapeutic strategy has extended survival without the toxicity associated with chemotherapy, but primary endocrine therapy resistance is common, and secondary resistance develops over time. Adjunct downstream inhibition of the cyclin-dependent kinase (CDK)4/6 pathway, intended to delay and prevent endocrine therapy resistance, has further extended progression-free survival in patients receiving endocrine therapy; however, resistance still eventually develops in these patients. Addition of phosphatidylinositol-3 kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitors to combined CDK4/6 and endocrine inhibitor regimens may help prolong CDK4/6 inhibitor sensitivity. Early trials combining CDK4/6 inhibitors, PI3K or mTOR inhibitors, and endocrine therapy have shown encouraging signs of clinical activity. However, further research is needed to help understand the extent of treatment benefit from triplet therapy and where this strategy will fit in the treatment sequence for patients with HR+ breast cancer.     

Incidence and prognostic significance of receptor discordance between primary breast cancer and paired bone metastases

ER, PgR and HER-2 status are the cornerstones of choosing systemic therapy for breast cancer, but can change during the disease course. Guidelines recommended the biopsy of the metastatic tumor to reassess receptor status. Bone is the most frequent metastatic site of breast cancer but remained technically difficult to biopsy. Our study aimed to evaluate the incidence and prognostic significance of receptor discordance between primary breast cancer and paired bone metastases. One hundred and fifty-five breast cancer patients were diagnosed with pathology-confirmed bone metastasis at Fudan University Shanghai Cancer Center. Ninety-three patients with receptor status available on both primary tumor and bone metastases were included in our study. ER, PgR and HER-2 status converted from positive to negative in 10.8% (10/93), 28.0% (26/93) and 8.6% (8/93) of the patients, while ER, PgR and HER-2 status converted from negative to positive in 3.2% (3/93), 4.3% (4/93) and 1.1% (1/93) of the patients, respectively. 40.4% (17/42) of the HER2-0 tumors converted to HER2-low, which enabled them to receive the treatment of new antibody-drug conjugates (ADCs). Prior endocrine and anti-HER2 therapy were the independent risk factors for receptor conversion. Loss of HR expression in bone metastases was significantly associated with worse first-line PFS (adjusted hazard ratio = 3.271, P-value = .039) and OS (adjusted hazard ratio = 6.09, P-value = .011). In conclusion, our study confirmed that patients may experience receptor conversion between primary breast cancer and bone metastases, possibly influenced by prior treatments, which significantly influenced prognosis. The rebiopsy of bone metastases in patients with primary HER2-0 tumors may benefit from the new ADC drugs.     

Outcomes of Transplant-Eligible Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Salvage Chemotherapy: The Gustave Roussy Experience

IntroductionAfter failure of frontline therapy, patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL) that does not respond to first-line salvage chemotherapy can be recommended second-line salvage chemotherapy. The available literature in this regard is weak, although many centers routinely offer this type of second-line salvage chemotherapy to their patients.Patients and MethodsThis retrospective study included transplant-eligible patients with RR-DLBCL treated at Gustave Roussy between January 2008 and April 2020. Eligible patients were those who received second-line salvage chemotherapy using R-DHAP or R-ICE in patients who experienced an insufficient partial response, stable disease, or progressive disease in response to first-line salvage chemoimmunotherapy using an alternative regimen.ResultsForty-six RR-DLBCL patients received second-line salvage regimen, which yielded an objective response rate of 33%, median progression-free survival of 2.1 months, and overall survival of 11.4 months. Twelve patients proceeded to autologous stem-cell transplantation (ASCT), of whom 70% remained alive 1 year after ASCT. To explore the impact of transplantation, a multivariate analysis (excluding response to the first-line salvage regimen because this covariate was totally embedded within the transplantation covariate), ASCT was associated with progression-free survival (hazard ratio = 0.16; 95% confidence interval, 0.06-0.42) and overall survival (hazard ratio = 0.27; 95% confidence interval, 0.08-0.88).ConclusionSecond-line salvage chemotherapy with R-DHAP or R-ICE followed by ASCT leads to a favorable outcome in almost one third of patients with RR-DLBCL and offers a median overall survival of approximately 1 year. These data support the administration of second-line salvage chemotherapy followed by ASCT.     

Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation

AimMERiDiAN evaluated plasma vascular endothelial growth factor-A (pVEGF-A) prospectively as a predictive biomarker for bevacizumab efficacy in metastatic breast cancer (mBC).MethodsIn this double-blind placebo-controlled randomised phase III trial, eligible patients had HER2-negative mBC previously untreated with chemotherapy. pVEGF-A was measured before randomisation to paclitaxel 90 mg/m² on days 1, 8 and 15 with either placebo or bevacizumab 10 mg/kg on days 1 and 15, repeated every 4 weeks until disease progression, unacceptable toxicity or consent withdrawal. Stratification factors were baseline pVEGF-A, prior adjuvant chemotherapy, hormone receptor status and geographic region. Co-primary end-points were investigator-assessed progression-free survival (PFS) in the intent-to-treat and pVEGF-A_high populations.ResultsOf 481 patients randomised (242 placebo–paclitaxel; 239 bevacizumab–paclitaxel), 471 received study treatment. The stratified PFS hazard ratio was 0.68 (99% confidence interval, 0.51–0.91; log-rank p = 0.0007) in the intent-to-treat population (median 8.8 months with placebo–paclitaxel versus 11.0 months with bevacizumab–paclitaxel) and 0.64 (96% confidence interval, 0.47–0.88; log-rank p = 0.0038) in the pVEGF-A_high subgroup. The PFS treatment-by-VEGF-A interaction p value (secondary end-point) was 0.4619. Bevacizumab was associated with increased incidences of bleeding (all grades: 45% versus 27% with placebo), neutropenia (all grades: 39% versus 29%; grade ≥3: 25% versus 13%) and hypertension (all grades: 31% versus 13%; grade ≥3: 11% versus 4%).ConclusionThe significant PFS improvement with bevacizumab is consistent with previous placebo-controlled first-line trials in mBC. Results do not support using baseline pVEGF-A to identify patients benefitting most from bevacizumab.Clinical trials registrationClinicalTrials.gov NCT01663727.     

Comparative efficacy and safety of CDK4/6 and PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive,HER2-negative metastatic breast cancer: a systematic review and network meta-analysis

BackgroundCDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors are both emerging agents for hormonal receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer. Evidence for the comparisons from head-to-head comparative trials is currently insufficient. This meta-analysis assessed the comparative efficacy and safety of these two groups of agents for HR+/HER2- metastatic breast cancer.MethodsSystematic searches of PubMed, Embase, CENTRAL, SciSearch between January 2010 to December 2019 were conducted. Randomized controlled trials (RCTs) which evaluated clinical benefits and toxicities of CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors plus endocrine therapy were adopted. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoint was treatment-related adverse event (TRAE). Pooled hazard ratio (HR) and risk rate (RR) were used to assess the differences between CDK4/6 and PI3K/AKT/mTOR inhibitors.ResultsA total of twenty RCTs including 9771 participants were identified in this study. Pooled results showed that PFS was considerably prolonged by targeted therapy plus endocrine therapy. PFS was relatively better in CDK4/6 inhibitors than that of PI3K inhibitor group (HR, 1.43; 95%CrI, 1.12-1.61). Similar results were demonstrated in results after balancing lines of therapy or metastatic sites, both in viscera and bone-only. Coalesced outcomes revealed that CDK4/6 inhibitors plus endocrine therapy could significantly improve OS (HR, 0.78; 95%CrI, 0.65-0.94) than PI3K/mTOR inhibitors. Safety profiles of diarrhea and rash were consistent between CDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors with no difference of estimated RR. Several TRAEs signified specificity, for instance, myelosuppression in CDK4/6 inhibitors or hyperglycemia in PI3K/mTOR inhibitors.ConclusionsClinical efficacy is in favor of CDK4/6 inhibitors, and safety profiles are comparable between CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors plus endocrine therapy.     

Combining Immune Checkpoint and VEGFR Inhibition in Favorable Risk and Elderly Patients With Metastatic Renal Cell Carcinoma

BackgroundImmune checkpoint inhibitors and vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are the most commonly used medications in metastatic renal cell carcinoma (mRCC). Recently, large clinical trials have shown favorable outcomes in patients treated with combined immune checkpoint plus VEGFR inhibition compared with VEGFR inhibition alone. However, the benefit among favorable risk (based on International Metastatic Renal Cell Carcinoma Database Consortium score) and elderly (age > 65 years) patients was not clear, leading to a discrepancy between United States Food and Drug Administration and European Association of Urology recommendations.Materials and MethodsWe searched available literature for phase III randomized clinical trials evaluating the efficacy of combining immunotherapy plus VEGF/VEGFR inhibitors versus standard of care in patients with previously untreated mRCC. Combinations that were included in United States Food and Drug Administration recommendations or European Association of Urology guidelines were used for analysis. We performed a meta-analysis with a random effects model to evaluate the efficacy of immunotherapy-VEGFR inhibitor combinations compared with sunitinib in favorable risk and elderly patients.ResultsOur analysis demonstrated that progression-free survival (PFS) was significantly prolonged with combination therapy compared with sunitinib in patients with age > 65 years (hazard ratio, 0.66; 95% confidence interval, 0.52-0.84; P = .001). The PFS in favorable risk disease was improved with combination therapy compared with sunitinib, but the difference was not statistically significant (hazard ratio, 0.68; 95% confidence interval, 0.46-1.01; P = .055).ConclusionOur meta-analysis strengthens the trend of beneficial effect in prolonging PFS in both subgroups compared with each trial alone, indicating that favorable risk and elderly patients with mRCC likely benefit from combining programmed cell death 1 or programmed cell death-ligand 1 and VEGFR inhibition.     

Landmark trials in the medical oncology management of metastatic breast cancer

Significant advances in the management of metastatic breast cancer (MBC) have guided more personalized treatment according to disease biology and led to improved survival outcomes and quality of life for patients. In this review, we discuss landmark clinical trials in medical oncology that have shaped the current standard of care for MBC. Combinations of endocrine therapy with cyclin-dependent kinase 4/6 inhibitors have led to substantial improvements in overall survival, thus becoming standard first-line treatment for patients with HR-positive MBC. Inhibition of the PI3K and mTOR pathway is another promising strategy to overcome resistance to endocrine therapy. HER2-targeted therapies have also evolved with the addition of pertuzumab to trastuzumab plus a taxane demonstrating remarkable overall survival advantage in patient with HER2-positive MBC. In second or later line therapies, novel anti-HER2 antibody-drug conjugates and TKIs have durable antitumor activity, survival benefit, and encouraging efficacy in the subgroup of patients with brain metastases. Triple negative breast cancer remains the most challenging subtype due to lack of druggable targets. Immunotherapy for patients with PDL-1 expression on tumor infiltrating immune cells and poly (ADP-ribose) polymerase inhibitors for those with germline BRCA1/2 mutations are the latest approved targeted strategies in this population. Numerous obstacles still exist in treating MBC, especially for patients whose disease develops resistance to available agents. Future research is eagerly awaited to address the optimal sequence or combination of therapies and to identify better biomarkers to guide precision medicine.     

Celecoxib and exemestane versus placebo and exemestane in postmenopausal metastatic breast cancer patients: a double-blind phase III GINECO study

The aim of this study was to evaluate antitumor effects of cyclooxygenase-2 inhibitors in breast carcinoma and their ability to act synergistically with aromatase inhibitors (AIs). Postmenopausal metastatic breast cancer patients without previous adjuvant AI treatment received exemestane 25 mg/days plus either celecoxib 400 mg twice daily or placebo. The primary endpoint was progression-free survival (PFS). This trial was prematurely terminated (N = 157 of 342 planned) after cardiovascular toxicity was reported in other celecoxib trials. Although no PFS difference was observed between the two arms (9.8 months for both, P = 0.72), a trend favoring celecoxib was observed in 60 tamoxifen-resistant patients (9.6 vs. 5.1 months; P = 0.14) and in 126 patients treated ≥3 months before study termination (12.2 vs. 9.8 months; P = 0.09). No severe adverse events were reported. Cyclooxygenase-2 inhibitors seemingly contribute to reverse endocrine resistance in breast cancer patients, although further study is necessary to allow development of a new therapeutic strategy.     

Primary metastatic breast cancer in the era of targeted therapy – Prognostic impact and the role of breast tumour surgery

BackgroundExcept for meeting the individual palliative need, the benefit of breast surgery in primary metastatic breast cancer (PMBC), also known as de novo metastatic breast cancer, on long-term outcomes remains controversial. Twenty-four hundred and one patients with metastatic breast cancer, enrolled between 2000 and 2011 in two prospective non-interventional studies on targeted therapy, were screened with respect to this question.MethodsOne study investigated trastuzumab therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer in addition to mainly first-line chemotherapy. The other observed bevacizumab added to chemotherapy as first-line treatment for mostly HER2-negative disease.ResultsFive-hundred and seventy (24%) patients presented with PMBC, and valid information on resection of the primary tumour was available for 568 women. Out of these, 426 (75%) underwent local resection. The latter group was characterised by less overall metastatic burden and a lower proportion of T4 tumours. No major differences were observed with respect to age, hormone receptor and HER2 status, visceral disease and performance status. Numerically, the surgery group showed a slightly favourable progression-free survival (PFS, medians: 13.6 versus 11.8 months; P = 0.18) and overall survival (OS, 34.1 versus 31.7; P = 0.23). However, in multivariable analysis, including all other univariably significant parameters, no trend for better outcome after surgery remained detectable, neither for PFS (hazard ratio 0.99; P = 0.92) nor for OS (0.95; P = 0.71).ConclusionsOur findings suggest no major survival benefit for local resection in the overall PMBC population treated with modern targeted therapies. However, further analyses are warranted to define specific risk groups, which may benefit from surgical removal of the primary.