Breast cancer represents an urgent global priority. While this is a universal issue, and as the burden of the disease is increasing globally, current estimates indicate that in the next couple of ...decades, much of the incidence and mortality related to breast cancer will be seen in underserved populations. The fragile and ill-prepared healthcare systems in low- and middle-income countries (LMIC) need to address this challenge and find solutions with their limited resources. Significant disparities can be identified in stage at presentation as the ability to detect the disease in earlier stages is compromised in these scenarios leading to worse outcomes associated to late diagnoses. Furthermore, access to healthcare in general and to basic surgical, radiotherapy and systemic care is suboptimal additionally limiting treatment results. With a small portion of their budget allocated to healthcare, LMIC need to make the most of their resources prioritizing cost-effective strategies that could offer the best possible results. Countries that invest in women's health do develop into healthier, more educated, and importantly, more productive societies with benefits seen across generations. Finally, recognition of inequities should stimulate a concerted effort engaging all involved stakeholders to find context-adapted solutions to improve healthcare outcomes.
Among patients with triple-negative breast cancer and high expression of PD-L1, pembrolizumab plus chemotherapy resulted in longer overall survival than chemotherapy alone.
Preferred neoadjuvant regimens for early-stage triple-negative breast cancer (TNBC) include anthracycline-cyclophosphamide and taxane-based chemotherapy. IMpassion031 compared efficacy and safety of ...atezolizumab versus placebo combined with nab-paclitaxel followed by doxorubicin plus cyclophosphamide as neoadjuvant treatment for early-stage TNBC.
This double-blind, randomised, phase 3 study enrolled patients in 75 academic and community sites in 13 countries. Patients aged 18 years or older with previously untreated stage II–III histologically documented TNBC were randomly assigned (1:1) to receive chemotherapy plus intravenous atezolizumab at 840 mg or placebo every 2 weeks. Chemotherapy comprised of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks, which was then followed by surgery. Stratification was by clinical breast cancer stage and programmed cell death ligand 1 (PD-L1) status. Co-primary endpoints were pathological complete response in all-randomised (ie, all randomly assigned patients in the intention-to-treat population) and PD-L1-positive (ie, patients with PD-L1-expressing tumour infiltrating immune cells covering ≥1% of tumour area) populations. This study is registered with ClinicalTrials.gov (NCT03197935), Eudra (CT2016-004734-22), and the Japan Pharmaceutical Information Center (JapicCTI-173630), and is ongoing.
Between July 7, 2017, and Sept 24, 2019, 455 patients were recruited and assessed for eligibility. Of the 333 eligible patients, 165 were randomly assigned to receive atezolizumab plus chemotherapy and 168 to placebo plus chemotherapy. At data cutoff (April 3, 2020), median follow-up was 20·6 months (IQR 8·7–24·9) in the atezolizumab plus chemotherapy group and 19·8 months (8·1–24·5) in the placebo plus chemotherapy group. Pathological complete response was documented in 95 (58%, 95% CI 50–65) patients in the atezolizumab plus chemotherapy group and 69 (41%, 34–49) patients in the placebo plus chemotherapy group (rate difference 17%, 95% CI 6–27; one-sided p=0·0044 significance boundary 0·0184). In the PD-L1-positive population, pathological complete response was documented in 53 (69%, 95% CI 57–79) of 77 patients in the atezolizumab plus chemotherapy group versus 37 (49%, 38–61) of 75 patients in the placebo plus chemotherapy group (rate difference 20%, 95% CI 4–35; one-sided p=0·021 significance boundary 0·0184). In the neoadjuvant phase, grade 3–4 adverse events were balanced and treatment-related serious adverse events occurred in 37 (23%) and 26 (16%) patients, with one patient per group experiencing an unrelated grade 5 adverse event (traffic accident in the atezolizumab plus chemotherapy group and pneumonia in the placebo plus chemotherapy group).
In patients with early-stage TNBC, neoadjuvant treatment with atezolizumab in combination with nab-paclitaxel and anthracycline-based chemotherapy significantly improved pathological complete response rates with an acceptable safety profile.
F Hoffmann-La Roche/Genentech.
In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III ...trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC.
Patients with ED-SCLC, Eastern Cooperative Oncology Group performance status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks, nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until progression or unacceptable toxicity. Primary end point was overall survival (OS) with nivolumab plus ipilimumab versus placebo. Secondary end points were hierarchically tested.
Overall, 834 patients were randomly assigned. The minimum follow-up was 8.9 months. OS was not significantly prolonged with nivolumab plus ipilimumab versus placebo (hazard ratio HR, 0.92; 95% CI, 0.75 to 1.12;
= .37; median, 9.2
9.6 months). The HR for OS with nivolumab versus placebo was 0.84 (95% CI, 0.69 to 1.02); the median OS for nivolumab was 10.4 months. Progression-free survival HRs versus placebo were 0.72 for nivolumab plus ipilimumab (95% CI, 0.60 to 0.87) and 0.67 for nivolumab (95% CI, 0.56 to 0.81). A trend toward OS benefit with nivolumab plus ipilimumab was observed in patients with tumor mutational burden ≥ 13 mutations per megabase. Rates of grade 3-4 treatment-related adverse events were nivolumab plus ipilimumab (52.2%), nivolumab (11.5%), and placebo (8.4%).
Maintenance therapy with nivolumab plus ipilimumab did not prolong OS for patients with ED-SCLC who did not progress on first-line chemotherapy. There were no new safety signals.
Abstract
Background
Understanding the impact of the tumor immune microenvironment and BRCA1/2-related DNA repair deficiencies on the clinical activity of immune checkpoint inhibitors may help ...optimize both patient and treatment selection in metastatic triple-negative breast cancer. In this substudy from the phase 3 IMpassion130 trial, immune biomarkers and BRCA1/2 alterations were evaluated for association with clinical benefit with atezolizumab and nab-paclitaxel (A+nP) vs placebo and nP in unresectable (P+nP) locally advanced or metastatic triple-negative breast cancer.
Methods
Patients were randomly assigned 1:1 to nab-paclitaxel 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) and atezolizumab 840 mg every 2 weeks or placebo until progression or toxicity. Progression-free survival and overall survival were evaluated based on programmed death-ligand 1 (PD-L1) expression on immune cells (IC) and tumor cells, intratumoral CD8, stromal tumor-infiltrating lymphocytes, and BRCA1/2 mutations.
Results
PD-L1 IC+ in either primary or metastatic tumor tissue was linked to progression-free survival and overall survival benefit with A+nP. PD-L1 IC+ low (26.9%; 243 of 902 patients) and high (13.9%; 125 of 902 patients) populations had improved outcomes that were comparable. Intratumoral CD8 and stromal tumor-infiltrating lymphocytes positivity (sTIL+) were associated with PD-L1 IC+ status; improved outcomes were observed with A+nP vs P+nP only in CD8+ and sTIL+ patients who were also PD-L1 IC+. BRCA1/2 mutations (occurring in 14.5% 89 of 612 patients) were not associated with PD-L1 IC status, and PD-L1 IC+ patients benefited from A+nP regardless of BRCA1/2 mutation status.
Conclusions
Although A+nP was more efficacious in patients with richer tumor immune microenvironment, clinical benefit was only observed in patients whose tumors were PD-L1 IC+.
Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 ...IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer.
In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice–web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m2 of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891.
Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6–22·8) in the atezolizumab group and 17·5 months (8·4–22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0–22·6) with atezolizumab and 18·7 months (16·9–20·3) with placebo (stratified hazard ratio HR 0·86, 95% CI 0·72–1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6–30·7) with atezolizumab versus 18·0 months (13·6–20·1) with placebo (stratified HR 0·71, 0·54–0·94). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3–4 adverse events were neutropenia (38 8% of 453 patients in the atezolizumab group vs 36 8% of 437 patients in the placebo group), peripheral neuropathy (25 6% vs 12 3%), decreased neutrophil count (22 5% vs 16 4%), and fatigue (17 4% vs 15 3%). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab n=1 and septic shock related to nab-paclitaxel n=1) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018).
Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need.
F Hoffmann-La Roche and Genentech.
Addition of the anti–PD-L1 antibody atezolizumab to nab-paclitaxel as first-line therapy for patients with advanced or metastatic triple-negative breast cancer significantly prolonged ...progression-free survival, particularly among those with PD-L1–positive tumors.
Enhancing global access to cancer medicines Cortes, Javier; Perez‐García, Jose Manuel; Llombart‐Cussac, Antonio ...
CA: a cancer journal for clinicians,
March/April 2020, Letnik:
70, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Globally, cancer is the second leading cause of death, with numbers greatly exceeding those for human immunodeficiency virus/acquired immunodeficiency syndrome, tuberculosis, and malaria combined. ...Limited access to timely diagnosis, to affordable, effective treatment, and to high‐quality care are just some of the factors that lead to disparities in cancer survival between countries and within countries. In this article, the authors consider various factors that prevent access to cancer medicines (particularly access to essential cancer medicines). Even if an essential cancer medicine is included on a national medicines list, cost might preclude its use, it might be prescribed or used inappropriately, weak infrastructure might prevent it being accessed by those who could benefit, or quality might not be guaranteed. Potential strategies to address the access problems are discussed, including universal health coverage for essential cancer medicines, fairer methods for pricing cancer medicines, reducing development costs, optimizing regulation, and improving reliability in the global supply chain. Optimizing schedules for cancer therapy could reduce not only costs, but also adverse events, and improve access. More and better biomarkers are required to target patients who are most likely to benefit from cancer medicines. The optimum use of cancer medicines depends on the effective delivery of several services allied to oncology (including laboratory, imaging, surgery, and radiotherapy). Investment is necessary in all aspects of cancer care, from these supportive services to technologies, and the training of health care workers and other staff.
To compare single-agent pemetrexed (P) versus the combination of carboplatin and pemetrexed (CP) in first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) with an Eastern ...Cooperative Oncology Group (ECOG) performance status (PS) of 2.
In a multicenter phase III randomized trial, patients with advanced NSCLC, ECOG PS of 2, any histology at first and later amended to nonsquamous only, no prior chemotherapy, and adequate organ function were randomly assigned to P alone (500 mg/m(2)) or CP (area under the curve of 5 and 500 mg/m(2), respectively) administered every 3 weeks for a total of four cycles. The primary end point was overall survival (OS).
A total of 205 eligible patients were enrolled from eight centers in Brazil and one in the United States from April 2008 to July 2011. The response rates were 10.3% for P and 23.8% for CP (P = .032). In the intent-to-treat population, the median PFS was 2.8 months for P and 5.8 months for CP (hazard ratio HR, 0.46; 95% CI, 0.35 to 0.63; P < .001), and the median OS was 5.3 months for P and 9.3 months for CP (HR, 0.62; 95% CI, 0.46 to 0.83; P = .001). One-year survival rates were 21.9% and 40.1%, respectively. Similar results were seen when patients with squamous disease were excluded from the analysis. Anemia (grade 3, 3.9%; grade 4, 11.7%) and neutropenia (grade 3, 1%; grade 4, 6.8%) were more frequent with CP. There were four treatment-related deaths in the CP arm.
Combination chemotherapy with CP significantly improves survival in patients with advanced NSCLC and ECOG PS of 2.
IMpower110 previously revealed significant overall survival (OS) benefit with atezolizumab versus chemotherapy in patients with treatment-naive EGFR- and ALK-negative (wild type WT) metastatic NSCLC ...with high programmed death-ligand 1 (PD-L1) expression (≥50% on tumor cells TCs or ≥10% on tumor-infiltrating immune cells ICs, per SP142 immunohistochemistry assay; p = 0.0106). We present primary OS analyses in lower PD-L1 expression groups and an updated, exploratory analysis in the high PD-L1 expression group.
This open-label, phase 3 trial randomized patients with PD-L1 expression on greater than or equal to 1% of TC or IC to receive atezolizumab or platinum-based chemotherapy. The primary end point was OS, hierarchically tested in PD-L1 expression WT subgroups: first the high PD-L1 expression subgroup, then the high-or-intermediate PD-L1 expression subgroup (≥5% on TC or IC), and then the any PD-L1 expression subgroup (≥1% on TC or IC).
The any PD-L1 expression WT population included 554 patients (excluded 18 EGFR- or ALK-positive patients). With 17 months’ additional follow-up, OS improvement in the atezolizumab versus chemotherapy arm was not statistically significant in high-or-intermediate PD-L1 expression WT patients (n = 328; hazard ratio = 0.87, 95% confidence interval: 0.66–1.14, p = 0.3091; median = 19.9 versus 16.1 mo), precluding formal OS testing in any PD-L1 expression WT patients. Exploratory analysis in high PD-L1 expression WT patients (n = 205) revealed maintained OS benefit in the atezolizumab arm (hazard ratio = 0.76, 95% confidence interval: 0.54–1.09; median = 20.2 versus 14.7 mo). Updated safety data continued to favor atezolizumab.
Statistical significance for OS was not revealed in the high-or-intermediate expression WT group, and, as a result, OS in the any PD-L1 expression WT group was not formally tested. No new safety signals were found. This updated analysis of IMpower110 supports using atezolizumab in treatment-naive, metastatic WT NSCLC with high PD-L1 expression.
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