Improving access to cancer clinical research in Brazil: recent advances and new opportunities. Expert opinions from the 4th CURA meeting, São Paulo, 2023.

Clinical research is the cornerstone of improvements in cancer care. However, it has been conducted predominantly in high-income countries with few clinical trials available in Brazil and other low-and-middle-income countries (LMIC). Of note, less than one-third of registered clinical trials addressing some of the most commonly diagnosed cancers (breast, lung and cervical) recruited patients from LMIC in the last years. The Institute Project CURA promoted the fourth CURA meeting, discussing barriers to cancer clinical research and proposing potential solutions. A meeting was held in São Paulo, Brazil, in June 2023 with representatives from different sectors: Brazilian Health Regulatory Agency (Anvisa), National Commission of Ethics in Research (CONEP), non-governmental organisations, such as the Latin American Cooperative Oncology Group, the Brazilian Society of Clinical Oncology (SBOC), Contract Research Organisations, pharmaceutical companies and investigators. A total of 16 experts pointed out achievements as shortening the time of regulatory processes involving Anvisa and CONEP, development of staff training programs, maintenance of the National Program of Oncological Attention (PRONON), and the foundation of qualified centres in North and Northeast Brazilian regions. Participants also highlighted the need to be more competitive in the field, which requires optimising ongoing policies and implementing new strategies as decentralisation of clinical research centres, public awareness campaigns, community-centered approaches, collaborations and partnerships, expansion of physicians-directed policies, exploring the role of the steering committee. Active and consistent reporting of the initiatives might help to propagate ongoing advances, increasing Brazilian participation in clinical cancer research. Engagement of all players is crucial to maintain continuous progress with further improvements in critical points including regulatory timelines and increments in qualified human resources which aligned with new educational initiatives focused on physicians and the general population will expand access to cancer clinical trials in Brazil.

Systemic Treatment of Patients With Metastatic Breast Cancer: ASCO Resource-Stratified Guideline.

PURPOSE: To guide clinicians and policymakers in three global resource-constrained settings on treating patients with metastatic breast cancer (MBC) when Maximal setting-guideline recommended treatment is unavailable. METHODS: A multidisciplinary, multinational panel reviewed existing ASCO guidelines and conducted modified ADAPTE and formal consensus processes. RESULTS: Four published resource-agnostic guidelines were adapted for resource-constrained settings; informing two rounds of formal consensus; recommendations received ≥75% agreement. RECOMMENDATIONS: Clinicians should recommend treatment according to menopausal status, pathological and biomarker features when quality results are available. In first-line, for hormone receptor (HR)-positive MBC, when a non-steroidal aromatase inhibitor and CDK 4/6 inhibitor combination is unavailable, use hormonal therapy alone. For life-threatening disease, use single-agent chemotherapy or surgery for local control. For premenopausal patients, use ovarian suppression or ablation plus hormone therapy in Basic settings. For human epidermal growth factor receptor 2 (HER2)-positive MBC, if trastuzumab, pertuzumab, and chemotherapy are unavailable, use trastuzumab and chemotherapy; if unavailable, use chemotherapy. For HER2-positive, HR-positive MBC, use standard first-line therapy, or endocrine therapy if contraindications. For triple-negative MBC with unknown PD-L1 status, or if PD-L1-positive and immunotherapy unavailable, use single-agent chemotherapy. For germline BRCA1/2 mutation-positive MBC, if poly(ADP-ribose) polymerase inhibitor is unavailable, use hormonal therapy (HR-positive MBC) and chemotherapy (HR-negative MBC). In second-line, for HR-positive MBC, Enhanced setting recommendations depend on prior treatment; for Limited, use tamoxifen or chemotherapy. For HER2-positive MBC, if trastuzumab deruxtecan is unavailable, use trastuzumab emtansine; if unavailable, capecitabine and lapatinib; if unavailable, trastuzumab and/or chemotherapy (hormonal therapy alone for HR-positive MBC).Additional information is available at www.asco.org/resource-stratified-guidelines. It is ASCO's view that healthcare providers and system decision-makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

First-Line Ipatasertib, Atezolizumab, and Taxane Triplet for Metastatic Triple-Negative Breast Cancer: Clinical and Biomarker Results.

PURPOSE: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance. RESULTS: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels. CONCLUSIONS: In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.

Health-Related Quality of Life With Pembrolizumab+Chemotherapy Versus Placebo+Chemotherapy for Advanced Triple-Negative Breast Cancer: KEYNOTE-355.

BACKGROUND: In KEYNOTE-355 (NCT02819518), addition of pembrolizumab to chemotherapy led to statistically significant improvements in progression-free survival and overall survival in patients with advanced triple-negative breast cancer (TNBC) with tumor PD-L1 combined positive score (CPS) ≥10. We report patient-reported outcomes (PROs) from KEYNOTE-355. METHODS: Patients were randomized 2:1 to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus investigator's choice chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin). QLQ-C30, QLQ-BR23, and EQ-5D visual analogue scale (VAS) were prespecified. PROs were analyzed for patients who received ≥1 dose of study treatment and completed ≥1 PRO assessment. Change in PRO scores from baseline were assessed at week 15 (latest time point at which completion/compliance rates were ≥60%/≥80%). Time to deterioration (TTD) in PROs was defined as time to first onset of ≥ 10-point worsening in score from baseline. RESULTS: PRO analyses included 317 patients with tumor PD-L1 CPS ≥10 (pembrolizumab plus chemotherapy; n = 217; placebo plus chemotherapy, n = 100). There were no between-group differences in change from baseline to week 15 in QLQ-C30 global health status/quality of life (GHS/QoL; least-squares mean difference, -1.81 [95% CI, -6.92 to 3.30]), emotional functioning (-1.43 [-7.03 to 4.16]), physical functioning (-1.05 [-6.59 to 4.50]), or EQ-5D VAS (0.18 [-5.04 to 5.39]), and no between-group difference in TTD in QLQ-C30 GHS/QoL, emotional functioning, or physical functioning. CONCLUSIONS: Together with the efficacy and safety findings, PRO results from KEYNOTE-355 support pembrolizumab plus chemotherapy as a standard of care for patients with advanced TNBC with tumor PD-L1 (CPS ≥10).

Clinical validation and diagnostic accuracy of 99mTc-EDDA/HYNIC-TOC compared to 111In-DTPA-octreotide in patients with neuroendocrine tumours: the LACOG 0214 study.

99mTc-EDDA/HYNIC-TOC is an easily available and cheaper radionuclide that could be used for somatostatin-receptor-based imaging of neuroendocrine tumours (NETs). We aimed to evaluate the diagnostic performance of 99mTc-EDDA/HYNIC-TOC compared to111In-DTPA-octreotide in patients (pts) with NETs. We performed a prospective diagnostic study including pts with biopsy-confirmed NET and at least one visible lesion at conventional imaging. Two independent nuclear medicine physicians evaluated pts who underwent 99mTc and 111In scans and images. The primary outcome was comparative diagnostic accuracy of 99mTc and 111In. Secondary outcomes include safety. Nine pts were included and performed 14 paired scans. Overall, 126 lesions were identified. 99mTc demonstrated superior sensitivity both when all images were analysed (93.7, 95% CI 88.1% - 96.8% versus 74.8%, 95% CI 66.6 - 81.6%, p < 0.001) and when liver-specific images were analysed (97.8%, 95% CI 92.7% - 99.5% versus 85.1%, 95% CI 76.6% - 91.0%, p < 0.001). 99mTc was also associated with a lower negative likelihood ratio (LR) (0.002, 95% CI 0.009 - 0.1 versus 0.19, 95% CI 0.12 - 0.42, p = 0.009) when evaluating hepatic lesions. Adverse events happened in 3 pts after 111In and in 2 pts after 99mTc, all grade 1. The 99mTc demonstrated a higher sensitivity overall and a better negative LR in liver-specific images compared to 111In in pts with NETs. Our findings suggest that 99mTc is an alternative to 111In and is especially useful in ruling out liver metastases. NCT02691078.

Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer.

Background: Ribociclib has demonstrated a statistically significant overall survival benefit in pre- and postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) advanced breast cancer. New Adjuvant Trial with Ribociclib [LEE011] (NATALEE) is a trial evaluating the efficacy and safety of adjuvant ribociclib plus endocrine therapy (ET) versus ET alone in patients with HR+/HER2- early nonmetastatic breast cancer (EBC). Methods/design: NATALEE is a multicenter, randomized, open-label, Phase III trial in patients with HR+/HER2- EBC. Eligible patients include women, regardless of menopausal status, and men aged ⩾18 years. Select patients with stage IIA, stage IIB, or stage III disease (per the anatomic classification in the AJCC Cancer Staging Manual, 8th edition) with an initial diagnosis ⩽18 months prior to randomization are eligible. Patients receiving standard (neo)adjuvant ET are eligible if treatment was initiated ⩽12 months before randomization. Patients undergo 1:1 randomization to ribociclib 400 mg/day (3 weeks on/1 week off) +ET (letrozole 2.5 mg/day or anastrozole 1 mg/day [investigator's discretion] plus goserelin [men or premenopausal women]) or ET alone. Ribociclib treatment duration is 36 months; ET treatment duration is ⩾60 months. The primary end point is invasive disease-free survival. Discussion: The 36-month treatment duration of ribociclib in NATALEE is extended compared with that in other adjuvant cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor trials and is intended to maximize efficacy due to longer duration of CDK4/6 inhibition. Compared with the 600-mg/day dose used in advanced breast cancer, the reduced ribociclib dose used in NATALEE may improve tolerability while maintaining efficacy. NATALEE includes the broadest population of patients with HR+/HER2- EBC of any Phase III trial currently evaluating adjuvant CDK4/6 inhibitor treatment. Trial registration: ClinicalTrials.gov identifier: NCT03701334 (https://clinicaltrials.gov/ct2/show/NCT03701334).

Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial.

PURPOSE: Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. RESULTS: Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION: Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.

Overall survival with neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): A randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: ExteNET showed that neratinib, an irreversible pan-HER tyrosine kinase inhibitor, given for 1 year after trastuzumab-based therapy significantly improved invasive disease-free survival in women with early-stage HER2-positive breast cancer. We report the final analysis of overall survival in ExteNET. METHODS: In this international, randomised, double-blind, placebo-controlled, phase 3 trial, women aged 18 years or older with stage 1-3c (amended to stage 2-3c) HER2-positive breast cancer who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab were eligible. Patients were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year. Randomisation was stratified according to hormone receptor (HR) status (HR-positive vs. HR-negative), nodal status (0, 1-3 or 4+), and trastuzumab regimen (sequentially vs. concurrently with chemotherapy). Overall survival was analysed by intention to treat. ExteNET is registered (Clinicaltrials.gov: NCT00878709) and is complete. RESULTS: Between July 9, 2009, and October 24, 2011, 2840 women received neratinib (n = 1420) or placebo (n = 1420). After a median follow-up of 8.1 (IQR, 7.0-8.8) years, 127 patients (8.9%) in the neratinib group and 137 patients (9.6%) in the placebo group in the intention-to-treat population had died. Eight-year overall survival rates were 90.1% (95% CI 88.3-91.6) with neratinib and 90.2% (95% CI 88.4-91.7) with placebo (stratified hazard ratio 0.95; 95% CI 0.75-1.21; p = 0.6914). CONCLUSIONS: Overall survival in the extended adjuvant setting was comparable for neratinib and placebo after a median follow-up of 8.1 years in women with early-stage HER2-positive breast cancer.

Current scenario and future perspectives of clinical research in Brazil: a national survey.

Background: Epidemiological and clinical cancer research is essential to understanding tumour behaviour and developing new therapies in oncology. However, several countries including Brazil as well as many other regions of the world have limited participation in cancer research. Despite 625,000 new cancer cases recorded in Brazil in 2022, only 2.2% of ongoing cancer clinical trials are available in the country. We conducted an online survey to describe physician engagement with research and to identify the main barriers precluding participation in and conduct of clinical cancer research in the country. Methods: An anonymous online survey of 23 objective questions was sent by e-mail to Brazilian members of the Latin American Cooperative Oncology Group and the Brazilian Society of Clinical Oncology. The first 13 questions addressed demographic information, medical training and previous research participation. In the second part, the main barriers to engagement and participation in clinical trials in Brazil were addressed. Continuous variables were measured by median and range. Analyses were performed using SAS statistical software (version 9.4; SAS Institute, Inc. Cary, NC). Results: 109 physicians answered the survey. Most participants were oncologists (N = 98, 89.9%), living in capital cities (N = 84, 77.1%), were from the Southeast region of Brazil (N = 63, 57.8%) and worked at institutions providing exclusively private healthcare (N = 59, 54.1%). Of the 109 respondents, 83 (76.1%) reported working in research centres (as investigators or sub-investigators). Surprisingly, 31.2% of physicians recognised they invite less than 1% of their patients to participate in clinical trials, even though 98 (89.9%) considered the participation of patients in clinical trials extremely relevant. The main barriers compromising the conduct of research in the country were the low number of available trials (48.2%) and the lack of qualified human resources to staff research sites (22.9%). Other reported barriers were the lengthy regulatory approval process (42.2%), followed by a lack of awareness of clinical research by patients resulting in low recruitment rates (24.1%). Of the 26 (23.8%) respondents not working with research, 25 (96.1%) reported interest in being involved, 31.8% have tried participating in research and 62.4% reported limited knowledge of trial procedures. Conclusion: These results suggest a clear need to further engage physicians in clinical research activities in Brazil. Patient education strategies should improve the low recruitment rates and secondarily increase the number of proposed trials in the country.

Impact of the COVID-19 Pandemic on Cancer Staging: An Analysis of Patients With Breast Cancer From a Community Practice in Brazil.

PURPOSE: A nationwide lockdown was enforced in Brazil starting in March 2020 because of the COVID-19 pandemic when cancer screening activities were reduced. In this study, we evaluated the impact of the COVID-19 pandemic on breast cancer (BC) diagnosis. METHODS: We extracted data from the medical records of patients age older than 18 years who were diagnosed with BC and started treatment or follow-up in private oncology institutions in Brazil between 2018 and 2021. The primary objective was to compare the stage distribution during the COVID-19 pandemic (2020-2021) with a historical prepandemic control cohort (2018-2019). Early BC was defined as stage I-II and advanced disease as stage IV. RESULTS: We collected data for 11,753 patients with an initial diagnosis of BC, with 6,493 patients in the pandemic (2020-2021) and 5,260 patients in the prepandemic period (2018-2019). We observed a lower prevalence of early-stage BC (63.6% v 68.4%) and a higher prevalence of advanced-stage BC (16.9 v 12.7%), after the onset of the pandemic (both P < .01). This pattern was similar for both estrogen receptor-positive/human epidermal growth factor receptor 2-negative and human epidermal growth factor receptor 2-positive tumors: significantly decreased in the early stage from 69% to 67% and 68% to 58%, respectively, and a considerable increase in advanced-stage disease from 13% to 15% and 13% to 20%, respectively. For triple-negative BC, there was a significantly higher percentage of patients with advanced-stage disease during the pandemic (17% v 11%). Overall, age 50 years or older and postmenopausal status were associated with a greater risk of advanced stage at diagnosis during the pandemic period. CONCLUSION: We observed a substantial increase in the number of cases of advanced-stage BC in Brazil during the COVID-19 pandemic.

GLORIA: phase III, open-label study of adagloxad simolenin/OBI-821 in patients with high-risk triple-negative breast cancer.

Triple-negative breast cancer (TNBC) has the highest rate of distant metastasis and poorest overall survival among breast cancer subtypes. In a phase II study, adagloxad simolenin (AdaSim), a synthetic Globo H conjugate vaccine administered with adjuvant OBI-821, was shown to induce IgM and IgG anti-Globo H humoral responses in patients with metastatic breast cancer overexpressing the glycosphingolipid Globo H. GLORIA is an ongoing phase III, randomized, open-label clinical trial to evaluate the safety and efficacy of AdaSim and the quality of life (QoL) of patients receiving AdaSim plus standard of care (SOC) versus SOC alone in high-risk, early-stage TNBC. The primary end point is invasive progression-free survival; secondary end points include overall survival, QoL, breast cancer-free interval, distant disease-free survival, safety, and tolerability.

Patients with triple-negative breast cancer generally do very poorly with the current available therapies. A vaccine with a totally different mechanism of action is being investigated in these patients to see how they do with this new therapy. This trial is a very early investigation and is currently ongoing. Clinical Trial Registration: NCT03562637 (ClinicalTrials.gov).

Patient-reported outcomes from a randomized trial of neoadjuvant atezolizumab-chemotherapy in early triple-negative breast cancer.

Patient-reported outcomes data assessing patients' experience of immunotherapy treatment burden in potentially curable early-stage triple-negative breast cancer (TNBC) are lacking. These patient-reported data inform clinical benefit and decision-making for adding atezolizumab to neoadjuvant chemotherapy in early-stage TNBC. IMpassion031 (NCT03197935) randomly assigned patients with stage II/III TNBC (T2-T4d primary tumors) to 5 cycles (4 weeks/cycle) of every 2-week neoadjuvant atezolizumab 840 mg or placebo with weekly nab-paclitaxel (3 cycles) followed by every 2-week dose-dense doxorubicin+cyclophosphamide (2 cycles). After surgery, the atezolizumab-chemotherapy arm received atezolizumab 1200 mg every 3 weeks (11 cycles). The placebo-chemotherapy arm was observed under standard of care. To assess treatment burden from the patients' perspective, which comprised measures of the treatment-related impact on patients' functioning and health-related quality of life (HRQoL), as well as patients' experience of treatment-related symptoms plus their associated bother, patients completed the EORTC QLQ-C30 and FACT-G single-item GP5. Predefined secondary endpoints included mean and mean change from baseline values in the QLQ-C30 function (role and physical) and global health status/quality of life scales. Exploratory endpoints included mean and mean change from baseline in treatment-related symptoms, and treatment side effect bother. Mean physical, role function, and HRQoL were similar between arms at baseline and throughout treatment. In the neoadjuvant period, both arms exhibited clinically meaningful declines of similar magnitude from baseline in physical, role function, and HRQoL, and reported similar treatment side effect to bother at each visit. Improved pathologic complete response from adding atezolizumab to neoadjuvant chemotherapy for early-stage TNBC occurred without imposing additional treatment burden on patients.

Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial.

Tumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)-an open-label, global, multicohort trial-evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 (N = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P = 0.053). Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted.

Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer.

BACKGROUND: In an interim analysis of this phase 3 trial, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100) of 10 or more. The results of the final analysis of overall survival have not been reported. METHODS: We randomly assigned patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator's choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine-carboplatin) or placebo plus chemotherapy. The primary end points were progression-free survival (reported previously) and overall survival among patients whose tumors expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumors expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed. RESULTS: A total of 847 patients underwent randomization: 566 were assigned to the pembrolizumab-chemotherapy group, and 281 to the placebo-chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab-chemotherapy group and 16.1 months in the placebo-chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.55 to 0.95; two-sided P = 0.0185 [criterion for significance met]); in the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (hazard ratio, 0.86; 95% CI, 0.72 to 1.04; two-sided P = 0.1125 [not significant]); and in the intention-to-treat population, the median overall survival was 17.2 and 15.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.76 to 1.05 [significance not tested]). Adverse events of grade 3, 4, or 5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab-chemotherapy group and in 66.9% in the placebo-chemotherapy group, including death in 0.4% of the patients in the pembrolizumab-chemotherapy group and in no patients in the placebo-chemotherapy group. CONCLUSIONS: Among patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone. (Funded by Merck Sharp and Dohme; KEYNOTE-355 ClinicalTrials.gov number, NCT02819518.).

Atezolizumab With Neoadjuvant Anti-Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial.

PURPOSE: Combining standard of care (pertuzumab-trastuzumab [PH], chemotherapy) with cancer immunotherapy may potentiate antitumor immunity, cytotoxic activity, and patient outcomes in high-risk, human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We report the phase III IMpassion050 primary analysis of neoadjuvant atezolizumab, PH, and chemotherapy in these patients. METHODS: Patients with a primary tumor of > 2 cm and histologically confirmed, positive lymph node status (T2-4, N1-3, M0) were randomly assigned 1:1 to atezolizumab/placebo with dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel, and PH. After surgery, patients were to continue atezolizumab/placebo and PH (total: 1 year of HER2-targeted therapy); those with residual disease could switch to ado-trastuzumab emtansine with atezolizumab/placebo. Coprimary efficacy end points were pathologic complete response (pCR; ypT0/is ypN0) rates in intention-to-treat (ITT) and programmed cell death-ligand 1 (PD-L1)-positive populations. RESULTS: At clinical cutoff (February 5, 2021), pCR rates in the placebo and atezolizumab groups in the ITT populations were 62.7% (n = 143/228) and 62.4% (n = 141/226), respectively (difference -0.33%; 95% CI, -9.2 to 8.6; P = .9551). The pCR rates in the placebo and atezolizumab groups in patients with PD-L1-positive tumors were 72.5% (n = 79/109) and 64.2% (n = 70/109), respectively (difference -8.26%; 95% CI, -20.6 to 4.0; P = .1846). Grade 3-4 and serious adverse events were more frequent in the atezolizumab versus placebo group. Five grade 5 adverse events occurred (four neoadjuvant, one adjuvant; two assigned to study treatment), all with atezolizumab. Overall, the safety profile was consistent with that of atezolizumab in other combination studies. CONCLUSION: Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide-paclitaxel and PH for high-risk, HER2-positive early breast cancer did not increase pCR rates versus placebo in the ITT or PD-L1-positive populations. PH and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.

Effects of capecitabine as part of neo-/adjuvant chemotherapy - A meta-analysis of individual breast cancer patient data from 13 randomised trials including 15,993 patients.

BACKGROUND: Despite the large number of patients with early breast cancer (EBC) who have been treated with capecitabine in randomised trials, no individual patient data meta-analysis has been conducted. The primary objective was to examine the effect of capecitabine on disease-free survival (DFS), and the secondary objectives were to analyse distant DFS (DDFS), overall survival (OS), pathological complete response (for neoadjuvant studies) and the interaction between capecitabine-related toxicity and treatment effect. METHODS: www. CLINICALTRIALS: gov and www.pubmed.ncbi.nlm.nih.gov were searched using the following criteria: use of capecitabine for EBC as adjuvant or neoadjuvant therapy; multicentre randomised trial with >100 patients; recruitment completed, and outcomes available. Required data were available for 13 trials. RESULTS: Individual data from 15,993 patients were collected. Cox regression analyses of all included patients revealed that the addition of capecitabine did not alter DFS significantly compared with treatment without capecitabine (hazard ratio [HR] 0.952; 95% CI 0.895-1.012; P value = 0.115). There was also no effect on DFS in the subset of studies where capecitabine was given instead of another drug (HR 1.035; 95% CI 0.945-1.134; P = 0.455). However, capecitabine administered in addition to the standard systemic treatment improved DFS (HR 0.888; 95% CI 0.817-0.965; P = 0.005). An OS improvement was observed in the entire cohort (HR 0.892; 95% CI 0.824-0.965, P = 0.005) and in the subset of capecitabine addition (HR 0.837; 95% CI 0.751, 0.933, P = 0.001). Subgroup analyses revealed that triple-negative breast cancer (TNBC) patients benefitted from treatment with capecitabine overall and in addition to other systemic treatments in terms of DFS and OS. CONCLUSION: Capecitabine was able to improve DFS and OS in patients with TNBC and in all patients with EBC when administered in addition to systemic treatment.

International Association for the Study of Lung Cancer Study of the Impact of Coronavirus Disease 2019 on International Lung Cancer Clinical Trials.

INTRODUCTION: To evaluate the effects of the global coronavirus disease 2019 (COVID-19) pandemic on lung cancer trials, we surveyed investigators and collected aggregate enrollment data for lung cancer trials across the world before and during the pandemic. METHODS: A Data Collection Survey collected aggregate monthly enrollment numbers from 294 global lung cancer trials for 2019 to 2020. A 64-question Action Survey evaluated the impact of COVID-19 on clinical trials and identified mitigation strategies implemented. RESULTS: Clinical trial enrollment declined from 2019 to 2020 by 14% globally. Most reductions in enrollment occurred in April to June where we found significant decreases in individual site enrollment (p = 0.0309). Enrollment was not significantly different in October 2019 to December of 2019 versus 2020 (p = 0.25). The most frequent challenges identified by the Action Survey (N = 172) were fewer eligible patients (63%), decrease in protocol compliance (56%), and suspension of trials (54%). Patient-specific challenges included access to trial site (49%), ability to travel (54%), and willingness to visit the site (59%). The most frequent mitigation strategies included modified monitoring requirements (47%), telehealth visits (45%), modified required visits (25%), mail-order medications (25%), and laboratory (27%) and radiology (21%) tests at nonstudy facilities. Sites that felt the most effective mitigation strategies were telehealth visits (85%), remote patient-reported symptom collection (85%), off-site procedures (85%), and remote consenting (89%). CONCLUSIONS: The COVID-19 pandemic created many challenges for lung cancer clinical trials conduct and enrollment. Mitigation strategies were used and, although the pandemic worsened, trial enrollment improved. A more flexible approach may improve enrollment and access to clinical trials, even beyond the pandemic.