Stereotactic radiosurgery versus whole brain radiotherapy in patients with intracranial metastatic disease and small-cell lung cancer: a systematic review and meta-analysis
BACKGROUND
Patients with small-cell lung cancer (SCLC) are at high risk for intracranial metastatic disease (IMD). Although stereotactic radiosurgery (SRS) has supplanted whole brain radiotherapy (WBRT) as first-line treatment for IMD in most solid cancers, WBRT remains first-line treatment for IMD in patients with SCLC. We aimed to evaluate the efficacy of SRS in comparison with WBRT and assess treatment outcomes following SRS.
METHODS
In this systematic review and meta-analysis, we searched MEDLINE, Embase, CENTRAL, and grey literature sources for controlled trials and cohort studies published in English reporting on SRS for IMD treatment in patients with SCLC from inception to March 23, 2022. Studies were excluded that did not report on SRS for IMD secondary to SCLC. Summary data were extracted. The primary outcome was overall survival, presented as pooled hazard ratios (HR) through random-effects meta-analysis for studies comparing SRS with WBRT with or without SRS boost, and as medians for single-arm SRS studies. This study is registered with the Open Science Framework, DOI 10.17605/OSF.IO/8M4HC, and PROSPERO, CRD42021258197.
FINDINGS
Of 3823 identified records, 31 were eligible for inclusion; seven were included in the meta-analysis. Overall survival following SRS was longer than following WBRT with or without SRS boost (HR 0·85; 95% CI 0·75–0·97; n=7 studies; n=18 130 patients), or WBRT alone (0·77; 0·72–0·83; n=7 studies; n=16 961 patients), but not WBRT plus SRS boost (1·17, 0·78–1·75; n=4 studies; n=1167 patients). Using single-arm studies, pooled median overall survival from SRS was 8·99 months (95% CI 7·86–10·16; n=14 studies; n=1682 patients). Between-study heterogeneity was considerable when pooled among all comparative studies (I2=71·9%).
INTERPRETATION
These results suggest survival outcomes are equitable following treatment with SRS compared with WBRT in patients with SCLC and IMD. Future prospective studies should focus on tumour burden and differences in local and distant intracranial progression between WBRT-treated and SRS-treated patients with SCLC.
Karolina Gaebe, BMath, Alyssa Y Li, BA, Amy Park, BSc, Ambica Parmar, MD, Benjamin H Lok, MD, Prof Arjun Sahgal, MD, et al
Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
BACKGROUND
21
METHODS
The CAPSTONE-1 study was a randomised, double-blind, placebo-controlled, phase 3 trial, done in 47 tertiary hospitals in China. Key inclusion criteria were patients aged 18–75 years, with previously untreated histologically or cytologically confirmed ES-SCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. Eligible patients were randomly assigned (1:1) to receive four to six cycles of carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m2 of body-surface area, on days 1–3 of each cycle) with either adebrelimab (20 mg/kg, day 1 of each cycle) or matching placebo, followed by maintenance therapy with adebrelimab or placebo. All treatments were given intravenously in 21-day cycles. Randomisation was done using a centralised interactive web response system with a block size of four, stratified by liver metastases, brain metastases, and lactate dehydrogenase concentration. The primary endpoint was overall survival in patients who received at least one dose of study medication. Safety was analysed in the as-treated population. This study is complete and registered with ClinicalTrials.gov, NCT03711305.
FINDINGS
Between Dec 26, 2018, and Sept 4, 2020, 462 eligible patients were enrolled and randomly assigned: 230 (50%) patients received adebrelimab plus chemotherapy (adebrelimab group) and 232 (50%) patients received placebo plus chemotherapy (placebo group). At data cutoff (Oct 8, 2021), median follow-up was 13·5 months (IQR 8·9–20·1). Median overall survival was significantly improved in the adebrelimab group (median 15·3 months [95% CI 13·2–17·5]) compared with the placebo group (12·8 months [11·3–13·7]; hazard ratio 0·72 [95% CI 0·58–0·90]; one-sided p=0·0017). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (174 [76%] patients in the adebrelimab group and 175 [75%] patients in the placebo group), decreased white blood cell count (106 [46%] and 88 [38%]), decreased platelet count (88 [38%] and 78 [34%]), and anaemia (64 [28%] and 66 [28%]). Treatment-related serious adverse events occurred in 89 (39%) patients in the adebrelimab group and 66 (28%) patients in the placebo group. Four treatment-related deaths were reported: two each in the adebrelimab group (respiratory failure and interstitial lung disease and pneumonia) and placebo group (multiple organ dysfunction and unknown cause of death).
INTERPRETATION
Adding adebrelimab to chemotherapy significantly improved overall survival with an acceptable safety profile in patients with ES-SCLC, supporting this combination as a new first-line treatment option for this population.
Expanded Lung and Colorectal Cancer Screening — Ensuring Equity and Safety under New Guidelines
In 2021, the U.S. Preventive Services Task Force (USPSTF) recommended major expansions of the populations that should undergo routine screening for lung or colorectal cancer. Both recommendations are evidence-based and, if implemented effectively, will most likely save lives. The changes were made with an eye toward reducing inequities in rates of early cancer detection among women and people who identify as Black, Indigenous, or Latinx. The guidelines, however, were released without adequate attention to how they would be implemented. Efforts to deploy complex, highly personalized screening methods using the patchwork approach that is typical of the U.S. health system could backfire, unless health care organizations, payers, and policymakers invest in preventive care infrastructure.
We believe regulatory and policy solutions are necessary to prevent unintended consequences associated with these important expansions in cancer-screening eligibility. To combat systemic racism and promote safety in ambulatory care, health care systems could collect and report data on disparities in preventive care, and they could design and deploy safety nets to ensure timely follow-up after abnormal screening results. In addition, we need policies that explicitly support equity and safety in preventive care.
When layered atop an already inequitable care delivery system, a substantial increase in the volume of preventive screening could exacerbate inequities in access based on race and other factors and lead to missed or delayed cancer diagnoses because of inadequate follow-up. Twenty million people between 45 and 49 years of age are newly eligible for routine colorectal cancer screening under the guidelines. Another 6.4 million people are newly eligible for lung cancer screening. The recommended age for starting lung cancer screening in current or former smokers dropped from 55 to 50 years, and the recommended number of pack-years of smoking history before screening is initiated dropped from 30 to 20 — which nearly doubles the population of eligible adults.1
Even before these changes, the preventive care system wasn’t functioning well. Under the previous USPSTF screening guidelines, only 5% of eligible people received lung cancer screening, and 69% of adults were up to date for colorectal cancer screening. Eligible populations now include younger people, who have historically had lower preventive-screening rates, are more racially and ethnically diverse, and are more likely to be underinsured than older people. Inequities in screening rates, cancer incidence, and mortality have persisted for decades, in part because health care systems haven’t invested in preventing systemic racism in the delivery of routine preventive care and don’t have functional systems to consistently follow up after test results indicating moderate or high cancer risk.2 Purposeful action will be required to overcome these challenges to meet the goals of the expanded USPSTF guidelines.
We believe the first step is for health care systems to create equity dashboards that report data on disparities in screening rates by race and ethnic group, sexual orientation and gender identity, and language. Because we can’t improve what we don’t measure, equity dashboards tracking key process and outcome measures should become part of the standard performance-management tools deployed throughout the U.S. health system. Our perspective could then shift from caring for only the individual patients who come into our offices to having a more complete understanding of the health of our populations, so that we can begin to systematically address the barriers our patients experience and promote the facilitators our patients need. Such an approach is critical to delivering on the potential of the new guidelines, and it will be required to begin addressing systemic racism and other inequities in our health care systems. Of course, reliable equity dashboards will not be possible unless health systems consistently ask patients to share key demographic data. This will require proactive education and outreach in close partnership with the community, as demonstrated in the “We Ask Because We Care” campaigns deployed by numerous U.S. health systems over the past decade.
Plans to address inequities in preventive care could be mandated by the Joint Commission, the National Committee for Quality Assurance, and other credentialing bodies. Health care systems will then need to focus on solutions for advancing equity, such as employing preventive care navigators, offering after-hours screening and diagnostic services to enhance access, supporting community-based screening sites, and broadly deploying programs offering home-based screening methods, such as fecal immunochemical testing or fecal DNA testing for colorectal cancer. By setting explicit goals regarding equitable access to preventive care and tracking improvement, we can avoid exacerbating health disparities and begin leveraging the USPSTF guidelines to correct long-standing inequities.
As health care systems reap the financial rewards of conducting the various diagnostic evaluations and surveillance tests that frequently follow screening, they could also be mandated to invest in a comprehensive cancer-screening safety-net program. Such a program could include registries and workflows to ensure that follow-up of abnormal test results is completed in a timely and highly reliable manner for all patients. Very few programs for colorectal cancer screening in the United States have a high-reliability system to track all patients who don’t follow up after an abnormal screening result. Although accredited facilities for lung cancer screening that bill Medicare are required to submit data to the Centers for Medicare and Medicaid Services using a registry, there’s no requirement that the registry then be employed to close the loop and ensure that follow-up occurs. An ideal cancer-screening safety-net program would track all patients for various preventive services, regardless of insurance status.
The goal of implementing equitable and safe cancer screening throughout the population will be difficult to achieve without payment and regulatory reform. Several types of reform would be beneficial. First, payers could recognize the role of health navigators as crucial members of the care team. Once navigators are funded, either by means of a fee-schedule adjustment or as part of a primary care subcapitation model, they could engage with the most marginalized patients in their communities to address social barriers to care, facilitate shared decision making, and order and schedule indicated tests. Navigators would also manage cancer-screening safety-net registries and perform patient outreach.
Second, the United States lacks the type of well-organized national screening program that has been adopted in many European countries.3 To address this gap, the federal government and state governments could enter into collaborative agreements with health care organizations to establish interoperable preventive care and safety-net registries that would allow the preventive-screening records of patients who move from one health care system or geographic region to another to be readily accessible to any clinician they see. Third, mandating that employers provide paid leave for preventive care is key to ensuring uptake among the younger populations that are included in the expanded USPSTF guidelines.4
Fourth, Congress could pass legislation that compels both commercial and government payers to immediately cover services that receive grade A or B recommendations from the USPSTF. The current 1-year lag before commercial payers must begin reimbursing providers for recommended services delays screening uptake and could therefore delay the diagnosis of new cancers. Finally, Medicaid expansion under the Affordable Care Act has driven substantial improvement in the provision of preventive care. We believe all efforts should be made to induce the 12 states that haven’t yet expanded Medicaid to do so.5
The expansion of eligibility for lung and colorectal cancer screening outlined by the USPSTF represents an opportunity for the United States to promote health equity, create safety-net registries to ensure adequate follow-up after screening, and implement regulatory and payment reform that facilitates rapid adoption of these and other preventive care guidelines. Given that we are building on a shaky foundation, all policy and regulatory levers should be pulled to generate incentives for the U.S. health system to invest in a more equitable and safer approach to preventive care.
Daniel M. Horn, M.D., and Jennifer S. Haas, M.D.
This article was published on January 8, 2022, at NEJM.org.
Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer
BACKGROUND
Human epidermal growth factor receptor 2 (HER2)–targeted therapies have not been approved for patients with non–small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody–drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively.
METHODS
We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed.
RESULTS
A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification.
CONCLUSIONS
Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710. opens in new tab.)
Bob T. Li, M.D., Ph.D., M.P.H., Egbert F. Smit, M.D., Ph.D., Yasushi Goto, M.D., Ph.D., Kazuhiko Nakagawa, M.D., Hibiki Udagawa, M.D., Julien Mazières, M.D., Misako Nagasaka, M.D., Ph.D., Lyudmila Bazhenova, M.D., Andreas N. Saltos, M.D., Enriqueta Felip, M.D., Ph.D., Jose M. Pacheco, M.D., Maurice Pérol, M.D., et al., for the DESTINY-Lung01 Trial Investigators
This article was published on September 18, 2021, at NEJM.org.
Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB–IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial
BACKGROUND
Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients.
METHODS
IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II–IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II–IIIA population, and finally the intention-to-treat (ITT) population (stage IB–IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting).
FINDINGS
Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4–38·3) in the stage II–IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II–IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50–0·88; p=0·0039) and in all patients in the stage II–IIIA population (0·79; 0·64–0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67–0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%).
INTERPRETATION
IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II–IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC.
Efficacy and safety of carboplatin with nab-paclitaxel versus docetaxel in older patients with squamous non-small-cell lung cancer (CAPITAL): a randomised, multicentre, open-label, phase 3 trial
Background
In Japan, docetaxel, a cytotoxic monotherapy, is the standard drug administered to older patients with advanced non-small-cell lung cancer (NSCLC). Carboplatin plus nab-paclitaxel has shown a high objective response rate in patients with squamous histology and was suggested to improve overall survival in patients aged 70 years and older. The CAPITAL trial aimed to assess the safety and efficacy of carboplatin plus nab-paclitaxel versus docetaxel as first-line therapy for patients aged 70 years and older with advanced squamous NSCLC.
Methods
This multicentre, open-label, randomised, phase 3 trial was carried out at 92 medical institutions in Japan. Eligible patients were aged 70 years and older, had advanced squamous NSCLC with no previous systemic chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Using an electronic data capture system, patients were randomly assigned (1:1) to intravenous carboplatin (area under the concentration-time curve of 6 mg/mL per min for 30 min) on day 1 of a 21-day cycle and intravenous nab-paclitaxel (100 mg/m2 for 60 min) on days 1, 8, and 15 every 3 weeks or intravenous docetaxel (60 mg/m2 for 60 min) on day 1 every 3 weeks. Randomisation was computer-generated per participant and stratified by ECOG performance status, clinical stage, sex, age, and institution. The primary endpoint was overall survival, measured in the full analysis set and defined as the time from registration to the date of death due to any cause. Safety was assessed in all patients who received at least one dose of the trial treatment. This trial is registered with the UMIN Clinical Trials Registry, UMIN000019843, and the Japan Registry of Clinical Trials, jRCTs041180110. After the planned interim analysis in Aug 3, 2020, the independent data monitoring committee recommended that the trial be stopped early. This report represents the final analysis.
Findings
Between Feb 24, 2016, and Aug 11, 2020, 196 patients were enrolled and were randomly assigned to the carboplatin plus nab-paclitaxel group (n=98) or the docetaxel group (n=98). Of these patients, four (carboplatin plus nab-paclitaxel group, n=3; docetaxel group, n=1) did not receive any treatment and two patients in the docetaxel group were excluded from the full analysis set. Median overall survival in the full analysis set was 16·9 months (95% CI 12·6–25·4) in the carboplatin plus nab-paclitaxel group and 10·9 months (8·5–12·4) in the docetaxel group (hazard ratio 0·52 [90% CI 0·38–0·70]; p=0·0003). Grade 3–4 adverse events occurred in 79 (83%) patients in the carboplatin plus nab-paclitaxel group and 77 (79%) patients in the docetaxel group (p=0·63). The most common grade 3–4 adverse events in the carboplatin plus nab-paclitaxel group and the docetaxel group were leukopenia (44 [46%] vs 55 [57%]; p=0·20), neutropenia (60 [63%] vs 75 [77%]; p=0·046), febrile neutropenia (nine [10%] vs 19 [20%]; p=0·073), and anaemia (37 [39%] vs two [2%]; p<0·0001). Serious treatment-related adverse events of all grades occurred in 13 (14%) patients in the carboplatin plus nab-paclitaxel group and 11 (11%) patients in the docetaxel group. Treatment-related deaths occurred in two (2%; respiratory failure n=1, visceral arterial ischaemia n=1) patients in the carboplatin plus nab-paclitaxel group and one (1%; sepsis) patient in the docetaxel group.
Interpretation
Our study showed that overall survival was longer with carboplatin plus nab-paclitaxel than with docetaxel, suggesting that carboplatin plus nab-paclitaxel can be used as standard first-line treatment for patients aged 70 years and older with advanced squamous NSCLC.
We aimed to examine cemiplimab, a programmed cell death 1 inhibitor, in the first-line treatment of advanced non-small-cell lung cancer with programmed cell death ligand 1 (PD-L1) of at least 50%.
Methods
In EMPOWER-Lung 1, a multicentre, open-label, global, phase 3 study, eligible patients recruited in 138 clinics from 24 countries (aged ≥18 years with histologically or cytologically confirmed advanced non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0–1; never-smokers were ineligible) were randomly assigned (1:1) to cemiplimab 350 mg every 3 weeks or platinum-doublet chemotherapy. Crossover from chemotherapy to cemiplimab was allowed following disease progression. Primary endpoints were overall survival and progression-free survival per masked independent review committee. Primary endpoints were assessed in the intention-to-treat population and in a prespecified PD-L1 of at least 50% population (per US Food and Drug Administration request to the sponsor), which consisted of patients with PD-L1 of at least 50% per 22C3 assay done according to instructions for use. Adverse events were assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT03088540 and is ongoing.
Findings
Between June 27, 2017 and Feb 27, 2020, 710 patients were randomly assigned (intention-to-treat population). In the PD-L1 of at least 50% population, which consisted of 563 patients, median overall survival was not reached (95% CI 17·9–not evaluable) with cemiplimab (n=283) versus 14·2 months (11·2–17·5) with chemotherapy (n=280; hazard ratio [HR] 0·57 [0·42–0·77]; p=0·0002). Median progression-free survival was 8·2 months (6·1–8·8) with cemiplimab versus 5·7 months (4·5–6·2) with chemotherapy (HR 0·54 [0·43–0·68]; p<0·0001). Significant improvements in overall survival and progression-free survival were also observed with cemiplimab in the intention-to-treat population despite a high crossover rate (74%). Grade 3–4 treatment-emergent adverse events occurred in 98 (28%) of 355 patients treated with cemiplimab and 135 (39%) of 342 patients treated with chemotherapy.
Interpretation
Cemiplimab monotherapy significantly improved overall survival and progression-free survival compared with chemotherapy in patients with advanced non-small-cell lung cancer with PD-L1 of at least 50%, providing a potential new treatment option for this patient population.
Funding
Regeneron Pharmaceuticals and Sanofi.
Ahmet Sezer, MD; Prof Saadettin Kilickap, MD; Prof Mahmut Gümüş, MD; Prof Igor Bondarenko, MD; Prof Mustafa Özgüroğlu, MD; Miranda Gogishvili, MD; et al.
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Karolina Gaebe, BMath, Alyssa Y Li, BA, Amy Park, BSc, Ambica Parmar, MD, Benjamin H Lok, MD, Prof Arjun Sahgal, MD, et al
