The phase III PACIFIC trial compared durvalumab with placebo in patients with unresectable, stage III non-small-cell lung cancer and no disease progression after concurrent chemoradiotherapy. ...Consolidation durvalumab was associated with significant improvements in the primary end points of overall survival (OS; stratified hazard ratio HR, 0.68; 95% CI, 0.53 to 0.87;
= .00251) and progression-free survival (PFS blinded independent central review; RECIST v1.1; stratified HR, 0.52; 95% CI, 0.42 to 0.65;
< .0001), with manageable safety. We report updated, exploratory analyses of survival, approximately 5 years after the last patient was randomly assigned.
Patients with WHO performance status 0 or 1 (any tumor programmed cell death-ligand 1 status) were randomly assigned (2:1) to durvalumab (10 mg/kg intravenously; administered once every 2 weeks for 12 months) or placebo, stratified by age, sex, and smoking history. Time-to-event end point analyses were performed using stratified log-rank tests. Medians and landmark survival rates were estimated using the Kaplan-Meier method.
Seven hundred and nine of 713 randomly assigned patients received durvalumab (473 of 476) or placebo (236 of 237). As of January 11, 2021 (median follow-up, 34.2 months all patients; 61.6 months censored patients), updated OS (stratified HR, 0.72; 95% CI, 0.59 to 0.89; median, 47.5
29.1 months) and PFS (stratified HR, 0.55; 95% CI, 0.45 to 0.68; median, 16.9
5.6 months) remained consistent with the primary analyses. Estimated 5-year rates (95% CI) for durvalumab and placebo were 42.9% (38.2 to 47.4) versus 33.4% (27.3 to 39.6) for OS and 33.1% (28.0 to 38.2) versus 19.0% (13.6 to 25.2) for PFS.
These updated analyses demonstrate robust and sustained OS and durable PFS benefit with durvalumab after chemoradiotherapy. An estimated 42.9% of patients randomly assigned to durvalumab remain alive at 5 years and 33.1% of patients randomly assigned to durvalumab remain alive and free of disease progression, establishing a new benchmark for standard of care in this setting.
In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in ...patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680).
Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis.
As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio HR, 0.56; 95% CI, 0.45 to 0.70). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups.
First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.
In a randomized trial involving patients with previously untreated advanced non–small-cell lung cancer, pembrolizumab was associated with a higher response rate, longer progression-free and overall ...survival, and fewer adverse events than was platinum-based chemotherapy.
Approximately 23 to 28% of patients with advanced non–small-cell lung cancer (NSCLC) have a high level of programmed death ligand 1 (PD-L1) expression, which is defined as membranous PD-L1 expression on at least 50% of tumor cells, regardless of the staining intensity (i.e., a PD-L1 tumor proportion score of 50% or greater).
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Data from the phase 1 KEYNOTE-001 and phase 3 KEYNOTE-010 studies indicated that patients with advanced NSCLC and a PD-L1 tumor proportion score of 50% or greater were more likely than those with lower tumor proportion scores to have a response to pembrolizumab, a highly selective, humanized . . .
2 dimensional (2D) strain analysis detects subclinical left ventricular (LV) systolic dysfunction. Our aim was to evaluate changes in LV systolic and diastolic function in breast cancer patients ...early after anthracycline chemotherapy, and to identify predisposing factors.
140 patients were assessed by detailed echocardiography before and within seven days post treatment. LV ejection fraction (LVEF), global longitudinal strain (GLS), strain rate and radial and circumferential strain were assessed. Additionally, left atrial volumes and LV diastolic parameters were evaluated. LVEF although reduced after treatment, remained within the normal range (60±3% vs. 59±3%, p = 0.04). Triplane GLS was significantly reduced after treatment (-20.0±1.6% vs. -19.1±1.8%, p<0.001). Subclinical LV dysfunction (>11% reduction in GLS compared to before therapy) occurred in 22% (29/135). Impaired diastolic function grade significantly increased from 46% to 57% (p<0.001) after treatment. Furthermore, diastolic dysfunction was more common in the subgroup group with reduced systolic GLS compared to those without changes in GLS (30% vs. 11%; p = 0.04). No risk factors or clinical parameters were associated with the development of subclinical LV dysfunction; however the percentage change in early diastolic strain rate and the E velocity were independent predictors of >11% reduction in GLS.
Twenty two percent of patients had subclinical LV dysfunction by GLS, whilst none had cardiotoxicity defined by LVEF, demonstrating that GLS is more sensitive for detection of subclinical LV systolic dysfunction immediately after anthracycline therapy. Diastolic dysfunction increased, particularly in the group with reduced GLS, demonstrating the close pathophysiological relationship between systolic and diastolic function.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Standard curative treatment of early-stage non-small cell lung cancer (NSCLC) involves surgery in combination with postoperative (adjuvant) platinum-based chemotherapy where indicated. Preoperative ...(neoadjuvant) therapies offer certain theoretical benefits compared with adjuvant approaches, including the ability to assess on-treatment response, reduce the tumor bulk prior to surgery, and enhance tolerability in the preoperative setting. Indeed, the use of neoadjuvant therapies are well established in other cancers such as breast and rectal cancers to debulk the tumor and guide ongoing therapy, and neoadjuvant chemotherapy has similar efficacy but less toxicity in NSCLC. More recently, immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD1)/PD1-ligand 1 (PD-L1) have transformed the treatment of advanced NSCLC; the unique mechanisms of action of ICI offer additional rationale for assessment in the neoadjuvant setting. Preclinical studies in mouse cancer models support the proof of concept of neoadjuvant ICI (NAICI) through improvement of T-cell effector function and long-term memory induction. Preliminary early-phase human trial data support the proposition that NAICI in NSCLC may provide an feasible and potentially efficacious future treatment strategy and large, randomized phase III trials are currently recruiting to assess this approach. However, outstanding issues include defining optimal treatment combinations which balance high efficacy with acceptable toxicity, validating biomarkers to aid in patient selection, and avoiding potential pitfalls such as missing a window for successful surgery, that is, choosing the right drugs, for the right patient, at the right time. Predictive biomarkers to direct selection of therapy are required, and the validation of major pathological response (MPR) as a surrogate for survival will be important in the uptake of the neoadjuvant approach.
AbstractContextPhysical activity for women with early-stage breast cancer is well recognized for managing cancer-related symptoms and improving quality of life. While typically excluded from ...interventions, women with metastatic breast cancer may also benefit from physical activity. ObjectiveTo 1) determine the safety and feasibility of a physical activity program for women with metastatic breast cancer and 2) explore the efficacy of the program. MethodsFourteen women with metastatic breast cancer were randomized to either a control group or an 8-week home-based physical activity intervention comprising twice weekly supervised resistance training and an unsupervized walking program. ResultsThe recruitment rate was 93%. Adherence to the resistance and walking components of the program was 100% and 25%, respectively. No adverse events were reported. When mean change scores from baseline to postintervention were compared, trends in favor of the exercise group over the control group were observed for the Functional Assessment of Chronic Illness Therapy-Fatigue score (+5.6 ± 3.2 vs. −1.8 ± 3.9, respectively), VO 2max (+1.6 ml/kg/minute ±1.8 mL/kg/minute vs. −0.2 mL/kg/minute ±0.1 mL/kg/minute, respectively) and six-minute walk test (+40 m ± 23 m vs. −46 m ± 56 m, respectively). ConclusionA partially supervised home-based physical activity program for women with metastatic breast cancer is feasible and safe. The dose of the resistance training component was well tolerated and achievable in this population. In contrast, adherence and compliance to the walking program were poor. Preliminary data suggest a physical activity program, comprising predominantly resistance training, may lead to improvements in physical capacity and may help women to live well with their disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BackgroundLymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ...ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab.MethodsEligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D).ResultsIn total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3, in tumor tissue at baseline.ConclusionsIeramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment.Trial registration numberNCT02460224.
Aims
There is robust trial evidence for improved overall survival (OS) with immunotherapy in advanced solid organ malignancies. The real‐world long‐term survival data and the predictive variables are ...not yet known. Our aim was to evaluate factors associated with 3‐year and 5‐year OS for patients treated with immune checkpoint inhibitors (ICIs).
Methods
We performed a retrospective study of patients who received ICIs as management of advanced solid organ malignancies in two tertiary Australian oncology centres from 2012–2017. Data pertaining to clinical characteristics, metastatic disease burden, immune‐related adverse events (IRAEs) and tumour responses were collected and their relationship to survival examined.
Results
In this analysis of 264 patients, 202 (76.5%) had melanoma, 46 (17.4%) had non‐small cell lung cancer (NSCLC), 12 (4.5%) had renal cell carcinoma (RCC) and 4 (1.5%) had mesothelioma. The 5‐year OS rates were 42.1% in patients with melanoma, 19.6% with NSCLC, 75% with RCC, and none of the mesothelioma patients were alive at 5 years.
In multivariate analysis, an ECOG score of 0 (Hazard ratio HR 0.39; 95% confidence interval CI 0.23–0.66; p < 0.001) and the occurrence of IRAE's of any grade (HR 0.61; 95% CI 0.37–0.95; p = 0.05) were associated with better 5‐year survival. The presence of bone metastases (HR 1.62; 95% CI 1.03–2.82; p = 0.05) and liver metastases (HR 1.76; 95% CI 1.07–2.89; p = 0.03) were associated with worse 5‐year survival.
Conclusions
These results support the long‐term benefits of immunotherapy that in some patients, extend to at least 5 years. ECOG performance status of 0 and the occurrence of irAEs are associated with better long‐term survival. Survival is significantly influenced by metastatic site and cancer type. These predictive clinical correlates aid discussions and planning in the delivery of ICIs to patients.
Immunotherapy in solid organ tumours has long term benefits. Patients with ECOG 0 and irAE have an increased likelihood of survival at 5 years. Patients with liver and bone metastases have an increased likelihood of survival at 5 years.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Durvalumab following concurrent chemoradiotherapy is standard treatment for unresectable stage III non‐small‐cell lung cancer based on the results of the PACIFIC trial. Based on trial ...criteria, not all patients are eligible for durvalumab in routine clinical practice.
Methods
We evaluated eligibility for durvalumab in a real‐world clinical setting and the impact of eligibility on outcomes. Consecutive patients treated with concurrent chemoradiotherapy at two tertiary centers between January 2015 and June 2022 were assessed. Clinical characteristics and outcomes were evaluated based on eligibility criteria for the PACIFIC trial.
Results
A total of 126 patients were included. Seventy patients (56%) were eligible for durvalumab. Ineligibility was associated with shorter progression‐free survival of 9.7 months versus 18.4 months (hazard ratio HR 0.61, 95% confidence interval CI 0.39–0.95, p = 0.029) and overall survival of 26.4 months versus 58.7 months (HR 0.47, 95% CI 0.28–0.80, p = 0.005). Common reasons for ineligibility were history of previous malignancy (32%) and progressive disease or death during chemoradiotherapy (25%). Ineligible patients who received durvalumab had similar outcomes to eligible patients who received durvalumab.
Conclusions
In a real‐world cohort, adjuvant durvalumab is safe and beneficial in a substantial proportion of patients who would not have been eligible for the PACIFIC trial.
We focused on a cohort of 126 patients with stage III non‐small‐cell lung cancer and evaluated eligibility for the PACIFIC study and durvalumab on outcomes. A large proportion of our cohort were ineligible for the PACIFIC study (44%). Trial eligibility led to improved outcome regardless of receipt of durvalumab. However, durvalumab was also safe and beneficial in many patients who were ineligible for the PACIFIC trial. This data provides further evidence that durvalumab use is safe and beneficial in a real‐world setting.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Immigrants with cancer often have professional and/or family interpreters to overcome challenges communicating with their health team. This study explored the rate and consequences of nonequivalent ...interpretation in medical oncology consultations.
Consecutive immigrant patients with newly diagnosed with incurable cancer, who spoke Arabic, Cantonese, Mandarin, or Greek, were recruited from the practices of 10 medical oncologists in nine hospitals. Their first two consultations were audio taped, transcribed, translated into English and coded.
Thirty-two of 78 participants had an interpreter at 49 consultations; 43% of interpreters were family, 35% professional, 18% both a professional and family, and 4% a health professional. Sixty-five percent of professional interpretations were equivalent to the original speech versus 50% for family interpreters (P= .02). Seventy percent of nonequivalent interpretations were inconsequential or positive; however, 10% could result in misunderstanding, in 5% the tone was more authoritarian than originally intended, and in 3% more certainty was conveyed. There were no significant differences in interpreter type for equivalency of interpretations.
Nonequivalent interpretation is common, and not always innocuous. Our study suggests that there may remain a role for family or telephone versus face-to-face professional interpreters.
careful communication between oncologists and interpreters is required to ensure optimal communication with the patient.
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