Overall survival is the optimal marker of treatment efficacy in randomized clinical trials (RCTs) but can take considerable time to mature. Progression-free survival (PFS) has served as an early ...surrogate of overall survival but is imperfect. Time to deterioration in quality of life (QOL) measures could be a surrogate for overall survival.
Phase 3 RCTs in solid malignancies that reported overall survival, PFS, and time to deterioration in QOL or physical function published between January 1, 2010, and June 30, 2022, were evaluated. Weighted regression analysis was used to assess the relationship between PFS, time to deterioration in QOL, and time to deterioration in physical function with overall survival. The coefficient of determination (R2) was used to quantify surrogacy.
In total, 138 phase 3 RCTs were included. Of these, 47 trials evaluated immune checkpoint inhibitors and 91 investigated non-immune checkpoint inhibitor agents. Time to deterioration in QOL (137 RCTs) and time to deterioration in physical function (75 RCTs) performed similarly to PFS as surrogates for overall survival (R2 = 0.18 vs R2 = 0.19 and R2 = 0.10 vs R2 = 0.09, respectively). For immune checkpoint inhibitor studies, time to deterioration in physical function had a higher association with overall survival than with PFS (R2 = 0.38 vs R2 = 0.19), and PFS and time to deterioration in physical function did not correlate with each other (R2 = 0). When time to deterioration in physical function and PFS are used together, the coefficient of determination increased (R2 = 0.57).
Time to deterioration in physical function appears to be an overall survival surrogate measure of particular importance for immune checkpoint inhibitor treatment efficacy. The combination of time to deterioration in physical function with PFS may enable better prediction of overall survival treatment benefit in RCTs of immune checkpoint inhibitors than either PFS or time to deterioration in physical function alone.
The anti-programmed death 1 monoclonal antibody pembrolizumab has shown antitumour activity and is a first-line and second-line treatment option for patients with programmed death ligand 1 ...(PD-L1)-expressing advanced non-small-cell lung cancer. We report updated 3-year safety and efficacy outcomes from the phase 1 study, KEYNOTE-001.
KEYNOTE-001 is a multicohort, open-label, phase 1 study of pembrolizumab (2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks) in treatment naive or previously treated patients with locally advanced or metastatic non-small-cell lung cancer with measurable disease at baseline. Two cohorts were randomly assigned to a pembrolizumab dose by use of a computer-generated randomisation schedule at cohort-dependent ratios, and a further four cohorts were assigned to a pembrolizumab dose without randomisation. We present 3-year outcomes for the full analysis set of patients who received at least one dose of study treatment, pooled for all pembrolizumab doses. The primary efficacy endpoint was proportion of patients with objective response, analysed here as investigator-assessed response according to immune-related response criteria. Secondary efficacy endpoints included overall survival, duration of response, and progression-free survival. Safety endpoints included incidence of adverse events. This study is registered at ClinicalTrials.gov, number NCT01295827, and is ongoing.
Between May 8, 2012 and July 13, 2014, 550 patients (101 treatment naive and 449 previously treated) were enrolled. Median follow-up was 34·5 months at data cutoff (Sept 1, 2016). At 36 months, investigator-assessed objective response according to immune-related response criteria was achieved for 41 of 101 treatment naive patients (41% 95% CI 30·9-50·8; median duration of response was 16·7 months 95% CI 12·6-not reached) and 102 of 449 previously treated patients (23% 18·9-26·9; 33·3 (22·5-not reached). The Kaplan-Meier estimate of overall survival at 36 months was 26·4% (95% CI 14·3-40·1) for treatment naive patients and 19·0% (15·0-23·4) for previously treated patients, with median overall survival of 22·3 months (95% CI 17·1-31·5) and 10·5 months (8·6-13·2). PD-L1 tumour proportion score ≥50% was associated with longer median overall survival (95% CI) versus tumour proportion score 1-49% (treatment naive: 34·9 20·3-not reached vs 19·5 10·7-26·3 months; previously treated: 15·4 10·5-18·5 vs 8·5 6·0-12·7 months). Grade 3-5 treatment-related adverse events occurred in 66 patients (12%), and 30 (6%) discontinued owing to a treatment-related adverse event. The most frequent grade 3-4 treatment-related adverse events were pneumonitis (10 2% of 550) and fatigue (5 1% of 550). Overall, 227 patients (41%) of 550 had serious adverse events, of which 50 (9%) were treatment related.
Pembrolizumab provides durable response and long-term effects on overall survival, with tolerable safety, for treatment naive and previously treated patients with advanced non-small-cell lung cancer expressing PD-L1.
Merck Sharp & Dohme Corp.
Refinements to conventional treatment and the development of new therapies have led to significant improvements in cancer survival. Yet, many frontline cancer treatments continue to be hindered by ...their significant side effects, amongst which cardiotoxicity is particularly important. Therefore, the focus of cancer management has changed; treatment is no longer aimed solely at overcoming malignancy, but emphasises early identification and treatment of potential side effects. In this regard, the cardiotoxic potential of certain anticancer agents mandate close monitoring of cardiac function, and the method of choice for monitoring is transthoracic echocardiography. Whilst this method has its limitations, a newer echocardiographic technique called myocardial strain imaging has the potential to detect early sub-clinical changes in cardiac function due to cardiotoxicity. Strain analysis has been the subject of several recent studies to evaluate its potential in monitoring cardiotoxicity, and this article reviews the recent literature and explores the potential role of myocardial strain imaging in cancer management and avenues for future research.
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The ExteNET trial demonstrated improved invasive disease-free survival (iDFS) with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, versus placebo in patients with human epidermal growth ...factor receptor 2-positive (HER2+)/hormone receptor-positive (HR+) early-stage breast cancer (eBC).
ExteNET was a multicenter, randomized, double-blind, phase III trial of 2840 patients with HER2+ eBC after neoadjuvant/adjuvant trastuzumab-based therapy. Patients were stratified by HR status and randomly assigned 1-year oral neratinib 240 mg/day or placebo. The primary endpoint was iDFS. Descriptive analyses were performed in patients with HR+ eBC who initiated treatment ≤ 1 year (HR+/≤ 1-year) and > 1 year (HR+/> 1-year) post-trastuzumab.
HR+/≤ 1-year and HR+/> 1-year populations comprised 1334 (neratinib, n = 670; placebo, n = 664) and 297 (neratinib, n = 146; placebo, n = 151) patients, respectively. Absolute iDFS benefits at 5 years were 5.1% in HR+/≤ 1-year (hazard ratio, 0.58; 95% confidence interval CI, 0.41-0.82) and 1.3% in HR+/>1-year (hazard ratio, 0.74; 95% CI, 0.29-1.84). In HR+/≤ 1-year, neratinib was associated with a numerical improvement in overall survival (OS) at 8 years (absolute benefit, 2.1%; hazard ratio, 0.79; 95% CI, 0.55-1.13). Of 354 patients in the HR+/≤ 1-year group who received neoadjuvant therapy, 295 had residual disease, and results showed absolute benefits of 7.4% at 5-year iDFS (hazard ratio, 0.60; 95% CI, 0.33-1.07) and 9.1% at 8-year OS (hazard ratio, 0.47; 95% CI, 0.23-0.92). There were fewer central nervous system events with neratinib. Adverse events were similar to those previously reported.
Neratinib significantly improved iDFS in the HER2+/HR+/≤ 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in central nervous system events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population.
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In the patient population with early-stage human epidermal growth factor receptor 2-positive/hormone receptor-positive breast cancer who initiate neratinib within 1 year of trastuzumab-based therapy, the absolute 5-year invasive disease-free survival benefit versus placebo is 5.1%, and absolute 8-year overall survival benefit is 2.1%. Among those with residual disease after neoadjuvant therapy (non-pathologic complete response), absolute gains with neratinib are 7.4% and 9.1%, respectively.
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With improved diagnosis and treatments, a greater percentage of breast cancer patients are achieving long-term survival. Consequently, long-term cardiotoxicity secondary to chemotherapy has become ...more prevalent, warranting improved cardiac surveillance. We evaluated changes in left atrial (LA) strain in breast cancer patients immediately post anthracycline (AC) therapy to assess its utility as a marker of diastolic dysfunction.
This was a prospective cohort study of 128 consecutive human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients who underwent transthoracic echocardiography prior to and immediately post AC treatment. Traditional left ventricular (LV) systolic and diastolic parameters and LA volumes were evaluated; additionally, LV global longitudinal strain (LV GLS) and LA phasic strain were measured.
All patients had normal LV ejection fraction (>53%) post AC, though LV GLS was significantly reduced. Peak E and é velocities were reduced post AC, with no change in LA volumes. LA reservoir strain (LASRES 34.8% vs 31.5%, p<0.001) and conduit strain (LASCD 17.2% vs 14.4%, p<0.001) were significantly lower post AC and correlated modestly with LV diastolic parameters. Reduction in LA strain post AC was evident even in patients with preserved LV systolic and diastolic function. More patients demonstrated alteration in diastolic function (≥15% reduction in LASRES from baseline) (32%) compared to alteration in systolic function (≥15% reduction in LV GLS) (23%).
LA strain is a promising marker of early diastolic dysfunction. We demonstrate its potential utility in surveillance of breast cancer patients treated with AC.
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Expression of programmed cell death ligand 1 (PD-L1) on tumor cells with or without immune cells is widely reported in clinical trials of programmed cell death receptor 1 (PD-1) blockade in ...metastatic non-small cell lung cancer. Various cutpoints have been studied.
We performed a systematic search of MEDLINE, EMBASE, and conference proceedings up to December 2019 for randomized and nonrandomized clinical trials of anti-PD-1 or anti-PD-L1 monotherapy in metastatic non-small cell lung cancer. We retrieved data on objective response rate (ORR), 1-year and 2-year progression-free survival (PFS), and 2-year and 3-year overall survival (OS) in various PD-L1 subgroups. Results were pooled and analyzed based on different cutpoints, with nonrandomized comparisons made with pooled chemotherapy outcomes.
A total of 9810 patients in 27 studies were included. In treatment-naïve patients, benefits with PD-1 blockade over chemotherapy were seen in ORR in patients having PD-L1 50% or greater, in 2-year OS for PD-L1 1% or greater, and in 1-year PFS, 2-year PFS, and 3-year OS for unselected patients. First-line PD-1 blockade compared with chemotherapy demonstrated higher ORR, 2-year PFS, and 3-year OS if PD-L1 was 50% or greater; lower ORR, higher 2-year PFS, and similar 3-year OS if PD-L1 was 1%-49%; and lower ORR, similar 1-year PFS, and lower 2-year OS if PD-L1 was less than 1%. In previously treated patients, PD-1 blockade demonstrated similar or superior outcomes to chemotherapy in all PD-L1 subgroups.
PD-L1 should guide the choice of PD-1 blockade vs chemotherapy in treatment-naïve patients. In previously treated patients, PD-1 blockade provides a favorable outcome profile to chemotherapy in all PD-L1 subgroups.
8019 Background: Recent studies on the perioperative treatment of Non-Small Cell Lung Cancer (NSCLC) have often excluded patients with stage IA. To address this issue and bridge the knowledge gap, we ...aim to investigate the impact of PD-L1 and EGFR status on survival in stage IA NSCLC. Methods: Our study aimed to determine the impact of PD-L1 expression on overall survival (OS) in patients with resectable stage IA-IIIB NSCLC who underwent curative resection between May 2010 and April 2020. We analyzed survival and clinicopathological data and categorized patients based on PD-L1 tumor proportion score (TPS). PD-L1 TPS ≥ 50% were categorized as PD-L1 high and < 50% as PD-L1 negative/low. Our primary objective was to assess the association between PD-L1 expression status and OS in resectable NSCLC patients. We also investigated the relationships between OS, PD-L1 expression, EGFR status, and tumor stage. Results: Among the 386 patients recruited, those with PD-L1 negative/low and high had a 5-year OS of 82% and 63%, respectively ( p = 0.00011). Among patients with stage IA NSCLC, those with PD-L1 negative/low demonstrated the most favorable 5-year OS (96%) compared to the other subgroups (stage IA PD-L1 high 63%, stage IB-IIIB PD-L1 negative/low 67% and stage IB-IIIB PD-L1 high 62%, p < 0.0001). Stage IA EGFR mutant NSCLC showed a significantly better 5-year OS compared to EGFR wildtype (97% versus 84%, p= 0.0028). In comparison, survival in stage IB-IIIB NSCLC was similar regardless of EGFR status (stage IB-IIIB/EGFR mutant 66% vs EGFR wildtype 65%, p= 0.13). Next, we addressed the impact of the co-occurrence of an EGFR mutation and PD-L1 expression on survival in stage IA. In stage IA, the PD-L1 high EGFR mutant and wildtype subgroups demonstrated a 5-year OS of 83% and 56%, respectively, while in the PD-L1 negative/low subgroup, the EGFR mutant and wildtype had a 98% and 93% OS ( p< 0.0001), respectively. Conclusions: Stage IA NSCLC patients with PD-L1 high and EGFR wildtype, surprisingly, were associated with poorer survival outcomes. These findings highlight the urgent need for clinical trials investigating perioperative management strategies in this population.
Overall survival (OS) results from randomized control trials (RCT) provide the strongest evidence for efficacy of anti-cancer treatments but can take a considerable amount of time to mature. ...Progression free survival (PFS) and objective response rate (ORR) are used as an early surrogate of OS treatment effect however their validity remains unclear. Our study aims to comprehensively evaluate ORR and PFS as surrogates for OS treatment effect across tumor groups and treatment types.
Phase 3 RCTs in solid malignancies that reported OS/PFS and ORR published between 1st of January 2010 and 30th of June 2022 were evaluated. The relationship of surrogate endpoints and OS treatment effect was assessed via weighted linear regression. The coefficient of determination (R2) quantified the fit of the regression model.
675 phase 3 RCT comprising of 350 112 patients were analysed. ORR (R2 of 0.10) and PFS (R2 of 0.38) were poor surrogate markers of OS treatment effect. The strength of surrogacy differed within treatment and tumour groups. PFS had the highest R2 for chemotherapy (0.56) and lowest for targeted therapy (0.40). PFS had the highest level of surrogacy for melanoma (R2 = 0.72) and pancreatic cancer (R2 = 0.70) compared to other tumour groups. Importantly ORR and PFS were also poorly correlated to each other (R2 = 0.33).
ORR and PFS were poor trial-level surrogate markers of OS. The surrogacy performance of ORR and PFS differed by treatment and malignancy sub-type.
•ORR and PFS are not strong surrogates of OS treatment effect.•Surrogacy of ORR and PFS for OS differs based on treatment and tumor.•surrogacy of ORR and PFS for OS treatment effect was highest for chemotherapy.•PFS was a better surrogate of OS treatment for melanoma and pancreatic cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The
gene is amplified in 14% of patients with HR
/HER2
breast cancer. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3, and PDGFRα/β, were assessed.
Patients with HR
/HER2
...metastatic breast cancer (MBC) received oral lucitanib in three centrally confirmed cohorts: (i)
amplified, (ii)
nonamplified, 11q13 amplified, and (iii)
and 11q13 nonamplified. Key inclusion criteria included Eastern Cooperative Oncology Group Performance Status ≤2, ≥1 line of anticancer therapy, but ≤2 lines of chemotherapy. Primary endpoint was overall response rates (ORR) by RECIST1.1. Simon's two-stage design was used: If ≥2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort.
copy-number variation (CNV) was determined by FISH and droplet digital PCR, whereas FGFR1 expression was determined by IHC.
Seventy-six patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The prespecified primary endpoint was met in cohort 1 with ORR of 19% 95% confidence interval (CI), 9%-35%, but not in cohorts 2 and 3 with ORR of 0% (95% CI, 0%-18%) and 15% (95% CI, 6%-34%), respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%), and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high
amplification (≥4 CNV) than those without high amplification (22% vs. 9%). ORR in patients with FGFR1-high tumors (IHC, H-score ≥50) was 25% versus 8% in FGFR1-low cancers.
Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR
/HER2
MBC. Although based on small sample sizes, exploratory biomarker analyses suggested that patients with high
amplification or expression might derive greater benefit.
•Trial enrollment was not stratified for variables related to mandatory prior CRT.•Clinical outcomes were assessed in subgroups defined by CRT-related variables.•As in the ITT population, PFS, OS and ...TTDM favored durvalumab use in all subgroups.•Durvalumab had a manageable safety profile irrespective of CRT-related variables.•Imbalances in baseline factors and subgroup sizes prevent robust conclusions.
The PACIFIC trial demonstrated that durvalumab significantly improved progression-free and overall survival (PFS/OS), versus placebo, in patients with Stage III NSCLC and stable or responding disease following concurrent, platinum-based chemoradiotherapy (CRT). A range of CT and RT regimens were permitted, and used, in the trial. We report post-hoc, exploratory analyses of clinical outcomes from PACIFIC according to CRT-related variables.
Patients were randomized 2:1 (1–42 days post-CRT) to up to 12 months durvalumab (10 mg/kg intravenously every 2 weeks) or placebo. Efficacy and safety were analyzed in patient subgroups defined by the following baseline variables: platinum-based CT (cisplatin/carboplatin); vinorelbine, etoposide, or taxane-based CT (all yes/no); total RT dose (<60 Gy/60–66 Gy/>66 Gy); time from last RT dose to randomization (<14 days/≥14 days); and use of pre-CRT induction CT (yes/no). Treatment effects for time-to-event endpoints were estimated by hazard ratios (HRs) from unstratified Cox-proportional-hazards models.
Overall, 713 patients were randomized, of whom 709 received treatment in either the durvalumab (n/N = 473/476) or placebo arms (n/N = 236/237). Durvalumab improved PFS, versus placebo, across all subgroups (median follow up, 14.5 months; HR range, 0.34–0.63). Durvalumab improved OS across most subgroups (median follow up, 25.2 months; HR range, 0.35–0.86); however, the 95 % confidence interval (CI) of the estimated treatment effect crossed one for the subgroups of patients who received induction CT (HR, 0.78 95 % CI, 0.51–1.20); carboplatin (0.86 0.60–1.23); vinorelbine (0.79 0.49–1.27); and taxane-based CT (0.73 0.51–1.04); and patients who were randomized ≥14 days post-RT (0.81 0.62–1.06). Safety was broadly similar across the CRT subgroups.
Durvalumab prolonged PFS and OS irrespective of treatment variables related to prior CRT to which patients with Stage III NSCLC had previously stabilized or responded. Limited patient numbers and imbalances in baseline factors in each subgroup preclude robust conclusions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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