BACKGROUND
The survival outcomes of patients with advanced non–small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) are variable. This study investigated whether pre‐ and ...on‐treatment lactate dehydrogenase (LDH) could better prognosticate and select patients for ICI therapy.
METHODS
Using data from the POPLAR and OAK trials of atezolizumab versus docetaxel in previously treated advanced NSCLC, the authors assessed the prognostic and predictive value of pretreatment LDH (less than or equal to vs greater than the upper limit of normal). They further examined changes in on‐treatment LDH by performing landmark analyses and estimated overall survival (OS) distributions according to the LDH level stratified by the response category (complete response CR/partial response PR vs stable disease SD). They repeated pretreatment analyses in subgroups defined by the programmed death ligand 1 (PD‐L1) status.
RESULTS
This study included 1327 patients with available pretreatment LDH. Elevated pretreatment LDH was associated with an adverse prognosis regardless of treatment (hazard ratio HR for atezolizumab OS, 1.49; P = .0001; HR for docetaxel OS, 1.30; P = .004; P for treatment by LDH interaction = .28). Findings for elevated pretreatment LDH were similar for patients with positive PD‐L1 expression treated with atezolizumab. Persistently elevated on‐treatment LDH was associated with a 1.3‐ to 2.8‐fold increased risk of death at weeks 6, 12, 18, and 24 regardless of treatment. Elevated LDH at 6 weeks was associated with significantly shorter OS regardless of radiological response (HR for CR/PR, 2.10; P = .04; HR for SD, 1.50; P < .01), with similar findings observed at 12 weeks.
CONCLUSIONS
In previously treated advanced NSCLC, elevated pretreatment LDH is an independent adverse prognostic marker. There is no evidence that pretreatment LDH predicts ICI benefit. Persistently elevated on‐treatment LDH is associated with worse OS despite radiologic response.
This analysis of 1327 patients with advanced non–small cell lung cancer from the POPLAR and OAK randomized controlled trials has found that lactate dehydrogenase (LDH) is a useful pre‐ and on‐treatment prognostic marker that can assist clinicians in counselling patients undergoing second‐ or later‐line atezolizumab or docetaxel. However, the findings fail to support the use of LDH as a predictive biomarker for immune checkpoint inhibitor therapy and reinforce the importance of rigorous validation of promising predictive biomarkers using randomized data.
Extrapulmonary small cell carcinomas (EPSCCs) are rare cancers, comprising 0.1-0.4% of all cancers. The scarcity of EPSCC studies has led current treatment strategies to be extrapolated from small ...cell lung cancer (SCLC), justified by analogous histological and clinical features.
We conducted a retrospective cohort study comparing the outcomes of extensive-stage (ES) SCLC and EPSCC.
Patients diagnosed with ES SCLC or EPSCC between 2010 and 2020 from four hospitals in Sydney were identified. Patients who received active treatment and best supportive care were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and overall response rates (ORRs).
Three hundred and eighty-four patients were included (43 EPSCC vs. 340 SCLC). EPSCC were of genitourinary (n = 15), unknown primary (n = 13) and gastrointestinal (n = 12) origin. Treatment modalities for EPSCC compared to SCLC included palliative chemotherapy (56% vs 73%), palliative radiotherapy (47% vs 59%) and consolidation chest radiotherapy (10% of SCLC). Overall, median OS was 6.4 versus 7 months for EPSCC versus SCLC respectively, but highest in prostate EPSCC (25.6 months). Of those who received chemotherapy (22 EPSCC vs 233 SCLC), median OS was 10.4 versus 8.4 months (HR OS 0.81, 95% confidence interval (CI): 0.5-1.31, P = 0.38); PFS was 5.4 versus 5.5 months (HR PFS 0.93, 95% CI: 0.58-1.46, P = 0.74) and ORR were 73% versus 68%.
EPSCC and SCLC appeared to have comparable OS and treatment outcomes. However, the wide range of OS in EPSCC highlights the need for an improved understanding of its genomics to explore alternative therapeutics.
Background
Overall survival (OS) is the gold‐standard end point for oncology trials. However, the availability of multiple therapeutic options after progression and crossover to receive ...investigational agents confound and delay OS data maturation. Progression‐free survival 2 (PFS‐2), defined as the time from randomization to progression on first subsequent therapy, has been proposed as a surrogate for OS. Using a meta‐analytic approach, the authors aimed to assess the association between OS and PFS‐2 and compare this with progression‐free survival 1 (PFS‐1) and the objective response rate (ORR).
Methods
An electronic literature search was performed to identify randomized trials of systemic therapies in advanced solid tumors that reported PFS‐2 as a prespecified end point. Correlations between OS and PFS‐2, OS and PFS‐1, and OS and ORR as hazard ratios (HRs) or odds ratios (ORs) were assessed via linear regression weighted by trial size.
Results
Thirty‐eight trials were included, and they comprised 19,031 patients across 8 tumor types. PFS‐2 displayed a moderate correlation with OS (r = 0.67; 95% confidence interval CI, 0.08‐0.69). Conversely, correlations of ORR (r = 0.12; 95% CI, 0.00‐0.13) and PFS‐1 (r = 0.21; 95% CI, 0.00‐0.33) were poor. The findings for PFS‐2 were consistent for subgroup analyses by treatment type (immunotherapy vs nonimmunotherapy: r = 0.67 vs 0.67), survival post progression (<12 vs ≥12 months: r = 0.86 vs 0.79), and percentage not receiving subsequent treatment (<50% vs ≥50%: r = 0.70 vs 0.63).
Conclusions
Across diverse tumors and therapies, the treatment effect on PFS‐2 correlated moderately with the treatment effect on OS. PFS‐2 performed consistently better than PFS‐1 and ORR, regardless of postprogression treatment and postprogression survival. PFS‐2 should be included as a key trial end point in future randomized trials of solid tumors.
The treatment effect on progression‐free survival 2 correlates moderately to strongly with the treatment effect on overall survival. Progression‐free survival 2 performs consistently better than progression‐free survival 1 and the objective response rate across key subgroups.
There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint ...inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma.
DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415.
Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5–30·2). 31 (57%; 95% CI 44–70) of 54 patients were alive and progression-free at 6 months. The most common grade 3–4 adverse events were neutropenia (seven 13% patients), nausea (six 11%), and anaemia (four 7%). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment.
The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial.
AstraZeneca.
BackgroundIn this study, we assessed the activity of durvalumab, an antibody to programmed death ligand-1, in two cohorts of women with advanced endometrial cancers (AEC)—mismatch repair proficient ...(pMMR) and mismatch repair deficient (dMMR).MethodsA multicenter phase two study was performed in women with AEC with pMMR tumor progressing after one to three lines of chemotherapy and women with AEC with dMMR tumor progressing after zero to three lines of chemotherapy. Mismatch repair status was based on immunohistochemistry expression. All women received durvalumab 1500 mg given every 4 weeks until progression or unacceptable toxicity. The primary endpoint was objective tumor response by RECIST V.1.1 modified for immune-based therapeutics.ResultsSeventy-one women were recruited: 35 dMMR and 36 pMMR. Median follow-up was 19 vs 21 months in dMMR versus pMMR, respectively. Median age was 67 years. Histology in dMMR versus pMMR included endometrioid (94% vs 57%) and serous (0% vs 31%) and was high grade in 26% vs 74%. The objective tumor response rate (OTRR) in the dMMR cohort was 47% (17/36, 95% CI 32 to 63), including 6 complete responses and 11 partial responses (PRs)) vs 3% in the pMMR cohort (1/35, 95% CI 1 to 15, PR). In the dMMR cohort, durvalumab was the first-line therapy in 58% (OTRR 57%) and the second-line therapy in 39% (OTRR 38%). Median progression-free survival was 8.3 months in the dMMR cohort vs 1.8 months in the pMMR cohort. The 12-month overall survival (OS) rate was 71% in dMMR vs 51% in pMMR, with median OS not reached for dMMR vs 12 months for pMMR. Immune-related adverse events occurred in 14 women, mostly grades 1–2.ConclusionDurvalumab monotherapy showed promising activity and acceptable safety in AEC with dMMR regardless of prior lines of chemotherapy, but activity was limited in AEC with pMMR.Trial registration numbersANZGOG1601, ACTRN12617000106336, and NCT03015129.
We sought to summarize the evidence for interventions aiming at enhanced recovery after surgery (ERAS) in ovarian cancer through a systematic review.
We searched MEDLINE, EMBASE, and The Cochrane ...Library for studies testing ERAS interventions in patients undergoing surgery for ovarian cancer. Study selection and data extraction were done independently by 2 reviewers with disagreements resolved by discussion with a senior, third reviewer.
We identified 25 studies including 1648 participants with ovarian cancer. Nine observational studies addressed ERAS protocols. Four of them were prospective, and 3 included historical controls. The other 16 studies reported single interventions, for example, early feeding, omission of pelvic drains, early orogastric tube removal, Doppler-guided fluid management, and patient-controlled epidural analgesia. Early feeding protocols were tested in 7 of the 12 randomized trials. Early feeding appeared to be safe and was associated with significantly faster recovery of bowel function.
Few studies have specifically studied ERAS interventions in ovarian cancer. All studies on protocols including multiple interventions were susceptible to bias. Early feeding is the intervention that is best supported by randomized trials. Application of evidence for ERAS derived from nonovarian cancer is challenged by the differences not only in the scope of surgery but also in ovarian cancer patients' comorbidities. Postoperative morbidity is particularly high in these patients because of their poor nutritional status, perioperative fluids shifts, and long operating times. These patients may also show excessive response to surgical stress. Innovative, randomized trials are needed to reliably determine the feasibility, safety, and effectiveness of specific ERAS interventions in ovarian cancer.
Purpose Patient-reported outcomes (PROs) provide the patient's perspective of the impact of treatment. Evidence suggests that PRO content of randomised controlled trials (RCTs) protocols is generally ...sub-optimal. This study aimed to describe and evaluate the PRO-specific content of ovarian cancer RCT protocols. Methods Published, phase III, ovarian cancer RCTs with PRO endpoints were identified following a systematic search of Mediine and Cochrane databases (Jan 2000 to Feb 2016). Corresponding RCT protocols were downloaded (if published) or obtained by contacting authors. Two investigators independently assessed adherence of PRO-specific content of included protocols to a checklist of 58 recommended PRO protocol items currently being developed by the International Society for Quality of Life Research. Discrepancies were resolved with a third investigator. Results Of 41 eligible trials identified, 26 protocols were assessed (developed 1995-2010). We were unable to obtain the remaining 15 protocols. Protocols addressed a mean of 28 % PRO checklist items (range 8-66 %). Fifteen (58 % of assessed protocols) provided a rationale for PRO assessment, 8 (31 %) described a PRO objective, 24 (92 %) included a PRO assessment schedule, but only 6 (23 %) justified timing of PRO assessments. Twelve protocols (46 %) provided staff data collection instructions, 4 (15 %) included plans for monitoring PRO compliance, and 16 (62 %) included a PRO analysis plan. Conclusions On average, protocols addressed less than one-third of PRO protocol checklist items. In some cases, key guidance regarding PRO administration was lacking, which may lead to inconsistent and sub-optimal PRO methodology. Efforts are needed to improve PRO protocol content in cancer trials.
Introduction Induction intravesical Bacillus Calmette-Guerin (BCG) followed by maintenance after transurethral resection of bladder tumor, is the standard adjuvant therapy for high-risk non-muscle ...invasive bladder cancer (NMIBC). There is sparse evidence on the practice of intravesical BCG in Australia. Our aim was to determine the outcomes of intravesical BCG therapy in NMIBC in Southwestern Sydney. Methods This was a multi-center retrospective audit of NMIBC patients who received intravesical BCG between January 2008 and June 2020. Data was collected across six tertiary hospitals in South Western Sydney. Primary outcome was disease-free survival (DFS). Secondary outcomes were overall survival (OS), BCG induction and maintenance rates. Results Of the 200 eligible patients over 12.5 years, median age was 77 years and 83% were male. Of these, 55%, 4.5%, 35% and 5% were Tis, Ta, T1 and unknown stage, respectively. All patients received induction BCG and 56% received maintenance BCG (range 3-36 months). Completion rate of induction BCG was 91%. Only 9% ceased treatment due to intolerance. The median duration of cystoscopy follow-up was 17 months. After a median follow-up time of 37 months, 55% developed recurrence (29% non-muscle invasive, 32% muscle-invasive disease, 8% distant metastasis). The 1-year and 5-year DFS rates were 72% and 41% (median DFS: 39 months). The 1-year and 5-year OS rates were 98% and 87% (median OS: not reached). Conclusion The DFS and OS rates were comparable to previous literature. This provides real-world data to assist future clinical trials in NMIBC.
The objective of this survey was to review the current standard of perioperative care of patients with suspected advanced ovarian cancer in Australia and New Zealand in order to determine the level ...of equipoise for specific interventions.
In May 2016, a web-based questionnaire (SurveyMonkey Inc, Palo Alto, CA) was sent to all gynecologic oncologists in Australia and New Zealand (n = 56). Descriptive statistics were used.
Response rate was 75%. Prevention of hypothermia, extended thromboembolic prophylaxis, antibiotic prophylaxis, and the avoidance of the routine use of drains were standard of care. Bowel preparation was given by 10% routinely and by 35% when bowel resection was planned. Fasting times for fluids of six hours or more were common (55%). Only 26% had shortened fasting times of two hours. Twelve percent used carbohydrate loading. The majority of patients started a light diet within the first postoperative day and advanced diet subsequently as tolerated. Six respondents (15%) used thoracic epidural, whereas the majority (73%) administered an opioid-based intravenous patient-controlled analgesia as the predominant postoperative analgesia, mainly as part of a multimodal pain management. The majority of respondents expressed an interest in a trial concept of individual ERAS interventions.
Only a minority of ERAS interventions can be considered standard of care in ovarian cancer surgery. The existing level of equipoise among gynecologic oncologists in Australia and New Zealand, and their interest in a trial concept of individual ERAS interventions allows further assessment of the feasibility and efficacy of interventions in a randomized controlled trial.
•Radiologic response and undetectable ctDNA are independently prognostic of PFS.•CtDNA clearance discriminates patients’ survival in those with stable disease.•In those with early PR and undetectable ...ctDNA, 93% had ongoing PR.•Parallel ctDNA and RECIST measurements improve accuracy of tumor assessment.
Response Evaluation Criteria in Solid Tumors (RECIST) has limitations but remains the conventional approach for tumor assessments. We explored whether circulating tumor DNA (ctDNA) can be incorporated into RECIST to provide a more robust measure of tumor response in advanced EGFR-mutant NSCLC.
In FASTACT-2, patients with advanced NSCLC received platinum/gemcitabine intercalated with erlotinib or placebo. EGFR mutation (tumor and plasma ctDNA) was detected using cobas v2. Patients selected for this hypothesis-generating analysis had EGFR mutations (on either tumor or plasma) at baseline and evaluable week 8 plasma EGFR. Week 8 ctDNA and radiologic response status were correlated with survival using landmark cox regression analyses.
Of the original 451 patients, 86 (19.1%) were eligible for this analysis. 73% (n = 63) had detectable ctDNA at baseline. At week 8, 40% (n = 34) had radiologic partial response (PR), 60% (n = 52) had stable disease (SD); 80% (n = 69) had a ctDNA response (undetectable ctDNA). In patients who had initial PR and undetectable ctDNA, 93% (28/30) had ongoing PR subsequently at week 16. The median duration of response was 14.9 months. In patients with SD and undetectable ctDNA at week 8, 28% had radiological PR at week 16. Amongst those with PR at week 8, survival outcomes for those with undetectable vs detectable ctDNA were not statistically significant (PFS HR 0.49, 95%CI 0.16–1.48, p = 0.21; OS HR 0.39, 95%CI 0.13–1.19, p = 0.10). Amongst those with SD at week 8, there was significantly longer survival for those with undetectable vs detectable ctDNA (PFS HR 0.27, 95% CI 0.13–0.57, p < 0.0001; OS HR 0.40, 95% CI 0.20–0.80, p = 0.009).
In patients with SD, undetectable ctDNA at week 8 correlated with survival improvement. Both radiologic and ctDNA responses are prognostic of PFS. Incorporation of ctDNA with RECIST may improve tumor response assessment in EGFR-mutant NSCLC.
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