Outcomes of intravesical Bacillus Calmette-Guerin in patients with non-muscle invasive bladder cancer: a retrospective study in Australia

IntroductionInduction 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.MethodsThis 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.ResultsOf 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).ConclusionThe DFS and OS rates were comparable to previous literature. This provides real-world data to assist future clinical trials in NMIBC

Validation of surrogate endpoints used in clinical trials of immune checkpoint inhibitors and targeted therapies in advanced cancers

This thesis evaluated the validity of surrogate endpoints used in trials of immune checkpoint inhibitors (ICIs) and molecular targeted therapies in advanced cancers. Many recent regulatory approvals of these novel agents have been based on improved objective response rate (ORR) and progression-free survival (PFS). However, such results may not necessarily translate to an overall survival (OS) benefit. Chapter 1 summarizes the background literature, motivation and structure of this thesis. Using a meta-analytic approach, Chapters 2 and 3 assess the validity of PFS, ORR, duration of response (DoR) and complete response rates in ICI RCTs. Within ICI arms, 6-month PFS rate, ORR, and 6-month DoR rate correlated strongly with 12-month OS rate (r= 0.83, 0.80 and 0.84 respectively), and therefore are strong prognostic endpoints. However, when comparing the relative treatment effect of ICI vs control, PFS hazard ratio (HR), ORR risk ratio and 6-month DoR ratio poorly correlated with OS HR (r=0.54, 0.58 and 0.62 respectively), indicating poor trial level surrogacy. Chapters 4 and 5 evaluate circulating tumour DNA (ctDNA) as a novel surrogate biomarker in lung cancer. Chapter 4 examines the prognostic and predictive value of baseline epidermal growth factor receptor (EGFR) ctDNA. I found that the PFS advantage for EGFR-TKI over chemotherapy was similar in both ctDNA+ and ctDNA- patients. A false negative rate of 43% limits the value of ctDNA for selecting EGFR-TKI. Chapter 5 shows that both ctDNA clearance and radiological tumour shrinkage are associated with longer PFS and OS. Dynamic changes in ctDNA provided strong discrimination of prognosis in patients with stable disease, supporting its incorporation for assessment of tumour response. Chapter 6 discusses lessons learned, limitations, new insights gained and future research directions. The findings of my work will improve trial design and inform regulatory bodies in assessing evidence for accelerated drug approvals

Outcomes of extensive stage extrapulmonary small cell cancer

Background: Extrapulmonary small cell cancer (EPSCC) is a rare malignancy with an incidence of approximately 0.1%–0.4% of all cancers. Treatment of this disease is often based on small cell lung cancer. Aims: We aimed to investigate real-world clinical outcomes of patients with extensive-stage (ES) ESPCC. Methods: Patients diagnosed with ES EPSCC between 2010 and 2020 from multiple centres in New South Wales were identified. Patient, disease and treatment characteristics were collected and presented using descriptive statistics. Survival was analysed using the Kaplan–Meier method. Univariate and multivariate Cox regression hazard models were used to identify potential prognostic factors. Results: Sixty eligible ES EPSCC patients were identified, including 65% male and 35% female. The mean age was 69 years (range 37–88). Forty-five per cent were never smokers, 42% ex-smokers and 13% current smokers, and 17% of patients had limited-stage disease prior to development of ES disease. The most common primary sites were genitourinary (42%; mainly prostate (n = 14) and bladder (n = 10)), gastrointestinal (28%; mainly oesophagus (n = 5) and colon (n = 4)) and unknown primary (22%). Treatments received included palliative chemotherapy (67%), palliative radiotherapy (53%), palliative surgery (13%) and best supportive care alone (13%). The median overall survival (OS) was 8.0 months. The median progression-free survival was 5.4 months, and response rate to first-line chemotherapy was 65%. Platinum-based chemotherapy was prognostic of longer OS (HR 0.27, CI 0.12–0.60, P = 0.001). Conclusions: Patients with ES EPSCC had good response to palliative chemotherapy, but OS remained poor. Further research is required to improve the prognosis in this population

A systematic evaluation of compliance and reporting of patient-reported outcome endpoints in ovarian cancer randomised controlled trials: implications for generalisability and clinical practice

Abstract Background This study aimed to evaluate the patient-reported outcome (PRO) content of ovarian cancer randomised-controlled trial (RCT) publications, describe PRO compliance, and explore potential relationships among these and completeness of PRO protocol content. Methods Publications of Phase III ovarian cancer RCTs with PRO endpoints were identified by Medline and Cochrane systematic search: January 2000 to February 2016. Two reviewers determined the number of Consolidated Standards of Reporting Trials (CONSORT)-PRO Extension items addressed in publications. Compliance rates (defined as the proportion of participants included in the principal PRO analysis, of those from whom PRO assessments were expected) were extracted. The relationship between CONSORT-PRO score and compliance rates was explored using scatter plots. Additionally CONSORT-PRO score and PRO compliance rates respectively were compared with corresponding PRO protocol scores obtained from a previous study. Results Thirty-six eligible RCTs (n = 33 with secondary PRO endpoint) were identified and analysed. The average number of CONSORT-PRO items addressed in publications was 6.7 (48%; Range 0–13.5/14). Three RCTs did not report PRO results; in 1 case due to poor compliance. Some compliance information was reported in 26 RCTs, but was considered complete for only 10 (28%) RCTs. Compliance rates were poor overall, ranging from 59 to 83%; therefore missing PRO data from 17 to 41% of participants in these trials could have been avoided. Of the 26 (73%) RCTs for which PRO protocol completeness scores were available, 6 RCTs reported complete compliance information and the 3 of these RCTs with highest PRO compliance had highest protocol checklist scores. Conclusions Few RCTs reported PRO compliance information in a manner enabling assessment of the generalisability of PRO results. This information is particularly important in RCTs of advanced ovarian cancer because it is important to be able to determine if missing data was due to worsening illness compared to methodological issues. Poor compliance appeared related to poor PRO protocol content, and in one case prevented PRO results from being reported, highlighting the need to address compliance strategies in the protocol. Adhering to protocol and CONSORT-PRO reporting guidance should improve PRO implementation and reporting respectively in ovarian cancer RCTs and allow results to meaningfully inform clinical practice

NIVORAD: A randomised phase 2 trial of nivolumab and stereotactic ablative body radiotherapy in advanced non-small cell lung cancer, progressing after first or second line chemotherapy.

Background: Recent data has demonstrated improvements in overall survival in patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab. Radiation may augment the immune response through abscopal effects - evidence of tumour control at sites other than those irradiated. We hypothesize that the addition of stereotactic ablative body radiotherapy (SABR) to immunotherapy with nivolumab will improve progression free survival (PFS) compared with nivolumab alone. Methods: DESIGN: Open label, randomised phase II trial with 25 sites across Australia and New Zealand. ELIGIBILITY: Metastatic NSCLC progressing after 1 or 2 lines of chemotherapy with an extrapulmonary metastasis suitable for SABR. STRATIFICATION: Age, lines of chemotherapy, histology and treating institution. TREATMENT: A single dose of SABR (18-20Gy) plus nivolumab or nivolumab alone (240mg 2-weekly) given until disease progression or prohibitive adverse events. ENDPOINTS: PFS at 6 months (PFS6; primary), objective tumour response rate, adverse events, overall survival, PFS at 1 and 2 years. Tertiary correlative objectives include associations between possible prognostic/ predictive biomarkers and outcomes (including PD-L1 expression). STATISTICS:Total sample size of 120 participants allocated in a ratio of 2:1, 80 to nivolumab + SABR and 40 nivolumab alone to provide 80% power, one-sided type I error rate of 5% for PFS6 of 50% (worthy of pursuit) vs 35% (not worthy of pursuit). BIOSPECIMENS: Tumour tissue and serial bloods (4 time points) will be collected for translational research. CURRENT ENROLLMENT (as of Feb 2017): 2 out of 20 sites are open. NIVORAD is an investigator-initiated, cooperative-group trial led by the ALTG in collaboration with the NHMRC Clinical Trials Centre, University of Sydney and the Trans Tasman Radiation Oncology Group (TROG). Australian New Zealand Clinical Trials Registry: ACTRN12616000352404

Validation of progression-free survival rate at 6 months and objective response for estimating overall survival in immune checkpoint inhibitor trials: A systematic review and meta-analysis

Importance: Progression-free survival (PFS) rate at 6 months has been proposed as a potential surrogate for overall survival (OS) rate at 12 months for immune checkpoint inhibitor (ICI) trials but requires further assessment for validation. Objective: To validate 6-month PFS and objective response rate (ORR) as estimators of 12-month OS in the ICI arms of randomized clinical trials (RCTs). Data Sources: Electronic databases (Medline, EMBASE, and the Cochrane Central Register of Controlled Trials) were searched for ICI RCTs published between January 2000 and June 2019. Study Selection: Eligible studies were phase 2 and phase 3 ICI RCTs in advanced solid cancers that reported ORR, PFS, and OS. A total of 99 articles (from 60 studies) of 2502 articles were selected by consensus. Data Extraction and Synthesis: Data were screened and extracted independently. Estimation models for 12-month OS and to assess correlation coefficient between end points were developed using linear regression. Data were extracted in July 2019, and analyses were conducted in September 2019. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: Validation of previously reported 6-month PFS and ORR estimation models for 12-month OS using contemporary RCTs. Calibration of 6-month PFS and ORR model-estimated vs observed 12-month OS in ICI arms were assessed by correlation coefficient (r) and weighted Brier scores. Secondary analyses were performed for subgroups (ie, ICI-only, ICI-combination, line of therapy, programmed cell death 1 ligand 1 selected, and unselected). Results: Data from 60 RCTs with 74 experimental ICI arms were used. The development data set included 25 arms from studies published January 2000 to January 2017. The estimation model for 12-month OS using 6-month PFS was: (1.06 × PFS6) + 0.16 + (0.04 × melanoma) − (0.03 × NSCLC) + (0 × other tumors), in which PFS6 indicates 6-month PFS and NSCLC indicates non–small cell lung cancer. The estimation model for 12-month OS using ORR was (0.15 × ORR) + 0.52 + (0 × melanoma) − (0.02 × NSCLC) − (0.01 × other tumors). A total of 49 arms from studies published after January 2017 to June 2019 formed the validation data set. When the models were applied on the validation data set, calibration between the 6-month PFS model estimated vs observed 12-month OS was good (r = 0.89; Brier score, 0.008), but poor for the ORR model (r = 0.47; Brier score, 0.03). Findings were similar across all subgroups. Conclusions and Relevance: The findings of this study suggest that the estimation model using 6-month PFS could reliably estimate 12-month OS in ICI trials. This study could assist in better selection and prioritization of ICI agents for testing in RCTs based on phase 2 single-arm RCT results

NIVORAD: A randomised phase 2 trial of nivolumab and stereotactic ablative body radiotherapy in advanced non-small cell lung cancer, progressing after first or second line chemotherapy

This abstract is freely available on the conference website at (see link below

PARAGON (ANZGOG-0903): a phase 2 study of anastrozole in asymptomatic patients with estrogen and progesterone receptor-positive recurrent ovarian cancer and CA125 progression

OBJECTIVE: A subset of patients with recurrent ovarian cancer (ROC) may benefit from antiestrogen therapy with higher response rates reported in tumors that are strongly estrogen receptor (ER)-positive (ER⁺). PARAGON is a basket trial that incorporates 7 phase 2 trials investigating the activity of anastrozole in patients with ER⁺ and/or progesterone receptor (PR)-positive (PR⁺) recurrent/metastatic gynecological cancers. METHODS: Postmenopausal women with ER⁺ and/or PR⁺ ROC, who were asymptomatic and had cancer antigen 125 (CA125) progression after response to first line chemotherapy, where chemotherapy was not clinically indicated. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. RESULTS: Fifty-four patients were enrolled (52 evaluable). Clinical benefit at three months (primary endpoint) was observed in 18 patients (34.6%; 95% confidence interval [CI]=23%-48%). Median progression-free survival (PFS) was 2.7 months (95% CI=2.1-3.1). The median duration of clinical benefit was 6.5 months (95% CI=2.8-11.7). Most patients progressed within 6 months of starting anastrozole but 12 (22%) continued treatment for longer than 6 months. Anastrozole was well tolerated. In the exploratory analysis, ER histoscores and the intensity of ER staining did not correlate with clinical benefit rate or PFS. CONCLUSION: A subset of asymptomatic patients with ER⁺ and/or PR⁺ ROC and CA125 progression had durable clinical benefit on anastrozole, with acceptable toxicity. Anastrozole may delay symptomatic progression and the time to subsequent chemotherapy. The future challenge is to identify the subset of patients most likely to benefit from an aromatase inhibitor and whether the clinical benefit could be increased by the addition of other agents.status: publishe

PARAGON (ANZGOG-0903) : a phase 2 study of anastrozole in asymptomatic patients with estrogen and progesterone receptor-positive recurrent ovarian cancer and CA125 progression

Objective: A subset of patients with recurrent ovarian cancer (ROC) may benefit from antiestrogen therapy with higher response rates reported in tumors that are strongly estrogen receptor (ER)-positive (ER⁺). PARAGON is a basket trial that incorporates 7 phase 2 trials investigating the activity of anastrozole in patients with ER⁺ and/or progesterone receptor (PR)-positive (PR⁺) recurrent/metastatic gynecological cancers. Methods: Postmenopausal women with ER⁺ and/or PR⁺ ROC, who were asymptomatic and had cancer antigen 125 (CA125) progression after response to first line chemotherapy, where chemotherapy was not clinically indicated. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. Results: Fifty-four patients were enrolled (52 evaluable). Clinical benefit at three months (primary endpoint) was observed in 18 patients (34.6%; 95% confidence interval [CI]=23%-48%). Median progression-free survival (PFS) was 2.7 months (95% CI=2.1-3.1). The median duration of clinical benefit was 6.5 months (95% CI=2.8-11.7). Most patients progressed within 6 months of starting anastrozole but 12 (22%) continued treatment for longer than 6 months. Anastrozole was well tolerated. In the exploratory analysis, ER histoscores and the intensity of ER staining did not correlate with clinical benefit rate or PFS. Conclusion: A subset of asymptomatic patients with ER⁺ and/or PR⁺ ROC and CA125 progression had durable clinical benefit on anastrozole, with acceptable toxicity. Anastrozole may delay symptomatic progression and the time to subsequent chemotherapy. The future challenge is to identify the subset of patients most likely to benefit from an aromatase inhibitor and whether the clinical benefit could be increased by the addition of other agents

DREAM – a phase 2 trial of DuRvalumab with first line chEmotherApy in mesothelioma: final result

Australia has the second highest incidence and death rate from malignant pleural mesothelioma (MPM) worldwide, after the United Kingdom. DREAM is an open-label, single arm, multi-centre, phase II trial designed to determine the activity, safety and tolerability of durvalumab combined with first-line chemotherapy in MPM. ACTRN12616001170415. Key eligibility criteria included all histological subtypes of MPM planned for first-line cisplatin and pemetrexed, unsuitability for radical surgery, no prior radiotherapy to measurement sites, and ECOG performance status of 0-1. Response was assessed using the mRECIST (modified Response Evaluation Criteria in Solid Tumors for MPM). Patients received durvalumab (1125mg), cisplatin (75mg/m2) and pemetrexed (500 mg/m2) 3-weekly for a maximum of six cycles, followed by durvalumab alone (1125 mg 3-weekly) up to 12 months or until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 6 months (PFS6). Between Dec 2016 and Sep 2017, 54 patients were recruited. The median age was 68 (42–82) with 82% male and 60% ECOG 0. Forty-five patients (82%) had epithelioid subtype MPM. 31/54 (57%) of patients met primary endpoint of PFS6 with a median PFS of 6.8 months (95% CI: 5.4–9.0), at a median follow up time of 12 months, successfully rejecting the null hypothesis. The objective response rate (ORR) was 48% using mRECIST and 50% using iRECIST. The median duration of response was 6.5 months. 36 patients experienced grade 3-5 adverse events. Of four deaths on study, none were considered related to durvalumab treatment. Seventeen patients had irAEs of any grade, including 8 with G3-5 irAEs. Overall survival is maturing and will be presented at the meeting. Combination durvalumab with first-line chemotherapy for unresectable MPM showed promising activity and acceptable tolerability, with expected immune toxicities. Further evaluation to compare with chemotherapy alone will be generated through a phase 3 randomised controlled trial