Lurbinectedin in small cell lung cancer: real-world experience of a multicentre national early access programme.

BACKGROUND AND AIMS: Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum-containing therapy. METHODS: Multicentre real-world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three-weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA). RESULTS: Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second- (83%, 38/46) or subsequent- (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high-grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six-month OS was 44% (95% confidence interval (CI): 29.0-57.1). Twelve-month OS was 15% (95% CI: 6.5-26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8-2.9) and OS was 4.5 months (95% CI: 3.5-7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0-17.2). Individuals with a longer chemotherapy-free interval prior to lurbinectedin had longer PFS and OS. CONCLUSION: This real-world national experience of lurbinectedin post-platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials.

Systemic treatment of advanced and metastatic urothelial cancer: The landscape in Australia.

The 5-year survival rate of metastatic urothelial carcinoma (mUC) is estimated to be as low as 5%. Currently, systemic platinum-based chemotherapy followed by avelumab maintenance therapy is the only first-line treatment for mUC that has an overall survival benefit. Cisplatin-based chemotherapy (usually in combination with gemcitabine) is the preferred treatment but carboplatin is substituted where contraindications to cisplatin exist. Treatment with immune checkpoint inhibitors, antibody-drug conjugates, and kinase inhibitors has not yet demonstrated superiority to chemotherapy as first-line therapy and remains investigational in this setting. A recent media release indicates that chemotherapy plus nivolumab gives an OS advantage as first-line treatment but results of this study have not yet been made public. Pembrolizumab remains an option in those having primary progression on first-line chemotherapy or within 12 months of neoadjuvant chemotherapy. The antibody-drug conjugate, enfortumab vedotin has TGA approval for patients whose cancer has progressed following chemotherapy and immunotherapy and has just received a positive Pharmaceutical Benefits Scheme recommendation. The use of molecular screens for somatic genetic mutations, gene amplifications, and protein expression is expanding as drugs that target such abnormalities show promise. However, despite these advances, a substantial proportion of patients with mUC have significant barriers to receiving any treatment, including advancing age, frailty, and comorbidities, and less toxic, effective therapies are needed.

LOREALAUS: LOrlatinib REAL-World AUStralian Experience in Advanced ALK-Rearranged NSCLC.

Introduction: Over the past decade, ALK tyrosine kinase inhibitors have delivered unprecedented survival for individuals with ALK-positive (ALK+) lung cancers. Real-world data enhance the understanding of optimal drug sequencing and expectations for survival. Methods: Multicenter real-world study of individuals with pretreated advanced ALK+ lung cancers managed on a lorlatinib access program between 2016 and 2020. Key outcomes were lorlatinib efficacy, tolerability, and treatment sequencing. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method among all individuals (PFSa and OSa), with at least 30 days (one-cycle) lorlatinib exposure (PFSb and OSb), and with good performance status (PFSc and OSc). Subgroups of interest were analyzed to assess signals of potential clinical applicability. Two OS index dates were analyzed, from lorlatinib initiation and advanced ALK+ diagnosis. Results: The population (N = 38, 10 sites) was heavily pretreated (23 had ≥2 previous treatment lines) with a high disease burden (26 had 2-4 sites and 11 had >4 sites of metastatic disease, 19 had brain metastases). The overall response rate was 44% and the disease control rate was 81%. Lorlatinib dose reduction (18%), interruption (16%), and discontinuation (3%) were consistent with the trial experience. From advanced ALK+ diagnosis, the median OS for populations a, b, and c was 45.0 months, 69.9 months and 61.2 months respectively. From lorlatinib initiation, the median PFSa, PFSb and PFSc was 7.3 months, 13.2 months and 27.7 months and the median OSa, OSb and OSc was 19.9 months, 25.1 months and 27.7 months. The median PFSa with versus without brain metastases was 34.6 months versus 5.8 months (p = 0.09). The intracranial median PFS was 14.2 months. Previous good response versus poor response to the first ALK-directed therapy median PFSa was 27.7 months versus 4.7 months with a hazard ratio of 0.3 (p = 0.01). Conclusions: Lorlatinib is a potent, highly active brain-penetrant third-generation ALK tyrosine kinase inhibitors with benefits for most individuals in the later-line setting in a real-world evaluation, consistent with clinical trial data.

Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors.

BACKGROUND: Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors. METHODS: Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab). Prior immunotherapy was permitted >28 days before study treatment. Patients received intravenous V937 on days 1, 3, and 5 (also on day 8 in part B) of the first 21-day cycle and on day 1 of subsequent cycles for eight cycles. Three ascending dose-escalation cohorts were studied. Dose-escalation proceeded if no dose-limiting toxicities (DLTs) occurred in cycle 1 of the previous cohort. In part B, patients also received pembrolizumab 200 mg every 3 weeks from day 8 for 2 years; dose-expansion occurred at the highest-dose cohort. Serial biopsies were performed. RESULTS: No DLTs occurred in parts A (n=18) or B (n=85). Grade 3-5 treatment-related adverse events (AEs) were not observed in part A and were experienced by 10 (12%) patients in part B. The most frequent treatment-related AEs (any grade) in part B were fatigue (36%), pruritus (18%), myalgia (14%), diarrhea (13%), pyrexia (13%), influenza-like illness (12%), and nausea (12%). At the highest tested dose, median intratumoral V937 concentrations were 117,631 copies/mL on day 8, cycle 1 in part A (n=6) and below the detection limit for most patients (86% (19/22)) on day 15, cycle 1 in part B. Objective response rates were 6% (part A), 9% in the NSCLC dose-expansion cohort (n=43), and 20% in the urothelial cancer dose-expansion cohort (n=35). CONCLUSIONS: Intravenous V937+pembrolizumab had a manageable safety profile. Although V937 was detected in tumor tissue, in NSCLC and urothelial cancer, efficacy was not greater than that observed in previous studies with pembrolizumab monotherapy. TRIAL REGISTRATION NUMBER: NCT02043665.

Acute effect of high-intensity interval aerobic exercise on serum myokine levels and resulting tumour-suppressive effect in trained patients with advanced prostate cancer.

PURPOSE: Although skeletal muscle releases cytokines called myokines during exercise, the kinetics of the acute myokine response to exercise (exercise-induced circulatory myokine level alteration) is unknown in patients with advanced prostate cancer. We measured myokine levels in serum obtained from patients with metastatic castrate-resistant prostate cancer (mCRPC) before and after exercise and assessed the growth-suppressive effect of the serum by applying it to a PCa cell line. METHODS: Nine patients with mCRPC (age = 67.8 ± 10.1 years, time since mCRPC diagnosis 36.2 ± 22.5 months) undertook 34 min of a high-intensity interval exercise session on a cycle ergometer. Blood was collected immediately pre, post and 30 min post. Serum levels of secreted protein acidic and rich in cysteine (SPARC), oncostatin M (OSM), interleukin-6 (IL-6), interleukin-15 (IL-15), decorin, irisin, and IGF-1 were determined. Growth of the androgen-independent PCa cell line DU-145 exposed to serum collected at three points was measured. RESULTS: There was a significant elevation of SPARC (19.9%, P = 0.048), OSM (11.5%, P = 0.001), IL-6 (10.2%, P = 0.02) and IL-15 (7.8%, P = 0.023) in serum collected immediately after exercise compared to baseline, returning to baseline after 30 min rest. A significant reduction in DU-145 Cell growth and the Cell Index area under the curve at 72 h incubation was observed with the presence of serum obtained immediately post-exercise (Cell Index at 72 h: 16.9%, P < 0.001; area under the curve: 15.2%, P < 0.001) and with the presence of serum obtained 30 min post-exercise compared to baseline (Cell Index at 72 h: 6.5%; area under the curve: 8.8%, P < 0.001). CONCLUSION: This study provides preliminary evidence for an acute exercise-induced myokine response and tumour growth suppression in serum after a bout of high-intensity interval exercise in patients with advanced PCa.

The impact of the 2022 Ukraine/Russian conflict on cancer clinical trials.

Since the invasion of Ukraine in February 2022, clinical trial conduct has become extremely challenging due to damage to the healthcare infrastructure and patient displacement. This current study aimed to estimate the number of cancer clinical trials at risk of impact from the conflict. A descriptive analysis and narrative review were completed using data from cancer clinical trials with sites in Russia or Ukraine using the 'clinical trials.gov' online database between February 2022 and May 2022. There were 508 clinical trials involving sites in Ukraine or Russia. Most were multinational studies (470 of 508; 93%). The majority of studies were phase 3 (344 of 508; 68%) and these also had the largest sample sizes (median 624, range 12-5637). The most common tumour types were lung (128 of 508; 25%), urogenital (94 of 508; 19%) and breast (78 of 508; 15%). A meaningful number of trials had curative intent (129 of 508; 25%). The most common intervention was immunotherapy-related (218 of 508; 43%), followed by other targeted therapy (185 of 508; 36%). Ukraine and Russia are both large centres for global clinical trial activity. The invasion of Ukraine may result in underpowering of international clinical trial results with loss of future recruitment sites for both countries.

Doctors' understanding of consent law.

BACKGROUND: Obtaining informed consent is an important responsibility of all doctors and is a major component of their day-to-day practice. However, little is known regarding practising doctors' understanding of consent in relation to medical law. AIMS: To gain insights into current doctors' understanding of the legal requisites that underpin the consent of patients to medical procedures in Australia. METHODS: A cross-sectional survey of Western Australian medical practitioners was conducted. A 15-question online questionnaire (SurveyMonkey, USA) was developed and distributed to Western Australia medical practitioners via social media, hospital-based Junior doctor society pages and through the email accounts of practitioners registered with MDA National - a large medical defence organisation. Doctors were questioned on their understanding of medicolegal responsibilities, informed consent practice and knowledge of a historically significant Australian medicolegal case (Rogers v Whitaker, 1992). RESULTS: A total of 172 responses was received during the survey period. The respondents came from various levels of seniority and from a variety of subspecialist areas. The survey demonstrated that among the respondents, the understanding of their medicolegal responsibilities around the issues of informed consent was deficient. Only 31% of respondents were aware that it is a court of law that defines the reasonable standard of care in relation to obtaining informed consent. Less than half of the respondents (48%) were aware of the High Court of Australia's definition by which the standard of reasonable care is defined. CONCLUSION: The results from our survey suggest that there is a requirement to enhance the education of medical practitioners to meet the medicolegal requirements and optimise consent.

Management of neutropenic fever in a private hospital oncology unit.

BACKGROUND: Neutropenic fever is a medical emergency, which poses a significant morbidity and mortality risk to cancer patients receiving chemotherapy. National guidelines recommend that patients presenting with suspected neutropenic fever receive appropriate intravenous antibiotics within 60 min of admission. AIM: We aimed to investigate the management of neutropenic fever in a large private oncology centre. METHODS: A retrospective audit of all patients who presented to St John of God Hospital, Subiaco, in the 2017 calendar year, with a known solid organ malignancy and a recorded diagnosis of neutropenic fever was conducted. Patients were identified through the hospitals Patient Administration System and ICD-10 codes. Information was collected from the hospital medical records using a standardised data collection tool. RESULTS: There were 98 admissions relating to 88 patients with neutropenic fever during the study period. The median age was 64 years (range: 23-85 years) with 57 (65%) females. Antibiotic selections consistent with the Australian guidelines were made in 88 (89%) admissions. The mean time to antibiotic administration was 279 min, with a median of 135 min (range: 15-5160 min). Antibiotics were administered within the recommended time frame in only eight (11%) admissions. CONCLUSION: Clinicians prescribed antibiotics in accordance with national guidelines; however, there were systemic inefficiencies which resulted in delayed antibiotic initiation. This has resulted in implementation of strategies to minimise delay.

Dabrafenib and trametinib treatment-associated fevers in metastatic melanoma causing extreme elevation in procalcitonin in the absence of infection.

Febrile illnesses are common in the management of metastatic solid organ malignancies. Traditionally they occur in the setting of immunosuppression and neutropenia owing to cytotoxic therapy necessitating consideration of systemic infections. Systemic markers of inflammation, such as C-reactive protein and procalcitonin (PCT), may be used to assist in determining the aetiology of a fever in such patients. Newer anticancer therapies may cause significant noninfectious fevers and may result in a rise in inflammatory markers, despite the absence of an infection. We present a case of a critically unwell febrile patient being treated with dabrafenib and trametinib for advanced melanoma. The patient had an extreme elevation in PCT in the absence of infection. We discuss the presentation of fevers related to dabrafenib and trametinib therapy in the management of advanced melanoma, and the utility of PCT in the management of fevers in advanced solid organ malignancies.

EGFR and KRAS mutations do not enrich for the activation of IL-6, JAK1 or phosphorylated STAT3 in resected lung adenocarcinoma.

Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) against EGFR mutant lung adenocarcinoma develops after a median of nine to thirteen months. Upregulation of the interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway may be a potential source of resistance to EGFR TKIs. We undertook a detailed assessment of the IL-6/JAK1/phosphorylated STAT3 (pSTAT3) pathway in resected lung adenocarcinoma specimens, with special interest in whether the presence of an EGFR mutation enriched for pSTAT3 positivity. Tumours from 143 patients with resected lung adenocarcinoma were assessed. EGFR and KRAS mutation status were scanned for with high-resolution melting and confirmed by polymerase chain reaction. Immunohistochemisty (IHC) was performed for IL-6, gp130, JAK1 and pSTAT3. Two methods for assigning IHC positivity were assessed (the presence of any positivity, and the presence of positivity at an H score >40). We found statistically significant associations between IL-6, JAK1 and pSTAT3 measured by IHC, consistent with the activation of the pathway in clinical specimens. No relationship was demonstrated between members of this pathway and oncogenic mutations in EGFR or KRAS. However, a proportion of tumours with EGFR mutations showed staining for IL-6, JAK1 and pSTAT3. No correlations with clinicopathologic features or survival outcomes were found for IL-6, JAK1 or pSTAT3 staining. The presence of EGFR or KRAS mutations did not enrich for the activation of IL-6, JAK1 or pSTAT3. pSTAT3 may still play a role in resistance to EGFR TKIs in clinical practice.

A finding with a diagnosis: I just can't put my finger on it.

A 72-year-old man with metastatic squamous cell carcinoma of the lung presents with new lesions in the distal phalanx of right fifth finger (painful) and left great toe (painless due to long-standing peripheral neuropathy). Initially a complication of cytotoxic chemotherapy is considered and a dermatological opinion is requested. Enlargement of the lesions over the space of a week leads to plain X-ray, with findings of destruction of the distal phalanx of the involved digits confirming metastatic disease. Palliative radiotherapy is administered to decrease pain and reduce the likelihood of cutaneous and infectious complications. The patient died from systemic disease progression soon after finishing his radiotherapy. Digital metastasis (acrometastasis) should be considered by clinicians in the workup of patients with persistent digital symptoms, particularly in those with known cancer or those at high risk of cancer.

The clinical relevance of pathologic subtypes in metastatic lung adenocarcinoma.

INTRODUCTION: The International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma recommends identification of pathologic patterns in metastatic samples where possible. We investigated the clinical relevance of these patterns. METHODS: Patients with a surgical biopsy of lung adenocarcinoma from a metastatic site were included. Slides were reviewed by an anatomical pathologist identifying the histologic patterns of solid with mucin, acinar, micropapillary, papillary, and assigning a major adenocarcinoma subtype according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. EGFR and KRAS mutation testing were performed on formalin-fixed, paraffin-embedded blocks. Mutations were detected by high resolution melting assay with high resolution melting-positive samples confirmed by Sanger sequencing. RESULTS: One-hundred patients were included. The major histologic subtype prevalence was as follows: solid (50), acinar (29), micropapillary (20), and papillary (1). Of 100 patients, 45 received no systemic therapy with no overall survival differences seen by histologic subtype and 55 received systemic therapy (chemoradiotherapy with curative intent or palliative chemotherapy). Worse survival was seen in the major solid histologic subtype compared with major acinar (hazard ratio 0.32 [95% confidence interval 0.15-0.68], p = 0.003) and micropapillary subtypes (hazard ratio 0.34 [95% confidence interval, 0.17-0.69], p = 0.003). The major solid histologic subtype was less likely to harbor EGFR mutations (p = 0.006) and was less frequent in never smokers (p = 0.010) compared with other histologic subtypes. CONCLUSION: The major solid histologic subtype of lung adenocarcinoma at metastatic sites is associated with shorter overall survival on systemic anticancer therapy. Furthermore, the major solid histologic subtype is less likely to harbor EGFR mutations. These results require validation in larger cohorts.

EGFR gene copy number alterations are not a useful screening tool for predicting EGFR mutation status in lung adenocarcinoma.

We investigated if gene copy number (GCN) alterations of the epidermal growth factor receptor (EGFR), as detected by silver enhanced in situ hybridisation (SISH), could be used to select patients for EGFR mutation testing. Resected lung adenocarcinoma specimens with adequate tumour were identified. EGFR SISH was performed using the Ventana Benchmark Ultra platform. EGFR GCN was classified according to the Colorado Classification System. EGFR mutations were scanned by high resolution melting and confirmed by Sanger sequencing. Thirty-four of 96 tumours were EGFR SISH positive (35%), and 31 of 96 tumours harboured one or more EGFR mutations (32%). Of 31 EGFR-mutant tumours, 18 were EGFR SISH positive (58%). There was a statistically significant relationship between the presence of an EGFR mutation and EGFR GCN (p = 0.003). Thirteen of 31 EGFR-mutant tumours were EGFR SISH negative (42%), and 16 of 65 EGFR-wild type tumours were EGFR SISH positive (24%). The sensitivity, specificity, positive predictive value and negative predictive value were 58%, 75%, 52.9% and 79%, respectively. Despite a significant relationship between EGFR GCN alterations and EGFR mutations, our results indicate that EGFR GCN as detected by SISH is not a suitable way to select patients for EGFR mutation testing.

Intravenous leiomyomatosis with intracardiac extension - a review of diagnosis and management with an illustrative case.

Intravenous leiomyomatosis with intracardiac extension is an uncommon pathologic progression of uterine leiomyomata. It is a histologically benign condition, however due to interfence with right sided cardiac function patients may present with marked cardiovascular compromise and present a diagnostic dilemma to clinicians who are unfamiliar with this condition. Given the rarity of this condition, experience in individual institutions is usually limited to a few cases. We present an illustrative case and provide a review of the clinical presentation, preoperative assessment, operative approach, pathology and postoperative issues. The importance of a multidisciplinary approach to diagnosis and management is highlighted. Operative management aims to completely resect all tumour in the safest manner for the patient, most commonly via single or two stage operation. Where complete resection is achieved, recurrence appears to be a rare event.

Acute pain associated with oxaliplatin infusion: case report and literature review.

Both acute and chronic neurotoxicities are well-described with the use of oxaliplatin. We describe the case of a 50-year-old man with Dukes C colon carcinoma being treated with an adjuvant FOLFOX4 (5-fluorouracil, leucovorin and oxaliplatin (85 mg/m(2) per cycle)) who developed a widespread acute pain 5 min after commencing his twelfth cycle of chemotherapy. The pain was disabling and distressing, and remained for 16 h despite multimodality analgesia. The patient was not rechallenged with oxaliplatin. We believe this presentation represents an acute neurological phenomenon relating to oxaliplatin. Of note, this acute reaction occurred after 11 cycles of treatment, significantly later in the treatment course than other reports of atypical acute reactions.

Effect of a single 'megadose' intramuscular vitamin D (600,000 IU) injection on vitamin D concentrations and bone mineral density following biliopancreatic diversion surgery.

BACKGROUND: Vitamin D (VitD) deficiency is common following biliopancreatic diversion (BPD). We conducted a prospective open-label study to evaluate the efficacy of a single intramuscular injection with 600,000 IU of cholecalciferol in an arachis oil depot formulation (VitD3, Arachitol Solvay Pharmacia) as an adjunct to regular oral VitD supplementation (Citrical+D) for a period of 12 months following BPD surgery. METHODS: Some 29 patients who had undergone BPD during 2000-2005 were recruited and received a single injection of 600,000 IU of cholecalciferol. Venous blood VitD, parathyroid hormone (PTH), alkaline phosphatase (ALP), ionised calcium and urinary N-telopeptide (NTX) were assessed at baseline and at 1.5, 3, 6, 9 and 12 months post-injection. Bone mineral density (BMD) was determined at baseline and 12 months post-injection. RESULTS: VitD concentrations (mean +/- SD) were significantly increased from baseline values (61.5 +/- 18.8 nmol/L) at 1.5 months (92.4 +/- 21.5, p < 0.001), 3 months (100.5 +/- 24.4, p < 0.001) and 6 months (79.1 +/- 20.9, p = 0.014) post-injection, with non-significant elevations at 9 months (73.3 +/- 15.1, p = 0.248) and 12 months (73.4 +/- 17.3, p = 0.278). The proportion of patients with 'normalised' VitD levels was significantly higher at all post-injection time points (range, 93-100%) compared with baseline (71.4%; p < 0.01). Ionised calcium and ALP remained within normal levels at baseline and all follow-up time points, although ionised calcium decreased by 3.4% (p = 0.015) and ALP increased by 14.6% (p = 0.021) at 12 months compared with baseline. No significant change in PTH, NTX or BMD was observed. CONCLUSIONS: Intramuscular cholecalciferol injection, as an adjunct to oral supplementation, appears a safe and effective method to increase and maintain VitD levels after BPD.