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.

A phase 1 safety and bioimaging trial of antibody DS-8895a against EphA2 in patients with advanced or metastatic EphA2 positive cancers.

Ephrin type-A 2 (EphA2) is a transmembrane receptor expressed in epithelial cancers. We report on a phase I dose escalation and biodistribution study of DS-8895a, an anti-EphA2 antibody, in patients with advanced EphA2 positive cancers. DS-8895a was administered at 1, 3, 10 or 20 mg/kg every 2 weeks to determine safety, pharmacokinetics and anti-tumor efficacy. All patients underwent 89Zr trace-labelled infusion of DS-8895a (89Zr-DS-8995a) positron emission tomography imaging to determine the biodistribution of DS-8895a, and correlate findings with EphA2 expression, receptor saturation and response. Nine patients were enrolled on study. Of patients enrolled, seven patients received at least one infusion of DS-8895a: four patients received 1 mg/kg dose (Cohort 1) and three patients received 3 mg/kg dose (Cohort 2). Median age was 67.0 years (range 52-81), majority male (71%), and median number of prior systemic therapies was three (range 0-8). The primary cancer diagnosis was colorectal cancer (two patients) and one patient each had gastric, head and neck, high-grade serous adenocarcinoma, lung, and pancreatic cancers. No dose-limiting toxicities or treatment-related adverse events reported. The best response for the patients in Cohort 1 was stable disease and in Cohort 2 was progressive disease. 89Zr-DS-8895a demonstrated no normal tissue uptake and specific low-grade uptake in most tumours. DS-8895a had limited therapeutic efficacy at doses evaluated and 89Zr-DS-8895a demonstrated low tumour uptake. The biodistribution data from this study were key in halting further development of DS-8895a, highlighting the importance of biodistribution studies in drug development. (Trial registration: ClinicalTrials.gov Identifier NCT02252211).

Poor correlation between preclinical and patient efficacy data for tumor targeted monotherapies in glioblastoma: the results of a systematic review.

PURPOSE: Limited progress has been made in treating glioblastoma, and we hypothesise that poor concordance between preclinical and clinical efficacy in this disease is a major barrier to drug development. We undertook a systematic review to quantify this issue. METHODS: We identified phase I trials (P1Ts) of tumor targeted drugs, subsequent trial results and preceding relevant preclinical data published in adult glioblastoma patients between 2006-2019 via structured searches of EMBASE/MEDLINE/PUBMED. Detailed clinical/preclinical information was extracted. Associations between preclinical and clinical efficacy metrics were determined using appropriate non-parametric statistical tests. RESULTS: A total of 28 eligible P1Ts were identified, with median ORR of 2.9% (range 0.0-33.3%). Twenty-three (82%) had published relevant preclinical data available. Five (18%) had relevant later phase clinical trial data available. There was overall poor correlation between preclinical and clinical efficacy metrics on univariate testing. However, drugs that had undergone in vivo testing had significantly longer median overall survival (7.9 vs 5.6mo, p = 0.02). Additionally, drugs tested in ≥ 2 biologically-distinct in vivo models ('multiple models') had a significantly better median response rate than those tested using only one ('single model') or those lacking in vivo data (6.8% vs 1.2% vs. 0.0% respectively, p = 0.027). CONCLUSION: Currently used preclinical models poorly predict subsequent activity in P1Ts, and generally over-estimate the anti-tumor activity of these drugs. This underscores the need for better preclinical models to aid the development of novel anti-glioblastoma drugs. Until these become widely available and used, the use of multiple biologically-distinct in vivo models should be strongly encouraged.

Current Development of Monoclonal Antibodies in Cancer Therapy.

Exploiting the unique specificity of monoclonal antibodies has revolutionized the treatment and diagnosis of haematological and solid organ malignancies; bringing benefit to millions of patients over the past decades. Recent achievements include conjugating antibodies with toxic payloads resulting in superior efficacy and/or reduced toxicity, development of molecular imaging techniques targeting specific antigens for use as predictive and prognostic biomarkers, the development of novel bi- and tri-specific antibodies to enhance therapeutic benefit and abrogate resistance and the success of immunotherapy agents. In this chapter, we review an overview of antibody structure and function relevant to cancer therapy and provide an overview of pivotal clinical trials which have led to regulatory approval of monoclonal antibodies in cancer treatment. We further discuss resistance mechanisms and the unique side effects of each class of antibody and provide an overview of emerging therapeutic agents.

Antibody-Drug Conjugates for Cancer Therapy.

Antibody-drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.

Delayed Autoimmune Toxicity Occurring Several Months After Cessation of Anti-PD-1 Therapy.

Treatment with anti-programmed cell death protein 1 (PD-1) antibodies has demonstrated clinical efficacy in a whole range of malignancies including advanced melanoma, renal cell cancer, bladder cancer, and non-small cell lung cancer. Immune-related adverse events are a unique side effect of checkpoint regulator therapy including anti-PD-1 antibodies. Treatment-related autoimmunity can occur in any organ system, with the median onset usually within 5-15 weeks from the commencement of therapy, depending on the organ system involved. This study describes for the first time a case of delayed autoimmunity occurring 8 months after discontinuing treatment with the anti-PD-1 antibody nivolumab in a patient with metastatic melanoma. The case highlights the need for ongoing surveillance of patients treated with immune checkpoint inhibitors even after cessation of therapy, especially as patients increasingly stop treatment after achieving durable responses.

Novel Approaches To Undergraduate Oncology Education.

With the increasing incidence of cancer and related survival, junior doctors are more commonly involved the management of oncology patients. A comprehensive oncology curriculum has been developed and adopted across medi-cal schools in Australia. However, it was not designed to inform how medical students should be taught, and whether curriculum content translates to knowledge and competency can depend on its implementation. We have conducted a literature review of PubMed, Embase and Cochrane databases to identify and summarise the evidence for novel approaches to delivering the undergraduate oncology curriculum. Numerous effective approaches have been developed across areas of prevention, clinical examination through simulation, the multidisciplinary team, psycho-oncology, palliative care and even research. There is growing focus on a holistic and multidisciplinary approach to cancer education although direct clinical exposure and interactions with cancer patients is still crucial. Medical schools may also have an under-recognised role in promoting positive health behaviour if their graduates are to convey these preventative measures to their patients. Application of such methods relies upon clinicians and medical educators to consider the practicability and relevance of specific implementation in their local context.

Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases.

BACKGROUND: There is limited data on the efficacy of anti-programmed death 1 (PD-1) antibodies in patients (pts) with melanoma brain metastasis (BM), particularly those which are symptomatic. METHOD: We retrospectively assessed pts with melanoma BM treated with PD-1 antibodies, nivolumab and pembrolizumab. Clinicopathologic and treatment parameters were collected and outcomes determined for intracranial (IC) response rate (RR) using a modified RECIST criteria, with up to five IC target lesions used to determine IC response, disease control rate (DCR) and progression-free survival (PFS). RESULTS: A total of 66 pts were identified with a median follow up of 7.0 months (range 0.8-24.5 months). A total of 68% were male and 45% BRAF V600 mutation positive. At PD-1 antibody commencement, 50% had an elevated LDH; 64% had local therapy to BM prior to commencing anti-PD1, of which 5% had surgical resection, 14% stereotactic radiosurgery (SRS), 18% whole-brain radiotherapy (WBRT), 27% had surgery and radiotherapy. Twenty-one per cent started anti-PD-1 as first line systemic therapy. No pt had prior anti-PD-1 treatment. The IC overall RR was 21 and DCR 56%. Responses occurred in 21% of pts with symptomatic BM. The median OS was 9.9 months (95% CI 6.93-17.74). Pts with symptomatic BM had shorter PFS than those without symptoms (2.7 vs 7.4 months, P=0.035) and numerically shorter OS (5.7 vs 13.0 months, P=0.068). Pts requiring corticosteroids also had a numerically shorter PFS (3.2 vs 7.4 months, P=0.081) and OS (4.8 vs 13.1 months, P=0.039). CONCLUSIONS: IC responses to anti-PD-1 antibodies occur in pts with BM, including those with symptomatic BM requiring corticosteroids. Prospective trials evaluating anti-PD-1 therapy in pts with BM are underway.

Late presentation of generalised bullous pemphigoid-like reaction in a patient treated with pembrolizumab for metastatic melanoma.

Dermatological toxicity is one of the most commonly reported immune-related adverse events in patients receiving checkpoint inhibitor immunotherapy. We report the gradual development of a widespread bullous pemphigoid-like reaction in a metastatic melanoma patient 8 months after commencing treatment with the programmed-death-1 (PD-1) inhibitor pembrolizumab, requiring prolonged corticosteroid therapy. This case highlights the potential for insidious and late development of severe cutaneous toxicity following PD-1 inhibitor therapy and suggests that even prolonged immunosuppression may not necessarily compromise the efficacy of PD-1 inhibition in advanced melanoma.

Implementation of a nurse-led, multidisciplinary model of care for older adults with cancer: a process evaluation protocol.

INTRODUCTION: Cancer is predominantly a disease of older adults, with an increasing number of cancer diagnoses in individuals aged 65 or older. Multiple geriatric factors have been shown to impact patient outcomes in cancer treatment. However, oncology specialists are not well adapted to incorporate geriatric assessment into practice due to a lack of resources and knowledge of the specialty.The primary aim of this study is to implement and evaluate a nurse-led, multidisciplinary model of care for older adults with cancer at two public tertiary hospitals in Melbourne, Australia. METHODS AND ANALYSIS: This study will aim to assess 200 patients across 2 sites. Both sites will assess individuals with lung cancer; the second site will also include individuals with genitourinary, upper gastrointestinal and colorectal cancers.This process evaluation will use quantitative and qualitative methods to explore the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) of the nurse-led, multidisciplinary model of care. ETHICS AND DISSEMINATION: Ethical approval and local governance approvals have been obtained by Austin Health and Monash Health Human Research Ethics committees. Dissemination will occur via publications, conferences, social medical and local engagement with clinicians, consumers and managers.

ALKTERNATE: A Pilot Study Alternating Lorlatinib With Crizotinib in ALK-Positive NSCLC With Prior ALK Inhibitor Resistance.

Introduction: ALK-positive lung cancers represent a molecularly diverse disease. With drug exposure, driving selection pressure, and resistance pathways, disease relapse will emerge. There is compelling rationale to investigate novel treatment strategies, informed by dynamic circulating tumor DNA (ctDNA) monitoring. Methods: The single-arm, pilot study ALKTERNATE investigated fixed alternating cycles of lorlatinib intercalated with crizotinib in individuals resistant to second-generation ALK inhibitors. Dynamic ctDNA explored the correlation with disease response and disease recurrence and defined disease resistance. The primary outcome was time-to-treatment failure, a composite of tolerability, feasibility, and efficacy. Secondary outcomes included standard survival measures, toxicity, pharmacokinetic analysis, and patient-reported outcomes. Tertiary outcomes were proteogenomic analyses of tissue and plasma. Results: A total of 15 individuals were enrolled; three encountered primary resistance to lorlatinib induction. There were 12 participants who received alternating therapy, and this approach revealed safety, feasibility, and effectiveness. Patient-reported outcomes were maintained or improved on therapy, and toxicity was consistent with previous reports. The pharmacokinetic measures were similar to the single-arm drug experience. Median time-to-treatment failure was 10 months; overall survival was 23 months. ctDNA profiles indicated inferior survival in those with preexistent TP53 mutations and those without clear or cleared ctDNA at trial induction. The study defined a vastly heterogeneous population with an abundance of ALK coexisting with non-ALK resistance variants. Conclusions: ALKTERNATE revealed feasibility with a novel alternating ALK inhibitor strategy in ALK-positive NSCLC. Results support progressing inquiry into this approach and propose a flexible design with drug(s) selected and alternating time frames, informed by real-time plasma profiling. Moving this concept to treatment naive may also optimize impact.

A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE.

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.

Real-World Analysis of Clinical Characteristics and Survival Outcomes in Patients With Extensive-Stage SCLC Treated With First-Line Chemoimmunotherapy.

Introduction: There are no clinically validated prognostic biomarkers in the management of extensive-stage SCLC (ES-SCLC). We explored the association between clinical characteristics and survival outcomes in patients with ES-SCLC treated with chemoimmunotherapy. Methods: In this retrospective cohort study, patients with ES-SCLC treated with first-line platinum-etoposide chemotherapy and atezolizumab were identified from medical records. Pretreatment clinical characteristics, biochemical parameters, and tumor and treatment characteristics were collected. Univariate and multivariate Cox regression were used to evaluate treatment effect on progression-free survival (PFS) and overall survival (OS). Results: We evaluated 75 patients in total. The median PFS and OS were 6.1 months and 9.2 months, respectively. Statistically significant associations were found with lower lactate dehydrogenase and improved OS (hazard ratio [HR] = 1.0, 95% confidence interval [CI]: 1.0-1.01, p = 0.006), whereas higher age (HR = 0.94, 95% CI: 0.90-0.98, p = 0.006) and lower neutrophil-to-lymphocyte ratio (HR = 1.08, 95% CI: 1.02-1.14, p = 0.005) were associated with improved PFS. The number of chemotherapy cycles received were associated with both an improved PFS (HR = 0.57, 95% CI: 0.37-0.89, p = 0.011) and OS (HR = 0.5, 95% CI: 0.30-0.84, p = 0.008). Conclusions: This study highlights the important effect of chemotherapy on survival. Furthermore, the association between lactate dehydrogenase and neutrophil-to-lymphocyte ratio on survival further suggests that baseline tumor burden and optimizing sarcopenia are important factors for clinicians to consider as we seek to develop personalized treatment for this disease.

Real-world challenges in undertaking NTRK fusion testing in non-small cell lung cancer.

Background: We performed a retrospective analysis to determine the incidence of neurotrophic tropomyosin-receptor kinase (NTRK) fusion in non-small cell lung cancer (NSCLC). Methods: Archival NSCLC tissues between 2018-2020 were screened by immunohistochemistry (IHC) with IHC-positive cases undergoing confirmatory molecular analysis. Correlative clinicopathologic parameters were collected. Results: Of 289 samples analyzed, 10 (3.5%) cases had NTRK expression on IHC. The median age of patients with NTRK-positivity on IHC was 74.9 (range, 44-88) years and 70% had a smoking history. The cohort included seven adenocarcinomas and one each squamous cell carcinoma, large-cell neuroendocrine and not otherwise specified histologies. PDL1 expression was ≤50% in five cases. Concurrent EGFR mutations were detected in three cases, with two cases also showing a PIK3CA E542K mutation and MET amplification, respectively. Due to insufficient tumor material, RNA-sequencing was undertaken in only one IHC-positive case, with the other nine cases analyzed by Fluorescent in-situ Hybridisation. A NTRK fusion, EML4-NTRK3 gene fusion was detected in one patient, a frequency of 0.35%. Conclusions: NTRK fusions in NSCLC are rare. This study highlights real world diagnostic challenges regarding NTRK testing, such as requirements of adequate tumor tissue and appropriate testing methodologies.

Antibody drug conjugates for glioblastoma: current progress towards clinical use.

INTRODUCTION: Antibody drug conjugates (ADCs) are now a proven therapeutic class for many cancers, combining highly specific targeting with the potency of high effective payloads. This review summarizes the experience with ADCs in brain tumors and examines future paths for their use in these tumors. AREAS COVERED: This review will cover all the key classes of ADCs which have been tested in primary brain tumors, including commentary on the major trials to date. The efficacy of these trials, as well as their limitations, will put in context of the overall landscape of drug development in brain tumors. Importantly, this review will summarize key learnings and insights from these trials that help provide the basis for rational ways in which these drugs can be effectively and appropriate developed for patients with primary brain tumors. EXPERT OPINION: ADC development in brain tumors has occurred in two major phases to date. Key learnings from previous trials provide a strong rationale for the continued development of these drugs for primary brain tumors. However, the unique biology of these tumors requires development strategies specifically tailored to maximize their optimal development.

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.

Antibody-drug conjugates: beyond current approvals and potential future strategies.

The recent approvals for antibody-drug conjugates (ADCs) in multiple malignancies in recent years have fuelled the ongoing development of this class of drugs. These novel agents combine the benefits of high specific targeting of oncogenic cell surface antigens with the additional cell kill from high potency cytotoxic payloads, thus achieving wider therapeutic windows. This review will summarise the clinical activity of ADCs in tumour types not covered elsewhere in this issue, such as gastrointestinal (GI) and genitourinary (GU) cancers and glioblastoma (GBM). In addition to the ongoing clinical testing of existing ADCs, there is substantial preclinical and early phase testing of newer ADCs or ADC incorporating strategies. This review will provide selected insights into such future development, focusing on the development of novel ADCs against new antigen targets in the tumour microenvironment (TME) and combination of ADCs with immuno-oncology (IO) agents.