Sir Peter MacCallum Department of Oncology - Research Publications
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ItemNo Preview AvailablePlain language summary of the CROWN study comparing lorlatinib with crizotinib for people with untreated non-small cell lung cancer(FUTURE MEDICINE LTD, 2021-08-24)This is a summary of a research study (known as a clinical trial) called CROWN. The study tested two medicines called lorlatinib and crizotinib in participants with untreated non-small cell lung cancer that had spread to other parts of their body. All those who took part had changes in a gene called ALK, which is involved in cell growth. In total, 296 participants from 23 countries took part. Half the participants took lorlatinib and half took crizotinib. After participants started taking lorlatinib or crizotinib, they were checked regularly to see if their tumors had grown or spread to other parts of their body (known as tumor progression) and to monitor any side effects. After 1 year of treatment, the participants who took lorlatinib were twice as likely to be alive with no tumor growth as the participants who took crizotinib. More participants who took lorlatinib had cancer that shrank (76%) compared with the participants who took crizotinib (58%). This was also true of the participants whose cancer had spread to their brain. The most common side effects in participants who took lorlatinib were increases in the amount of cholesterol and triglycerides (a type of fat) in their blood, swelling, weight gain, nerve damage, unclear thoughts, and diarrhea. Among the participants who took crizotinib, the most common side effects were diarrhea, feeling like you want to throw up, sight problems, swelling, vomiting, changes in liver function, and feeling tired. Overall, the CROWN study showed that fewer participants with advanced ALK+ non-small cell lung cancer died or had tumor growth with lorlatinib compared with crizotinib treatment. ClinicalTrials.gov NCT number: NCT03052608.
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ItemContinuation of Lorlatinib in ALK-Positive NSCLC Beyond Progressive Disease(ELSEVIER SCIENCE INC, 2022-04-01)INTRODUCTION: Lorlatinib, a potent, selective third-generation ALK tyrosine kinase inhibitor (TKI), exhibited overall and intracranial antitumor activity in patients with ALK-positive NSCLC. METHODS: Retrospective analyses in the ongoing phase 2 trial (NCT01970865) investigated the clinical benefit of continuing lorlatinib beyond progressive disease (LBPD). Patients with previous crizotinib treatment as the only ALK TKI were group A (n = 28); those with at least one previous second-generation ALK TKIs were group B (n = 74). LBPD was defined as greater than 3 weeks of lorlatinib treatment after investigator-assessed progressive disease. Only patients with the best overall response of complete or partial response or stable disease were included. RESULTS: There were no major differences in baseline characteristics between groups. The median duration of treatment for patients who continued LBPD was 32.4 months (group A) and 16.4 months (group B) versus 12.5 months (group A) and 7.7 months (group B) for patients who did not continue LBPD. The median overall survival in group A was not reached (NR) in patients who continued LBPD versus 24.4 months (95% confidence interval [CI]: 12.1-NR); group B's median was 26.5 months (95% CI: 18.7-35.5) in patients who continued LBPD versus 14.7 months (95% CI: 9.3-38.5) in patients who did not continue LBPD. The median overall survival postprogression for groups A and B was NR (95% CI: 21.4-NR) and 14.6 months (95% CI: 11.2-19.2) in patients who continued LBPD and 8.0 months (95% CI: 1.5-NR) versus 5.3 months (95% CI: 2.8-14.3) in patients who did not continue LBPD. CONCLUSIONS: Continuing LBPD is a viable treatment strategy for select patients with ALK-positive NSCLC who progressed on lorlatinib.
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ItemEfficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion-Positive Lung Cancers.(American Society of Clinical Oncology (ASCO), 2022-01)PURPOSE: Larotrectinib is a highly selective and CNS-active tropomyosin receptor kinase (TRK) inhibitor that has demonstrated efficacy across TRK fusion-positive cancers, regardless of the tumor type. The aim of this study was to assess the efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancers. MATERIALS AND METHODS: Data from two global, multicenter, registrational clinical trials of patients treated with larotrectinib were analyzed: a phase II adult and young adult basket trial (NCT02576431) and a phase I adult trial (NCT02122913). The primary end point was objective response rate (ORR). RESULTS: By July 20, 2020, 20 patients with TRK fusion-positive lung cancer had been treated. The ORR by investigator assessment among 15 evaluable patients was 73% (95% CI, 45 to 92); one (7%) patient had a complete response, 10 (67%) had a partial response, three (20%) had stable disease, and one (7%) had progressive disease as best response. The median duration of response, progression-free survival, and overall survival were 33.9 months (95% CI, 5.6 to 33.9), 35.4 months (95% CI, 5.3 to 35.4), and 40.7 months (95% CI, 17.2 to not estimable), respectively. Among patients with baseline CNS metastases, the ORR was 63% (95% CI, 25 to 91). Adverse events were mainly grade 1 or 2. CONCLUSION: Larotrectinib is highly active with rapid and durable responses, extended survival benefit, and a favorable long-term safety profile in patients with advanced lung cancer harboring NTRK gene fusions, including those with CNS metastases. These findings support routine testing for NTRK fusions in patients with lung cancer.
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ItemCorrelation between treatment effects on response rate and progression-free survival and overall survival in trials of targeted therapies in molecularly enriched populations(ELSEVIER, 2022-04-01)BACKGROUND: The number of randomized trials of agents targeting oncogene-addicted tumors has surged in the past 10 years. Using a meta-analysis, we explored whether improvements in objective response rate (ORR) in comparative trials using targeted agents could serve as a potential surrogate endpoint for improvements in progression-free survival (PFS) or overall survival (OS) in populations with oncogene-addicted cancer. PATIENTS AND METHODS: Using commercial text mining software I2E, we searched ClinicalTrials.gov and MEDLINE databases for randomized, phase III trials based on prospectively defined criteria, including (i) use of agents targeting EGFR activating mutations, ALK rearrangements, BRAF V600E or V600K mutations, and BCR-ABL fusion protein; (ii) molecularly enriched trial population or subpopulation; (iii) control arm only randomized to chemo/cytotoxic therapy. Correlative analyses were performed using ORR, OS, and PFS data from trials that met these criteria. RESULTS: A total of 62 trials were identified; 15 met all of the prespecified criteria. The ORR effect size (both the difference in ORR between arms and the log odds ratio) and log PFS hazard ratio were strongly correlated: -0.78 (P = 0.0007) for the ORR difference model; -0.74 (P = 0.0017) for the log odds ratio model. ORR effect size was positively correlated with the log OS hazard ratio, but more weakly: -0.67 (P = 0.013) for the ORR difference model and -0.58 (P = 0.036) for the log odds ratio model. Analysis of the treatment effects between OS and PFS found no correlation. CONCLUSIONS: These analyses identified a strong correlation between treatment effects on ORR and PFS in randomized clinical trials investigating agents targeting oncogene-driven cancers. A weaker correlation was observed between ORR and OS. These meta-analysis results support the use of a high ORR forming the basis of an initial regulatory approval in biomarker-driven studies.
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ItemPitfalls and progress in adrenocortical carcinoma diagnosis: the utility of a multidisciplinary approach, immunohistochemistry and genomics(BIOSCIENTIFICA LTD, 2022-01-01)SUMMARY: Adrenocortical carcinoma is a rare disease with poor prognosis whose clinical heterogeneity can at times present a challenge to accurate and timely diagnosis. We present the case of a patient who presented with extensive pulmonary lesions, mediastinal and hilar lymphadenopathy and an adrenal mass in whom the oncological diagnosis was initially uncertain. Through the use of immunohistochemistry, biochemistry and genomic testing, an accurate diagnosis of adrenocortical carcinoma was ultimately made which resulted in more directed treatment being administered. The use of multidisciplinary input and genomics to aid in diagnosis and prognosis of adrenocortical carcinoma is discussed. LEARNING POINTS: Adrenocortical carcinomas can present a diagnostic challenge to clinicians given it is a rare malignancy with significant clinical heterogeneity. Specialist multidisciplinary team input is vital in the diagnosis and management of adrenocortical carcinomas. Hormonal testing is recommended in the diagnostic workup of adrenal masses, even in the absence of overt clinical signs/symptoms of hormone excess. Immunostaining for the highly sensitive and specific steroidogenic factor-1 is vital for accurate diagnosis. Genomics can provide prognostic utility in management of adrenocortical carcinoma.
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ItemMolecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations(AMER ASSOC CANCER RESEARCH, 2021-12-01)NTRK chromosomal rearrangements yield oncogenic TRK fusion proteins that are sensitive to TRK inhibitors (larotrectinib and entrectinib) but often mutate, limiting the durability of response for NTRK + patients. Next-generation inhibitors with compact macrocyclic structures (repotrectinib and selitrectinib) were designed to avoid resistance mutations. Head-to-head potency comparisons of TRK inhibitors and molecular characterization of binding interactions are incomplete, obscuring a detailed understanding of how molecular characteristics translate to potency. Larotrectinib, entrectinib, selitrectinib, and repotrectinib were characterized using cellular models of wild-type TRKA/B/C fusions and resistance mutant variants with a subset evaluated in xenograft tumor models. Crystal structures were determined for repotrectinib bound to TRKA (wild-type, solvent-front mutant). TKI-naïve and pretreated case studies are presented. Repotrectinib was the most potent inhibitor of wild-type TRKA/B/C fusions and was more potent than selitrectinib against all tested resistance mutations, underscoring the importance of distinct features of the macrocycle structures. Cocrystal structures of repotrectinib with wild-type TRKA and the TRKAG595R SFM variant elucidated how differences in macrocyclic inhibitor structure, binding orientation, and conformational flexibility affect potency and mutant selectivity. The SFM crystal structure revealed an unexpected intramolecular arginine sidechain interaction. Repotrectinib caused tumor regression in LMNA-NTRK1 xenograft models harboring GKM, SFM, xDFG, and GKM + SFM compound mutations. Durable responses were observed in TKI-naïve and -pretreated patients with NTRK + cancers treated with repotrectinib (NCT03093116). This comprehensive analysis of first- and second-generation TRK inhibitors informs the clinical utility, structural determinants of inhibitor potency, and design of new generations of macrocyclic inhibitors.
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ItemMelanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES)(BMJ PUBLISHING GROUP, 2021-10-01)BACKGROUND: Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib-trametinib and ipilimumab-nivolumab have similar intracranial response rates (50%-55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab-nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance. METHODS: Patients who received first-line ipilimumab-nivolumab for MBMs or second/third line ipilimumab-nivolumab for intracranial metastases with BRAFV600 mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded samples of BRAFV600 mutant MBMs that were naïve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs naïve to systemic treatment versus BRAF-MEKi progression were performed. RESULTS: Twenty-five and 30 patients who received first and second/third line ipilimumab-nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5 mm for the first and second/third line ipilimumab-nivolumab groups, respectively. Intracranial response rate was 75.0% (12/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab-nivolumab. Efficacy of second/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab-nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between naïve and MBMs with progression on BRAF-MEKi treatment (p value <0.05, false discovery rate (FDR) <0.1). No distinct pathways were identified from gene set enrichment analyses using Kyoto Encyclopedia of Genes and Genomes, Gene Ontogeny or Hallmark libraries; however, enrichment of DEG from the Innate Anti-PD1 Resistance Signature (IPRES) was identified (p value=0.007, FDR=0.03). CONCLUSIONS: Second-line ipilimumab-nivolumab for MBMs after BRAF-MEKi progression has poor activity. MBMs that are resistant to BRAF-MEKi that also conferred resistance to second-line ipilimumab-nivolumab showed enrichment of the IPRES gene signature.
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ItemBiology and Treatment Advances in Cutaneous Squamous Cell Carcinoma(MDPI, 2021-11-01)Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer diagnosed worldwide. CSCC is generally localized and managed with local therapies such as excision and/or radiotherapy. For patients with unresectable or metastatic disease, recent improvements in our understanding of the underlying biology have led to significant advancements in treatment approaches-including the use of immune checkpoint inhibition (ICI)-which have resulted in substantial gains in response and survival compared to traditional cytotoxic approaches. However, there is a lack of understanding of the biology underpinning CSCC in immunocompromised patients, in whom the risk of developing CSCC is hundreds of times higher compared to immunocompetent patients. Furthermore, current ICI approaches are associated with significant risk of graft rejection in organ transplant recipients who make up a significant proportion of immunocompromised patients. Ongoing scientific and clinical research efforts are needed in order to maintain momentum to increase our understanding and refine our therapeutic approaches for patients with CSCC.
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ItemLocal ablative therapies in oligometastatic NSCLC-upfront or outback?-a narrative review(AME PUBL CO, 2021-03-17)Patients with oligometastatic (OM) non-small cell lung cancer (NSCLC) have favorable outcomes compared to patients presenting with diffuse metastatic disease. Recent randomized trials have demonstrated safety and efficacy signals for local ablative therapies with radiotherapy, surgery, or radiofrequency ablation for OM-NSCLC patients alongside systemic therapies. However, it remains unclear whether local ablative therapy (LAT) should be offered either upfront preceding systemic therapies or following initial systemic therapies as local consolidative therapy (LCT). Establishing optimal timing of RT and systemic therapy combinations is essential to maximize efficacy while maintaining safety. Most published randomized trial evidence surrounding the benefits of LAT and systemic therapies were generated from OM-NSCLC patients receiving cytotoxic chemotherapy agents. With increasing use of novel agents such as targeted therapies (i.e., tyrosine kinase inhibitors) and immune checkpoint inhibitors in management of metastatic NSCLC patients, LAT timing may need to be modulated based on the use of specific agents. This narrative review will discuss the current evidence on either upfront LAT or LCT for OM-NSCLC based on published trials and cohort studies. We briefly explored the possible biological mechanisms of the potential clinical advantages of either approach. This review also summarized the ongoing trials incorporating both upfront LAT and LCT, and considerations for future LAT strategies.
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ItemImmunotherapy in oncogene addicted non-small cell lung cancer(AME PUBL CO, 2021-06-01)The use of immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) has led to notable changes in treatment strategies for patients with advanced non-small cell lung cancer (NSCLC) and now forms a part of standard of care treatment in patients with advanced disease. However, most patients do not respond to ICI monotherapy, which may be explained by significant variations in efficacy according to different immune and molecular profiles in tumours. Improved response rates have been observed in smokers and are associated with tumors that have high mutation loads, with a higher tendency to form neoantigens. This premise itself defies the eventual significance of ICIs for oncogene-driven NSCLC, which in general are more common in never smokers and potentially have reduced capacity for neoantigen formation. Furthermore, pivotal trials investigating ICIs in advanced NSCLC have usually excluded patients with oncogenic drivers, hence the outcome of these agents in this population is poorly characterized. In this article, we aim to review the most current evidence, encompassing clinical and preclinical data focused on a wide range of oncogene-addicted NSCLCs.