Sir Peter MacCallum Department of Oncology - Research Publications
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ItemReal-World Experience of Immune-Checkpoint Inhibitors in Older Patients with Advanced Cutaneous Squamous Cell Carcinoma(ADIS INT LTD, 2024-03)BACKGROUND: Older patients are often underrepresented in clinical trials owing to exclusionary comorbidities, which are more common with age. Chemotherapy is poorly tolerated in older comorbid advanced cutaneous squamous cell carcinoma (CSCC) patients; however, little is known on the efficacy and tolerability of immune-checkpoint inhibitors (ICIs) in this population. To our knowledge, this is the largest dedicated report on a cohort of older patients with advanced CSCC treated with immunotherapy to date. OBJECTIVE: The aim was to report outcomes of ICI use in a real-world older cohort with advanced CSCC. PATIENTS AND METHODS: A single-centre retrospective audit of all patients treated via an access scheme providing ICIs to patients with advanced CSCC was conducted. Participants were ≥ 70 years of age and had advanced CSCC not amenable to curative surgery or radiotherapy. Best overall response rate (ORR), 12-month overall survival (OS) and progression-free survival (PFS), and toxicity rates were assessed. RESULTS: A total of 53 patients were analysed. The median age was 81.8 years (range 70.1-96.8); 81% were male; 34% were immunocompromised; and 34% had an Eastern Cooperative Oncology Group (ECOG) performance status score of ≥ 2. The ORR was 57%, and 12-month OS and PFS were 63% (95% confidence interval [CI] 44-78) and 41% (95% CI 25-57), respectively. Thirty-two per cent developed an immune-related adverse event (irAE), but only two patients experienced a grade 3 irAE, with no treatment-related deaths. Higher ECOG score was associated with worse OS and PFS. No significant association was identified for increasing age, sex, Charlson Comorbidity Index score, or immunocompromised status. CONCLUSIONS: ICIs have demonstrated efficacy and have an acceptable safety profile among older patients with advanced CSCC, with comparable efficacy to what has been demonstrated in current clinical trials.
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ItemNo Preview AvailableCharacterising B cell expression and prognostic significance in human papillomavirus positive oropharyngeal cancer(ELSEVIER, 2024-03)OBJECTIVES: The incidence of human papillomavirus positive oropharyngeal cancer (HPV+OPC) is increasing, and new biomarkers are required to better define prognostic groups and guide treatment. Infiltrating T cells have been well studied in head and neck cancer, however the presence and role of B cells and tertiary lymphoid structures (TLS) in the tumor microenvironment has not, even though the interplay between T and B cells is increasingly being recognised. MATERIALS AND METHODS: Using CD20 immunohistochemistry (IHC) to identify B cells and TLS in a cohort of 159 HPV + OPC patients, we semi-quantitatively scored abundance and location (intra-tumoral or stromal) and correlated findings with patient survival. RESULTS: 32% (51/157) of patients had high intra-tumoral (IT) abundance of CD20+ B cells (≥5%) and this was prognostic for improved overall survival (OS) with an adjusted hazard ratio (HR) of 0.2 (95 % CI 0.0-0.7, p = 0.014). We validated our results in an independent cohort comprising 171 HPV + OPC where 14% (23/171) were IT CD20+ high, again showing improved survival with an adjusted HR for OS of 0.2 (95 % CI 0.0-1.4, p = 0.003). Neither stromal abundance nor the presence of TLS were prognostic in either cohort. B cells were subtyped by multispectral IHC, identifying CD20+CD27+ cells, consistent with memory B cells, as the predominant subtype. Combined with validated biomarker CD103, a marker of tissue-resident memory T cells, IT CD20+ B cells abundance was able to prognostically stratify patients further. CONCLUSIONS: CD20+ B cell abundance has the potential to be used as a biomarker to identify good and poor prognosis HPV + OPC patients.
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ItemNo Preview AvailableThe Current Treatment Landscape of Cutaneous Squamous Cell Carcinoma(ADIS INT LTD, 2023-01-01)Non-melanoma skin cancers (NMSCs) are the most common form of skin cancer worldwide. The global incidence of cutaneous squamous cell carcinoma (CSCC) is rising, with an estimated 2.4 million cases diagnosed in 2019. Chronic exposure to ultraviolet (UV) radiation is a major risk factor for developing CSCC. Most early-stage CSCCs are treated successfully with surgery or radiotherapy; however, locally advanced or metastatic disease can be associated with significant morbidity or mortality. Recently, the treatment paradigm for advanced CSCC has been revolutionised by the introduction of immunotherapy, which can achieve a response rate of approximately 50% with durable cancer control, and significant improvement in quality of life. With the regulatory approval of programmed death-1 (PD-1)-targeting drugs since 2018, immunotherapy is now recognised as the standard of care for first-line systemic therapy in advanced or metastatic CSCC.
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ItemImmunotherapy to Avoid Orbital Exenteration in Patients With Cutaneous Squamous Cell Carcinoma(FRONTIERS MEDIA SA, 2022-01-18)BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) of the head and neck can require complex and disfiguring surgery in order to achieve cure, which can be morbid and negatively impact patient quality of life. The management of advanced CSCC has been revolutionized by immunotherapy with current clinical trials also exploring its role in the neoadjuvant and adjuvant settings. Patients may decline morbid curative surgery, such as orbital exenteration, and the outcomes of immunotherapy use in this unique group of patients require further investigation. METHODS: We reviewed the records of 119 patients treated at a major Australian quaternary oncology centre with immunotherapy (either cemiplimab or pembrolizumab) for advanced CSCC. RESULTS: We identified 7 patients recommended curative surgery involving orbital exenteration after multidisciplinary discussion, who declined surgery due to concerns about morbidity and/or disfigurement. All 7 patients demonstrated a response to treatment, and six avoided orbital exenteration. Two patients experienced pseudoprogression. CONCLUSIONS: The management of CSCC can be complex and requires the input of a multidisciplinary team. Immunotherapy to avoid or reduce the extent of morbid definitive surgery is an emerging treatment option.
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ItemFDG-PET/CT imaging for evaluating durable responses to immune check point inhibitors in patients with advanced cutaneous squamous cell carcinoma(BMC, 2021-10-13)BACKGROUND: The role of FDG-PET/CT imaging in assessing response to immunotherapy in advanced cutaneous squamous cell carcinoma (CSCC) is unknown. This study compared complete metabolic response (CMR) rates by FDG-PET and RECIST1.1 via CT or MRI in patients on cemiplimab for > 10 months. METHODS: This was a single-centre retrospective study of 15 patients treated with cemiplimab for advanced CSCC who had CT/MRI and FDG-PET/CT at > 10 months to assess metabolic treatment response. The median age was 73 years (range 55-84) and 93% were male. RECIST1.1 and PERCIST1.0 tumor responses were evaluated by blinded readers. RESULTS: Seventy-three percent (11/15) (95%CI 44.9, 92.2%) achieved a CMR on PET. Of these 11, on RECIST1.1 there was one complete response, 9 partial responses and one stable disease. CONCLUSIONS: In patients on cemiplimab for > 10 months, there was discordance between CR rates on FDG-PET versus RECIST1.1. FDG-PET/CT may have utility for clarifying depth of response in patients treated with immunotherapy for CSCC.
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ItemBiology and Treatment Advances in Cutaneous Squamous Cell Carcinoma(MDPI, 2021-11)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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ItemIntegrated analysis of a phase 2 study of cemiplimab in advanced cutaneous squamous cell carcinoma: extended follow-up of outcomes and quality of life analysis(BMJ PUBLISHING GROUP, 2021)BACKGROUND: To provide pooled longer term data from three groups of a phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), and to determine duration of response (DOR) and impact on quality of life (QoL). METHODS: Patients received cemiplimab 3 mg/kg every 2 weeks (group 1, metastatic CSCC [mCSCC], n=59; group 2, locally advanced CSCC, n=78) or cemiplimab 350 mg every 3 weeks (group 3, mCSCC, n=56). Primary endpoint was objective response rate (ORR) per independent central review (ICR). QoL was repeatedly measured at day 1 of each treatment cycle (groups 1 and 2: 8 weeks; group 3: 9 weeks). RESULTS: Median duration of follow-up was 15.7 months. Overall, ORR per ICR was 46.1% (95% CI: 38.9% to 53.4%). Complete response (CR) rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3, respectively. Median time to CR was 11.2 months. Among patients with partial response or CR, the estimated proportion of patients with ongoing response at 12 months from the first objective response was 87.8% (95% CI: 78.5% to 93.3%), with median DOR not reached. Kaplan-Meier estimated probability of overall survival (OS) was 73.3% (95% CI: 66.1% to 79.2%) at 24 months, with median OS not reached. Global Health Status (GHS)/QoL improvements were observed as early as cycle 2 and were significantly improved and durable until last assessment. Kaplan-Meier estimate of median time to first clinically meaningful improvement for pain was 2.1 (95% CI: 2.0 to 3.7) months and was significantly improved in responders versus non-responders (p<0.0001). CONCLUSIONS: This is the largest (n=193) clinical dataset for a programmed cell death-1 inhibitor against advanced CSCC, confirming the sustained substantial clinical activity of cemiplimab in these patients, including new findings of improved CR rates over time, increasing DOR, and durable pain control and GHS/QoL improvement. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02760498), https://clinicaltrialsgov/ct2/show/NCT02760498.
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ItemDelayed Response After Confirmed Progression (DR) and Other Unique Immunotherapy-Related Treatment Concepts in Cutaneous Squamous Cell Carcinoma(FRONTIERS MEDIA SA, 2021-04-15)Non-melanoma skin cancers are one of the most common cancers diagnosed worldwide, with the highest incidence in Australia and New Zealand. Systemic treatment of locally advanced and metastatic cutaneous squamous cell carcinomas has been revolutionized by immune checkpoint inhibition with PD-1 blockade. We highlight treatment issues distinct to the management of the disease including expansion of the traditional concept of pseudoprogression and describe delayed responses after immune-specific response criteria confirmed progressive disease with and without clinical deterioration. We term this phenomenon "delayed response after confirmed progression (DR)". We also discuss the common development of second primary tumors, heterogeneous disease responses, and expanding clinical boundaries for immunotherapy use.
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ItemPhase 2 study of cemiplimab in patients with metastatic cutaneous squamous cell carcinoma: primary analysis of fixed-dosing, long-term outcome of weight-based dosing(BMJ PUBLISHING GROUP, 2020)BACKGROUND: Cemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort (NCT02383212) and the pivotal Phase 2 study (NCT02760498). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study (NCT02760498). METHODS: The primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability. RESULTS: For Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan-Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%). CONCLUSION: In patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, NCT02760498. Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498.