No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is ...high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma.
We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review.
In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval CI, 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event.
Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).
The review will highlight recent advances in development of ALK-TKIs and management of patients with ALK-positive nonsmall cell lung cancer.
There has been rapid progress in the use of targeted ...therapies for ALK-positive NSCLC. Since the discovery, development and approval of crizotinib in 2011, three second-generation ALK-TKIs, ceritinib, alectinib and brigatinib have been approved by the FDA. A range of newer generation ALK inhibitors with improved potency against ALK and against mutations that confer resistance to crizotinib are in clinical development.
Our review will discuss the recent phase III data with ceritinib and alectinib as well as clinical trials with other ALK inhibitors. We will also address two important issues in the management of ALK-positive NSCLC, prevention and treatment of brain metastases and management of emergent ALK-TKI resistance mechanisms.
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.
Cutaneous squamous cell carcinomas (CSCC) are the second most diagnosed skin cancer worldwide, however, little is known about the pathobiological factors contributing to the diverse clinical outcomes ...observed.
To comprehensively profile CSCC and identify pathological processes contributing to the disparities in clinical behaviour observed.
We characterised the genomic, transcriptomic and immunohistochemical profiles of 206 CSCC tumours, including 37 CSCC from immunocompromised patients.
CSCC from immunocompromised patients are characterised by the lack of B cells in the peri-tumoural stromal compared to immunocompetent patients. Further, the abundance of a memory B cell-like population in the peritumoural stroma is associated with better prognosis in all patients (immunocompetent and immunocompromised) as well as only immunocompetent patients. No differences in genetic variants, tumour mutational burden or mutational signatures were observed between CSCC from immunocompetent and immunocompromised patients. Thus, differences in survival between CSCC from immunocompromised patients and immunocompetent patients are not likely to be driven by tumour genomic factors, but rather associated with differential host immune response. Non-head and neck primary site CSCC have lower tumour mutational burden and exhibit upregulation of the epithelial-mesenchymal transition programme compared to head and neck CSCC. Both factors are implicated with poorer responses to immune checkpoint inhibition, and the latter with poorer survival.
In summary, we identify tumour and host immune factors that contribute to the disparate clinical behaviour of CSCC with broad translational application including prognostication, treatment prediction to current therapies and identifying novel anti-cancer therapy approaches in CSCC.
BackgroundTo 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).MethodsPatients 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).ResultsMedian 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).ConclusionsThis 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 numberClinicalTrials.gov Registry (NCT02760498), https://clinicaltrialsgov/ct2/show/NCT02760498.
•Novel treatments are not always well understood by patients and their carers.•Identification of immunotherapy side-effects can be challenging for patients.•Videos can be an effective medium for ...providing health information.•Patient stories are powerful and relatable sources of information.•Experienced-based co-design is an effective method for developing resources.
Patients receiving novel treatments like immune checkpoint inhibitor therapy (ICI or immunotherapy) to treat their cancer require comprehensive information so they know what to expect and to encourage the identification and reporting of possible side-effects. Videos using patient stories can be reassuring and an effective method for conveying health information.
The objective of this study was to use a co-design process to develop video resources about immunotherapy to identify a) the key informational and supportive care needs of patients and family carers and b) topics clinicians recommended be addressed during pre-treatment nurse-led education.
Experience Based Co-design (EBCD) provided the framework for video development, to facilitate patient and carer involvement in every stage of research design and implementation, and video design and development.
Data were collected and used in four stages: 1) qualitative interviews, 2) co-design workshop, 3) filming plan and 4) feedback and editing.
Thirty-five individuals contributed to the development of a suite of five videos called “Immunotherapy: What to Expect”. Videos covered general treatment information, preparation for infusion, potential side-effects, balancing lifestyle with treatment and seeking support. Video run time ranges from 6 to 15 min.
The EBCD process ensured that videos were developed to meet patient and carer identified needs associated with commencing and managing ICI therapy. The structure of EBCD in facilitating patient and carer involvement throughout the research and video development process ensured transparency throughout the project, and continuity of message, scope and outcomes.
EBCD is a useful framework for developing patient-centred health resources. The videos developed are now available for patients and carers via YouTube, and provide education and support tailored to this groups’ needs regarding ICI therapy for cancer.
Non-melanomatous cutaneous spindle cell neoplasms are a rare group of malignancies that present a diagnostic challenge, and for which there is a lack of consensus on how to best manage patients with ...advanced disease and only limited reports of immune-checkpoint inhibitor (ICI) responses. In this study, we performed a single-center retrospective review of treatment outcomes for all advanced non-melanomatous cutaneous spindle cell neoplasms treated with ICIs. Blinded histopathology reviews occurred to confirm each diagnosis. Comprehensive tumour profiling included whole exome sequencing for tumour mutational burden (TMB) and ultraviolet(UV) signatures, and immunohistochemistry for immune-cell infiltration (CD4/CD3/CD8/CD103/CD20) and immune-checkpoint expression (PD-L1/LAG3/TIGIT). Seven patients were identified. The objective response rate was 86% (6/7) with five complete responses (CR). Responses were durable with two patients in CR > 30 months after ICI commencement. All patients had high TMB and UV signatures. One patient had PD-L1 100% (combined positive score) with abundant immune-cell infiltration and LAG3 expression. In advanced non-melanomatous cutaneous spindle cell neoplasms, excellent responses to ICIs with durable disease control were observed. ICIs are worthy of further exploration in these patients. UV signatures and high TMB could be used to help select patients for treatment.
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.
•Intratumoral CD20+ B cell abundance is prognostic for improved overall survival.•CD20+CD27+ Memory B cells are the predominant B cell subtype.•Intratumoral CD20+ and CD103+ immune cells ...prognostically stratify HPV + OPC patients.•B cell abundance has the potential to be used as a prognostic biomarker in HPV + OPC.•Adding CD20+ to CD103+ abundance may have utility in selecting low risk HPV + OPC.
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.
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.
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.
CD20+ B cell abundance has the potential to be used as a biomarker to identify good and poor prognosis HPV + OPC patients.
Globally, racial and ethnic disparities exist in treatments and outcomes for cancer patients. In Australia, there are few published data related to cancer patients from culturally and linguistically ...diverse (CALD) backgrounds.
To explore disparities in adjuvant chemotherapy utilisation in cancer patients from CALD groups.
Retrospective analysis of patients who were recommended adjuvant chemotherapy for early stage breast cancer or early stage colorectal cancer between July 2011 and October 2014 was performed. Rates of adjuvant chemotherapy uptake were analysed between those who identified English as their first-preferred language, versus those who did not, as well as between patients who were born in a country where English is the main language (non-CALD), versus those born in a country where English is not the main language (CALD).
Two hundred and eleven patients were identified. One hundred and forty-three (67.7%) patients had early stage breast cancer and 68 (32.2%) patients had early stage colorectal cancer. No difference was detected in the acceptance of adjuvant chemotherapy between non-CALD (80.9%) and CALD patients (81.3%, P = 0.984) or between patients who identified English as their first-preferred language (80.8%) and those who did not (81.8%, P = 0.870). There was no difference in the rate of chemotherapy completion, with 75.6% completion in the non-English-speaking group and 81.1% in the English-speaking group (P = 0.426).
No difference was observed in adjuvant chemotherapy utilisation in patients who identified English as their first-preferred language compared to those who did not, as well as between non-CALD and CALD groups. This is the first study to assess these differences in Australia.
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