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First-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC.This open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety.A total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6-19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6-18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67-1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5-8.5) and 3.2 months (95% CI: 2.7-5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52-0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04-2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS.The addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.

Objectives: Attaining tumour material from lung cancer patients can be challenging with limited sample availability. Therefore, non-invasive means of assessing tumour material is becoming increasingly more important. Circulating tumour DNA (ctDNA), extracted from a blood sample is appealing for the patient, and can be performed serially over the course of treatment. Materials and Methods: Here, we describe an approach for profiling the blood samples of 103 NSCLC patients for 73 variants in ctDNA across a panel of actionable lung cancer mutations using the UltraSEEK lung Panel (Agena Biosciences). Results: Our cross-sectional study showed tumour and blood concordance in the detection of KRAS mutations (G12C, G12D, G12A/V, G12R, G12RC, Q61H) in 17/27 (63%), EGFR mutations (e746_a750del, e747_A750, T790M, L861Q) in 16/20 (80%) with additional PIK3CA_p545K mutations across both cohorts. In patients without reported tumour mutations, 11/56 (19.6%) presented with plasma mutations across EGFR, KRAS and PIK3CA. Where ctDNA mutations were measured longitudinally (n = 4 patients), the individual mutations mirrored the response to therapy/progression of disease. Conclusion: Whilst preliminary, this study demonstrates the utility of detecting clinically actionable mutations in the blood samples of NSCLC patients at the time of presentation, and over the course of therapy.

Introduction Pembrolizumab provided durable responses and acceptable safety in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC) in the KEYNOTE-629 study. In this elderly, fragile population with disfiguring tumours, preservation of health-related quality of life (HRQoL) is critical. Here, we present pre-specified exploratory HRQoL analyses from the first interim analysis of KEYNOTE-629. Methods Patients with R/M cSCC not amenable to surgery or radiation therapy received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. HRQoL end points included change from baseline to week 12 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status (GHS)/QoL, functioning, symptom and European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) scores and change from baseline through week 48 in EORTC QLQ-C30 GHS/QoL and physical functioning scores. Improvement (≥ 10-point increase post-baseline with confirmation) was assessed using the exact binomial method. Results Analyses included 99 patients for EORTC QLQ-C30 and 100 for EQ-5D-5L. Compliance was > 80% at week 12. Mean scores were stable from baseline to week 12 for GHS/QoL (4.95 points; 95% confidence interval, −1.00 to 10.90) and physical functioning (−3.38 points; 95% confidence interval, −8.80 to 2.04). EORTC-QLQ-C30 functioning, symptom, and EQ-5D-5L scores remained stable at week 12. Post-baseline scores were improved in 29.3% of patients for GHS/QoL, 17.2% for physical functioning, and in a numerically higher proportion of responders versus non-responders (GHS/QoL, 55.6% versus 16.1%; physical functioning, 36.1% versus 7.1%). Conclusions In elderly patients with R/M cSCC, the clinical efficacy of pembrolizumab translates into a benefit validated by HRQoL preservation or improvement during treatment. Trial Registration ClinicalTrials.gov identifier: NCT03284424. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-021-00598-6., Plain Language Summary Cutaneous squamous cell carcinoma (cSCC) is the second most common type of non-melanoma skin cancer. cSCC is usually caused by cumulative exposure to sunlight and often occurs in exposed parts of the body such as the head and neck. cSCC is most often seen in older people. If cSCC is detected early, it can be removed by surgery; however, if left untreated, the cancer can spread throughout the body and cause death. The disease itself and its treatment can be painful, cause scarring, or change the patient’s physical appearance. Hence, people with cSCC often have poor quality of life. It is therefore important to develop new drugs to help patients with cSCC live longer without worsening their quality of life. The phase 2 KEYNOTE-629 study investigated how well the drug pembrolizumab treated cSCC and whether it was safe. KEYNOTE-629 included patients who were mostly older and had advanced cSCC. The results showed that pembrolizumab was effective and safe. Here, we investigated how pembrolizumab affected the quality of life of these patients. To do this, we asked patients to answer questionnaires on important aspects of their experience, such as their general health status, physical functioning, emotional wellbeing, and symptoms. We found that patients who were treated with pembrolizumab had stable quality of life during treatment. Furthermore, patients whose cancer responded well to pembrolizumab were more likely to have an improved quality of life. These results support the use of pembrolizumab in patients with advanced cSCC. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-021-00598-6.

Background Patients with unresectable advanced cutaneous squamous cell carcinoma (cSCC) are generally treated with palliative intent. Immune checkpoint blockade has significant activity in the palliative setting in patients with recurrent or metastatic cSCC. This single arm phase 2 prospective study aims to investigate the combination of curative intent chemoradiation and durvalumab (anti-PD-L1 checkpoint inhibitor) for this patient cohort. Methods Patients with unresectable locally and or regionally advanced pathologically confirmed cSCC (stage III-IVa) deemed fit for CRIO by consensus of the Multidisciplinary meeting will be eligible. In the first stage of a two-stage minimax design, we aim to recruit a total of 15 patients. If fewer than 7 patients achieved a complete response in the first stage, we will conclude the treatment is not more effective than standard treatment. The co-primary endpoints of CRIO are the safety of treatment (acute and late toxicities) and the rate of complete response. Secondary endpoints would include overall survival, progression free survival, and locoregional control. Translational research endpoints including biomarkers (CD73, CD39, PD-1, PD-L1) will also be explored utilising multiplex immunohistochemistry on tumour biopsy samples obtained prior to commencing treatment and during treatment (week 2). In addition, the utility of CXCR-4 PET/CT scan will be explored. Discussion CRIO is a novel trial evaluating the combination of curative intent chemoradiotherapy with concurrent and adjuvant durvalumab for patients with unresectable stage III-IVa cSCC. Trial registration: Trial registered with the Australian New Zealand Clinical Trial Registry (ACTRN12618001573246)

Summary Background There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma. Methods DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415. Findings Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5–30·2). 31 (57%; 95% CI 44–70) of 54 patients were alive and progression-free at 6 months. The most common grade 3–4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment. Interpretation The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial. Funding AstraZeneca.

Given that oropharyngeal squamous cell carcinoma (OPSCC) have now surpassed cervical cancer as the most common human papillomavirus (HPV)‐driven cancer, there is an interest in developing non‐invasive predictive biomarkers to early detect HPV‐driven OPSCC. In total, 665 cancer‐free individuals were recruited from Queensland, Australia. Oral HPV16 DNA positivity in those individuals was determined by our in‐house developed sensitive PCR method. Individuals with (n = 9) or without (n = 12) oral HPV16 infections at baseline were followed for a median duration of 24 mo. Individuals with persistent oral HPV16 infection (≥ 30 mo) were invited for clinical examination of their oral cavity and oropharynx by an otolaryngologist. Oral HPV16 DNA was detected in 12 out of 650 cancer‐free individuals (1.8%; 95% confidence interval [CI]: 1.0‐3.2). Of the 3 individuals with persistent oral HPV16 infection, the first individual showed no clinical evidence of pathology. The second individual was diagnosed with a 2 mm invasive squamous cell carcinoma (T1N0M0) positive for both p16INK4a expression and HPV16 DNA. The third individual was found to have a mildly dysplastic lesion in the tonsillar region that was negative for p16INK4a expression and HPV16 DNA and she continues to have HPV16 DNA in her saliva. Taken together, our data support the value of using an oral HPV16 DNA assay as a potential screening tool for the detection of microscopic HPV‐driven OPSCC. Larger multicenter studies across various geographic regions recruiting populations at a higher risk of developing HPV‐driven OPSCC are warranted to extend and confirm the results of the current investigation., 1. This study gives unique insights into the use of serial saliva sampling to detect human papillomavirus as a screening tool.2. The serial measurements of HPV16 viral load in oral rinse samples can identify individuals at risk of developing oropharyngeal lesions.

Background: Activity-based funding (ABF) is a means of healthcare reimbursement, where hospitals are allocated funding based on the number and mix of clinical activity. The ABF model is based solely on Australian refined diagnosis-related group (AR-DRG) classifications of hospital encounters. Each AR-DRG is allocated a weighted activity unit (WAU) translating to cost value to determine ongoing funding allocations for each hospital annually. Aim: We explored cost consequences of AR-DRG coding variances within our Medical Oncology department over a 6-month period. Methods: All inpatient encounters for medical oncology from 1 January to 30 June 2014 were identified and paired with actual AR-DRG coding sheets submitted by the hospital coders. Inpatient charts were manually reviewed by a Medical Oncology Registrar to capture any changes or additional AR-DRGs, which were subsequently evaluated for total WAU value variance. Applying 1 WAU = $4676 as per the 2014 Queensland model, cost consequences were calculated. Results: A total of 116 encounters was identified for 72 patients. Of 116 patients, 95 (81%) had additional diagnoses captured, leading to an AR-DRG and WAU change in 26 encounters. The total reimbursement variance for this period was $143 404.07. Cost consequences resulted from: (i) use of abbreviations in clinical notes unable to be coded; and (ii) diagnoses not documented despite treatment delivered as per medication charts. Conclusion: Clinical note documentation ultimately determines the future funding of our healthcare system. Appropriate communication and education of medical staff and hospital coders are vital to ensure precise documentation and accurate AR-DRG coding for optimal and appropriate reimbursement in this funding model.

Background Neoadjuvant immunotherapy targeting immune checkpoint programmed death-1 (PD-1) is under investigation in various tumour settings including non-small-cell lung cancer (NSCLC). Preclinical models demonstrate the superior power of the immunotherapy provided in a neoadjuvant (pre-operative) compared with an adjuvant (post-operative) setting to eradicate metastatic disease and induce long-lasting antigen-specific immunity. Novel effective immunotherapy combinations are widely sought in the oncology field, targeting non-redundant mechanisms of immune evasion. A promising combination partner with anti-PD1 in NSCLC is denosumab, a monoclonal antibody blocking receptor activator of NF-κB ligand (RANKL). In preclinical cancer models and in a large retrospective case series in NSCLC, anti-cancer activity has been reported for the combination of immune checkpoint inhibition (ICI) and denosumab. Furthermore, clinical trials of ICI and denosumab are underway in advanced melanoma and clear-cell renal cell carcinoma. However, the mechanism of action of combination anti-PD1 and anti-RANKL is poorly defined. Methods This open-label multicentre trial will randomise by minimisation 30 patients with resectable stage IA (primary > 2 cm) to IIIA NSCLC to a neoadjuvant treatment regime of either two doses of nivolumab (3 mg/kg every 2 weeks) or two doses of nivolumab (same regimen) plus denosumab (120 mg every 2 weeks, following nivolumab). Each treatment arm is of equal size and will be approximately balanced with respect to histology (squamous vs. non-squamous) and clinical stage (I-II vs. IIIA). All patients will receive surgery for their tumour 2 weeks after the final dose of neoadjuvant therapy. The primary outcome will be translational research to define the tumour-immune correlates of combination therapy compared with monotherapy. Key secondary outcomes will include a comparison of rates of the following between each arm: toxicity, response (pathological and radiological), and microscopically complete resection. Discussion The POPCORN study provides a unique platform for translational research to determine the mechanism of action of a novel proposed combination immunotherapy for cancer. Trial registration Prospectively registered on Australian New Zealand Clinical Trials Registry (ACTRN12618001121257) on 06/07/2018.

AIMS Weight loss and malnutrition occur frequently in patients with head and neck cancer and are associated with reduced survival. This pragmatic study aimed to determine the effect of a novel pre-treatment model of nutrition care on nutrition outcomes for patients with head and neck cancer receiving chemoradiotherapy. METHODS This health service evaluation consisted of an evaluation of the new model of care implementation (Phase 1) and an evaluation of patient outcomes (Phase 2) in pre- and post-implementation cohorts (n = 64 and n = 47, respectively). All Phase 2 patients received a prophylactic gastrostomy. The new model of care consisted of dietary counselling and commencement of proactive supplementary enteral nutrition via a prophylactic gastrostomy, in addition to normal oral intake, prior to treatment commencement. Nutrition outcomes were collected at baseline (pre-treatment) and 3 months post-radiotherapy completion. RESULTS The new model of care was successfully incorporated into practice with high referral (96.5%) and attendance (91.5%) rates to the counselling session, and high adherence rates to proactive tube feeding (80.9%). Patients in the post-implementation cohort had less weight-loss (1.2%; p = 0.338) and saw less of a decline in nutritional status compared to patients in the pre-implementation cohort (23% vs. 30%, respectively; p = 0.572), deemed clinically important. However, patients still experienced critical weight loss overall (mean 9.9%). CONCLUSION Pre-treatment nutrition care was feasible in standard clinical practice and demonstrated clinically relevant outcome improvements for patients. Future high-quality research is warranted to investigate further multidisciplinary strategies to attenuate weight-loss further, inclusive of patient-reported barriers and enablers to nutrition interventions.

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 (pConclusionsThis 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.

Background Lenvatinib is a multikinase inhibitor approved to treat radioiodine-refractory differentiated thyroid cancer (RR-DTC) at a starting dose of 24 mg/day. This study explored, in a double-blinded fashion, whether a starting dose of 18 mg/day would provide comparable efficacy with reduced toxicity. Methods Patients with RR-DTC were randomized to lenvatinib 24 mg/day or 18 mg/day. The primary efficacy endpoint was objective response rate as of week 24 (ORRwk24); the odds ratio noninferiority margin was 0.4. The primary safety endpoint was frequency of grade ≥3 treatment-emergent adverse events (TEAEs) as of week 24. Tumors were assessed using RECIST v1.1. TEAEs were monitored and recorded. Results The ORRwk24 was 57.3% (95% CI 46.1, 68.5) in the lenvatinib 24-mg arm and 40.3% (95% CI 29.3, 51.2) in the lenvatinib 18-mg arm, with an odds ratio (18/24 mg) of 0.50 (95% CI 0.26, 0.96). As of week 24, the rates of TEAEs grade ≥3 were 61.3% in the lenvatinib 24-mg arm and 57.1% in the lenvatinib 18-mg arm, a difference of −4.2% (95% CI −19.8, 11.4). Conclusion A starting dose of lenvatinib 18 mg/day did not demonstrate noninferiority compared to a starting dose of 24 mg/day as assessed by ORRwk24 in patients with RR-DTC. The results represent a clinically meaningful difference in ORRwk24. The safety profile was comparable, with no clinically relevant difference between arms. These results support the continued use of the approved starting dose of lenvatinib 24 mg/day in patients with RR-DTC and adjusting the dose as necessary.

Background: Studies suggest that combining radiotherapy (RT) with programmed cell death protein 1 (PD-1) blockade may elicit a synergistic antitumor response. We aimed to assess whether prior or concurrent RT was associated with improved disease control in patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab. Methods: We conducted a retrospective study of patients receiving nivolumab as second or subsequent line therapy for metastatic NSCLC. Patients were categorized into those who received any RT for NSCLC prior to or during nivolumab therapy, and those with no history of RT for NSCLC. Results: A total of 85 patients received nivolumab between July 2015 and December 2016 and were followed up for a median of 15 months. Sixty-five patients (76.4%) received RT prior to or during nivolumab and 20 patients (23.6%) received nivolumab alone. Baseline characteristics of age, performance status, histology, smoking status and previous therapy were similar between the two groups. Prior or concurrent RT was associated with a superior PFS, median 2.8 months with RT versus 1.3 months without RT (Hazard Ratio (HR) = 0.494; 95% Confidence Interval (CI), 0.279-0.873; P = 0.02). The median OS of the group receiving RT was 6.4 months versus 4.2 months for the no RT group (P = 0.20). RT was not associated with an increase in toxicity. Conclusion: RT prior to or concurrent with nivolumab for metastatic NSCLC was associated with a modest improvement in PFS over nivolumab alone with no evidence of increase in adverse effects. RT may potentiate the effect of anti-PD-1 immunotherapy in NSCLC.

There are no evidence-based guidelines informing which patients with head and neck cancer (HNC) require regular speech pathology (SP) support during radiation treatment (RT). Hence, some services use a “one-size-fits-all” model, potentially over-servicing those patients at low risk for dysphagia. This study evaluated the clinical safety and efficiency of an interdisciplinary service model for patients identified prospectively as “low risk” for dysphagia during RT. A prospective cohort of 65 patients with HNCs of the skin, thyroid, parotid, nose, and salivary glands, receiving curative RT, were managed on a low-risk pathway. Patients with baseline dysphagia (functional oral intake score ≤ 5) were excluded. The model involved dietitians conducting dysphagia screening at weeks 3, 5, and 6/7 within scheduled appointments. Patients at risk of dysphagia were referred to SP for assessment, then management if required. To validate the model, SP assessed swallow status/toxicities at week 5/6/7 during RT and confirmed dysphagia status at weeks 2 and 6 post RT. Most (89.3%) patients did not require dysphagia support from SP services. Of the 18 patients identified on screening, only 7 (10.7%) had sufficient issues to return to SP care. Week 5/6/7 SP review confirmed low levels of toxicity. No post-treatment dysphagia was observed. There was an incremental benefit of A$15.02 for SP staff costs and a recovery of 5.31 appointments per patient. The pathway is a safe and effective service model to manage patients with HNC at low risk for dysphagia during RT, avoiding unnecessary SP appointments for the patient and service.

PURPOSE Travel for patients with cancer has become more achievable because of gains in quality of life and overall survival. The risk assessment of these patients is complex, and there is a paucity of data to which clinicians can refer. We present the challenges of traveling with cancer and a review of the literature. METHODS A review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. A search using the terms ”cancer,” “advanced cancer,” ”metastases,” “brain edema,” “lymphoedema,” “pneumothorax,” ”pleural effusion,” “pericardial effusion,” pneumonitis,” “hypoxia,” “end-of-life,” and “shunt,” combined with “flying” and “air travel,” was conducted. The PubMed and Cochrane databases were searched for English-language studies up to December 2018. Studies, case reports, or guidelines referring to travel in the context of adult patients with malignancies were included. A total of 745 published articles were identified; 16 studies were included. An inclusive approach to data extraction was used. RESULTS There were no specific criteria to deem a patient with cancer fit to travel. Neurologic, respiratory, and cardiac implications, and time from recent surgery or procedure need to be considered There was a lack of high-quality studies to inform decisions, but the British Thoracic Society and Aerospace Medical Association Medical Guidelines included recommendations for fitness to fly for patients with cancer. CONCLUSION In the absence of large prospective studies, individual fitness to travel should be assessed on a case-by-case basis, bearing in mind that maximizing a patient’s ability to safely travel is an important goal for many individuals with cancer.

Stage III non-small cell lung cancer (NSCLC) makes up a third of all NSCLC cases and is potentially curable. Despite this 5-year survival rates remain between 15% and 20% with chemoradiation treatment alone given with curative intent. With the recent exciting breakthroughs in immunotherapy use (durvalumab) for stage III NSCLC, further improvements in patient survival can be expected. Most patients with stage III NSCLC present initially to their general practitioner (GP). The recommended time from GP referral to first specialist appointment is less than 14 days with treatment initiated within 42 days. Our review found that there is a shortfall in meeting these recommendations, however a number of initiatives have been established in Australia to improve timely and accurate diagnosis and treatment patterns. The lung cancer multidisciplinary team (MDT) is critical to consistency of evidence-based diagnosis and treatment and can improve patient survival. We aimed to review current patterns of care and clinical practice recommendations for stage III NSCLC across Australia and identify opportunities to improve practice in referral, diagnosis and treatment pathways.

TPS8599 Background: Combination PD1/CTLA4 immune checkpoint blockade and platinum-pemetrexed (CP) chemotherapy are standard first-line options for the treatment of unresectable malignant pleural mesothelioma (MPM). Two recent, single-arm, phase 2 trials (DREAM and PrE0505) combining the PD-L1 inhibitor durvalumab and standard first line CP both exceeded pre-specified efficacy criteria. The Phase 3 DREAM3R trial aims to determine the effectiveness of including durvalumab with first line CP chemotherapy in advanced MPM. Methods: Treatment-naïve patients with advanced MPM will be randomized (2:1) to either durvalumab 1500 mg every 3 weeks plus chemotherapy (cisplatin 75 mg/m2 or carboplatin AUC 5 and pemetrexed 500 mg/m2) every 3 weeks for 4-6 cycles (Arm A), followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal, versus doublet chemotherapy alone for 4-6 cycles with all patients monitored for progression. The target sample size is 480 patients recruited over 27 months, with follow up for an additional 24 months. This provides over 85% power if the true hazard ratio for overall survival (OS) is 0.70, with 2-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Key eligibility criteria include: MPM of any histological subtype; measurable disease per RECIST 1.1 modified for mesothelioma (mRECIST 1.1); ECOG PS 0-1; and adequate hematologic, renal, and liver function. Exclusions: Prior systemic anticancer treatment for MPM, diagnosis based solely on cytology or fine needle aspiration biopsy, contraindication to immunotherapy or conditions requiring immunosuppressive agents or corticosteroids. Patients will be further stratified at randomization by: Age (18-70 years vs. > 70), sex, histology (epithelioid vs. non-epithelioid), planned platinum (cisplatin vs. carboplatin) and geographic region (USA vs. ANZ). The primary endpoint is OS. Secondary endpoints include progression-free survival; objective tumor response; adverse events; health-related quality of life; and healthcare resource use in ANZ. Tertiary correlative objectives aim to further explore and validate potential prognostic and/or predictive biomarkers (including those identified in the DREAM and PrE0505 studies, PD-L1 expression, tumor mutation burden, genomic characteristics, and HLA subtypes) via tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. The study is active and enrolling in both ANZ and in the US. Clinical trial information: NCT04334759 and ACTRN 12620001199909.

Background Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). Patients and methods KEYNOTE-629 was a global, open-label, nonrandomized, phase II trial of patients with locally advanced (LA) or R/M cSCC conducted at 59 centers. Eligible patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR), by blinded independent central review as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included duration of response (DOR), disease control rate, progression-free survival, overall survival, and safety and tolerability. Efficacy and safety were analyzed in patients who were treated with at least one dose of pembrolizumab. Results Between 29 November 2017 and 25 September 2019, 159 patients were enrolled and treated with pembrolizumab (LA cohort, n = 54; R/M cohort, n = 105). The median time from the first dose to data cut-off date (29 July 2020) was 14.9 [interquartile range (IQR), 12.6-17.2] months for the LA cohort and 27.2 (IQR, 25.6-29.2) months for the R/M cohort. In the LA cohort, ORR was 50.0% [95% confidence interval (CI), 36.1% to 63.9%], including 16.7% of patients with a CR and 33.3% with a PR. In the R/M cohort, ORR was 35.2% (95% CI, 26.2% to 45.2%), including 10.5% of patients with a CR and 24.8% with a PR. Median DOR was not reached in either cohort. Grade 3-5 treatment-related adverse events occurred in 11.9% of patients. Conclusions The robust antitumor activity of pembrolizumab in both LA and R/M cSCC was confirmed and demonstrated to be durable without unexpected safety signals. Our findings establish pembrolizumab as a promising treatment option for cSCC.

IntroductionSars-CoV-2 is a novel coronavirus responsible for COVID-19 officially declared pandemic in March 2020. Health systems worldwide responded with swift changes to increase workflow capacity while protecting the vulnerable, including those with cancer. This led to unprecedented and rapid restructuring of health service provision. Published data from the 2003 SARS pandemic focuses on medical and nursing staff, overlooking other departmental employees such as administration officers or food service workers. Our protocol aims to document directives and adjustments communicated to staff in two cancer care departments and correlate this with measures of distress and perceived preparedness across the spectrum of all staff involved in cancer care.Methods and analysisWe use a semiqualitative approach comprising weekly diarising of events and simultaneous staff surveys. Principal investigators will document changes at a metropolitan quaternary cancer centre and a regional cancer centre. Communications, directives and changes will be diarised in real time in four executional domains. Simultaneously, prospective voluntary self-administered online surveys will be conducted at regular intervals by staff. The survey assesses the perceived institutional preparedness and personal well-being, with a combination of Likert scaled and open response questions. A semiquantitative self-assessment of distress adapted from National Comprehensive Cancer Network distress thermometer is incorporated. Additionally, open-text personal reflections on themes including difficult decisions will be invited. Survey participants will be drawn from various work areas of the cancer care departments: administrative staff, health professionals, for example, allied health, ancillary workers, nursing and medical.Ethics and disseminationThe study has been reviewed and approved by the Human Research Ethics Committee (LNR/2020/QRBW/62982). Published literature on domains of distress neglects categories of healthcare worker who form an essential part of the care delivery team. Our study hopes to gather insights about psychosocial impact and adjustment which could direct responses in future emergencies.

Background Epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20-ins) mutations are an uncommon and heterogeneous group of non–small cell lung cancers (NSCLCs), resistant to conventional EGFR tyrosine kinase inhibitors (TKIs). Characteristics and outcomes of patients with EGFR ex20-ins have not been fully established; we sought to clarify them using a multinational patient database. Patients and Methods Patients with NSCLC from six Australian institutions with EGFR exon 20 mutations (ex20-mut), excluding T790M, were retrospectively reviewed. Clinical characteristics and outcomes with systemic treatments were collected and analyzed using comparative statistics. Results Among 109 patients with ex20-mut, 61% were females and 75% were Caucasians. More males presented with de novo metastatic disease (84% vs. 51%; P = .002). Central nervous system (48%) and liver (24%) metastases were common within metastatic patients (n = 86). Thirty-nine patients received platinum-based chemotherapy (PBC) and achieved a 43% objective response rate (ORR), median progression-free survival (mPFS) of 6.9 months, and median overall survival (mOS) of 31.0 months. Twenty-three of the patients with ex20-ins received conventional TKIs, resulting in an ORR of 13%, mPFS of 3.4 months (95% confidence interval [CI], 1.91-6.25), and mOS of 31.0 months (95% CI, 15.09-not reached). Nine patients with S786I mutations received TKIs, resulting in an ORR of 50%, mPFS of 18.2 months (2.79-not reached), and mOS of 33.4 months (95% CI, 16.14-not reached). Twenty-three patients received immune checkpoint inhibitor monotherapy (ICIm), resulting in an ORR of 4%, mPFS of 2.6 months (95% CI, 1.91-4.83), and mOS of 30.8 months (95% CI, 17.62-41.62). Conclusion Although phenotypically similar to patients with common EGFR mutations, patients with EGFR ex20-mut had worse survival, perhaps due to the lack of targeted therapies. Chemotherapy was superior to conventional EGFR TKIs in patients with EGFR ex20-ins, although there was moderate activity of TKIs in S768I mutations. ICIm was ineffective.

Purpose The excellent prognosis of patients with low-risk human papillomavirus (HPV)- associated oropharyngeal squamous cell carcinoma has led to concerns about overtreatment and excessive toxicity with radiation therapy and cisplatin, leading to interest in de-intensification trials. We investigated whether cetuximab, an epidermal growth factor receptor targeting antibody, when combined with radiation therapy would result in a decrease in symptom burden and toxicity with similar efficacy compared with weekly cisplatin. Methods and Materials TROG12.01, a randomized, multicenter trial involving 15 sites in Australia and New Zealand enrolled patients with HPV-associated oropharyngeal squamous cell carcinoma, American Joint Committee on Cancer 7th edition stage III (excluding T1-2N1) or stage IV (excluding T4 and/or N3 and/or N2b-c if smoking history >10 pack years and/or distant metastases). Patients were randomized (1:1) to receive radiation therapy (70 Gy in 35 fractions) with either weekly cisplatin, 7 doses of 40 mg/m2, or cetuximab, loading dose of 400 mg/m2 followed by 7 weekly doses of 250 mg/m2. The primary outcome was symptom severity assessed by the MD Anderson Symptom Inventory Head and Neck Symptom Severity Scale from baseline to 13 weeks postcompletion of radiation therapy using the area under the curve. Trial was registered on ClinicalTrials.gov: NCT01855451. Results Between June 17, 2013, and June 7, 2018, 189 patients were enrolled, with 92 in cisplatin arm and 90 in cetuximab included in the main analysis. There was no difference in the primary endpoint of symptom severity; difference in area under the curve cetuximab-cisplatin was 0.05 (95% confidence interval [CI], –0.19, 0.30), P = .66. The T-score (mean number of ≥grade 3 acute adverse events) was 4.35 (standard deviation 2.48) in the cisplatin arm and 3.82 (standard deviation 1.8) in the cetuximab arm, P = .108. The 3-year failure-free survival rates were 93% (95% CI, 86%-97%) in the cisplatin arm and 80% (95% CI, 70%-87%) in the cetuximab arm (hazard ratio = 3.0 [95% CI, 1.2-7.7]); P = .015. Conclusions For patients with low-risk HPV-associated oropharyngeal cancer, radiation therapy and cetuximab had inferior failure-free survival without improvement in symptom burden or toxicity compared with radiation therapy and weekly cisplatin. Radiation therapy and cisplatin remain the standard of care.

PURPOSE Treatment options are limited for patients with recurrent and/or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC); mortality rates exceed 70% in patients with distant metastases. Here, we present the first interim analysis of the R/M cSCC cohort from the 2-cohort—locally advanced and R/M—phase II KEYNOTE-629 study. PATIENTS AND METHODS Patients with R/M cSCC not amenable to surgery or radiation received pembrolizumab 200 mg every 3 weeks. The primary end point was objective response rate per RECIST v1.1. Secondary end points were duration of response, disease control rate, progression-free survival, overall survival, and safety. RESULTS At data cutoff (April 8, 2019), median follow-up of 105 enrolled patients in the R/M cohort was 11.4 months (range, 0.4 to 16.3 months). Objective response rate was 34.3% (95% CI, 25.3% to 44.2%; 4 complete responses, 32 partial responses), and disease control rate was 52.4% (95% CI, 42.4% to 62.2%). Median duration of response was not reached (range, 2.7 to 13.1+ months; ‘+’ refers to ongoing response at data cutoff). Median progression-free survival was 6.9 months (95% CI, 3.1 months to 8.5 months). Median overall survival was not reached (95% CI, 10.7 months to not reached). Treatment-related adverse events occurred in 66.7% of patients (n = 70), the most common of which were pruritus (n = 15; 14.3%), asthenia (n = 14; 13.3%), and fatigue (n = 13; 12.4%). Grade 3 to 5 treatment-related adverse events occurred in 5.7% (n = 6) of patients. One patient died of treatment-related cranial nerve neuropathy. CONCLUSION Pembrolizumab demonstrated effective antitumor activity; clinically meaningful, durable responses; and acceptable safety in primarily elderly patients with R/M cSCC, supporting its use in clinical practice. Pembrolizumab adverse events in this study were consistent with its established safety profile.

Aim Hospital admissions secondary to immune-related adverse events (irAE) arising from immune checkpoint inhibitors (ICI) are likely to increase with increasing use of this class of drug. We sought to determine the characteristics and outcomes of hospital admissions due to irAE. Methods A retrospective analysis of patients treated with ICI at two tertiary hospitals in Queensland (Australia) was performed. Patients who received at least one dose of ICI for a nonhaematological malignancy between the 1st January 2016 and 1st January 2017 were included. All subsequent hospital admissions were analyzed. Results A total of 140 patients were included, with the most common malignancies being non-small-cell-cell lung cancer (41%) and melanoma (18%), and most patients received anti-PD1 treatment (78%). A sum of 76 patients accounted for 116 admissions. Comparing admissions due to irAE and non-irAE, those admitted for irAE had a significantly longer duration on ICI prior to admission (173 vs 105 days, P = 0.04) but durations of admissions were similar (9.0 vs 8.5 days, P = 0.85). Fifteen patients (11% overall cohort) accounted for 18 admissions attributable to 16 separate irAE. irAE was not considered as a differential diagnosis on admission in 7 patients (38%). In those patients, commencement of corticosteroids was delayed (1.5 days, P = 0.01) but this did not translate into adverse outcomes such as prolonged admissions, prolonged steroid use or long-term complications. All patients with irAE were managed with high-dose corticosteroids. One death resulted from irAE (pneumonitis). Conclusions A sum of 11% patients receiving ICI required hospital admission for irAE. The relatively high rate of irAE as a missed differential diagnosis on admission suggests a need for improved cross-discipline awareness, education, and institutional management guidelines.

Current treatment guidelines for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) recommend multimodal treatment, including chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. The immune checkpoint inhibitor pembrolizumab has previously demonstrated antitumor activity in recurrent and/or metastatic HNSCC in large Phase III trials. For patients with locally advanced disease, Phase Ib data on the use of pembrolizumab in combination with chemoradiation have shown the approach to be safe and feasible. We describe here the design and rationale for KEYNOTE-412, a randomized, double-blind, Phase III trial investigating pembrolizumab or placebo administered concurrently with CRT and as maintenance treatment in patients with locally advanced HNSCC. Clinical Trial Registration: NCT03040999 ( ClinicalTrials.gov ).

Oropharyngeal cancer (OPC) caused by human papillomavirus (HPV) is a rising global concern. Early lesions are small and are often located in difficult to access areas (such as the crypts of the tonsils or base of tongue). Unlike cervical cancer, there is no standard or routine screening program for HPV-driven OPC. HPV DNA from OPC tumors may shed directly into saliva, and this can be used as a biomarker for early diagnosis. In this study, we report the first-ever clinically occult OPC in an asymptomatic patient discovered through a saliva test. This case relied upon serial measurements of HPV-16 DNA in saliva, which fell to undetectable levels following low morbidity, curative treatment.

Background: Cisplatin and pemetrexed chemotherapy provides modest survival benefits for malignant pleural mesothelioma (MPM). This study evaluated cisplatin and pemetrexed with, and followed by, the anti-PD-L1 (programmed death ligand-1) antibody durvalumab in advanced MPM. Methods: DREAM was a single-arm, multicentre open label phase 2 study in patients with treatment-naive advanced MPM. Eligible patients had Eastern Cooperative Oncology Group performance status 0 or 1 and measurable disease. The first six patients were treated on a two-cycle safety lead-in. All patients received cisplatin 75mg/m2, pemetrexed 500mg/m2, and durvalumab 1125mg fixed dose on day 1 of a three-weekly schedule to maximum six cycles chemotherapy. Change from cisplatin to carboplatin AUC5 was permitted. Durvalumab was continued to complete up to 12 months total treatment. The primary endpoint was progression-free survival at six months (PFS6); secondary outcomes included objective tumour response rate (RR), overall survival (OS), and adverse event (AE) rates. Findings: Fifty-four patients were registered and treated. Most were male (83%), with epithelioid subtype (83%), and a median age of 68 years. The proportion alive and progression-free at six months was 54%; median PFS was 6.9 months (95% CI 5.5–9.0). Median OS was 18.4 months (95% CI 13.1–24.8). RR according to modified RECIST for MPM was 48% (95% CI 36–61%), with partial responses in 26 (48%) and stable disease in 21 (37%) patients, respectively. AEs reflected the expected toxicities of combining chemotherapy and durvalumab. None of the five deaths during study treatment were attributed to durvalumab. There was no association between tumour expression of PD-L1 and PFS. Interpretation: This single-arm phase 2 trial demonstrated that the combination of durvalumab, cisplatin, and pemetrexed has promising activity and safety to warrant the conduct of a randomised phase 3 trial. Funding: AstraZeneca provided study drug and funding. Declaration of Interest: The other authors declared no conflicts of interest. Ethical Approval: DREAM conformed to ethical principles of the Declaration of Helsinki and the International Council on Harmonization guidelines on Good Clinical Practice. The protocol was approved by a central Human Research Ethics Committee (HREC), and all site HRECs. All patients provided written informed consent before any screening procedures. Patients confirmed eligible after screening were registered to the study.

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti–PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. Significance: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti–PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. See related commentary by Sitkovsky, p. 16. This article is highlighted in the In This Issue feature, p. 1

Introduction There is no approved second-line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off-label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD-L1). Methods Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD-L1 expression was categorized as negative ( Results A total of 93 patients (48 from Switzerland and 45 from Australia) were treated; 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second-line treatment in 48 of 93 patients (52%). PD-L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD-L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression-free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD-L1 expression, high PD-L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected. Conclusion These real-world data demonstrate similar response rates but inferior survival compared with those in early-phase trials. High PD-L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti–PD-L1 immunotherapy is a reasonable second-line therapy in patients with MPM.

Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade.We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations.Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history.EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.

Reports of acute treatment-related dysphagia and toxicities for patients with parotid tumours or cutaneous head and neck cancer (HNC) are limited. This study aimed to describe the severity and timing of dysphagia and related toxicities experienced during radiotherapy for cutaneous HNC and parotid tumours, to inform the nature of future speech pathology (SP) service models required during treatment. Prospective study of 32 patients with parotid tumours and 36 with cutaneous HNC undergoing curative non-surgical management. Dysphagia and acute toxicity data was collected weekly during treatment and at 2, 4 and 12 weeks post-treatment using the Functional Oral Intake Scale, diet descriptors and CTCAE v4.0. In both groups, minimal treatment toxicities (grades 0–1) were observed. Xerostomia and dysgeusia were the most frequently reported grade 2 toxicities. Only 3% of parotid patients and 6% with cutaneous HNC experienced grade 3 dysphagia. Full or soft texture diets were maintained by > 70% of patients in both groups. Symptoms peaked in the final week of treatment and rapidly improved thereafter. Apart from xerostomia

Background Perineural spread (PNS) is a marker of aggressiveness and has been shown to occur in cranial nerves due to advanced mucosal and cutaneous head and neck cancer. Receptors CXC chemokine receptor 4 (CXCR4) and programmed cell death-1 (PD-1) have been shown to be overexpressed in a variety of cancers with PNS, with the inhibition of these pathways offering a potential future treatment. Methods Retrospective immunohistochemical staining for the CXCR4 and PD-1 receptors was performed on 28 head and neck specimens that demonstrated PNS from January 2017 to August 2017, at Royal Brisbane and Women's Hospital, Brisbane, Australia. Results CXCR4 staining was positive in 52 and 60% of the squamous cell carcinoma (SCC) and adenoid cystic carcinoma PNS specimens, respectively. Cutaneous SCC tumors with no PNS stained positively in 33%. No significant staining for PD-1 in peritumoral lymphocytes or tumor specimens was seen. Conclusion CXCR4 is overexpressed in advanced skin cancer and head and neck tumors that demonstrated PNS to large cranial nerves. Overall, these results provide strong support for using CXCR4 as a biomarker and further investigation of immunotherapeutic agents that could inhibit tumor progression via targeting CXCR4 expression.

BackgroundMupadolimab (mupa) is a humanized FcγR binding-deficient IgG1 anti-CD73 antibody that has agonistic properties.1 CD73 is involved in production of adenosine and in cellular trafficking. Mupa reacts with the majority of circulating B cells leading to activation and expression of differentiation markers CD69, CD138 and CD38, and transformation into plasmablasts with secretion of IgM and IgG. B cell activation provided the rationale to develop mupa for immunotherapy of cancer and Covid-19. Intratumor HPV specific B cells have been reported in HNSCC.2 This report describes properties of mupa and the early signs of clinical activity in HPV+ HNSCC.MethodsELISA and flow cytometry were used to measure binding of anti-CD73. Humanized NSG-SGM3 mice were used to evaluate effects of Mupa on human anti-SARS CoV2 spike protein (SP) response. CD73 expression in biopsies was measured by immunohistochemistry. Mupa (IV q 3 weeks) with or without pembrolizumab is being evaluated in an ongoing phase 1 trial in patients with refractory cancers.ResultsMupa binding to CD73 was blocked by APCP, an analog of adenosine diphosphate that locks CD73 in the closed conformation, indicating mupa binding to the open conformation. Cross blocking and cellular internalization studies showed that mupa is distinct from other anti-CD73 antibodies such as MEDI9447 and AD2. NSG-SGM3 mice were immunized with 50 µg SP subcutaneously and treated with mupa 10mg/kg or control IgG IP. Mupa treated animals mounted an antigen specific human anti-SP response; no antibody responses were seen in controls (P=0.02). In the dose-escalation portion of the phase 1 trial, mupa doses of ≥12 mg/kg saturated CD73 sites on circulating B cells. High stromal CD73 expression was observed in HPV+ HNSCC biopsies from 5 evaluable patients with chemotherapy and anti-PD1 refractory disease, and tumor regression was seen in 2 of these patients receiving 7 and 16 cycles of ≥12 mg/kg mupa without pembrolizumab. Safety of mupa+pembrolizumab was evaluated in 16 patients with no MTD reached and no changes in serum immunoglobulins. Transient reductions in circulating CD73 B cells were observed consistent with redistribution to lymphoid tissues.ConclusionsCD73 plays a role in B cell activation and differentiation. Mupa is an antibody with agonistic activity that stimulates B cells and enhances antigen specific antibody production. This activity supports a strategy to combine mupa with pembrolizumab to enhance both humoral and cellular immunity in the treatment of viral associated cancers such as HPV+HNSCC, and viral infections.Trial RegistrationNCT03454451ReferencesWillingham S, Criner G, Hill C, Hu S, Rudnick J, Daine-Matsuoka B, Hsieh J, Mashhedi H, Hotson A, Brody J, Marron T, Piccione E, Buggy J, Mahabhashyam S, Jones W, Mobasher M, Miller R. Characterization and Phase 1 trial of a B cell activating anti-CD73 antibody for the immunotherapy of COVID-19. medRxiv, 2020; https://doi.org/10.1101/2020.09.10.20191486.Wieland A, Patel M, Cardenas M, Eberhardt C, Hudson W, Obeng R, Griffith C, Wang X, Chen Z, Kissick H, Saba N, Ahmed R. Defining HPV-specific B cell responses in patients with head and neck cancer. Nature 2020; https://doi.org/10.1038/s41586-020-2931-3.Ethics ApprovalThe study was approved by Western IRB, approval number 1-1066703-1. Participants gave informed consent before taking part.

Background: Metastases remains the major cause of death in head and neck cancer (HNC) patients. Circulating tumour cells (CTCs) that are shed from primary and metastatic sites and circulate in patients' peripheral blood, represent an important window into disease status. Minimally invasive techniques are required to identify at time of diagnosis, which patients will have worse prognosis due to distant relapse. Method: We collected bloods from treatment naïve, locoregionally advanced HNC patients (n=72) at the time of diagnosis, and CTCs were isolated using a spiral microfluidic device. CTCs were then immobilised onto glass slides and identified by using immunofluorescence staining (Cytokeratin/CD45/DAPI). We then correlated the CTC numbers of each patient to their clinical outcome based on either PET/CT scan and/or clinical assessment after definitive treatment. Results: CTCs were detected in 39/72 (54%) of patients (ranging from 1-18 CTCs/10 mL blood) at diagnosis. CTC numbers were correlated to TNM staging (p Conclusion: We were able to predict disease progression based on CTC numbers, thus providing potential additional prognostic information for locally advanced HNC patients. The ability to detect CTCs at diagnosis allows us to stratify the risk in patients as well as to understand the fundamental mechanisms by which CTCs spread. The clinical benefit of establishing the use of CTCs in HNC is likely to translate into better patient selection for treatment intensification and/or de-intensification strategies. Citation Format: Xi Zhang, Kai Tang, Brett Hughes, Sarj Vasani, Zhen Liu, Majid Warkiani, Gunter Hartel, Rahul Ladwa, Liz Kenny, Chamindie Punyadeera. Prognostic utility of circulating tumor cells/cell clusters in head and neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 602.

Background: In the multicenter, open-label, nonrandomized, phase 2 KEYNOTE-629 trial, pembro has demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile for R/M cSCC based on the first interim analysis (IA). Here, we present the second IA of KEYNOTE-629, which reports the initial efficacy and safety data for the LA cohort and updated data for the R/M cohort in cSCC.Methods: Eligible patients (pts) were ≥18 years old, had histologically confirmed cSCC (LA or R/M) with measurable disease per RECIST 1.1 by blinded independent central review (BICR), an ECOG PS score of 0 or 1, and adequate organ function. Pts received intravenous pembro 200 mg every 3 weeks for up to 35 infusions (~ 2 years) or until protocol-specified treatment discontinuation criteria were met. The primary endpoint was ORR per RECIST 1.1 by BICR. Secondary endpoints were DOR, DCR, and PFS, all per RECIST 1.1 by BICR; OS; and safety and tolerability. Results: A total of 159 pts were enrolled and treated with pembro (LA, n=54; R/M, n=105). The median time from the first dose to data cutoff (July 29, 2020) was 14.9 (range, 10.1-19.4) mo for the LA cohort and 27.2 (range, 24.6-32.0) mo for the R/M cohort. In the LA cohort, 22.2% of pts were treated with prior systemic therapy with curative intent. In the R/M cohort, 86.7% of pts received ≥1 prior systemic therapy. Updated efficacy outcomes are summarized in the table. Across cohorts, grade 3-5 treatment-related AEs occurred in 11.9% of pts. Grade 3-5 immune-related AEs occurred in 8.2% of pts. Conclusions: Pembro confirmed robust and durable antitumor activity, with promising survival in LA and R/M cSCC. AEs with pembro in this study were generally consistent with its established safety profile. These data support the use of pembro for cSCC. LA cSCC(N=54)R/M cSCC(N=105)Total(N=159)ORR, % (95% CI)50.0 (36.1-63.9)35.2 (26.2-45.2)40.3 (32.6-48.3)DCR (SD ≥12 wks + ORR), % (95% CI)64.8 (50.6-77.3)52.4 (42.4-62.2)56.6 (48.5-64.4)Best overall response, n (%)CR9 (16.7)11 (10.5)20 (12.6)PR18 (33.3)26 (24.8)44 (27.7)SD13 (24.1)30 (28.6)43 (27.0)SD≥12 wks8 (14.8)18 (17.1)26 (16.4)PD9 (16.7)28 (26.7)37 (23.3)NE1 (1.9)2 (1.9)3 (1.9)No assessment4 (7.4)8 (7.6)12 (7.5)DOR, median (range), moNR (1.0+-17.2+)NR (2.7-30.4+)NR (1.0+-30.4+)Patients with extended responses≥12 months, n (%)10 (84.1)25 (77.8)35 (80.3)PFS, median (95% CI), moNR (5.5-NR)5.7 (3.1-8.5)7.8 (5.3-12.3)12-mo PFS rate, % (95% CI)54.4 (39.6-67.0)36.4 (27.0- 45.9)42.4 (34.3-50.2)OS, median (95% CI), moNR (NR-NR)23.8 (13.4-29.8)26.4 (19.5-NR)12-mo OS rate, % (95% CI)73.6 (59.5-83.4)61.0 (50.9-69.5)65.1 (57.1-72.0) Citation Format: Brett G.M. Hughes, Eva Munoz-Couselo, Laurent Mortier, Åse Bratland, Ralf Gutzmer, Osama Roshdy, Rene González Mendoza, Jacob Schachter, Ana Arance, Florent Grange, Nicolas Meyer, Abhishek Joshi, Salem Billan, Pingye Zhang, Burak Gumuscu, Ramona F. Swaby, Jean-Jacques Grob. Phase 2 study of pembrolizumab (pembro) for locally advanced (LA) or recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC): KEYNOTE-629 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT006.

Standard curative treatment of early-stage non-small cell lung cancer (NSCLC) involves surgery in combination with postoperative (adjuvant) platinum-based chemotherapy where indicated. Preoperative (neoadjuvant) therapies offer certain theoretical benefits compared with adjuvant approaches, including the ability to assess on-treatment response, reduce the tumor bulk prior to surgery, and enhance tolerability in the preoperative setting. Indeed, the use of neoadjuvant therapies are well established in other cancers such as breast and rectal cancers to debulk the tumor and guide ongoing therapy, and neoadjuvant chemotherapy has similar efficacy but less toxicity in NSCLC. More recently, immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD1)/PD1-ligand 1 (PD-L1) have transformed the treatment of advanced NSCLC; the unique mechanisms of action of ICI offer additional rationale for assessment in the neoadjuvant setting. Preclinical studies in mouse cancer models support the proof of concept of neoadjuvant ICI (NAICI) through improvement of T-cell effector function and long-term memory induction. Preliminary early-phase human trial data support the proposition that NAICI in NSCLC may provide an feasible and potentially efficacious future treatment strategy and large, randomized phase III trials are currently recruiting to assess this approach. However, outstanding issues include defining optimal treatment combinations which balance high efficacy with acceptable toxicity, validating biomarkers to aid in patient selection, and avoiding potential pitfalls such as missing a window for successful surgery, that is, choosing the right drugs, for the right patient, at the right time. Predictive biomarkers to direct selection of therapy are required, and the validation of major pathological response (MPR) as a surrogate for survival will be important in the uptake of the neoadjuvant approach.

Objectives The main aim was to investigate the incidence of patient adherence to nutritional tube feeding recommendations in patients with head and neck cancer and to determine patient barriers to meeting tube feeding prescription. Materials and methods This was an observational study from a randomised controlled trial in patients with head and neck cancer deemed at high nutritional risk with prophylactic gastrostomy (n = 125). Patients were randomised to receive early tube feeding prior to treatment (intervention group) or standard care. All patients in the intervention and standard care groups then commenced clinical tube feeding as required during treatment. Patients maintained a daily record of gastrostomy intake, main nutrition impact symptom necessitating gastrostomy use, and reasons for not meeting nutrition prescription. Adherence was defined as meeting ≥75% of total prescribed intake. Results Patients were predominantly male (89%), median age 60, with oropharyngeal tumours (78%), stage IV disease (87%) treated with chemoradiotherapy (87%). Primary reasons for gastrostomy use were poor appetite/dysgeusia (week 2–3) and odynophagia/mucositis (week 4–7). Early tube feeding adherence was 51%. Clinical tube feeding adherence was significantly higher in the intervention group (58% vs 38%, p = 0.037). Key barriers to both phases of tube feeding were; nausea, early satiety and treatment factors (related to hospital healthcare processes). Conclusions Early tube feeding can improve patient adherence to clinically indicated tube feeding during treatment. Low adherence overall is a likely explanation for clinically significant weight loss despite intensive nutrition interventions. Optimising symptom management and strategies to overcome other barriers are key to improving adherence. Clinical trial registration: This trial has been registered in the Australian New Zealand Clinical Trials registry as ACTRN12612000579897 .

Background: Central nervous system (CNS) progression is common in patients with anaplastic lymphoma kinaseepositive (ALK+) non-small-cell lung cancer (NSCLC) receiving crizotinib. Next-generation ALK inhibitors have shown activity against CNS metastases, but accurate assessment of response and progression is vital. Data from two phase II studies in crizotinib-refractory ALK+ NSCLC were pooled to examine the CNS efficacy of alectinib, a CNS-active ALK inhibitor, using Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) and Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria.Methods: Both studies enrolled patients aged >= 18 years who had previously received crizotinib. NP28761 was conducted in North America and NP28673 was a global study. All patients received 600 mg oral alectinib twice daily and had baseline CNS imaging. CNS response for those with baseline CNS metastases was determined by an independent review committee.Results: Baseline measurable CNS disease was identified in 50 patients by RECIST and 43 by RANO-HGG. CNS objective response rate was 64.0% by RECIST (95% confidence interval [CI]: 49.2-77.1; 11 CNS complete responses [CCRs]) and 53.5% by RANO-HGG (95% CI: 37.7-68.8; eight CCRs). CNS responses were durable, with consistent estimates of median duration of 10.8 months with RECIST and 11.1 months with RANO-HGG. Of the 39 patients with measurable CNS disease by both RECIST and RANO-HGG, only three (8%) had CNS progression according to one criteria but not the other (92% concordance rate).Conclusion: Alectinib demonstrated promising efficacy in the CNS for ALK+ NSCLC patients pretreated with crizotinib, regardless of the assessment criteria used. (C) 2017 Elsevier Ltd. All rights reserved.

Immune checkpoint inhibitors have recently emerged as an exciting new treatment paradigm across a broad spectrum of malignancies. This new class of agents also challenges oncologists with a unique set of immune-based toxicities. Early recognition and precise management of these toxicities can result in better outcomes, with minimization of toxicity and harm to the patient. This article provides a comprehensive review of immune-based toxicities caused by immune checkpoint inhibitors, including recommendations for their investigation and guidelines for specific management.

The purpose of this study was to determine if p16 status, chemotherapy regimen, or other nutrition markers could improve protocol accuracy in predicting proactive gastrostomy in patients with head and neck cancer. Patients who received curative treatment from July 2010 to June 2011 were included (n = 269). Associations among dependent variables (age, sex, tumor site, staging, treatment, p16 status, albumin, and Malnutrition Screening Tool [MST] score), the protocol risk rating, and requirement for proactive gastrostomy were examined. Current protocol correctly identified 81 of 88 high-risk patients (92%) for gastrostomy, but incorrectly classified 32 of 181 low-risk patients (18%). Analysis of low-risk patients with oral or oropharyngeal cancers, found p16-positive disease had 4.4 times greater odds (p = .049), and those at risk of malnutrition had 4.5 times greater odds (p = .019) of requiring gastrostomy. Malnutrition risk and p16 status could be used to identify further patients who may benefit from proactive gastrostomy. © 2017 Wiley Periodicals, Inc. Head Neck 39: 868-875, 2017.

Aim: Despite recent advances, outcomes for patients with stage III non–small cell lung cancer (NSCLC) with concurrent chemoradiotherapy (CRT) remain poor. We evaluated the combination of ciplatin/vinorelbine and concurrent thoracic radiotherapy followed by consolidation oral vinorelbine in this phase II study. Methods: Eligible patients with unresectable stage III NSCLC received cisplatin intravenous (IV) 40 mg/m and vinorelbine IV 20 mg/m on days 1, 8, 22 and 29 concurrent with thoracic radiotherapy of 60 Gy in 30 fractions. Four to eight weeks later, oral vinorelbine 60 mg/m day 1 and 8 every 3 weeks was given for 3 cycles. The primary end point was overall response rate (ORR). Secondary end points were safety, quality of life, progression-free survival (PFS) and overall survival (OS). Results: Twenty-seven eligible patients were enrolled from December 2007 to June 2010 before the trial was prematurely closed due to toxicity concerns. The median age was 63 years (range, 42–71), 56% were male, 52% ECOG 0 and 52% stage IIIa. The ORR was 81% (including 37% complete response rate) and disease control rate of 93%. The median PFS was 11 months and median OS was 26 months. Consolidation vinorelbine was associated with significant grade 3/4 toxicity (68%) including grade 3–5 febrile neutropenia (27%) and respiratory infections (36%) including two deaths in the consolidation phase (9%). Conclusions: Consolidation oral vinorelbine after CRT was associated with significant toxicity. Overall, this regimen achieved a high ORR and survival results comparable to other CRT protocols but the significant toxicity precludes further evaluation of this approach.

Background The purpose of this study was to present our evaluation of the outcomes of concurrent chemoradiotherapy (CRT) in patients with locally advanced cutaneous squamous cell carcinoma (SCC). Methods This was a prospective phase II study. The primary endpoint was complete response (CR). Patients with locally/regionally advanced cutaneous SCC deemed unsuitable for surgery received definitive radiotherapy (RT; 70 Gy in 35fractions) and concurrent weekly platinum-based chemotherapy (cisplatin 40 mg/m2 or carboplatin area under the curve 2). Results Twenty-one patients were enrolled in this study. Eighteen patients had a locally advanced primary or nodal disease in the head and neck region with 66% having stage IV nonmetastatic disease. Of 19 evaluable patients, 10 achieved a CR to definitive CRT with 2 further patients rendered disease-free by salvage surgery for an overall CR of 63%. Conclusion This is the only prospective series of CRT for cutaneous SCC. A high CR rate was documented in patients with locoregional advanced disease who were unable to undergo surgery. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

Aim: To determine the incidence of symptomatic versus incidental pulmonary embolism (PE) in oncology patients, characterize the nature and extent of incidental PE and the factors contributing to diagnosis. Methods: Specialized web search engine was used to identify oncology patients with positive imaging studies for PE. PE identified at staging CT scans were classified as incidental PEs, whereas PE diagnosed by CTPA/VQ scan were classified as symptomatic PEs. Results: A total of 111 patients with PE were identified over the period of three years. Of these, 67 (60%) patients had symptomatic whereas 44 (40%) patients had incidental PE. Most PEs were segmental and non-occlusive irrespective of the type of PE or stage of the disease. Incidence of PE was equal with/without chemotherapy. Platinum-based chemotherapy was more commonly associated with PE. Most patients received anticoagulation irrespective of type of PE. Conclusion: Forty percent of the diagnosed PEs were incidental, more common in the metastatic group. This may be due to the increased frequency of staging scans performed in patients with metastatic disease, as well as the inherent disease biology of metastatic compared with localized disease. Further prospective analysis of survival by PE subtype and optimal length of anticoagulation in incidental PE is warranted.

Introduction: Local and distant metastatic disease occurs in approximately half of head and neck squamous cell carcinoma (HNSCC) patients, representing an ongoing cause for treatment failure. Circulating tumor cells (CTCs) are transient cancer cells which have the capacity to metastasize to distant sites such as the lungs and liver in HNSCC. When metastatic disease is radiographically evident, the patient prognosis is often poor. Therefore, methodologies to assess micrometastatic disease are needed to (1) identify patients likely to develop metastatic disease and (2) treat and monitor these patients more aggressively. Whilst CTCs are well documented in other tumor streams such as breast, colorectal cancer and prostate cancers, the data and clinical utility in HNSCC remains limited.Areas covered: Here we summarize the recent advances of CTCs and applications in HNSCC.Expert opinion: CTC enumeration can be prognostic in HNSCC; further studies are warranted to investigate the role of CTC clusters in HNSCC; CTC culture (in vivo/ex vivo) may present a possibility to expand these rare cells to a critical mass for functional testing; PD-L1 expression of HNSCC CTCs may present a means by which to determine patients likely to respond to therapy; a HNSCC CTC-specific marker is warranted.

Objectives: This study aimed to describe the longitudinal thromboembolism (TE) risk relative to the natural history of disease and clinical course of ROS1 rearranged non-small cell lung cancer (NSCLC). Materials and Methods Cases of ROS1-rearranged NSCLC from six Australian hospitals were pooled and evaluated for incidence, timing, predictors and outcomes of venous or arterial TE, as well as objective response rate (ORR) to active therapy and overall survival (OS). Results Of 42 patients recruited, 20 (48%) experienced TE; one (2%) arterial, 13 (31%) a pulmonary emboli (PE), and 12 (29%) a deep vein thrombosis. Among those with TE, six (30%) experienced multiple events, three as concurrent and three as recurrent diagnoses. The cumulative incidence of TE over time, adjusted for death as a competing risk factor, approached 50%. TE occurred prior to, during and post the peri-diagnostic period and occurred irrespective of treatment strategy. A thrombophilia was identified in n = 3/10 (30%) cases screened: in two factor V Leiden and in one anti-thrombin III (ATIII) deficiency. Median OS was 21.3 months in those with TE vs. 28.8 months in those without; hazard ratio 1.16 (95%CI 0.43–3.15). Respective ORR to first-line therapy with TE was 50% vs. 44% without TE in the chemotherapy arm and 67% vs. 50% in the targeted therapy arm. Conclusion In the rare cancer subtype, ROS1, these real-world data demonstrate sustained TE risk beyond the diagnostic period irrespective of therapeutic strategy. High incidence of PE, concurrent TE, and recurrent TE warrant validation in larger cohorts. Consideration of primary thromboprophylaxis in ROS1 populations is recommended.

9546 Background: KEYNOTE-629 is a single-arm phase 2 study of pembro for cSCC. At second interim analysis (IA), pembro had robust and durable antitumor activity and manageable safety in LA and R/M cohorts. At first IA, pembro maintained HRQoL in the R/M cohort; LA was not analyzed because of ongoing accrual. HRQoL of pts with LA or R/M cSCC at second IA (database cutoff July 29, 2020; additional 15-mo follow-up since IA1 for the R/M cohort) is shown. Methods: Pts with LA or R/M cSCC received pembro 200 mg IV Q3W for ≤35 cycles. HRQoL was a prespecified exploratory end point assessed using EORTC QLQ-30 and EuroQol EQ-5D-5L instruments administered at baseline, wk 3, and wk 6; then Q6W through y 1; then Q9W until treatment end/discontinuation; and at the 30-day safety follow-up. HRQoL was analyzed in pts who received ≥1 pembro dose and completed baseline and ≥1 postbaseline HRQoL assessments. Mean change from baseline in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL), physical functioning (PF), and EQ-5D-5L visual analog scale (VAS) scores were evaluated at wk 12 to ensure adequate completion rate and through last pt visit at wk 75 for EORTC QLQ-C30 GHS/QoL and PF scores. HRQoL was categorized as improved or deteriorated based on ≥10-point change in EORTC QLQ-C30 scores (considered clinically meaningful). Results: The HRQoL analysis population for LA had 47 pts for EORTC QLQ-C30 and EQ-5D-5L; the R/M cohort had 99 pts for EORTC QLQ-C30 and 100 for EQ-5D-5L. At wk 12, compliance rates were >75% for LA and >80% for R/M cohorts for EORTC QLQ-C30 and EQ-5D-5L. Mean change from baseline to wk 12 was minimal for EORTC QLQ-C30 GHS/QoL, PF, and EQ-5D-5L VAS scores for both cohorts (Table). Mean change from baseline in EORTC QLQ-C30 GHS/QoL and PF scores remained stable over 48 wk in the LA cohort (75-wk data unavailable) and over 75 wk in the R/M cohort. Most pts had improved or stable EORTC QLQ-C30 GHS/QoL and PF scores relative to baseline during follow-up. Conclusions: HRQoL was generally maintained with pembro in LA and R/M cSCC cohorts and was not negatively impacted by tumor progression or AEs. Clinical trial information: NCT03284424. [Table: see text]