Pre-encoded responsiveness to type I interferon in the peripheral immune system defines outcome of PD1 blockade therapy.

Type I interferons (IFN-Is) are central regulators of anti-tumor immunity and responses to immunotherapy, but they also drive the feedback inhibition underlying therapeutic resistance. In the present study, we developed a mass cytometry approach to quantify IFN-I-stimulated protein expression across immune cells and used multi-omics to uncover pre-therapy cellular states encoding responsiveness to inflammation. Analyzing peripheral blood cells from multiple cancer types revealed that differential responsiveness to IFN-Is before anti-programmed cell death protein 1 (PD1) treatment was highly predictive of long-term survival after therapy. Unexpectedly, IFN-I hyporesponsiveness efficiently predicted long-term survival, whereas high responsiveness to IFN-I was strongly associated with treatment failure and diminished survival time. Peripheral IFN-I responsive states were not associated with tumor inflammation, identifying a disconnect between systemic immune potential and 'cold' or 'hot' tumor states. Mechanistically, IFN-I responsiveness was epigenetically imprinted before therapy, poising cells for differential inflammatory responses and dysfunctional T cell effector programs. Thus, we identify physiological cell states with clinical importance that can predict success and long-term survival of PD1-blocking immunotherapy.

Prospective manipulation of the gut microbiome with microbial ecosystem therapeutic 4 (MET4) in HPV-related locoregionally-advanced oropharyngeal cancer squamous cell carcinoma (LA-OPSCC) undergoing primary chemoradiation: ROMA2 study.

BACKGROUND: Gut microbiome modulation to boost antitumor immune responses is under investigation. METHODS: ROMA-2 evaluated the microbial ecosystem therapeutic (MET)-4 oral consortia, a mixture of cultured human stool-derived immune-responsiveness associated bacteria, given with chemoradiation (CRT) in HPV-related oropharyngeal cancer patients. Co-primary endpoints were safety and changes in stool cumulative MET-4 taxa relative abundance (RA) by 16SRNA sequencing. Stools and plasma were collected pre/post-MET-4 intervention for microbiome and metabolome analysis. RESULTS: Twenty-nine patients received ≥1 dose of MET-4 and were evaluable for safety: drug-related adverse events (AEs) occurred in 13/29 patients: all grade 1-2 except one grade 3 (diarrhea). MET-4 was discontinued early in 7/29 patients due to CRT-induced toxicity, and in 1/29 due to MET-4 AEs. Twenty patients were evaluable for ecological endpoints: there was no increase in stool MET-4 RA post-intervention but trended to increase in stage III patients (p = 0.06). MET-4 RA was higher in stage III vs I-II patients at week 4 (p = 0.03) and 2-month follow-up (p = 0.01), which correlated with changes in plasma and stool targeted metabolomics. CONCLUSIONS: ROMA-2 did not meet its primary ecologic endpoint, as no engraftment was observed in the overall cohort. Exploratory findings of engraftment in stage III patients warrants further investigation of microbiome interventions in this subgroup.

Sensitive tumour detection and classification using plasma cell-free DNA methylomes.

The use of liquid biopsies for cancer detection and management is rapidly gaining prominence1. Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations2-5. By contrast, large-scale epigenetic alterations-which are tissue- and cancer-type specific-are not similarly constrained6 and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns.

Cigarette smoking cessation, duration of smoking abstinence, and head and neck squamous cell carcinoma prognosis.

BACKGROUND: Tobacco use is a major risk factor for developing head and neck squamous cell carcinoma (HNSCC). However, the prognostic associations with smoking cessation are limited. The authors assessed whether smoking cessation and increased duration of abstinence were associated with improved overall (OS) and HNSCC-specific survival. METHODS: Clinicodemographic and smoking data from patients with HNSCC at Princess Margaret Cancer Center (2006-2019) were prospectively collected. Multivariable Cox and Fine and Gray competing-risk models were used to assess the impact of smoking cessation and duration of abstinence on overall mortality and HNSCC-specific/noncancer mortality, respectively. RESULTS: Among 2482 patients who had HNSCC, former smokers (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.58-0.87; p = .001; N = 841) had a reduced risk of overall mortality compared with current smokers (N = 931). Compared with current smokers, former smokers who quit >10 years before diagnosis (long-term abstinence; n = 615) had the most improved OS (aHR, 0.72; 95% CI, 0.56-0.93; p = .001). The 5-year actuarial rates of HNSCC-specific and noncancer deaths were 16.8% and 9.4%, respectively. Former smokers (aHR, 0.71; 95% CI, 0.54-0.95; p = .019) had reduced HNSCC-specific mortality compared with current smokers, but there was no difference in noncancer mortality. Abstinence for >10 years was associated with decreased HNSCC-specific death compared with current smoking (aHR, 0.64; 95% CI, 0.46-0.91; p = .012). Smoking cessation with a longer duration of quitting was significantly associated with reduced overall and HNSCC-specific mortality in patients who received primary radiation. CONCLUSIONS: Smoking cessation before the time of diagnosis reduced overall mortality and cancer-specific mortality among patients with HNSCC, but no difference was observed in noncancer mortality. Long-term abstinence (>10 pack-years) had a significant OS and HNSCC-specific survival benefit.

A tailored phase I-specific patient-reported outcome (PRO) survey to capture the patient experience of symptomatic adverse events.

BACKGROUND: Patient perspectives are fundamental to defining tolerability of investigational anti-neoplastic therapies in clinical trials. Phase I trials present a unique challenge in designing tools for efficiently collecting patient-reported outcomes (PROs) given the difficulty of anticipating adverse events of relevance. However, phase I trials also offer an opportunity for investigators to optimize drug dosing based on tolerability for future larger-scale trials and in eventual clinical practice. Existing tools for comprehensively capturing PROs are generally cumbersome and are not routinely used in phase I trials. METHODS: Here, we describe the creation of a tailored survey based on the National Cancer Institute's PRO-CTCAE for collecting patients' perspectives on symptomatic adverse events in phase I trials in oncology. RESULTS: We describe our stepwise approach to condensing the original 78-symptom library into a modified 30 term core list of symptoms which can be efficiently applied. We further show that our tailored survey aligns with phase I trialists' perspectives on symptoms of relevance. CONCLUSIONS: This tailored survey represents the first PRO tool developed specifically for assessing tolerability in the phase I oncology population. We provide recommendations for future work aimed at integrating this survey into clinical practice.

Associations between Human Papillomavirus Status, Weight Change, and Survival of Oropharyngeal Cancer Patients.

This study examined associations between HPV status and weight change in oropharyngeal cancer (OPC). OPC patients receiving concurrent chemoradiotherapy in Toronto, Canada were included. Relationships were assessed between HPV status and weight loss grade (WLG, combining weight loss and current body mass index); weight change during treatment; and HPV status and WLG/weight change on overall (OS) and cancer-specific (CSS) survival. Of 717 patients, WLG pre-radiation was less severe among HPV-positive compared to HPV-negative, though weight loss during treatment was greater. The adjusted odds ratio for greater WLG among HPV-positive versus HPV-negative was 0.47 (95%CI 0.28-0.78). Grade-4 WLG (worst category) experienced poorer OS and CSS (OS adjusted hazard ratio (aHR) 4.08; 95%CI 1.48-11.2, compared to Grade-0); and was non-significant for HPV-negative (aHR 2.34; 95%CI 0.69-7.95). Relationships between weight change before/during treatment and survival had similar direction between HPV-positive and HPV-negative, but of greater magnitude in HPV-positive patients.

Shaping the Future of Immunotherapy Targets and Biomarkers in Melanoma and Non-Melanoma Cutaneous Cancers.

Recent advances in treating cutaneous melanoma have resulted in impressive patient survival gains. Refinement of disease staging and accurate patient risk classification have significantly improved our prognostic knowledge and ability to accurately stratify treatment. Undoubtedly, the most important step towards optimizing patient outcomes has been the advent of cancer immunotherapy, in the form of immune checkpoint inhibition (ICI). Immunotherapy has established its cardinal role in the management of both early and late-stage melanoma. Through leveraging outcomes in melanoma, immunotherapy has also extended its benefit to other types of skin cancers. In this review, we endeavor to summarize the current role of immunotherapy in melanoma and non-melanoma skin cancers, highlight the most pertinent immunotherapy-related molecular biomarkers, and lastly, shed light on future research directions.

Treatment outcomes and survival following definitive (chemo)radiotherapy in HPV-positive oropharynx cancer: Large-scale comparison of DAHANCA vs PMH cohorts.

We compare outcomes in two large-scale contemporaneously treated HPV-positive (HPV+) oropharynx cancer (OPC) cohorts treated with definitive radiotherapy/chemoradiotherapy (RT/CRT). p16-confirmed HPV+ OPC treated between 2007 and 2015 at PMH and DAHANCA were identified. Locoregional failure (LRF), distant metastasis (DM), and overall survival (OS) were compared. Multivariable analysis (MVA) calculated adjusted-hazard-ratio (aHR) with 95% confidence interval (95% CI), adjusting for cohort, age, gender, performance status, smoking pack-years, T-category and N-category and chemotherapy. Compared to PMH (n = 701), DAHANCA (n = 1174) contained lower TNM-8T-categories (T1-T2: 77% vs 56%), N-categories (N0-N1: 77% vs 67%) and stages (stage I: 63% vs 44% (all P < .001). PMH used standard-fractionation CRT in 69% (481) while 31% (220) received hypofractionated or moderately accelerated RT-alone. All DAHANCA patients were treated with moderately accelerated RT; 96% (1129) received nimorazole (NIM) and 73% (856) concurrent weekly cisplatin. DAHANCA had shorter overall-treatment-time (P < .001), lower gross tumor (66-68 vs 70 Gy) and elective neck (50 vs 56 Gy) doses. Median follow-up was 4.8 years. DAHANCA had higher 5-year LRF (13% vs 7%, aHR = 0.47 [0.34-0.67]), comparable DM (7% vs 12%, aHR = 1.32 [0.95-1.82]), but better OS (85% vs 80%, aHR = 1.30 [1.01-1.68]). CRT patients had a lower risk of LRF (aHR 0.56 [0.39-0.82]), DM (aHR 0.70 [0.50-1.00]) and death (aHR 0.39 [0.29-0.52]) vs RT-alone. We observed exemplary outcomes for two large-scale trans-Atlantic HPV+ OPC cohorts treated in a similar manner. Concurrent chemotherapy was a strong, independent prognostic factor for all endpoints. Our findings underscore the need for a very careful approach to de-intensification of treatment for this disease.

Clinical presentation and outcome of human papillomavirus-positive nasopharyngeal carcinoma in a North American cohort.

BACKGROUND: The objective of this study was to describe the clinical presentation and outcomes of human papillomavirus (HPV)-positive nasopharyngeal cancer (NPC) versus Epstein-Barr virus (EBV)-positive NPC and HPV-positive oropharyngeal cancer (OPC). METHODS: Clinical characteristics and presenting signs/symptoms were compared between patients who had viral-related NPC versus viral-related OPC treated with intensity-modulated radiotherapy from 2005 to 2020 and who were matched 1:1 (by tumor and lymph node categories, smoking, age, sex, histology, and year of diagnosis). Locoregional control (LRC), distant control (DC), and overall survival (OS) were compared using the 2005-2018 cohort to maintain 2 years of minimum follow-up. Multivariable analysis was used to evaluate the cohort effect. RESULTS: Similar to HPV-positive OPC (n = 1531), HPV-positive NPC (n = 29) occurred mostly in White patients compared with EBV-positive NPC (n = 422; 86% vs. 15%; p < .001). Primary tumor volumes were larger in HPV-positive NPC versus EBV-positive NPC (median volume, 51 vs. 23 cm3 ; p = .002), with marginally more Level IB nodal involvement. More patients with HPV-positive NPC complained of local pain (38% vs. 3%; p = .002). The median follow-up for the 2005-2018 cohort was 5.3 years. Patients who had HPV-positive NPC (n = 20) had rates of 3-year LRC (95% vs. 90%; p = .360), DC (75% vs. 87%; p = .188), and OS (84% vs. 89%; p = .311) similar to the rates in those who had EBV-positive NPC (n = 374). Patients who had HPV-positive NPC also had rates of LRC (95% vs. 94%; p = .709) and OS (84% vs. 87%; p = .440) similar to the rates in those who had HPV-positive OPC (n = 1287). The DC rate was lower in patients who had HPV-positive disease (75% vs. 90%; p = .046), but the difference became nonsignificant (p = .220) when the analysis was adjusted for tumor and lymph node categories, smoking, and chemotherapy. CONCLUSIONS: HPV-positive NPC and EBV-positive NPC seem to be mutually exclusive diseases. Patients who have HPV-positive NPC have greater local symptom burden and larger primary tumors but have similar outcomes compared with patients who have EBV-positive NPC or HPV-positive OPC.

Longitudinal health utility and symptom-toxicity trajectories in patients with head and neck cancers.

BACKGROUND: This study examined long-term health utility and symptom-toxicity trajectories among patients with head and neck cancer (HNC). METHODS: For patients diagnosed with HNC (2014-2019), Health Utility Index 3 (HUI-3), Edmonton Symptom Assessment Scale (ESAS), and MD Anderson Symptom Inventory (MDASI) surveys (including both the core and head and neck cancer modules) were prospectively collected at multiple time points (at the baseline, after surgery, during radiotherapy, and 3, 6, 12, and 24 months after treatment). Locally estimated scatterplot smoothing plots were generated to describe HUI-3, ESAS, and MDASI trajectories over time by clinicodemographic factors, treatment modality, and tumor subsite. Contributions of clinical factors were assessed with univariable and multivariable analyses. RESULTS: In 800 patients, the treatment modality and the tumor subsite produced unique HUI-3, ESAS, and MDASI trajectories. Patients treated with surgery alone experienced rapid improvements in HUI-3, ESAS, and MDASI scores postoperatively. Among patients treated with chemoradiotherapy, patients with nasopharyngeal carcinoma had greater declines in HUI-3 during treatment in comparison with patients with oropharyngeal carcinoma, but they had similar ESAS/MDASI scores. Among patients treated with radiotherapy, patients with laryngeal carcinoma had better HUI-3/ESAS/MDASI scores than those with oropharyngeal carcinoma during treatment, but they slowly converged after treatment. Female sex, an age > 75 years, a household income < $40,000, a Charlson comorbidity score > 1, an Eastern Cooperative Oncology Group performance status > 0 (at the baseline), and current smoking were independently associated with worse HUI-3 trajectories. HUI-3 had mild to moderate correlations (ρ = 0.2-0.5) with individual symptom-toxicity trajectories. CONCLUSIONS: Long-term HUI-3 trajectories are associated with tumor subsite, clinicodemographic, and treatment factors, and this may be partly explained by relationships with symptoms/toxicities. Separate evaluations by subsite and treatment should occur in health utility and symptom-toxicity studies of HNC. LAY SUMMARY: This study indicates that the long-term health utility and symptoms/toxicities of patients with the most common head and neck cancers (ie, squamous cell carcinomas and nasopharyngeal carcinomas) differ over time with a variety of factors, including the tumor anatomic site, treatment volume, clinicodemographic characteristics (eg, age, human papillomavirus status, tumor stage, gender, smoking status, alcohol status, education, and comorbidities), and treatment modalities. Generalizations across all head and neck cancers should be strongly discouraged. Future studies should evaluate health utility, symptoms and toxicities, and patient need assessments separately for each anatomic site and treatment modality.

Evaluation of the patient experience of symptomatic adverse events on Phase I clinical trials using PRO-CTCAE.

BACKGROUND: Adverse event (AE) reporting in early-phase clinical trials is essential in determining the tolerability of experimental anticancer therapies. The patient-reported outcome version of the CTCAE (PRO-CTCAE) evaluates AE components such as severity and interference in daily life. The aim of this study was to correlate the grade of clinician-reported AEs with patients' reported experience of these toxicities using PRO-CTCAE. METHODS: Patients with advanced solid tumours enrolled on Phase I clinical trials were surveyed using the PRO-CTCAE. Symptomatic AEs were recorded by physicians using the CTCAE. A logistic regression model was used to assess associations between CTCAE grade and PRO responses. RESULTS: Of 219 evaluable patients, 81 experienced a high-grade (3/4) clinician-reported symptom, and of these, only 32 (40%) and 26 (32%) patients concordantly reported these as either severe or very severe, and interfering with daily life either 'quite a bit' or 'very much', respectively. Of the 137 patients who experienced a low-grade (1/2) clinician-reported AE as their worst symptom, 98 (72%) and 118 (86%) patients concordantly reported these as either mild-moderate severity and minimally interfering with daily life, respectively. There was a statistically significant association between clinician-reported AE grade and interference. Interference scores were also associated with dose reductions. CONCLUSION: This is the first study to explore patient-reported severity and interference from symptomatic toxicities and compare clinician grading of the same toxicities. The study provided further evidence to support the added value of the PRO-CTCAE in Phase I oncology trials, which would make AE reporting patient-centred. Further work is needed to determine how this would affect the assessment of tolerability.

Transitions in oral and gut microbiome of HPV+ oropharyngeal squamous cell carcinoma following definitive chemoradiotherapy (ROMA LA-OPSCC study).

BACKGROUND: Oral and gut microbiomes have emerged as potential biomarkers in cancer. We characterised the oral and gut microbiomes in a prospective observational cohort of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) patients and evaluated the impact of chemoradiotherapy (CRT). METHODS: Saliva, oropharyngeal swabs over the tumour site and stool were collected at baseline and post-CRT. 16S RNA and shotgun metagenomic sequencing were used to generate taxonomic profiles, including relative abundance (RA), bacterial density, α-diversity and ß-diversity. RESULTS: A total of 132 samples from 22 patients were analysed. Baseline saliva and swabs had similar taxonomic composition (R2 = 0.006; p = 0.827). Oropharyngeal swabs and stool taxonomic composition varied significantly by stage, with increased oral RA of Fusobacterium nucleatum observed in stage III disease (p < 0.05). CRT significantly reduced the species richness and increased the RA of gut-associated taxa in oropharyngeal swabs (p < 0.05), while it had no effect in stool samples. These findings remained significant when adjusted by stage, smoking status and antibiotic use. CONCLUSIONS: Baseline oral and gut microbiomes differ by stage in this HPV+ cohort. CRT caused a shift towards a gut-like microbiome composition in oropharyngeal swabs. Stage-specific features and the transitions in oral microbiome might have prognostic and therapeutic implications.

Phase 1 study of the immunotoxin LMB-100 in patients with mesothelioma and other solid tumors expressing mesothelin.

BACKGROUND: LMB-100 is an antibody-toxin conjugate with an antimesothelin Fab linked to a 24-kilodalton portion of Pseudomonas exotoxin A with mutations that decrease immunogenicity. The objective of the current first-in-human phase 1 study was to determine the maximum tolerated dose (MTD) and safety in patients with advanced solid tumors expressing mesothelin. METHODS: Cohorts of 1 to 7 patients received intravenous LMB-100 at 7 dose levels from 40 µg/kg to 250 µg/kg intravenously on days 1, 3, and 5 of a 21-day cycle. RESULTS: Of the 25 patients accrued, 17 had mesothelioma, 3 each had ovarian or pancreatic cancer, and 2 patients had gastric cancer. Dose-limiting toxicities occurred in 2 of 4 patients treated at a dose of 250 µg/kg (capillary leak syndrome) and in 3 of 7 patients treated at a dose of 170 µg/kg (creatinine increase). The MTD of LMB-100 was 140 µg/kg. Of the 10 patients with mesothelioma who were treated at doses of 170 µg/kg or 140 µg/kg, 8 had stable disease and 2 developed progressive disease. Peak LMB-100 plasma concentrations were dose-dependent during cycle 1. The development of antidrug antibodies decreased LMB-100 blood levels in 8 of 21 patients (38%) who received cycle 2 and 9 of 11 patients (81.8%) who received cycle 3. CONCLUSIONS: The MTD for single-agent LMB-100 was found to be 140 µg/kg given on a schedule of every other day for 3 doses every 3 weeks. Although less immunogenic than the first-generation antimesothelin immunotoxin SS1P, the majority of patients developed antidrug antibodies after 2 cycles, indicating that LMB-100 has limited antitumor efficacy as a single agent. Phase 2 studies of LMB-100 plus pembrolizumab currently are ongoing for patients with mesothelioma and lung cancer. LAY SUMMARY: Mesothelin, a cell surface antigen, is an attractive target for cancer therapy given its limited expression in normal human tissues and high expression in many human cancers. LMB-100 is a recombinant antimesothelin immunotoxin consisting of a humanized antimesothelin antibody fragment fused to a truncated Pseudomonas exotoxin A. In the current study, the authors determined the safety, maximum tolerated dose, and pharmacokinetics of LMB-100, as well as the generation of antidrug antibodies. Ongoing phase 2 clinical trials are evaluating the combination of LMB-100 plus pembrolizumab in patients with treatment-refractory mesothelioma and non-small cell lung cancer.

Hypofractionated radiotherapy alone with 2.4 Gy per fraction for head and neck cancer during the COVID-19 pandemic: The Princess Margaret experience and proposal.

BACKGROUND: The objective of this study was to identify a subgroup of patients with head and neck squamous cell carcinoma (HNSCC) who might be suitable for hypofractionated radiotherapy (RT-hypo) during the COVID-19 pandemic. METHODS: HNSCC cases (oropharynx/larynx/hypopharynx) treated with definitive RT-hypo (60 Gy in 25 fractions over 5 weeks), moderately accelerated radiotherapy (RT-acc) alone (70 Gy in 35 fractions over 6 weeks), or concurrent chemoradiotherapy (CCRT) during 2005-2017 were included. Locoregional control (LRC) and distant control (DC) after RT-hypo, RT-acc, and CCRT were compared for various subgroups. RESULTS: The study identified 994 human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma cases (with 61, 254, and 679 receiving RT-hypo, RT-acc, and CCRT, respectively) and 1045 HPV- HNSCC cases (with 263, 451, and 331 receiving RT-hypo, RT-acc, and CCRT, respectively). The CCRT cohort had higher T/N categories, whereas the radiotherapy-alone patients were older. The median follow-up was 4.6 years. RT-hypo, RT-acc, and CCRT produced comparable 3-year LRC and DC for HPV+ T1-2N0-N2a disease (seventh edition of the TNM system [TNM-7]; LRC, 94%, 100%, and 94%; P = .769; DC, 94%, 100%, and 94%; P = .272), T1-T2N2b disease (LRC, 90%, 94%, and 97%; P = .445; DC, 100%, 96%, and 95%; P = .697), and T1-2N2c/T3N0-N2c disease (LRC, 89%, 93%, and 95%; P = .494; DC, 89%, 90%, and 87%; P = .838). Although LRC was also similar for T4/N3 disease (78%, 84%, and 88%; P = .677), DC was significantly lower with RT-hypo or RT-acc versus CCRT (67%, 65%, and 87%; P = .005). For HPV- HNSCC, 3-year LRC and DC were similar with RT-hypo, RT-acc, and CCRT in stages I and II (LRC, 85%, 89%, and 100%; P = .320; DC, 99%, 98%, and 100%; P = .446); however, RT-hypo and RT-acc had significantly lower LRC in stage III (76%, 69%, and 91%; P = .006), whereas DC rates were similar (92%, 85%, and 90%; P = .410). Lower LRC in stage III predominated in patients with laryngeal squamous cell carcinoma receiving RT-acc (62%) but not RT-hypo (80%) or CCRT (92%; RT-hypo vs CCRT: P = .270; RT-acc vs CCRT: P = .004). CCRT had numerically higher LRC in comparison with RT-hypo or RT-acc in stage IV (73%, 65%, and 66%; P = .336). CONCLUSIONS: It is proposed that RT-hypo be considered in place of CCRT for HPV+ T1-T3N0-N2c (TNM-7) HNSCCs, HPV- T1-T2N0 HNSCCs, and select stage III HNSCCs during the COVID-19 outbreak.

Development of the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM): A toxicity subscale to measure quality of life in patients with cancer who are treated with ICMs.

BACKGROUND: Patients with cancer who are treated with immune checkpoint modulators (ICMs) have their health-related quality of life (HRQOL) measured using general patient-reported outcome (PRO) tools. To the authors' knowledge, no instrument has been developed to date specifically for patients treated with ICMs. The objective of the current study was to develop a toxicity subscale PRO instrument for patients treated with ICMs to assess HRQOL. METHODS: Input was collected from a systematic review as well as patients and physicians experienced with ICM treatment. Descriptive thematic analysis was used to evaluate the qualitative data obtained from patient focus groups and interviews, which informed an initial list of items that described ICM side effects and their impact on HRQOL. These inputs informed item generation and/or reduction to develop a toxicity subscale. RESULTS: Focus groups and individual interviews with 37 ICM-treated patients generated an initial list of 176 items. After a first round of item reduction that produced a shortened list of 76 items, 16 physicians who care for patients who are treated with ICMs were surveyed with a list of 49 patient-reported side effects and 11 physicians participated in follow-up interviews. A second round of item reduction was informed by the physician responses to produce a list of 25 items. CONCLUSIONS: To the authors' knowledge, this 25-item list is the first HRQOL-focused toxicity subscale for patients treated with ICMs and was developed in accordance with US Food and Drug Administration guidelines, which prioritize patient input in developing PRO tools. The subscale will be combined with the Functional Assessment of Cancer Therapy-General (FACT-G) to form the FACT-ICM. Prior to recommending the formal use of this PRO instrument, the authors will evaluate its validity and reliability in longitudinal studies involving substantially more patients.

Increasing operational and scientific efficiency in clinical trials.

Operational and scientific inefficiencies in clinical trials represent roadblocks that need to be identified and circumvented to advance drug development in oncology. The collaboration of key stakeholders to advance this agenda is crucial to accelerate clinical research and ultimately benefit patient care through the optimal allocation of time and resources.

Novel strategies in immune checkpoint inhibitor drug development: How far are we from the paradigm shift?

The development of immune checkpoint inhibitors (ICI) represents a major milestone in immune-oncology. Over the years these agents have demonstrated efficacy in an increasing array of malignancies. Despite this success however, significant challenges remain. Novel approaches to both drug development and trial design are required to incorporate the unique pharmacokinetic and pharmacodynamic properties of ICIs. Further, it has also been established that the benefit of ICIs is limited to only a subset of patients. The molecular interactions between native immune cells and tumorigenesis and progression represent an active area of biomarker research, and elucidating the mechanisms of response and resistance is crucial to develop rational trial designs for the next wave of immune-oncology (IO) clinical trials, particularly in patients with primary and/or acquired resistance. Efforts are now being made to integrate both biological and clinical information using novel multi-omic approaches which are now being developed to further elucidate the molecular signatures associated with IO treatment response and resistance and enable rational drug development and trial design processes. As such, precision IO and the ability to deliver patient-specific choices for ICI monotherapies or combination therapies has become an increasingly tangible goal. We herein describe the current landscape in ICI drug development and discuss the challenges and future directions in this exciting and evolving era in immune-oncology.

Hyperprogressive disease in early-phase immunotherapy trials: Clinical predictors and association with immune-related toxicities.

BACKGROUND: A subset of patients treated with immune checkpoint inhibitors experience an accelerated tumor growth rate (TGR) in comparison with pretreatment kinetics; this is known as hyperprogression. This study assessed the relation between hyperprogressive disease (HPD) and treatment-related toxicity and clinical factors. METHODS: This study reviewed patients with solid tumors who were enrolled in early-phase immunotherapy trials at Princess Margaret Cancer Centre between August 2012 and September 2016 and had computed tomography scans in the pre-immunotherapy (reference) and on-immunotherapy (experimental) periods. HPD was defined as progression according to Response Evaluation Criteria in Solid Tumors 1.1 at the first on-treatment scan and a ≥2-fold increase in TGR between the reference and experimental periods. Treatment-related toxicities requiring systemic therapy, drug delays, or discontinuation were considered clinically significant adverse events (CSAEs). RESULTS: Of 352 patients, 182 were eligible for analysis. The median age was 60 years, and 54% were male. The Eastern Cooperative Oncology Group performance status was 0 (32%) or 1 (68%). The Royal Marsden Hospital (RMH) prognostic score was 0/1 in 59%. Single-agent immunotherapy was given to 80% of the patients. Most patients (89%) received anti-programmed death (ligand) 1 antibodies alone or in combination with other therapies. HPD occurred in 12 of 182 patients (7%). A higher proportion of females was seen among HPD patients (P = .01), but no association with age, performance status, tumor type, RMH prognostic score, combination immunotherapy, or CSAEs was found. The 1-year overall survival rate was 28% for HPD patients and 53% for non-HPD patients (hazard ratio, 1.7; 95% confidence interval, 0.9-3.3; P = .11). CONCLUSIONS: HPD was observed in 7% of patients with solid tumors treated with immunotherapy. HPD was not associated with CSAEs, age, tumor type, or the type of immunotherapy but was more common in females.

Feasibility Assessment of Using the Complete Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item Library.

The patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) complements capture of symptomatic adverse events (AEs) by clinicians. Previous trials have typically used a limited subset of relevant symptomatic AEs to reduce patient burden. We aimed to determine the feasibility of administering all 80 AEs included in the PRO-CTCAE library by approaching consecutive patients enrolled in a large academic phase I program at three points in time. Here, we report a preplanned analysis after enrolling the first 20 patients. All items were answered on 51 of 56 potential visits (adherence 91%). Three (5%) additional PRO-CTCAE assessments were partially completed, and two (4%) were missed because of conflicting appointments. No patient withdrew consent or chose not to complete the assessments once enrolled on study. Future trials of experimental drugs that incorporate the PRO-CTCAE should consider using this unselected approach to identify adverse events more completely.

Referrals to a Phase I Clinic and Trial Enrollment in the Molecular Screening Era.

BACKGROUND: Enrichment of patients based on molecular biomarkers is increasingly used in early phase clinical trials. Molecular profiling of patients with advanced cancers can identify specific genomic alterations to inform decisions about investigational treatment(s). Our aim was to evaluate the outcomes of new patient referrals to a large academic solid tumor phase I clinical trial program after the implementation of molecular profiling. MATERIALS AND METHODS: Retrospective chart review of all new referrals to the Princess Margaret Cancer Centre (PM) phase I clinic from May 2012 to December 2014. Molecular profiling using either MALDI-TOF hotspot mutation genotyping or targeted panel DNA sequencing was performed for patients at PM or community hospitals through the institutional IMPACT/COMPACT trials. RESULTS: A total of 971 new patient referrals were included for this analysis. Twenty-seven percent of referrals assessed in clinic were subsequently enrolled in phase I trials. Of all new referrals, 41% had prior molecular profiling, of whom 11% (n = 42) were enrolled in genotype-matched trials. Patients with prior molecular profiling were younger, more heavily pretreated, and had more favorable Princess Margaret Hospital Index (PMHI) scores. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (p = .002), internal referrals within PM (p = .002), and PMHI (p ≤ .001) were independently associated with successful trial enrollment in multivariable analysis. CONCLUSION: Although nearly half of new patients referred to a phase I clinic had prior molecular profiling, the proportion subsequently enrolled into clinical trials was low. Prior molecular profiling was not an independent predictor of clinical trial enrollment. IMPLICATIONS FOR PRACTICE: The landscape of oncology drug development is evolving alongside technological advancements. Recently, large academic medical centers have implemented clinical sequencing protocols to identify patients with actionable genomic alterations to enroll in therapeutic clinical trials. This study evaluates patient referral and enrollment patterns in a large academic phase I clinical trials program following the implementation of a molecular profiling program. Performance status and referral from a physician within the institution were associated with successful trial enrollment, whereas prior molecular profiling was not an independent predictor.