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.
Hyperprogressive disease occurs in 7% of patients with mixed solid tumors treated with immunotherapy (predominantly anti–programmed death ligand 1 antibodies). Hyperprogressive disease is more common among females, but no association with other clinical factors or treatment‐related toxicity has been found.
Older patients are significantly underrepresented in cancer clinical trials. A literature review was undertaken to identify the barriers that impede the accrual of this vulnerable population onto ...clinical trials and to determine what specific strategies are needed to improve the representation of older patients in research studies.
A systematic literature search was undertaken using several different strategies to identify relevant articles.
Nine of 31 relevant papers from 159 citations were included. Age is a significant barrier to recruitment; only a quarter to one third of potentially eligible older patients are enrolled onto trials. Physicians' perceptions, protocol eligibility criteria with restrictions on comorbid conditions, and functional status to optimize treatment tolerability are the most important reasons resulting in the exclusion of older patients. Other barriers include the lack of social support and the need for extra time and resources to enroll these patients. Conversely, older patients do not view their age as an important reason for refusing trials.
Specific clinical trials confined to older patients should be conducted to evaluate tumor biology, treatment tolerability, and the effect of comorbid conditions. Protocol designs need to stratify for age and be less restrictive with respect to exclusions on functional status, comorbidity, and previous cancers, such that results are generalizable to older patients. Physician education to dispel unfounded perceptions, improved access to available clinical trials, and provision of personnel and resources to accommodate the unique requirements of an older population are possible solutions to remove the barriers of ageism.
Molecular-targeted agents are increasingly used for the treatment of cancer. However, the attrition rate for drugs that enter early clinical trials is higher than for other branches of internal ...medicine, suggesting that preclinical development has not been successful in identifying agents that can modify the outcome of human cancer. New preclinical strategies including genetically engineered mouse models and small-interfering RNAs are being used to evaluate novel agents, and have aided in the development of compounds, such as inhibitors of phosphatidylinositol 3-kinase or poly(ADP-ribose) polymerase. In addition, these techniques have helped in the identification of promising combinations of targeted drugs. In this Review, we describe methods for the preclinical evaluation of novel agents, their limitations, and strategies for improvement.
To report atypical clinical behavior observed in human papillomavirus (HPV)-related oropharyngeal carcinoma (OPC) treated with radiotherapy.
A retrospective cohort study was conducted for all newly ...diagnosed OPC cases treated with radiotherapy on July 1, 2003 to April 30, 2009. HPV positivity was determined by p16 immunostaining in tumors. The incidence of additional malignancies and the pattern of distant metastases (DMs) were compared between the HPV-positive (HPV+) and HPV-negative (HPV-) cohorts.
HPV status was evaluated in 318 of 613 consecutive OPC cases (52%), showing 236 HPV+ and 82 HPV- patients. Compared with HPV-, HPV+ cases were less likely to have additional malignancies (prior: 11% vs. 20%, p = 0.038; synchronous: 1% vs. 9%, p = 0.001; metachronous: 6% vs. 16%, p = 0.003). Whereas the majority (10 of 12) of HPV- additional head-and-neck (HN) mucosal malignancies were in the oral cavity, there was none (0 of 7) in the HPV+ cohort (p < 0.001). HPV+ synchronous HN second primaries (SPs) were in the supraglottis, post-cricoid, and nasopharynx; metachronous HN SPs were in the glottis, supraglottis, and ethmoid plus glottis/post-cricoid region. All SPs that could be tested were HPV+. There was no difference in DM rate (10% vs. 15%, p = 0.272), but HPV+ DMs were more likely to involve multiple organs (46% vs. 0%, p = 0.005) and unusual sites.
This study reports atypical clinical behavior seen in HPV+ OPC, including multicentric lesions in HN mucosa and DM to multiple organs and unusual sites. The frequency of these events is low, but they may have clinical implications. The routine assessment of HPV status for all OPC is warranted.
To refine stage and prognostic group for human papillomavirus (HPV) -related nonmetastatic (M0) oropharyngeal cancer (OPC).
All patients with nonmetastatic (M0) p16-confirmed OPC treated with ...radiotherapy with or without chemotherapy from 2000 to 2010 were included. Overall survival (OS) was compared among TNM stages for patients with HPV-related and HPV-unrelated OPC separately. For HPV-related OPC, recursive partitioning analysis (RPA) derived new RPA stages objectively. Cox regression was used to calculate adjusted hazard ratios (AHRs) to derive AHR stages. The performance of survival prediction of RPA stage and AHR stage was assessed against the current seventh edition TNM stages. Prognostic groups were derived by RPA, combining RPA stage and nonanatomic factors.
The cohort comprised 573 patients with HPV-related OPC and 237 patients with HPV-unrelated OPC, with a median follow-up of 5.1 years. Lower 5-year OS with higher TNM stage was evident for patients with HPV-unrelated OPC (stage I, II, III, and IV 5-year OS: 70%, 58%, 50%, and 30%, respectively; P = .004) but not for patients with HPV-related OPC (stage I, II, III, and IV 5-year OS: 88%, 78%, 71%, and 74%, respectively; P = .56). RPA divided HPV-related OPC into RPA-I (T1-3N0-2b), RPA-II (T1-3N2c), and RPA-III (T4 or N3; 5-year OS: 82%, 76%, and 54%, respectively; P < .001). AHR also yielded a valid classification, but RPA stage demonstrated better survival prediction. A further RPA (including RPA stage, age, and smoking pack-years PYs) derived the following four valid prognostic groups for survival: group I (T1-3N0-N2c_≤ 20 PY), group II (T1-3N0-N2c_> 20 PY), group III (T4 or N3_age ≤ 70), and group IVA (T4 or N3_age > 70; 5-year OS: 89%, 64%, 57%, and 40%, respectively; P < .001).
An RPA-based TNM stage grouping (stage I/II/III: T1-3N0-N2b/T1-3N2c/T4 or N3, with M1 as stage IV) is proposed for HPV-related OPC as a result of significantly improved survival prediction compared with the seventh edition TNM, and prognostication is further improved by an RPA-based prognostic grouping within the American Joint Committee on Cancer/Union for International Cancer Control TNM framework for HPV-related OPC.
Investigation and utilization of molecularly targeted agents has induced a number of drug adverse effects that are not typically associated with conventional chemotherapy. QT interval prolongation, a ...cardiac toxicity that increases the risk of fatal arrhythmia, is associated with several novel oncology therapies. Classes of molecularly targeted agents with described QT effects include histone deacetylase inhibitors, multitargeted tyrosine kinase inhibitors, vascular disruption agents, farnesyl protein transferase inhibitors, Src/Abl kinase inhibitors, and protein kinase C inhibitors. Concurrently, guidelines for monitoring the QT-prolonging effects of drugs under development have become increasingly rigorous. Although these guidelines apply to anticancer agents, they were not specifically designed for the oncology patient population. This article will review the pathophysiology of QT prolongation, methods of preclinical QT assessment, and current guidelines for QT evaluation in early phase trials. Additionally, molecularly targeted agents with QT effects will be summarized, and mechanisms of addressing this toxicity in the context of oncology drug development will be explored.
An ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership after publication or presentation of potentially practice-changing data from major studies. This provisional ...clinical opinion addresses the role of treatment deintensification in the management of p16+ oropharyngeal cancer (OPC).
For patients with p16+ OPC, current treatment approaches are well established. In the good-prognosis subset of nonsmoking p16+ patients with early-stage disease, these treatments have been highly successful, albeit with significant associated acute and late toxicity. Deintensification of surgical, radiation, and medical treatment in an effort to reduce toxicity while preserving high survival rates is an appropriate therapeutic objective currently being explored in patients who are experiencing the best treatment results. However, careful delineation of this good-risk subset is essential. While the current eighth edition of the American Joint Committee on Cancer staging system is prognostically robust, it should not be interpreted as reason to alter therapeutic decisions or justify treatment deintensification. The development of transoral surgical techniques and the adoption of intensity-modulated radiation therapy planning have been transformative in disease management and suggest potentially beneficial approaches. Recent advances in systemic treatments have been notable. The optimal integration and modification of these modalities to ameliorate toxicity has not been defined and remains an important focus of current investigation.
The hypothesis that de-escalation of treatment intensity for patients with p16+ OPC can reduce long-term toxicity without compromising survival is compelling and necessitates careful study and the analysis of well-designed clinical trials before changing current treatment standards. Treatment deintensification for these patients should only be undertaken in a clinical trial. Additional information is available at www.asco.org/head-neck-cancer-guidelines .
Rapidly accruing knowledge of the mutational landscape of malignant neoplasms, the increasing facility of massively parallel genomic sequencing, and the availability of drugs targeting many "driver" ...molecular abnormalities have spurred the oncologic community to consider how to use these new tools to improve cancer treatment. In order to assure that assignment of patients to a particular targeted treatment is likely to be beneficial to the patient, it will be necessary to conduct appropriate clinical research. It is clear that clinical (histology and stage) eligibility criteria are not sufficient for most clinical trials using agents that target mutations that are present in only a minority of patients. Recently, several clinical trial designs have been suggested to test the benefit of targeted treatment in molecular and/or clinical subgroups of patients. However, challenges remain in the implementation of such trials, including choice of assay, levels of evidence regarding gene variants, tumor heterogeneity, identifying resistance mechanisms, the necessity of screening large numbers of patients, infrastructure needs, and collaboration of investigators and industry. This article reviews current trial designs and discusses some of the considerations, advantages, and drawbacks of designing clinical trials that depend on particular molecular variants as eligibility criteria.
PF-00562271 is a novel inhibitor of focal adhesion kinase (FAK). The objectives of this study were to identify the recommended phase II dose (RP2D) and assess safety and tolerability, ...pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of PF-00562271.
Part 1 was a dose escalation without and with food. Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF-00562271 on single-dose midazolam PK in a subgroup of patients.
Ninety-nine patients (median age, 60 years; 98% with Eastern Cooperative Oncology Group performance status of 0 or 1) were treated in 12 fasting and three fed cohorts. The 125-mg twice-per-day fed dose was deemed the maximum-tolerated dose (MTD) and RP2D. Grade 3 dose-limiting toxicities included headache, nausea/vomiting, dehydration, and edema. Nausea was the most frequently observed toxicity (60% of patients, all grades 1 or 2 at RP2D). PF-00562271 exposure increased with increasing dose; serum concentration-time profiles showed characteristic nonlinear disposition. Steady-state exposures were reached within 1 week. On coadministration, geometric mean values of midazolam maximal observed serum concentration and area under the serum concentration-time curve increased by 60% and more than two-fold, respectively. Of 14 patients evaluable by (18)Ffluorodeoxyglucose positron emission tomography in the expansion cohorts, seven metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans, and 15 of these remained stable for six or more cycles.
The MTD and RP2D of PF-00562271 is 125 mg twice per day with food. PF-00562271 displayed time- and dose-dependent nonlinear PK and is likely a potent CYP 3A inhibitor. This first-in-class study supports further investigation of FAK as a promising therapeutic target.
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