Immunotherapy has revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall ...survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials.
Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m
once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated.
After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3-5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs.
At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.
HPV-Associated Head and Neck Cancer Vokes, Everett E; Agrawal, Nishant; Seiwert, Tanguy Y
JNCI : Journal of the National Cancer Institute
107, Issue:
12
Journal Article
Peer reviewed
Open access
Over the last two decades, it has been recognized that head and neck cancers, primarily in the oropharynx, can be a distinct entity that is causally related to human papilloma virus (HPV). Fakhry et ...al. established in 2008 that such tumors have a strikingly better prognosis with improved responsiveness to chemotherapy as well as chemoradiotherapy and favorable survival rates. Since then, new studies have contributed to our increased understanding of this new entity, ranging from a detailed understanding of the genetic fingerprint and risk modifiers such as smoking to successful early attempts to personalize therapy with de-escalation in the definitive intent treatment setting and specific evaluation of targeted therapies in this patient population. This Commentary seeks to summarize the state of the art of our understanding of HPV-associated head and neck cancers that has emerged since the publication of seminal findings by Fakhry et al.
The genetic differences between human papilloma virus (HPV)-positive and -negative head and neck squamous cell carcinomas (HNSCC) remain largely unknown. To identify differential biology and novel ...therapeutic targets for both entities, we determined mutations and copy-number aberrations in a large cohort of locoregionally advanced HNSCC.
We performed massively parallel sequencing of 617 cancer-associated genes in 120 matched tumor/normal samples (42.5% HPV-positive). Mutations and copy-number aberrations were determined and results validated with a secondary method.
The overall mutational burden in HPV-negative and HPV-positive HNSCC was similar with an average of 15.2 versus 14.4 somatic exonic mutations in the targeted cancer-associated genes. HPV-negative tumors showed a mutational spectrum concordant with published lung squamous cell carcinoma analyses with enrichment for mutations in TP53, CDKN2A, MLL2, CUL3, NSD1, PIK3CA, and NOTCH genes. HPV-positive tumors showed unique mutations in DDX3X, FGFR2/3 and aberrations in PIK3CA, KRAS, MLL2/3, and NOTCH1 were enriched in HPV-positive tumors. Currently targetable genomic alterations were identified in FGFR1, DDR2, EGFR, FGFR2/3, EPHA2, and PIK3CA. EGFR, CCND1, and FGFR1 amplifications occurred in HPV-negative tumors, whereas 17.6% of HPV-positive tumors harbored mutations in fibroblast growth factor receptor genes (FGFR2/3), including six recurrent FGFR3 S249C mutations. HPV-positive tumors showed a 5.8% incidence of KRAS mutations, and DNA-repair gene aberrations, including 7.8% BRCA1/2 mutations, were identified.
The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly, including targetable genes. HNSCC harbors multiple therapeutically important genetic aberrations, including frequent aberrations in the FGFR and PI3K pathway genes. See related commentary by Krigsfeld and Chung, p. 495.
Treatment of locoregionally advanced head and neck squamous cell carcinoma involves a multidisciplinary approach that combines surgery, radiotherapy, and systemic therapy. These curative strategies ...are associated with significant acute and long‐term toxicities. With the emergence of human papillomavirus (HPV) as an etiologic factor associated primarily with oropharyngeal squamous cell carcinoma, higher cure rates juxtaposed with substantial treatment‐related morbidity and mortality has led to interest in de‐escalated therapeutic strategies, with the goal of optimizing oncologic outcomes while reducing treatment‐related toxicity. Currently explored strategies include replacing, reducing, or omitting cytotoxic chemotherapy; reducing dose or volume of radiotherapy; and incorporation of less‐invasive surgical approaches. Potential biomarkers to select patients for treatment de‐escalation include clinical risk stratification, adjuvant de‐escalation based on pathologic features, response to induction therapy, and molecular markers. The optimal patient selection and de‐escalation strategy is critically important in the evolving treatment of locoregional head and neck cancer. Recently, two large phase III trials, RTOG 1016 and De‐ESCALaTE, failed to de‐escalate treatment in HPV‐associated head and neck cancer by demonstrating inferior outcomes by replacing cisplatin with cetuximab in combination with radiation. This serves as a cautionary tale in the future design of de‐escalation trials in this patient population, which will need to leverage toxicity and efficacy endpoints. Our review summarizes completed and ongoing de‐escalation trials in head and neck cancer, with particular emphasis on biomarkers for patient selection and clinical trial design.
Implications for Practice
The toxicity associated with standard multimodality treatment for head and neck cancer underscores the need to seek less‐intensive therapies with a reduced long‐term symptom burden through de‐escalated treatment paradigms that minimize toxicity while maintaining oncologic control in appropriately selected patients. Controversy regarding the optimal de‐escalation strategy and criteria for patient selection for de‐escalated therapy has led to multiple parallel strategies undergoing clinical investigation. Well‐designed trials that optimize multimodal strategies are needed. Given the absence of positive randomized trials testing de‐escalated therapy to date, practicing oncologists should exercise caution and administer established standard‐of‐care therapy outside the context of a clinical trial.
This review summarizes completed and ongoing clinical trials evaluating treatment de‐escalation in head and neck cancer, with an emphasis on biomarkers for patient selection and trial design.
Patients with non–small-cell lung cancer were randomly assigned to three cycles of chemotherapy with or without nivolumab, an anti–PD-1 antibody. Event-free survival was longer with nivolumab than ...without it (31.6 months vs. 20.8 months), and the percentage of patients with a pathological complete response was 24.0% and 2.2%, respectively.
In a randomized study of second-line therapy, treatment with nivolumab, an anti–PD-1 antibody, resulted in responses in more people and in better overall survival than did docetaxel.
Squamous-cell ...carcinoma represents approximately 30% of all cases of non–small-cell lung cancer (NSCLC).
1
Treatment for advanced squamous-cell NSCLC remains an unmet need; little therapeutic progress has been made since the approval of docetaxel for second-line treatment in 1999.
2
–
4
Most new agents for the treatment of NSCLC are not indicated for this subtype because of their toxicity or lack of efficacy or because their activity is limited to tumors with specific genetic alterations that are rarely found in squamous-cell NSCLC.
5
–
7
Furthermore, no single-agent therapy has resulted in better survival than that seen with docetaxel.
The programmed death 1 (PD-1) . . .
A model's ability to express its own predictive uncertainty is an essential attribute for maintaining clinical user confidence as computational biomarkers are deployed into real-world medical ...settings. In the domain of cancer digital histopathology, we describe a clinically-oriented approach to uncertainty quantification for whole-slide images, estimating uncertainty using dropout and calculating thresholds on training data to establish cutoffs for low- and high-confidence predictions. We train models to identify lung adenocarcinoma vs. squamous cell carcinoma and show that high-confidence predictions outperform predictions without uncertainty, in both cross-validation and testing on two large external datasets spanning multiple institutions. Our testing strategy closely approximates real-world application, with predictions generated on unsupervised, unannotated slides using predetermined thresholds. Furthermore, we show that uncertainty thresholding remains reliable in the setting of domain shift, with accurate high-confidence predictions of adenocarcinoma vs. squamous cell carcinoma for out-of-distribution, non-lung cancer cohorts.
PDF
