Maura L. Gillison

NCCN Guidelines Insights: Head and Neck Cancers, Version 2.2017

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panels discussion and most recent recommendations regarding the increase in human papillomavirus-associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.

Development and validation of nomograms predictive of overall and progression-free survival in patients with oropharyngeal cancer

Purpose Treatment of oropharyngeal squamous cell carcinoma (OPSCC) is evolving toward risk-based modification of therapeutic intensity, which requires patient-specific estimates of overall survival (OS) and progression-free survival (PFS). Methods To develop and validate nomograms for OS and PFS, we used a derivation cohort of 493 patients with OPSCC with known p16 tumor status (surrogate of human papillomavirus) and cigarette smoking history (pack-years) randomly assigned to clinical trials using platinum-based chemoradiotherapy (NRG Oncology Radiation Therapy Oncology Group [RTOG] 0129 and 0522). Nomograms were created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index. Nomograms were externally validated in a cohort of 153 patients with OPSCC randomly assigned to a third trial, NRG Oncology RTOG 9003. Results Both models included age, Zubrod performance status, pack-years, education, p16 status, and T and N stage; the OS model also included anemia and age × pack-years interaction; and the PFS model also included marital status, weight loss, and p16 × Zubrod interaction. Predictions correlated well with observed 2-year and 5-year outcomes. The uncorrected concordance index was 0.76 (95% CI, 0.72 to 0.80) for OS and 0.70 (95% CI, 0.66 to 0.74) for PFS, and bias-corrected indices were similar. In the validation set, OS and PFS models were well calibrated, and OS and PFS were significantly different across tertiles of nomogram scores (log-rank P = .003;< .001). Conclusion The validated nomograms provided useful prediction of OS and PFS for patients with OPSCC treated with primary radiation-based therapy.

NCCN guidelines® insights: Head and neck cancers, version 1.2018 featured updates to the NCCN guidelines

The NCCN Guidelines for Head and Neck (H&N) Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the H&N, and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panels discussion and most recent recommendations regarding evaluation and treatment of nasopharyngeal carcinoma.

Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression

OBJECTIVESnWe report 2-year results from CheckMate 141 to establish the long-term efficacy and safety profile of nivolumab and outcomes by tumor PD-L1 expression in patients with recurrent or metastatic (R/M),platinum-refractory squamous cell carcinoma of the head and neck (SCCHN).nnnMETHODSnPatients with R/M SCCHN with tumor progression/recurrence within 6u202fmonths of platinum therapy were randomized 2:1 to nivolumab 3u202fmg/kg every 2u202fweeks or investigators choice (IC). Primary endpoint: overall survival (OS). Data cutoff: September 2017.nnnRESULTSnWith 24.2u202fmonths minimum follow-up, nivolumab (nu202f=u202f240) continued to improve OS vs IC (nu202f=u202f121), hazard ratio (HR)u202f=u202f0.68 (95% CI 0.54-0.86). Nivolumab nearly tripled the estimated 24-month OS rate (16.9%) vs IC (6.0%), and demonstrated OS benefit across patients with tumor PD-L1 expression ≥1% (HR [95% CI]u202f=u202f0.55 [0.39-0.78]) and u202f<u202f1% (HR [95% CI]u202f=u202f0.73 [0.49-1.09]), and regardless of tumor HPV status. Estimated OS rates at 18, 24, and 30u202fmonths with nivolumab were consistent irrespective of PD-L1 expression (<1%/≥1%). In the nivolumab arm, there were no observed differences in baseline characteristics or safety profile between long-term survivors and the overall population. Grade 3-4 treatment-related adverse event rates were 15.3% and 36.9% for nivolumab and IC, respectively.nnnCONCLUSIONnNivolumab significantly improved OS at the primary analysis and demonstrated prolonged OS benefit vs IC and maintenance of a manageable and consistent safety profile with 2-year follow-up. OS benefit was observed with nivolumab irrespective of PD-L1 expression and HPV status. (Clinicaltrials.gov: NCT02105636).

Abstract CT021: Tumor-associated immune cell PD-L1 expression and peripheral immune profiling: Analyses from CheckMate 141

Introduction: In the phase 3 study CheckMate 141 (NCT02105636), patients with platinum-refractory head and neck squamous cell carcinoma treated with nivolumab (NIVO) had longer median overall survival (OS) (7.5 vs 5.1 months; P=0.01) and a higher objective response rate (all: 13.3 vs 5.8%; tumor PD-L1 ≥1%: 17 vs 1.6%) compared with investigator’s choice (IC) (Ferris et al. NEJM. 2016). This exploratory analysis evaluated the immune profile of patients from CheckMate 141, in context of tumor PD-L1 expression, and assessed the relationship with treatment (txt) outcomes. Methods: PD-L1 expression in tumor and tumor-associated immune cells (TAIC) was analyzed at baseline (n=252) and assessed for association with clinical outcome. Tumor PD-L1 expression was quantitatively assessed using Dako IHC 28-8 pharmDx assay. TAIC PD-L1 abundance (numerous/intermediate, rare) and location (intra/intra-peritumoral, peritumoral) were qualitatively assessed (unvalidated). Peripheral blood (n=36) at baseline and day 43 was assessed for immune cell biomarkers by flow cytometry and analyzed by 2-way ANOVA with Sidak’s multiple comparisons test correction. Results: Abundant PD-L1+ TAICs (numerous/intermediate) were associated with greater median OS with NIVO vs IC in tumors with PD-L1 ≥1% (abundant: 8.7 vs 4.4 months, hazard ratio [HR] and 95% CI 0.44 [0.27, 0.71] and rare: 6.7 vs 4.9 months, HR 0.88 [0.42, 1.86]) and PD-L1 Conclusion: In this exploratory, qualitative immune profile analysis, abundance of PD-L1+ TAICs was associated with higher median OS and greater likelihood of response to NIVO vs IC. Response to NIVO may be associated with higher circulating CD8+ T cells and lower Tregs at baseline, and abundant PD-L1+ TAICs in the tumor microenvironment. Citation Format: Robert L. Ferris, George Blumenschein, Kevin Harrington, Jerome Fayette, Joel Guigay, A. Dimitrios Colevas, Lisa Licitra, Stefan Kasper, Caroline Even, Francis Worden, Nabil F. Saba, Everett Vokes, Cheryl Ho, Fernando Concha-Benavente, Danielle Greenawalt, Chelsea Jin, Mark Lynch, Makoto Tahara, Robert Haddad, Manish Monga, Henry Kao, Maura Gillison. Tumor-associated immune cell PD-L1 expression and peripheral immune profiling: Analyses from CheckMate 141 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT021. doi:10.1158/1538-7445.AM2017-CT021

CheckMate 141: 1‐Year Update and Subgroup Analysis of Nivolumab as First‐Line Therapy in Patients with Recurrent/Metastatic Head and Neck Cancer

Nivolumab significantly improved overall survival (OS) vs investigators choice (IC) of chemotherapy at the primary analysis of randomized, open-label, phase 3 CheckMate 141 in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). Here, we report that OS benefit with nivolumab was maintained at a minimum follow-up of 11.4 months. Further, OS benefit with nivolumab vs IC was also noted among patients who received first-line treatment for R/M SCCHN after progressing on platinum therapy for locally advanced disease in the adjuvant or primary (i.e., with radiation) setting.

Prognostic impact of leukocyte counts before and during radiotherapy for oropharyngeal cancer

Highlights • The prognostic value of pretreatment blood counts is investigated.• This is also done for the nadir neutrophil & lymphocyte levels during radiotherapy.• The impact of treatment modality (IMPT and IMRT) on these nadir levels is examined.• Pretreatment neutrophilia and leukocytosis were associated with worse outcomes.• Treatment modality did not affect blood counts during radiotherapy.

Abstract CT157: Treatment beyond progression with nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck in the phase 3 Checkmate 141 study

Background: Responses in patients (pts) treated with immune checkpoint inhibitors may occur after initial evidence of radiological disease progression. In CheckMate 141, a randomized phase 3 study of nivolumab (nivo) vs investigator’s choice (IC) of standard single-agent therapy in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN), nivo demonstrated prolonged OS compared with IC therapy, hazard ratio = 0.70 (97.73% confidence interval [CI]: 0.51, 0.96). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 13.1% of nivo-treated pts and 35.1% of IC-treated pts. Patient-reported quality of life was stable with nivo and worsened with IC therapy. Here we assessed safety and efficacy in pts treated beyond progression (TBP) with nivo in CheckMate 141. Methods: Treatment beyond investigator-assessed RECIST 1.1-defined progression was permitted in pts in the nivo arm if all criteria prespecified in the protocol were met. Otherwise, pts were not treated beyond progression and discontinued treatment after first progression. Pts without progression, or those who died or discontinued without a tumor assessment to determine progression, were excluded from this analysis. Results: Of the 240 pts randomized to nivo, 139 (58%) experienced RECIST-defined disease progression. Among these pts, 57 (41%) received ≥1 subsequent dose of nivo after progression (TBP group), and 82 (59%) were not treated beyond progression (NTBP group). The mean duration of treatment beyond progression was 2.0 months (range: 0, 9). Median OS was 12.7 months (95% CI: 9.7, not reached) in the TBP group and 6.1 months (95% CI: 4.8, 7.8) in the NTBP group. The objective response rate from randomization to initial progression was 12.3% and 4.9% for the TBP and NTBP groups, respectively; 31.6% and 19.5% of pts, respectively, had stable disease. After initial progression, 13 pts (23%) in the TBP group had tumor burden reduction, with >30% reduction in 2 pts. Of these 13 pts, 7 were HPV+, 3 were PD-L1+, and 4 had ≥20% tumor size increase at first progression. In the TBP and NTBP groups, select TRAEs were similar, with a higher frequency of skin/subcutaneous tissue disorders in the TBP group (29.8% and 11.0%; none were grade 3-4). Select endocrine TRAEs occurred in 10.5% (TBP) and 8.5% (NTBP) of pts; none were grade 3-4. Grade 3-4 TRAEs occurred in 12.3% and 13.4% of pts in the TBP and NTBP groups, respectively. Patient-reported quality of life from randomization through week 21 was generally stable in the TBP group, consistent with trends observed in the overall nivo-treated population. Additional analyses to further characterize TBP and NTBP pts will be presented. Conclusions: These results suggest that nivo treatment beyond RECIST-defined disease progression was tolerable in R/M SCCHN, with some pts experiencing tumor reduction after initial progression. Citation Format: Robert Haddad, Robert L. Ferris, George Blumenschein, Jerome Fayette, Joel Guigay, Alexander D. Colevas, Lisa Licitra, Stefan Kasper, Everett E. Vokes, Francis Worden, Nabil F. Saba, Makoto Tahara, Manish Monga, Mark Lynch, Jin Zhu, James W. Shaw, Maura L. Gillison, Kevin Harrington. Treatment beyond progression with nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck in the phase 3 Checkmate 141 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT157. doi:10.1158/1538-7445.AM2017-CT157