James W. Shaw

Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial

BACKGROUND Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigators choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs). METHODS CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigators choice (n=121) of methotrexate (40-60 mg/m2 of body surface area), docetaxel (30-40 mg/m2), or cetuximab (250 mg/m2 after a loading dose of 400 mg/m2) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigators choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigators choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life-5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636. FINDINGS Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigators choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigators choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from -2·1 to 5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigators choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, -24·5 to 2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigators choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigators choice group (7·3 vs -7·8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigators choice for 13 (37%) of 35 domains assessed across the three questionnaires. INTERPRETATION In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigators choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigators choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting. FUNDING Bristol-Myers Squibb.

Abstract CT099: Nivolumab (nivo) vs investigator's choice (IC) for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): CheckMate-141

Background: Patients (pts) with platinum-refractory R/M SCCHN have an extremely poor prognosis and no chemotherapy (CT) options to extend survival. Nivo, a fully human anti-programmed death-1 monoclonal antibody, is FDA-approved and improves survival in other tumor types. Methods: A randomized, open-label, phase 3 trial (NCT02105636) assigned pts (stratified by prior cetuximab) with SCCHN who progressed within 6 mo of platinum-based CT in a 2:1 ratio to nivo 3 mg/kg Q2W or weekly single-agent IC (methotrexate 40-60 mg/m2, docetaxel 30-40 mg/m2, or cetuximab 400-mg/m2 loading dose followed by 250 mg/m2 weekly). Pts must not have received systemic therapy subsequent to biopsy and prior to screening. Pts could receive nivo beyond disease progression if there was evidence of clinical benefit. The primary endpoint was OS. Secondary endpoints were PFS and objective response rate (ORR) by RECIST 1.1. Additional endpoints included safety and outcomes by PD-L1 and HPV (p16 IHC) status. An interim analysis (IA) was planned after at least 195 deaths. Results: Of 361 randomized pts, median age was 60.0 yr, 76.5% were current/former smokers, 54.8% had received ?2 prior lines of CT, 91.4% had prior radiotherapy, and 98.3% had ECOG score ?1. At IA, 133 of 240 pts (55.4%) on nivo and 85 of 121 pts (70.2%) on IC had died. Nivo-treated pts had a 30% reduction in risk of death (HR, 0.70; 97.73% CI, 0.51-0.96; P = 0.010); median OS was 7.5 mo (95% CI, 5.5-9.1) with nivo vs 5.1 mo (95% CI, 4.0-6.0) with IC. Tumor PD-L1 status was evaluable in 260 pts (72.0%). Median OS in pts with PD-L1 ?1% was 8.7 mo with nivo vs 4.6 mo with IC (HR, 0.55; 95% CI, 0.36-0.83) and, in pts with PD-L1 Conclusions: Nivo improved OS in pts with platinum-refractory R/M SCCHN compared to single-agent IC therapy. Pts with PD-L1 ?1% and HPV+ pts had significantly longer median OS with nivo than with IC, but nivo was effective regardless of PD-L1 or HPV status. As the first immunotherapy agent to increase survival in a randomized phase 3 study in R/M SCCHN, nivo is a new standard of care option for these pts. Citation Format: Maura L. Gillison, George Blumenschein, Jerome Fayette, Joel Guigay, A. Dimitrios Colevas, Lisa Licitra, Kevin Harrington, Stefan Kasper, Everett E. Vokes, Caroline Even, Francis Worden, Nabil F. Saba, Lara Carmen Iglesias Docampo, Robert Haddad, Tamara Rordorf, Naomi Kiyota, Makoto Tahara, Manish Monga, Mark Lynch, William J. Geese, Mark Schactman, Justin Kopit, James W. Shaw, Robert L. Ferris. Nivolumab (nivo) vs investigator9s choice (IC) for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): CheckMate-141. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT099.

Overall Survival (Os), Quality Of Life (Qol), And Neurocognitive Function (Nf) In Recurrent Glioblastoma Multiforme (Gbm): A Systematic Literature Review.

• Patient-reported outcome (PRO) instruments used to assess QoL among patients with recurrent GBM included the European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30), the EORTC QLQ Brain Cancer Module (EORTC QLQBN20), the Functional Assessment of Cancer Therapy (FACT)–General (FACT-G), the FACT–Brain (FACT-Br), and the 36-Item Short-Form Health Survey (SF-36) (Table 2)

Patient-reported outcomes with nivolumab in advanced solid cancers

Patients with recurrent or metastatic cancer commonly suffer from debilitating toxicity associated with conventional treatment modalities, as well as disease-related symptoms, often with a concomitant negative impact on health-related quality of life (HRQoL). Patient-reported outcomes (PROs) provide important insights into the patient experience in clinical trials. Nivolumab is a programmed death-1 receptor inhibitor that extends survival in patients with recurrent or metastatic disease in multiple tumor types. In this review, we summarize published PRO analyses from eight phase II-IV clinical trials with nivolumab for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma (RCC), and squamous cell carcinoma of the head and neck (SCCHN). Symptom burden, physical functioning, and HRQoL were measured using generic, cancer-specific, and tumor type-specific validated PRO instruments. Nivolumab showed sustained stabilization across all tumor types and, in some cases, clinically meaningful improvement in HRQoL, whereas standard of care therapies often led to deteriorations. Exploratory analyses found a positive correlation between baseline HRQoL scores and overall survival in RCC, and between baseline HRQoL scores and healthcare resource utilization in SCCHN, suggesting that patient-reported symptoms at treatment initiation may have clinical value. In the era of value-based oncology care, stakeholders are increasingly interested in PRO findings to guide clinical, regulatory, and reimbursement decisions. However, missing data remain a significant challenge in PRO analyses, including in nivolumab trials. Future clinical trials in immuno-oncology should incorporate PRO data collection, including beyond treatment discontinuation or trial completion to assess the long-term effects of treatment on HRQoL.

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