Manish Monga

Phase I and Pharmacokinetic Study of MS-275, a Histone Deacetylase Inhibitor, in Patients With Advanced and Refractory Solid Tumors or Lymphoma

PURPOSE The objective of this study was to define the maximum-tolerated dose (MTD), the recommended phase II dose, the dose-limiting toxicity, and determine the pharmacokinetic (PK) and pharmacodynamic profiles of MS-275. PATIENTS AND METHODS Patients with advanced solid tumors or lymphoma were treated with MS-275 orally initially on a once daily x 28 every 6 weeks (daily) and later on once every-14-days (q14-day) schedules. The starting dose was 2 mg/m2 and the dose was escalated in three- to six-patient cohorts based on toxicity assessments. RESULTS With the daily schedule, the MTD was exceeded at the first dose level. Preliminary PK analysis suggested the half-life of MS-275 in humans was 39 to 80 hours, substantially longer than predicted by preclinical studies. With the q14-day schedule, 28 patients were treated. The MTD was 10 mg/m2 and dose-limiting toxicities were nausea, vomiting, anorexia, and fatigue. Exposure to MS-275 was dose dependent, suggesting linear PK. Increased histone H3 acetylation in peripheral-blood mononuclear-cells was apparent at all dose levels by immunofluorescence analysis. Ten of 29 patients remained on treatment for > or = 3 months. CONCLUSION The MS-275 oral formulation on the daily schedule was intolerable at a dose and schedule explored. The q14-day schedule is reasonably well tolerated. Histone deacetylase inhibition was observed in peripheral-blood mononuclear-cells. Based on PK data from the q14-day schedule, a more frequent dosing schedule, weekly x 4, repeated every 6 weeks is presently being evaluated.

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.

A randomized, open-label, Phase III clinical trial of nivolumab vs. therapy of investigator’s choice in recurrent squamous cell carcinoma of the head and neck: A subanalysis of Asian patients versus the global population in checkmate 141

OBJECTIVES To assess efficacy and safety of nivolumab versus investigators choice of therapy (IC) in Asian patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS Thirty-four patients from Japan, Taiwan, Hong Kong, and Korea received nivolumab 3mg/kg (n=23) every 2weeks or IC (n=11), as part of a global trial (n=361), until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS). RESULTS Median OS was 9.5months (95% confidence interval [CI] 9.1-NR) with nivolumab and 6.2months (95% CI 2.6-NR) with IC. Seven (30.4%) patients receiving nivolumab and six (54.5%) receiving IC died. The hazard ratio (HR) for risk of death (nivolumab vs. IC) was 0.50 (95% CI 0.17-1.48). Median progression-free survival was 1.9months (95% CI 1.6-7.5) with nivolumab and 1.8months (95% CI 0.4-6.1) with IC (HR 0.57 [95% CI 0.25-1.33]). Objective response rates (complete+partial responses) were 26.1% (6/23 patients; 95% CI 10.2-48.4) for nivolumab and 0% (0/11 patients; 95% CI 0.0-28.5) for IC. Sixteen (69.6%) nivolumab-treated patients and 10 (90.9%) patients receiving IC had a treatment-related adverse event, most commonly decreased appetite (21.7%), pruritus, rash, and fatigue (17.4% each) with nivolumab, and nausea, stomatitis, and decreased appetite (27.3% each) with IC. CONCLUSION Nivolumab demonstrated a survival advantage compared with conventional treatments in Asian patients with platinum-refractory recurrent or metastatic SCCHN, and was well tolerated. Clinical trial registration 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.

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

General Approach for Targeting Toxins

Targeted toxins are molecules synthesized to contain an intoxicating domain coupled by either chemical or recombinant approaches to a targeting domain (Fig. 1). The original basis for developing agents of this type was presaged by Ehrlich’s concepts of antibodies as representing a means to create “magic bullets” for the therapy of human neoplastic diseases.