Expanding Treatment Options in SCCHN: What Role Do Cancer Immunotherapies Have? - PowerPoint Presentation

Expanding Treatment Options in SCCHN: What Role Do Cancer Immunotherapies Have? Moderator Robert Haddad, MD Associate Professor of Medicine Harvard Medical School Disease Center Leader Head and Neck Oncology Program Dana Farber Cancer Institute Boston, Massachusetts

Panelists Jessica Bauman, MD Assistant Professor Department of Hematology/Oncology Fox Chase Cancer CenterPhiladelphia, Pennsylvania Ranee Mehra, MD Associate Professor of Oncology Johns Hopkins School of Medicine Baltimore, Maryland

This program will include a discussion of off-label treatment and investigational agents not approved by the FDA for use in the United States, and data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal.

NCCN Guidelines®. V.2.2017. Introduction Immune checkpoint inhibition has emerged as a treatment option for patients with recurrent, metastatic squamous cell carcinoma of the head and neck, with approvals for the PD-1 inhibitors nivolumab and pembrolizumab NCCN guidelines recommend nivolumab with a category 1 recommendation and pembrolizumab with a category 2a recommendation for patients with SCCHN who have progressed on or following platinum-based chemotherapy Current research directions include novel agents and combinations in the second line, as well as movement of immune checkpoint antibodies up to the first line

PD-1/PD-L1 Interactions © Medscape, LLC Tumor cell PD-1 PD-L1 T cell MHC TCR Antigen PD-1 PD-L2

Ferris RL, et al. N Engl J Med. 2016;375:1856-1867. CheckMate 141 Study Design Randomized, phase 3 trial of anti-PD-1 nivolumab vs chemotherapy Primary endpoint: OS Secondary endpoints: PFS, ORR Patients (n = 361) Inclusion criteria included Recurrent SCCHN: tumor progression or recurrence within 6 mo of platinum-containing chemotherapy administered as adjuvant or recurrent disease ECOG PS 0 or 1Measurable disease, RECIST 1.1(n = 240)IV nivolumab 3 mg/kg q2w(n = 121)Docetaxel 30 to 40 mg/m2 ORMethotrexate 40 to 60 mg/m2 ORCetuximab-loading 400 mg/m2 followed by 250 mg/m2R2:1

Ferris RL, et al. N Engl J Med. 2016;375:1856-1867. CheckMate 141 Results Grade 3/4 TRAEs: 13.1% on the nivolumab arm vs 35.1% on the chemotherapy arm IMAGE NO LONGER AVAILABLE From N Engl J Med , Ferris RL, et al., Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck, 375, 1856-1867. Copyright © 2016 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Harrington KJ, et al. Lancet Oncol. 2017;18:1104-1115. QoL in Patients Receiving Nivolumab Patients in CheckMate 141 (n = 129) completed PRO questionnaires to assess QoL at weeks 9 and 15 Nivolumab was associated with stable or clinically meaningful improvements in a number of domains as well as delayed time to deterioration of patient-reported QoL Reprinted from Lancet Oncol 18, Harrington KJ, et al., 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, 1104-1115, Copyright 2017, with permission from Elsevier. IMAGE NO LONGER AVAILABLE

a. Chow LQ, et al. J Clin Oncol. 2016. [Epub ahead of print] b. Bauml J, et al. J Clin Oncol. 2017;35:1542-1549. Pembrolizumab Background Approval in recurrent/metastatic SCCHN was based on the results of the phase 1b KEYNOTE-012 trial and phase 2 KEYNOTE-055 results KEYNOTE-012 [a] (n = 132) KEYNOTE-055 [b] (n = 171) ORR, % 18 16 DoR, mo NR8Gr 3/4 TRAEs, %915

Cohen EE, et al. ESMO 2017. Abstract LBA45. KEYNOTE-040Study Design Randomized, phase 3 trial of anti-PD-1 pembrolizumab vs chemotherapy (n = 495) Key Eligibility Criteria SCC of the oral cavity, oropharynx, hypopharynx, or larynx PD after platinum-containing regimen for R/M HNSCC or recurrence or PD within 3 to 6 mo of multimodal therapy using platinum ECOG PS 0 or 1 Known p16 status (oropharynx ) Tissue sample for PD-L1 assessment(n = 247)Pembrolizumab200 mg IV q3wfor 2 y(n = 248)Methotrexate 40 mg/m2 ORDocetaxel 75 mg/m2 ORCetuximab 250 mg/m2 R1:1Stratification FactorsECOG PS (0 vs 1)p16 status (positive vs negative)PD-L1 TPS (≥ 50% vs < 50%)Primary endpoint: OS in the ITT populationSecondary endpoints:OS in the CPS ≥ 1 populationPFS in the ITT and CPS ≥ 1 populationsORR in the ITT and CPS ≥ 1 populationsDoR in the ITT and CPS ≥ 1 populationsSafety and tolerability

KEYNOTE-040Results Gr 3/4 TRAEs: 13.4% with pembrolizumab vs 36.3% with standard of care IMAGE NO LONGER AVAILABE Cohen EE, et al. ESMO 2017. Abstract LBA45. Reproduced with permission from author.

a. Ferris RL, et al. N Engl J Med. 2016;375:1856-1867; b. Cohen EE, et al. ESMO 2017. Abstract LBA45. Nivolumab and Pembrolizumab The results for pembrolizumab and nivolumab themselves are similar; the standard of care arm in the pembrolizumab trial was surprisingly high Some differences between trials Docetaxel schedule Randomization: 1:1 with pembrolizumab and 2:1 with nivolumab Eligibility: patients were required to have ≥ 3-mo PFS period with pembrolizumab; any progression was eligible with nivolumab Nivolumab [a] Pembrolizumab [b] mOS, mo 7.5 8.4 mPFS, mo 2.02.1ORR, %13.314.6Gr 3/4 TRAEs, %13.113.4

Ferris RL, et al. N Engl J Med. 2016;375:1856-1867. Cohen EE, et al. ESMO 2017. Abstract LBA45. Implications for Practice Both nivolumab and pembrolizumab have activity It is possible results of the pembrolizumab trial were confounded because 12.5% of patients in the standard care did crossover to receive checkpoint inhibitors Toxicity was consistently lower for PD-1 antibody therapy than for standard of care It appears both agents will continue to be used

a. Cohen EE, et al. ESMO 2017. Abstract LBA45. b. Ferris RL, et al. N Engl J Med. 2016;375:1856-1867. Biomarkers PD-L1 Patients in both trials with tumors that did not express PD-L1 still had responses KEYNOTE-040 a Used measurements of CPS (all PD-L1) and TPS (tumor PD-L1) OS using CPS was 8.7 mo with pembrolizumab vs 7.1 mo with SOC ( P = .0078) OS using TPS was 11.6 mo with pembrolizumab vs 7.9 mo with SOC ( P = .0017) CheckMate-141 [b]OS using PD-L1 ≥ 1% was 8.7 mo with nivolumab vs 4.6 mo with SOC

Ferris RL, et al. N Engl J Med. 2016;375:1856-1867. Biomarkers HPV HPV (p16) is a positive prognostic indicator in SCCHN, but it does not predict response to immunotherapy Still, HPV-negative tumors can respond to checkpoint inhibition Other biomarkers are being explored, including tumor mutational burden and gene expression profile p16-Positive Patients in Nivolumab Arm p16-Negative Patients in Nivolumab Arm mOS, mo 9.1 7.5

Haddad R, et al. ESMO 2017. Abstract 10430. Treatment Beyond Progression In CheckMate 141, 146 patients (61%) randomly assigned to nivolumab experienced progression 62 patients (42%) received ≥ 1 dose nivolumab after progression and 84 (58%) did not mOS of those treated beyond progression: 12.7 mo Haddad R, et al. ESMO 2017. Abstract 10430. Reproduced with permission from author. IMAGE NO LONGER AVAILABLE

Deciding to Treat Beyond Progression Decision to treat beyond progression rests primarily with the patient's presentation A patient whose scans show progression but who has a good ECOG PS and continues to feel well may be a candidate to continue to receive treatment A patient whose scans show progression and who is also feeling worse, whose ECOG PS has declined, should no longer receive treatment

Haanen JB, et al. Ann Oncol. 2017;28:iv119-iv142. irAEs irAEs can affect any organ system Patients should be educated on symptoms and importance of communication, as early detection is critical irAEs such as pneumonitis and colitis can be life-threatening if not caught early Endocrinopathies, particularly hypothyroidism, occur more often in patients with SCCHN Thyroid function should be monitored routinely Nonspecific symptoms include fatigue, nausea, headache, and depression Hypothyroidism, even subclinical cases, should be treated with thyroid hormone replacement; this is usually permanent; treatment with checkpoint inhibition does not need to be interrupted β-blockers may be used in symptomatic patients Steroids and carbimazole are rarely required, but when they are, treatment with checkpoint inhibition should be interrupted until recovery from symptoms

Moon YW, et al. J Immunothera Cancer. 2015;3:51. IDO T reg TC DC MΦ FB TC EC IDO ↑ Krn↑ Trp↓ mTORC1↓ GCN2↑ AHR↑ Anergy Activation ↑T cell apoptosis ↓T cell proliferation ↓Antitumor immune response

a. Hamid O, et al. ASCO® 2017. Abstract 6010. b. Perez RP, et al. ASCO® 2017. Abstract 3003. Epacadostat IDO Inhibitor ECHO-202/KEYNOTE-037 [a] : phase 1/2 trial of epacadostat + pembrolizumab in multiple tumor types with ≥ 1 prior chemotherapy regimen SCCHN cohort (n = 38) ORR: 34% Gr 3/4 AEs: 18% ECHO-204 [b] : phase 1/2 trial of epacadostat + nivolumab in advanced solid tumors with ≥ 1 prior chemotherapy regimenSCHHN cohort (n = 31)ORR: 23%Gr 3/4 TRAEs for full tumors: 7% (100 mg) to 39% (300 mg)

a. Zandberg D, et al. ESMO 2017. Abstract 10420. b. ClinicalTrials.gov. NCT02369874. Durvalumab Durvalumab is a PD-L1 inhibitor approved in bladder cancer HAWK [a] : p hase 2 trial of durvalumab in patients with recurrent , metastatic SCCHN (n = 112) who had prior platinum-based chemotherapyPatients all had PD-L1 high expression ( TC ≥ 25%)ORR: 16.2% mOS: 7.1 moGr 3/4 TRAEs: 8%EAGLE[b]: phase 3 trial of durvalumab +/− anti-CTLA4 inhibitor tremelimumab vs SOC in patients with R/M SCCHN who have received prior platinum-based chemotherapy was recently completed

a. Argiris A, et al. ESMO 2016. Abstract 1016TiP; b. Seiwert TY, et al. ASCO® 2016. Abstract TPS6101; c. Klochikhin A, et al. Ann Oncol. 2015;26(suppl). Abstract 11TiP. Moving to the First Line Trials are ongoing in the use of checkpoint inhibition in the first-line setting These include patients who are eligible for EXTREME or patients who have been free from progression for 6 mo after platinum-based therapy CheckMate-651 [a] : phase 3 trial of nivolumab + ipilimumab vs EXTREME as first-line therapy in R/M SCCHN KESTREL [b] : p hase 3 trial durvalumab +/− tremelimumab vs SOC EXTREME as first-line therapy in R/M SCCHN KEYNOTE-048[c]: phase 3 trial of pembrolizumab +/− SOC vs SOC as first-line therapy in R/M SCCHN

a. Lee NY, et al. ASCO® 2017. Abstract TPS6093. b. Machiels JP, et al. ASCO® 2017. Abstract TPS6090. Moving to the Curative Setting Trials are ongoing in the use of checkpoint inhibition in patients with previously untreated, locally advanced disease JAVELIN [a] : phase 3 trial of avelumab with CRT vs CRT alone for first-line treatment of locally advanced SCCHN KEYNOTE-412 [b] : phase 3 trial of pembrolizumab with CRT and as maintenance therapy vs CRT alone in locally advanced SCCHN Need to identify patients at high risk for recurrence (eg, HPV-negative cases) who may be better candidates for the additional therapy

a. Uppaluri R, et al. ASCO® 2017. Abstract 6012. b. Ferris RL, et al. ESMO 2017. Abstract LBA46. The Future Neoadjuvant therapy starting to be explored Ongoing phase 2 trial [a] using pembrolizumab as neoadjuvant plus postoperative adjuvant therapy in patients with surgically resectable HPV-negative, stage III/IV SCCHN Ongoing phase 1/2 trial [b] using nivolumab as neoadjuvant therapy in patients with resectable, HPV+ or HPV− SCCHN Research is starting to reach all stages of the disease Results are anxiously anticipated Coordinated, multidisciplinary care will continue to be essential

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