Management of metastatic and recurrent head and neck cancer Erin Alesi, MD Medical Oncology, Palliative Medicine

Objectives Define clinical scenarios for palliative chemotherapy in head and neck cancer Discuss 1st line therapy Discuss immunotherapy Discuss subsequent treatment options

Metastatic and recurrent settings Stage IVC Recurrent Relapse of malignancy in an area not amenable to further surgery or radiation therapy Treatment = Palliative Systemic Therapy + Best Supportive Care Poor Prognosis Average OS 6-9 months

Metastatic and recurrent settings FACTORS Associated with Longer Survival Factors associated with Shorter Survival ECOG PS 0-1 Poorly differentiated histology Response to chemotherapy HPV-associated OP SCCa Poor ECOG PS Weight Loss Prior radiation therapy Active smoking Significant comorbidity

Metastatic and recurrent settings Age Elderly = age >70 Elderly patients generally have more comorbidities Healthy elderly patients have similar survival to younger counterparts but often experience increased treatment-related toxicity

1st line therapy Factors influencing choice of therapy Prior treatment Type Timing Patient characteristics Performance status Comorbidities

1st line therapy Molecularly Targeted Agents Combination therapy Cytotoxic Agents Platinum-based Molecularly Targeted Agents Single Agent Therapy Immunotherapy (select cases)

1st line therapy Cytotoxic Chemotherapy Platinum Agents Cisplatin, Carboplatin Taxanes Docetaxel, Paclitaxel, Nab-Paclitaxel 5-Fluorouracil Methotrexate

1st line therapy Molecularly Targeted Agent Cetuximab EGFR Receptor Antagonist Immunotherapy Pembrolizumab, Nivolumab Immune checkpoint inhibitors of PD-1 Within 6 months of having received platinum in adjuvant or definitive setting

1st Line Therapy Cisplatin vs. Carboplatin Cisplatin thought to be more effective, yet very little data to support Carboplatin Less neurotoxic, nephrotoxic, and emetogenic More myelosuppressive Cisplatin Generally reserved for patients with excellent performance status and organ function

1st Line Therapy – Previously untreated patients

1st Line Therapy – Previously untreated patients EXTREME Trial Phase III, 442 patients, Cisplatin or Carboplatin + 5FU with or without Cetuximab Cisplatin 100mg/m2 D1 or Carboplatin 5 AUC D1 every 21 D x 6 cycles 5FU 1000mg/m2/day x 4 D every 21 D x 6 cycles +/- Cetuximab 400mg/m2 loading dose, followed by weekly 250mg/m2 until disease progression

First Line Therapy – Previously untreated patients EXTREME Trial – 2008 Chemo + Cetuximab = significantly prolonged survival compared to chemo alone Median OS 10.1 vs 7.4 months HR for death 0.8 (95% CI 0.64-0.99) Similar in HPV+ and HPV- patients, though low numbers of HPV+ (HPV+ trended toward better PFS, OS, ORR) Similar overall incidence of severe AE in chemo + cetuximab vs. chemo alone (82 vs 76%)

1st Line Therapy – Previously untreated patients EXTREME Trial Cetuximab patients more likely to experience: Severe hypomagnesemia (5 vs 1%) Severe skin reactions (9 vs <1%) Sepsis (4 vs <1%) Severe infusion-related cetuximab reactions 3%

1st Line Therapy – Previously untreated patients Combination Cytotoxic Chemotherapy Typically platinum-based doublet therapy Better response rates, but no improved survival compared to single-agent chemotherapy Platinum + 5FU 30% RR (better than single agent cisplatin or methotrexate)

1st Line Therapy – Previously untreated patients

1st Line Therapy – Previously untreated patients SWOG Trial 1992 Phase III, 261 patients Cis + 5FU vs. Carbo + 5FU vs. Methotrexate Cisplatin 100mg/m2 D1, 5FU 1000mg/m2/d x 4D every 21 D Carboplatin 300mg/m2 D1, 5FU 1000mg/m2/d x 4D every 28 D Methotrexate 40mg/m2 weekly ORR 32 vs. 21 vs. 10% (combination chemo significantly better) OS 6.6 vs. 5.0 vs. 5.6 mo (no statistical significance) Grade 3-4 toxicity 33 vs. 26 vs. 16%

1st Line Therapy – Previously untreated patients Platinum + Taxane Cisplatin or Carboplatin + Paclitaxel or Docetaxel Similar efficacy to Cisplatin + 5FU ECOG 2005, Phase III, 204 patients Cis + 5FU vs. Cis (75mg/m2) + Paclitaxel (175mg/m2) every 21 D OS 8.7 vs. 8.1 mo (not statistically significant) ORR 27 vs. 26% GI and hematologic toxicity worse in Cis + 5FU group

1st Line Therapy – Previously untreated patients Platinum + Taxane Phase II studies: Cisplatin (70-75mg/m2) + Docetaxel 75- 100mg/m2) every 21 D 25-44 patients ORR 32-55%, higher RR associated with more severe AE OS 11 mo in one trial No Phase III trial comparisons with Cis + 5FU Weekly schedule (Cis 25mg/m2 + D 35mg/m2 x 3 weeks every 28 D) may have similar efficacy with improved toxicity

1st Line Therapy – Previously untreated patients Platinum + Taxane Phase II studies: Carboplatin (6-7 AUC) + Paclitaxel (200mg/m2) or Docetaxel (65mg/m2) every 21 D 24-68 patients ORR 25-43% OS 4.5-15.7 mo in 1 trial (C+P), 7.4 mo in 1 trial (C+D) No randomized trials

1st Line Therapy – Previously untreated patients 3 or 4 cytotoxic drug combinations Phase II trials Cis + 5FU + Taxane or Cis/Carbo + Ifosfamide + Paclitaxel Cis + MTX + Vinblastine + Doxorubicin Greater toxicity, no evidence of superiority to doublet or single- agent cytotoxic chemo

1st Line Therapy – Previously untreated patients Non-platinum Regimens Phase II studies, 46-57 patients Gemcitabine 3000mg/m2 + Paclitaxel 150mg/m2 D1 and 15 every 28 D (GEMTAX) ORR 28%, PFS 4 mo, OS 8 mo Unclear if superior to single-agent taxane therapy Weekly Paclitaxel (80mg/m2) + Cetuximab (400/250mg/m2) ORR 54%, PFS 4 mo, OS 8 mo Poor prognosis patients, unfit for platinum therapy

1st Line Therapy – Previously treated patients Pts who have received induction chemotherapy or concurrent chemoRT in the definitive setting Choice of therapy depends on: Original chemotherapy agents used Response to prior therapy Interval between initial treatment and disease progression Performance status, comorbidities of patient

1st Line Therapy – Previously treated patients EXTREME Trial 39% of patients had received prior induction chemo and/or concurrent chemoradiotherapy at least 6 months prior to trial No significant difference in PFS between pts who had received prior therapy and those who did not Patients without response to initial therapy or relapse within 6 months of therapy are presumed refractory and should be considered for 2nd line therapy

1st Line Therapy Single-agent therapy Poor performance status Cisplatin Carboplatin Paclitaxel Cetuximab

2nd line therapy Immunotherapy Cytotoxic chemotherapy Targeted therapy Consider Prior treatments PS and comorbidities Potential toxicities of available regimens

2nd line therapy PD-1 Inhibitor Immunotherapy Pembrolizumab – FDA approval 8/2016 Nivolumab –FDA approval 11/2016

2nd line therapy

2nd line therapy Pembrolizumab Accelerated approval for pts with progression on or after Platinum-based therapy Conditional upon completion of randomized Phase III trials KEYNOTE-040 (pembro vs. MTX, docetaxel or cetuximab) KEYNOTE-012 Phase Ib, international, open-label, multi-center trial 174 patients with recurrent or metastatic HNSCCa with progression on or after platinum-based therapy Pembrolizumab 200mg (flat dose) every 3 weeks Recommended dose and schedule (vs. 10mg/kg every 2 weeks)

2nd Line Therapy KEYNOTE-012 ORR 16%, CR in 8 pts (5%) Median duration of response not reached (range 2.4-27.7 mo), 82% of pts with response >6 months HPV positive 33% - no effect on response rate Toxicity similar to pembro in other trials, except higher incidence of hypothyroidism (15%) Most common AE: fatigue, anorexia, dyspnea

2nd Line Therapy KEYNOTE-012 Update at ASCO 2016 Treatment at 10mg/kg IV every 2 weeks OS 8 mo 6 mo survival 58% 12 mo survival 38%

2nd line therapy

2nd line therapy CheckMate-141 Phase III RCT, 361 patients with recurrent HNSCCa progressed within 6 months after platinum-based therapy (in any setting) Nivolumab 3mg/kg every 2 weeks vs. single agent cytotoxic chemotherapy MTX 40-60mg/m2 weekly Docetaxel 30-40mg/m2 weekly Cetuximab 400/250mg/m2 weekly

2nd Line therapy CheckMate-141: Nivolumab vs. single agent weekly cytotoxic chemotherapy OS 7.5 vs 5.1 mo (HR 0.7, 98% CI 0.51-0.96) Significantly increased with PD-L1 expression >1% (8.7 vs. 4.6 mo; HR 0.55, 95%CI 0.36-0.83), not significant with PD-L1 <1% Better in HPV+ (9.1 vs 4.4 mo; HR 0.56, 95%CI 0.32-0.99), not significant in HPV- patients (7.5 vs 5.8 mo, HR 0.73, 95% CI 0.42-1.25). 1y survival 36 vs. 16.6% ORR 13.3 vs. 5.8%

2nd line Therapy Cytotoxic Chemotherapy ORR are uncommon after 1st line therapy No evidence of prolonged survival MTX 40-60mg/m2 weekly Docetaxel 30-40mg/m2 weekly Gemcitabine 1250mg/m2 D1 and 8 every 15 D

2nd Line Therapy Molecularly Targeted Therapy Cetuximab Phase II trials, ORR 10%, OS 7.5 mo Alternative dosing 500mg/m2 every 2 weeks has similar efficacy (ORR 11%)

2nd Line Therapy Molecularly Targeted Therapy Small molecule TKIs Some positive data but no clear clinical role established yet

2nd Line Therapy Molecularly Targeted Therapy – Small molecule TKIs Afatinib (EGFR inhibitor) Phase III RCT, 483 pts, Afatinib vs. weekly MTX – LUX-Head & Neck 1 Improved PFS 2.6 vs. 1.7mo (HR 0.8, 95% CI 0.65-0.98) No improvement in OS (6.8 vs 6.0 mo) Afatinib = increased toxicity but fewer treatment discontinuations and delay in deterioration of EORTC global health status (QOL indicator) Better PFS if no prior EGFR MoAb inhibitor therapy, HPV -, locally recurrent disease, non-oropharyngeal primary

2nd Line Therapy Molecularly Targeted Therapy – Small molecule TKIs Gefitinib (EGFR inhibitor) Phase III RCT, 482 pts, gefitinib vs. weekly MTX No difference in OS – approx. 6 months No difference in ORR – 3-8% Phase III RCT, 278 pts, gefitinib + weekly docetaxel vs. placebo + weekly docetaxel No difference in OS (7.3 vs. 6.0 mo) Gefitinib + docetaxel = increased grade 3-4 diarrhea

Upcoming studies 1st Line Therapy KEYNOTE-048 – Phase III, Pembrolizumab vs. Pembro + Platinum + 5FU vs. Cetuximab + Platinum + 5FU in R/M HNSCCa 2nd Line Therapy KEYNOTE-040 – Phase III, Pembro vs. SOC (docetaxel, MTX, or Cetuximab) in R/M HNSCCa after platinum therapy AZ Eagle – Phase III, Durvalumab monotx vs. Durvalumab + Tremelimumab vs. SOC in R/M HNSCCa after platinum therapy LUX-Head & Neck 3 – Phase III, Afatinib vs. MTX in R/M HNSCCa after platinum therapy in pts without prior EGFR inhibitor therapy

Summary Recurrent and metastatic HNSCCa generally has a poor prognosis 1st line combination therapy reserved for patients with good PS Platinum + 5FU + Cetuximab improves survival over Platinum + 5FU alone Excellent PS and organ function Doublet cytotoxic chemotherapy (without cetuximab) improves RR but not OS compared to single-agent cytotoxic chemotherapy Platinum + Paclitaxel has similar efficacy and decreased toxicity compared to Platinum + 5FU 1st line single agent therapy is best for patients with poor PS Platinum, Taxane, Cetuximab *If within 6 months of platinum therapy in adjuvant or definitive setting, can use immunotherapy*

Summary 2nd line therapy Immunotherapy (nivolumab) improves RR and OS compared to single- agent cytotoxic chemotherapy Response rates are still low overall at 13-16% with immunotherapy Single agent cytotoxic chemotherapy Very low response rates No evidence of improved survival Single agent Cetuximab Low response rate (10%) but potentially better than cytotoxic chemo; phase II data only Single agent EGFR TKIs No defined role No difference in survival compared to single-agent MTX