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SYSTEMIC THERAPY IN HEAD & NECK CANCER Radiation Oncology Grand Rounds Tuesday, December 3, 2013 Michelle T. Ashworth, MD Clinical Fellow, Hematology-Oncology

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Epidemiology: World 560,000 cases per year 300,000 deaths per year M:F 2-4:1 #5 cancer

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Epidemiology: US 53,000 cases per year 11,500 deaths per year M:F 2-4:1

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Epidemiology: US 3% of all cancers in US $3.6B per year

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Anatomic structures

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Nasal cavity & paranasal sinuses

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Oral cavity

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Salivary glands

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Pharynx

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Larynx

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Lymph nodes

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Weight loss Mass Cough Presenting symptoms Dysphagia Ulcer Voice change Pain

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Occult primary Nasopharynx Anatomic divisions per NCCN guidelines Hypopharynx Oropharynx Oral cavity Lip Maxillary sinus Ethmoid sinus Supraglottic larynx Glottic larynx

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Cartilage Tissues of origin Bone Blood vessels Muscle Lymph nodes Nerves Glands Squamous mucosal epithelium 90% SCCHN

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Risk factors #1: tobacco & alcohol HPV (16): >60% oropharyngeal cancer EBV: Nasopharyngeal cancer HIV: 2-3x RR Betel nut Occ Exp Diet RT Agent Orange Genetics

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HPV as prognostic biomarker in oropharyngeal SCCHN

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SCCHN Pathogenesis Field cancerization Pre- malignant lesions Stepwise progression May be reversible EGFR 90% p53 50-80% HER2 50% PTEN 10% PI3KCA 6-8% HRAS 5%

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Pretreatment & staging evaluation

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Role of systemic therapy (ST) Adjuvant (after surgery) [early stage, adverse features discovered at time of surgery] Concurrently with RT, as a radiosensitizer Definitive-intent [later stage, adverse features apparent prior to surgery] Concurrently with RT, as a radiosensitizer, or Induction followed by concurrent chemo/RT Controversial: careful patient selection and expert management of toxicities required Possibly followed by surgery for residual or recurrent disease Palliative-intent (unresectable/metastatic) Concurrently with RT or alone; combination regimens or monotherapy Intended to control symptoms, prolong life

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Treatment paradigms for early stage SCCHN Lip, oral cavity & oropharynx: Surgery ST/RT VAHNC Hypopharynx: RT or ST or ST/RT assess for response surgery or ST/RT Nasopharynx: RT or ST/RT +/- adjuvant ST or ST ST/RT or ST Glottic & supraglottic larynx: RT or surgery +/- adjuvant ST or ST/RT or ST assess for response surgery or ST/RT Ethmoid sinus: Surgery RT or ST/RT observation or RT or ST/RT

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Very advanced SCCHN Very advanced SCCHN of lip, oral cavity, oropharynx, hypopharynx, glottic larynx, supraglottic larynx T4b, N any, M0 or unresectable nodal disease or, if patient is not a surgical candidate Clinical trial preferred For PS 1: ST/RT or ST RT or ST/RT For PS 2: RT +/- ST For PS 3: RT or single- agent ST or best supportive care (BSC) If primary controlled + residual disease, follow with salvage surgery / neck dissection if possible

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Systemic therapy agents Cytotoxic chemotherapy Cisplatin or carboplatin 5-FU Docetaxel or paclitaxel Hydroxyurea Epirubicin Methotrexate Ifosfamide Bleomycin Gemcitabine (NPC) Vinorelbine Capecitabine Targeted therapy EGFR/HER1 inhibitor cetuximab Clinical trial agents Anti-PD1 or anti-PDL1 antibody, e.g. MK-3475 Injectable oncolytic virus, e.g. TVEC Other targeted agents, e.g. dasatinib

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Systemic therapy agents Cisplatin or Carboplatin Cetuximab Docetaxel or paclitaxel 5-FU Hydroxy- urea Epirubicin MTX Ifos Bleo Gem Cape Vin

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Commonly used SCCHN treatment regimens Concurrent systemic therapy as radiosensitizer Cisplatin 100 mg/m 2 IV every 3 weeks, or 40 mg/m 2 IV weekly Carboplatin AUC 5-6 IV every 3 weeks Cetuximab 400 mg/m 2 IV week 1, then 250 mg/m 2 weekly thereafter Induction PF, Cisplatin 100 mg/m 2 IV d1 + 5-FU 1000 mg/m 2 daily IV d1-5 TPF, taxane, platinum, 5-FU: docetaxel 75 mg/m 2 + cisplatin 80 mg/m 2 + 5-FU 800 mg/m 2 /day x96h CIVI every 3 weeks x3 Palliative-intent Single-agent or combination regimens

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Outcomes: Concurrent ST/RT in SCCHN Metaanalysis of chemotherapy trials in SCCHN: MACH-NC 87 trials 16,665 patients Median follow-up of 5.5 years Concurrent treatment, platinum-based

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MACH-NC

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Weekly vs every 3 weeks concurrent cisplatin/RT in SCCHN Series of patients treated with cisplatin/RT: younger patients with ECOG PS 0-1 were treated with cisplatin every 3 weeks and older patients with ECOG 2 were treated with cisplatin weekly CR 50% vs 40%, p>0.05 ORR 92% vs 90%, p>0.05 G3-4 AEs 53% vs 40%, p>0.05

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Concurrent cetuximab/RT in SCCHN Phase III study in advanced/ inoperable SCCHN with XRT +/- cetuximab 400 mg/m 2 then 250 mg/m 2 weekly showed median locoregional control 24.4 mo vs 14.9 mo and OS 49 mo vs 29.3 mo, with acneiform rash and infusion reactions in cetuximab-treated group but otherwise no difference in grade 3 AEs (Bonner, Ang et al N Engl J Med 2006 Feb 9;354(6):567- 78)

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Concurrent cetuximab/RT in SCCHN Phase III study in recurrent/metastatic SCCHN of PF+XRT +/- cetuximab 400 mg/m 2 then 250 mg/m 2 weekly maintenance showed response rate 36% vs 20%, median PFS 5.6 vs 3.3 mo, and OS 10.1 mo vs 7.4 mo (Vermorken, Hitt et al N Engl J Med 2008 Sep 11;359(11):1116-27)

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Subgroup Analysis

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Cetuximab-related rash as predictive biomarker in SCCHN

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Recurrent/metastatic SCCHN Overall survival 6-9 mo Factors correlating with good prognosis: ECOG 0-1, poorly differentiated histology, h/o response to chemotherapy Factors correlating with poor prognosis: ECOG 2, weight loss, recurrence after RT, current smoking, significant medical comorbidity Combination therapy regimens increase PFS but have not been shown to increase OS Treatment varies by PS, prior treatment, goals of care, and medical comorbidities

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Treatment outcomes Combination therapy in metastatic SCCHN Cisplatin 100 mg/m 2 or carboplatin AUC 5 + 5-FU 1000 mg/m 2 /d d1-4 +/- cetuximab every 3 weeks, up to 6 cycles, + maintenance cetuximab Limited to patients not previously treated for advanced cancer, KPS 70, largely age 65 Median PFS 5.6 mo vs 3.3 mo; median OS 10.1 mo vs 7.4 mo

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Treatment outcomes Combination chemotherapy in recurrent/ metastatic SCCHN A Cisplatin 100 mg/m2 IV d1 + 5-FU 1000 mg/m2 IV/d d1-4 every 21d vs. B carboplatin 300 mg/m2 IV d1 + 5-FU 1000 mg/m2 IV d1-4 every 28d vs. C MTX 40 mg/m2 IV weekly ORR 32% vs. 21% vs. 10%; however, similar median OS across all 3 groups

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Treatment outcomes Cetuximab in metastatic SCCHN Platinum-refractory patients ORR 13%; disease control rate 46% Median PFS 70 days; median OS 178 days

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Future directions in SCCHN RTOG 1016 RT/cisplatin vs RT/cetuximab in HPV+ oropharyngeal cancer Stratification by stage, PS, smoking hx

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Future directions targeted therapy in SCCHN Afatinib: TKI of HER2, EGFR PII study in R/M SCCHN comparing afatanib 50 mg PO daily vs cetuximab 400 mg/m2 then 250 mg/m2 weekly showed 6/34 (18%) vs 3/40 (8%) PR, 18/34 (53%) vs 20/40 (50%) SD, 10/34 (30%) vs 17/40 (43%) with PD, and comparable safety profile (Siewert, Cohen et al J Clin Oncol 28:15s, 2010 suppl; abstr 5501) Recent FDA approval in NSCLC; multiple clinical trials in SCCHN now open

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Future directions targeted therapy in SCCHN Panitumumab: humanized mAb EGFR inhibitor PIII study in R/M SCCHN comparing panitumumab + CT to CT reported efficacy of panitumamab in pts with HPV+ vs HPV- tumors (retrospectively) and showed median OS in HPV+ PCT 11 mo vs CT 12.6 mo, and HPV- PCT 11.7 mo vs CT 8.6 mo*, i.e. improvement in OS with P only in HPV- ( Vermorken et al Lancet Oncol 2013 Jul; 14(8):697-710) Open clinical trials in SCCHN Nimotuzumab: humanized mAb EGFR inhibitor PIII study in A/I SCCHN comparing nimotuzumab 200 mg weekly x 6-7 wks with or without cisplatin + XRT showed 24/25 (96%) vs. 18/25 (72%) objective response rate at 6 mo, without increased toxicity (Bhatnagur, Kumbaj et al J Clin Oncol 30, 2012 suppl; abstr e16012) Open clinical trials in SCCHN

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Future directions targeted therapy in SCCHN Combination therapy?

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Future directions immunotherapy in SCCHN Ipilimumab: mAb CTLA-4 inhibitor Experience in NSCLC: PII trial in stage IIIB/IV NSCLC comparing paclitaxel 175 mg/m2 + carboplatin AUC 6 with ipilimumab 3 mg/m2 q3 wks x4 then q12 wks showed median irPFS of 5.7, 5.5, and 4.6 mo; in phased arm, HR 0.55 in SCC vs 0.82 in NSCC. Phase III trial open in squamous NSCLC (Lynch, Reck et al J Clin Oncol 2012 Jun 10;30(17):2046-54)

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Future directions immunotherapy in SCCHN Various mAb PD-1 or PDL-1 inhibitors Evidence for PD-1:PDL-1 pathway in HPV+ SCCHN, with membranous expression of PDL-1 in tonsillar crypts (site of primary HPV infection), on tumor cells, and on tumor-associated macrophages, and high PD-1 expression on CD8+ TILs (Lyford-Pike, Pai et al Cancer Res 2013 Mar 15;73(6):1733-41) In-vitro blockade of tumor growth in oral SCC cell line with anti- PD-1 mAb (Tsushima, Azuma et al Oral Oncol 2006 Mar;42(3):268-74) Clinical trial now open T-VEC: talimogene laherparepvec, injectable oncolytic herpesvirus

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Salivary gland tumors Adenoid cystic carcinoma, adenocarcinoma, mucoepidermoid carcinoma High grade (more likely to invade) vs low grade (more likely to be cured with local treatment) Epidemiology: not related to tobacco + ETOH, but prior RT may increase risk Standard of care is surgery +/- RT Systemic therapy as radiosensitizer or with palliative intent in advanced disease is often used; however, due to rarity of disease and mixed histology in trials, there is not clear evidence to support or contradict this KIT mutation noted in 80% of ACC; however, ORR of 0% in one trial of imatinib given to KIT-mutation-unknown patients with ACC Clinical trial recommended: targeted therapy, e.g. EGFR or VEGF Salivary duct carcinoma may express androgen receptors or overexpress HER2 or EGFR; responses reported to anti-androgen therapy, trial of trastuzumab ongoing

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Nasopharyngeal carcinoma Nasopharynx: RT or ST/RT +/- adjuvant ST or ST ST/RT or ST Concurrent cisplatin 100 mg/m 2 IV every 3 weeks +RT, then cisplatin 80 mg/m 2 + 5-FU 1000 mg/m 2 /d d1-4 every 4 weeks 5-year PFS 62 vs 53%, 5-year OS 68 vs 64% Single-arm study of concurrent carboplatin AUC 6 every 3 weeks then carboplatin AUC 5 + 5-FU 1000 mg/m 2 /d d1-4 every 4 weeks

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Nasopharyngeal carcinoma Concurrent cisplatin 40 mg/m 2 IV weekly + RT

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Advanced nasopharyngeal carcinoma Induction with TPF: docetaxel 70 mg/m 2 d1 + cisplatin 75 mg/m 2 d1 + 5-FU 1000 mg/m 2 /d IV d1-4 x3 cycles, then RT + cisplatin 100 mg/m 2 every 3 weeks 3-year PFS 75.6%, 3-year OS 86.1%

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Mucosal melanoma 4% of all sinonasal malignancies Melanocytes are found in the mucosa in the sinonasal cavity in 21% of individuals Mean age of presentation 64.3 years RT improves local control; 50% will have local (vs. distant) recurrence Historically, studies have shown no difference in OS in treated with surgery vs surgery + RT or ST or all 3 5-year OS 25-42%

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Mucosal melanoma

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Up to stage T4aN1: Surgery RT Stage IVB onwards: Clinical trial preferred or RT or ST Systemic therapy in advanced disease: KIT mutation present in 30-40% of mucosal melanoma; responses reported to KIT inhibitors e.g. imatinib, and targeted therapy is available off-label or on clinical trials Imatinib: ORR 21%, median OS 46.3 weeks Ipilimumab: CR in 1/30 patients, PR 1/30, median OS 6.4 mo Anti-PD1 antibody on clinical trial: early reports of observed response Palliative-intent chemotherapy

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Conclusion Systemic therapy is generally used as a radiosensitizer or as palliative-intent treatment in head & neck cancer Advanced head & neck cancer has a generally poor prognosis despite systemic therapy New directions: Immunotherapy Targeted therapy Dont forget: Prevention Early detection (screening algorithms)

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Thank You Dr. Alain Algazi

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Indications for adjuvant ST/RT after surgery adverse pathologic findings Lip: For ECE and/or pos margin; consider for multiple positive LNs, perineural/lymphatic/vascular invasion Oral cavity: For ECE and/or pos margin; consider for pT3 or pT4 primary, N2 or N3 inv, levels IV or V, PNI, vascular embolism Oropharynx: For ECE +/- pos margin; consider for pos margin, pT3 or pT4, N2 or N3, levels IV or V, PNI, vascular embolism Hypopharynx: For ECE and/or pos margin; consider for pT3 or pT4, N2 or N3, PNI, vascular embolism Nasopharynx: n/a Glottic larynx: For ECE +/- pos margin; consider for pos margin, pT3 or pT4, N2 or N3, PNI, vascular embolism Supraglottic larynx: For ECE and/or pos margin; consider for pT4 primary, N2 or N3, PNI, vascular embolism Ethmoid sinus: Consider for pos margins, intracranial extension