Concurrent Chemo- and Radiotherapy for Ororpharynx Cancer Faye Johnson MD, PhD Associate Professor Thoracic/Head and Neck Medical Oncology August 2017
Objectives Review data that support concurrent chemo- and radiotherapy for locally advanced oropharynx cancer. Alternatives to cisplatin 100 mg/m2 days 1, 22, and 43 Future directions De-intensification Immunotherapy
No relevant COI Conflict of Interest Research funding from PIQUR pharmaceuticals for unrelated lab based research.
Background: Why concurrent? Updated MACH-NC Meta-analysis of trials 1965-2000. 50 trials, 9615 patients. Absolute benefit of 6.5% at 5 years. Pignon, et. al. Radiotherapy and Oncology 2009
Background: Why concurrent? Updated MACH-NC Recent trials had data on cause of death. Benefit of chemo was due to effect on cancer-related death. Chemo was not associated with change in non-cancer related death. Pignon, et. al. Radiotherapy and Oncology 2009
Background: Who benefits? Pignon, et. al. Radiotherapy and Oncology 2009
Which chemotherapy? Pignon, et. al. Radiotherapy and Oncology 2009 No significant difference (p = 0.19) between mono-chemo and poly-chemo. In the monochemo group the effect of chemotherapy was significantly higher with platin than with other types of chemo. Only 2 trials used carbo alone.
OPC Concurrent Guidelines: NCCN The preferred chemoradiotherapy approach for fit patients is cisplatin (100 mg/m2 q 3 weeks). Other regimens listed by NCCN: Cetuximab Carboplatin/infusional 5-FU 5-FU/hydroxyurea Cisplatin/paclitaxel Cisplatin/infusional 5-FU Carboplatin/paclitaxel Weekly cisplatin 40 mg/m2 Red = category 1
Chemoradiotherapy with platinum analogs significantly prolongs 3-yr survival Stage III/IV HNSCC (n=128) Cisplatin 100 mg/m2 d2, 22, 42 (B) Carboplatin AUC 7 d2, 22, 42 (C) XRT alone (A) Fountzilas, et. al. Medical Oncology 2004
Concurrent low-dose daily cisplatin or carboplatin Stage III/IV HNSCC 6 mg/m2 daily cisplatin (II) 25 mg/m2 carbo (III) Jeremic, et. al. Radiotherapy and Oncology 1997
Concomitant boost accelerated radiation plus concurrent weekly cisplatin Stage III/IV HNSCC n=94 40 mg/m2 cisplatin weekly x 4 weeks median overall survival 27 mos. Median TTP 25 mos 4 years OS = 41%. Medina, et. al. Radiotherapy and Oncology 2006
HYPERFRACTIONATED ACCELERATED RADIOTHERAPY IN COMBINATION WITH WEEKLY CISPLATIN Stage III/IV OPC and hypopharynx n=37 40 mg/m2 cisplatin weekly x 4 weeks median overall survival 36 mos. Median TTP 31 mos 2 years OS = 67%. Beckmann, et. al. Head & Neck 2005
Mendelsohn & Baselga 2006 Cetuximab: anti EGFR Ab Common side effects: Rash and infusion-related events.
Bonner, et al Lancet Oncology 2010 The addition of cetuximab to radiotherapy improves survival 5-year overall survival 46% vs. 36%
Bonner, et al Lancet Oncology 2010 Associations of factors with the effect of cetuximab on overall survival
The addition of cetuximab to radiotherapy improves survival in P16+ Rosenthal, et. al. JCO 2016
Bonner, et al Lancet Oncology 2010 Rash severity correlates with survival in those who received cetuximab
Randomized Phase III Trial of Concurrent Accelerated Radiation Plus Cisplatin With or Without Cetuximab for Stage III to IV Head and Neck Carcinoma: RTOG 0522
Ang, et al JCO 2014 Adding cetuximab to radiationcisplatin did not improve outcome
Immuno-Oncology as a Therapeutic Modality Immuno-oncology (I-O) therapies are different from other treatment modalities 1 Rather than directly targeting the tumor, I-O therapies use the natural capability of the patient s own immune system to fight cancer 1 Chemotherapy/ Targeted therapy Surgery Radiation Immuno-Oncology 1. Borghaei H, et al. Eur J Pharmacol. 2009;625:41-54.
Targeting T-Cell Response as an Approach to Cancer Therapy Activating receptors* Inhibitory receptors* CD27 CTLA-4 OX40 CD137 T cell 1 PD-1 TIM-3 LAG-3 Tumors may exploit immune checkpoint pathways to evade immune detection 1 * The image shows only a selection of the receptors/pathways involved. CTLA-4, cytotoxic T-lymphocyte antigen-4; LAG-3; lymphocyte activation gene-3; PD-1, programmed death-1; TIM-3, T-cell immunoglobulin and mucin domain-3. 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 22
Anti-PD1: Mechanism of Action Recognition of tumor by T cell through MHC/antigen/TCR interaction mediates IFN-γ release and PD-L1/2 up-regulation on tumor Priming and activation of T cells through MHC/antigen/TCR and CD28/B7 interactions with antigen-presenting cells IFNγ IFNγR MHC Antigen T cell receptor T cell receptor Antigen MHC Tumor cell PD-L1 PD-1 Shp-2 PI3K NFκB Other T cell CD28 PD-1 B7 PD-L1 Dendritic cell Shp-2 PD-L2 PD-L2 PD-1 PD-1 Figure adapted from Pardoll DM, et al. Nat Rev Cancer. 2012. Abbreviations, references, and footnotes can be found in the speaker notes.
Overall Survival (% of patients) Immunotherapy works in recurrent HNSCC: CheckMate 141 100 90 Median OS, mo (95% CI) HR (97.73% CI) P- value 80 70 60 50 40 Nivolumab (n = 240) 7.5 (5.5, 9.1) 0.70 Investigator s Choice (n (0.51, 5.1 (4.0, 6.0) = 121) 0.96) 1-year OS rate (95% CI) 36.0% (28.5, 43.4) 0.0101 30 20 10 16.6% (8.6, 26.8) 0 0 3 6 9 12 15 18 Months No. at Risk Nivolumab 240 167 109 52 24 7 0 Investigator s Choice 121 87 42 17 5 1 0
Immunotherapy is being tested in all stages of HNSCC Pre-malignant (high risk - LOH) Neoadjuvant Single dose Pembrolizumab pre-op (ASCO 2017): safe and pathological response in 42%. Multiple trials on going. Adjuvant Concurrent ipilimumab + cetuximab +IMRT Pembro + cisplatin + IMRT Metastatic / recurrent Combinations of IO agents. First line. Combinations with chemotherapy.
Safety of pembrolizumab with chemoradiation in HNSCC
ASCO 2017: Steven Francis Powell, Mark Mutuota Gitau, Christopher Joseph Sumey, John T. Reynolds, Michele Lohr, Steven McGraw, Ryan Kenneth Nowak, Andrew M Terrell, Ashley Wayne Jensen, Miran Joel Blanchard, Christie Ellison, Lora Jane Black, Paul A. Thompson, Kathryn A. Gold, Ezra E.W. Cohen, John H. Lee, William Charles Spanos
Discontinuation due to immune related AE was uncommon
No significant compromise of cisplatin and radiotherapy delivery
Early efficacy data in this small cohort is promising
Rationale Future: de-intensification Better prognosis for HPV+ Increased sensitivity to existing therapy. Younger patients who have to live with long term, permanent toxicities. Strategies: Decrease radiotherapy dose: ECOG1308, Quarterback, ECOG3311. Omit or replace cisplatin: ADEPT, RTOG1016, TROG12.01, De-ESCALATE, NRG-HN002
ECOG 1308: HPV+ Stage III-IV OPC Cisplatin 75mg/m2, paclitaxel 90 mg/m2, cetuximab 400-250 mg/m2. Concurrent cetuximab. Dysphagia at 1 yr 54 vs. 69 Gy (40% vs. 89%). 2 yr PFS/OS 96% if <T4, <N2C, <10 pack year CR then 54 Gy. > 10 pack-years smoking history: 2-year PFS 57% Marur el al JCO 2017
De intensification Trials for HPV+ OPC ADEPT: ECE+ randomized to PORT 60Gy +/- Cisplatin. De-ESCALATE (UK) & TROG12.01 (Australia): standard cisplatin-xrt vs. cetuximab-xrt. NRG-HN002: a randomized phase II study dose-reduced cisplatin +XRT vs. accelerated XRT alone. End point of 2- year PFS and swallow function
Conclusions and Unanswered Questions for Concurrent Cisplatin remains the gold standard. Cetuximab is a reasonable option. No biomarkers consistently predict response to a specific systemic therapy (with or without XRT). On going trials will address key issues: Cisplatin vs. cetuximab. Role of immunotherapy. Role of targeted therapy.