New Agents for Head and Neck Cancer Ezra Cohen, MD Associate Professor of Medicine University of Chicago Chicago, IL
Disclosure Dr. Cohen has the following relevant financial relationships with commercial interests to disclose: Consultant: Boehringer Ingelheim, and Eli-Lilly
Overview Signaling Pathways EGFR PI3K/AKT/mTOR Angiogenesis
Single Agent Response Rates of EGFRtargeted mabs and TKIs in SCCHN Drug Phase Reference RR Cetuximab II Vermorken et al, 2007 13% Erlotinib II Soulieres et al, 2004 4% Gefitnib II Cohen et al, 2003 11% II Cohen et al, 2005 2% III Stewart et al, 2009 8% Lapatinib II Abidoye et al, 2006 (ASCO) Zalutumumab III Machiels et al, 2010 (ASCO) 0% 6% Vermorken JB, et al. J Clin Oncol 2007;25:2171; Soulieres D, et al. J Clin Oncol 2004;22:77; Cohen EE, et al. J Clin Oncol 2003;21:1980; Cohen EE, et al. Clin Cancer Res 2005;11:8418; Kirby AM, et al. Br J Cancer 2006;94:631; Stewart JSW, et al. J Clin Oncol 2009;27:1864; Abidoye OO, et al. J Clin Oncol 2006;24:18S:5568; Machiels JH, et al. J Clin Oncol 2010;28:185; - LBA5506; Seiwert TY, et al. ESMO. 2010;1010PD.
EGFR as a Target in SCCHN Modest improvement when added to RT or CRT Modest efficacy as single agent
Rationale for Pan-HER Blockade in SCCHN All HER/erb-B family members are expressed at high levels in SCCHN Preclinical evidence suggests that blockade of EGFR and HER2 dimerization is active (Erjala K et al. 2006) Erjala K et al. Clin Cancer Res 2006;12:4103-4111
Mutation of HER2 within a gefitinib-responsive tumour Cohen E E et al. Clin Cancer Res 2005;11:8105-8108
Pan-HER Blockade: Afatinib vs. Cetuximab Randomized Phase 2 Major eligibility criteria: Metastatic or recurrent HNSCC Documented PD following prior platinum-based CT Measurable disease according to RECIST ECOG PS 0, 1 No PD within 3 months after curative intended treatment for L/LRA disease Primary endpoint: Tumor shrinkage of target lesions before cross-over Key secondary endpoints: ORR (Stage 1) PFS (Stage1) AEs (Stage 1)
Primary endpoint: tumour shrinkage after treatment * (Stage 1) Mean tumour shrinkage Mean percentage change -1.49 p=0.76 * Maximum reduction in the sum of the longest diameters (SLD) of the target lesions compared to baseline. Only patients with baseline and at least one post-baseline measurement are included in these analyses.
Maximum decrease from baseline (%) Maximum decrease from baseline (%) Maximum tumour shrinkage percentage in targeted lesions Cetuximab (n=55) Afatinib (n=50) 20% n=8 0 % & <20% n=16 > 30% & <0% n=10 30% n=16 20% n=12 0 % & <20% n=17 > 30% & <0% n=19 30% n=7 Patient index sorted by maximum decrease (%) Patient index sorted by maximum decrease (%)
Response to therapy (randomized set) Afatinib Cetuximab Total randomized, n (%) 62 (100.0) 62 (100.0) Disease control (CR, PR, SD), n (%) 31 (50.0) 35 (56.5) 95% CI 37.0%, 63.0% 43.3%, 69.0% Objective response (CR, PR), n (%) (Confirmed* in randomized patients) 10 (16.1) 4 (6.5) 95% CI 8.0%, 27.7% 1.8%, 15.7% Objective response (CR, PR), % (Confirmed* in evaluable patients) 19.2 7.3 Partial response, n (%) 10 (16.1) 2 (3.2) Stable disease, n (%) 21 (33.9) 31 (50.0) * Confirmation was made per protocol after 8 weeks CR = complete response; PR = partial response; SD = stable disease; CI = confidence interval.
Final results: PFS (Stage 1)
Biomarker correlative analysis p16 Afatinib No. with response/total no. (%) Cetuximab No. with response/total no. (%) Positive 1/9 (11.1) 0/8 (0.0) Negative 5/25 (20.0) 2/23 (8.7) EGFR viii mutation Positive 0/0 (0.0) 0/0 (0.0) Negative 6/25 (24.0) 2/28 (7.1) 13
Poor Risk Adjuvant Study 014 Newly diagnosed LA HNSCC Concomitant CRT 6-8 wks MRI or CT scan 8-12 weeks post CRT Non-evaluable or Disease progression or residual primary disease Nodal disease followed by neck dissection Not eligible for the trial No evidence of disease R 2:1 Strata ECOG PS: 0 vs. 1 Nodal status: N0-2a vs. N2b-N3 Afatinib N = 446 Placebo N = 223 IVRS/IWRS Excludes non smokers with oropharynx Start treatment no later than 16 weeks after CRT Treatment for up to 80 weeks (about 18 months) or until recurrence or undue side effects
EGFR Signaling Pathways: Mechanisms of Resistance To EGFRi Chen L F et al. Clin Cancer Res 2010;16:2489-2495 2010 by American Association for Cancer Research
In Vitro Effects of Temsirolimus (CCI-779) Nathan, C.-A. O. et al. Cancer Res 2007;67:2160-2168 Copyright 2007 American Association for Cancer Research
Effects of Temsirolimus in MRD Model Nathan, C.-A. O. et al. Cancer Res 2007;67:2160-2168 Copyright 2007 American Association for Cancer Research
Randomized Phase II Trial of Everolimus Versus Placebo as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck (SCCHN)
RANDOMIZE Screening Enrollment -assess eligibility -sign ICF -obtain tissue Study Design Randomization (n=160) Treatment Everolimus 10mg OD Curative Intent Therapy Confirmed 8-16 Weeks Primary Endpoint: 2-year PFS Placebo Double-blinded Stratification: Treatment Center Stage (IVa vs. IVb)
ROLE OF ANGIOGENESIS INHIBITORS IN HNC TREATMENT
The VEGF Family and Its Receptors PIGF VEGF (VEGF-A) VEGF-B VEGF-C VEGF-D VEGFR-1 (Flt-1) VEGFR-2 (Flk-1/KDR) VEGFR-3 (Flt-4) Angiogenesis Angiogenesis Lymphangiogenesis Lymphangiogenesis PlGF = placenta growth factor. Ferrara et al. Nat Med. 2003;9:669.
Angiogenesis Inhibition in SCCHN Single agent activity modest Sunitinib, Sorafenib, SU5416 <5% RR Rates of vascular toxicities similar to other disease sites but recurrent SCCHN tumors are often close to major blood vessels
IS ANGIOGENESIS INHIBITION VIABLE IN SCCHN?
Lesion Progression 4NQO Oral Cancer Model Normal Hyperkeratosis Dysplasia SCC
Vandetanib (ZD6474): Effects both VEGFR and EGFR pathways EGFR TGF ZD6474 Cancer cell ras MEK VEGF Endothelial cell KDR Cyclin D1 Block of cancer cell proliferation Block of endothelial cell proliferation Wedge SR, et al. Cancer Res 2002;62:4645 4655. Slide courtesy of D. Rabin
Vandetanib Inhibits OSCC Development
Vandetanib Inhibits Proliferation, MVD
Randomized Phase 2 Study of Vandetanib in High Risk Patients
CONCLUSIONS EGFR inhibitors are continuing to be developed in SCCHN Better understanding of mechanisms of sensitivity/resistance would greatly enhance patient selection and efficacy Additional pathways and phenotypes are now being targeted in clinical trials Many more than can fit in a 20 minute talk
REALITY Expectation should be that only a minority of patients will benefit from a specific agent however, benefit would be substantial Efforts must focus on comprehensive molecular phenotyping and classification of SCCHN tumors The era of Clinical Practice Guidelines based on anatomy and tumor site is over