Recurrent or Metastatic H&N Cancer Advances and New Strategies

Transcription

1 Recurrent or Metastatic H&N Cancer Advances and New Strategies Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium II International Symposium on Head and Neck Cancer, Hilton São Paulo Morumbi, Sao Paulo, Brazil, August 2 and 3, 2013

2 Outline of the Presentation EXTREME and beyond The interaction of cetuximab with taxanes HPV important in recurrent/metastatic disease? Problem of resistence New drugs in head and neck cancer Studies from ASCO 2013 in R/M-SCCHN Conclusions

3 Development of Chemotherapy in R/M SCCHN 1977: cisplatin shows efficacy in 1 st -line SCCHN N Regimen ORR (%) Median OS (months) Significant OS benefit Grose et al Methotrexate Cisplatin No Forastiere et al Cisplatin + 5-FU Carboplatin + 5-FU Methotrexate 32* No Clavel et al CABO Cisplatin + 5-FU Cisplatin 34* 31* No Gibson et al Cisplatin + 5-FU Cisplatin + paclitaxel No Vermorken et al Platinum + 5-FU Platinum + 5-FU + Cetuximab 20 36* * Yes CABO, cisplatin, methotrexate, bleomycin, vincristine *significant Clavel et al. Ann Oncol 1994; Forastiere et al. JCO 1992; Gibson et al. JCO 2005; Grose et al. Cancer Treat Rep 1985; Vermorken et al. NEJM 2008; Wittes et al. Cancer Treat Rep 1977

4 CT plus Cetuximab in 1 st -Line SCCHN: Consistent Efficacy Regardless of CT Type Author Phase N Regimen ORR (%) Median PFS (months) Median OS (months) Vermorken 2008 III 442 PF PF + cetuximab 20 36* * * Burtness 2005 III 117 Cis + Placebo Cis + cetuximab 10 26* Buentzel 2007 II 23 Pacli/Carbo + cetuximab ** 8.0 Hitt 2011 Guigay 2012 II 46 Pacli + cetuximab II 54 Doce/Cis /cetuximab *Significant; **TTP Vermorken et al. NEJM 2008; Burtness et al. JCO 2005; Hitt et al. Ann Oncol 2011; Buentzel et al. ASCO 2007; Guigay et al. ASCO 2012

5 Taxanes Enhance in vitro NK Cell Cytotoxicity Paclitaxel enhances cytotoxicity of NKcells against breast carcinoma cells by increasing perforin production (Kubo et al, 2005) ADCC efficiency ratio XnM/0nM Healthy donors PBMCs treated for 24h with different concentration of Paclitaxel 2,0 1,5 1,0 0,5 1nM 10nM 100nM The enhanced efficacy of ADCC induced by Palitaxel is more prominent in purified NK cells ADCC efficiency ratio XnM/0nM 4 3,5 3 2,5 2 1,5 1 0,5 From Kubo et al, Cancer Immunol Immunother (2005) 54: Paclitaxel modulates Trastuzumab-dependent ADCC against breast cancer cell lines Healthy donors PBMCs and purified NK cells treated for 24h with different concentration of Paclitaxel 1nM 10nM 100nM PBMCs NK

6 Cetuximab + Paclitaxel, 1 st -line: A Phase II Study Eligibility KPS 70 Prior systemic chemotherapy allowed if given as part of a multimodal treatment for locally advanced disease which was completed >6 months before study entry Recurrent/metastatic SCCHN Cetuximab (initial dose 400 mg/m 2 then 250 mg/m 2, qw) + Paclitaxel (80 mg/m 2, qw) Until disease progression or toxicity Response (RECIST) assessed by CT/MRI every 6 weeks Primary endpoint: Objective response rate Secondary endpoints: Duration of response, PFS, OS, safety, and exploration of possible efficacy predictive factors Hitt R, et al. Annals of Oncology 23: , 2012

7 Cetuximab + Paclitaxel: Safety Commonly TR-AE (G1-3) TR-SAE (G3-4) - Conjunctivitis (G1/2: 15%) - Acne like rash (24%) - PNP (G1/2: 4%) - Asthenia (17%) - Alopecia (13%) - Neutropenia (13%) - Diarrhea (G1-2: 22%) - Mucositis (7%) - Vomiting (22%) - Conjunctivitis (4%) - Onycholysis (24%) - IRR (4%) - Hypo Mg (G1-2: 15%) - Neuropathy/paresth. (11%)

8 Treatment schedule Chemotherapy + cetuximab:up to 4 cycles Maintenance: cetuximab alone 1e 1 cycle Docetaxel Cisplatin Until progression or unacceptable toxicity Every 2 weeks Cetuximab Day 1 Day 8 Day 15 Day 22 Day 29 Evaluation after 2 cycles: if ORR or SD 2 additional cycles Docetaxel i.v. (75 mg/m² every 3 weeks) Cisplatin i.v. (75 mg/m² every 3 weeks) Cetuximab i.v. (400 mg/m² at day 1 then 250 mg/m² once a week) G-CSF (lenograstim) delivered after every cycle Cetuximab i.v. (500 mg/m² every 2 weeks) Guigay et al (ASCO 2012; abstract 5505)

9 Cetuximab + Docetaxel + Cisplatin: Safety >5% Grade 3+4 Toxicity Grade 3 (%) Grade 4 (%) Skin rash 15 - HSR 6 - Febrile neutropenia 6 - Non-febrile neutropenia 6 11 Diarrhea 3.7 -

10 Cetuximab every 2 nd Week* after Chemotherapy as Maintenance in 31 Patients with R/M SCCHN Mean Erbitux dose intensity in the maintenance phase was 93% Erbitux dosing every 2nd week* was well tolerated and did not worsen toxicity that occurred during CT Adverse events (n=31) Grade 2 Grade 3 Grade 4 Skin rash, % Fatigue, % Diarrhea, % Hypomagnesemia, % Mucositis, % * Note: Off-label regimen for Erbitux Bossi P, et al. Head Neck 2012 [Epub ahead of print]

11 Non-Cetuximab Containing Randomized Trials in Recurrent/Metastatic SCCHN Anti-EGFR therapies Study/Reference N Regimen RR (%) PFS (mo) OS (mo) SPECTRUM/ Vermorken et al PF 2 + panitumumab PF 2 36 * 25* 5.8** 4.6** ZALUTE Machiels et al, Z + BSC (-MTX) 6 BSC (optional MTX) a IMEX Stewart et al, Gefitinib (250 mg) Gefitinib (500 mg) Methotrexate ND ND ND ECOG 1302 Argiris et al, D + Gefitinib D + placebo b 2.1 b a 87% received MTX; b Time to progression *p=0.007; **p=0.004; p=0.001; p=0.0648

12 HPV Status and Anti-EGFR Treatment Head and Cancer Drug Type of Study Study Group Disease Site Assessment Locoregionally advanced disease - Cetuximab Phase III RTOG OPC p16 - Panitumumab Phase II CONCERT All p16 - Lapatinib Phase II European All p 16 Recurrent/metastatic disease - Cetuximab Phase III EXTREME All* p 16/HPV (PCR) - Panitumumab Phase III SPECTRUM All* p 16 - Afatinib/cetuximab Phase II PoC All p 16 * Hypopharynx, oral cavity, larynx and oropharynx (OPC)

13 HRs are CT + cetuximab vs CT. CI, confidence interval; HR, hazard ratio. Overall Survival in EXTREME by p16 Status p16+ patients p16 patients HR (95% CI) 0.63 ( ) p-value HR (95% CI) 0.82 ( ) p-value Overall survival Overall survival CT + cetuximab (n=18) CT (n=23) Months CT + cetuximab (n=178) CT (n=162) Months Number of patients at risk Number of patients at risk

14 Overall Survival by HPV Status HPV+ patients HPV patients HR (95% CI) 0.72 ( ) p-value HR (95% CI) 0.73 ( ) p-value Overall survival Overall survival CT + cetuximab (n=11) CT (n=13) Months CT + cetuximab (145) CT (n=152) Months Number of patients at risk Number of patients at risk HRs are CT + cetuximab vs CT CI, confidence interval; HR, hazard ratio

15 SPECTRUM: Study Design R Arm 1: Pmab 9.0 mg/kg Day 1 + Cisplatin 100 mg/m 2 Day FU 1000 mg/m 2 per day Days 1-4 Q21 days for 6 cycles Arm 2: Pmab 9.0 mg/kg Q3W until PD/Intolerability OPTIONAL E N D O F F O L L O W Cisplatin 100 mg/m 2 Day FU 1000 mg/m 2 per day Days 1-4 T x U P Carboplatin could be substituted for Cisplatin if neurotoxicity or if CrCl = to < 50 ml/min. Q3 months until ~36 months after last patient randomized Randomization Stratification Prior CRT or RT Site of primary tumor ECOG PS score Key Eligibility Criteria ECOG PS of 0 or 1 No prior systemic CT for R/M-SCCHN - Exception: initial multimodality treatment for locally advanced disease No prior anti-egfr therapy

16 Overall Survival in SPECTRUM by p16 Status p16 + patients p16 - patients 100% 90% 80% HR = 0.96 (95%CI: ) p-value = % 90% 80% HR = 0.73 (95%CI: ) p-value = 0.02 Proportion Alive 70% 60% 50% 40% 30% Proportion Alive 70% 60% 50% 40% 30% 20% 20% 10% 10% 0% Months Median OS (95% CI) months Pmab + CT (n = 56) 10.9 ( ) CT alone (n = 37) 12.1 ( ) 0% Months Median OS (95% CI) months Pmab + CT (n = 165) 11.8 ( ) CT alone (n = 153) 8.6 ( ) Quantitative interaction test p-value = 0.332

17 PoC : Study Design Open-label, randomized, Phase II crossover study Stage 1 Stage 2 Afatinib 50 mg po daily Cetuximab 400*/250 mg/m 2 IV weekly Patients with R and\or M HNSCC N=124 (62/arm) RANDOMIZATION Stratum: No. prior chemotherapies for R/M disease (0 or 1) Continue until PD or undue AEs Continue until PD or undue AEs Cetuximab 400*/250 mg/m 2 IV weekly Afatinib 50 mg po daily Response assessed with CT/MRI every 8 weeks *Loading dose. AEs = adverse events; CT = computed tomography; IV = intravenous; MRI = magnetic resonance imaging; PD = disease progression; po = orally. Response assessed with CT/MRI prior to crossover; at 4 weeks and every 8 weeks thereafter

18 Correlative Analysis: Biomarker vs. Response by ICR Afatinib (n=62) Cetuximab (n=62) Randomized 62 (100) 62 (100) p16 No. samples (%)/No. missing (%) 34 (54.8)/28 (45.2) 31 (50.0)/31 (50.0) No. with response,* total no. (%) Positive Negative 1/9 (11.1) 5/25 (20.0) 0/8 (0.0) 2/23 (8.7) *Confirmed per protocol after 8 weeks. ICR = independent central review.

19 The Problem of Resistance EGFR is a validated therapeutic target in SCCHN Discordance between EGFR expression and response Possible mechanisms of resistance EGFR mutations Increased EGFR internalization Parallel signaling pathways IGF-1R, MET, erbb2 PI3K/AKT mutations Cycline D1 amplification

20 Schmitz et al. Submitted

21 Other Novel Targeted Agents in SCCHN Anti-angiogenesis VEGF VEGFR Integrin inhibitors Histone deacetylase inhibitors PI3K/Akt/mTOR Proteasome inhibitors IGFR inhibitors SRC inhibitors No phase III data!

22 Recurrent/Metastatic SCCHN: Important Messages and Targeted Therapies Tested Topic Presenter Abstract Afatinib Seiwert et al 6001 (0) Sym004 Machiels et al 6002 (0) HPV & ERCC1 Mehra et al 6006 (0) Gene expression profile Bossi et al 6027 (PD) Panitumumab Wirth et al 6029 (PD) Cixutumumab ± cetuximab Kakhry et al 6030 (PD) Cetuximab ± sorafenib Gilbert et al 6047 (GD) Zalutumumab Saloura et al 6065 (GD) Everolimus + erlotinib Massarelli et al 6067 (GP) Carbo + cetuximab +everolimus Lapatinib + capecitabine Saba et al Weiss et al 6083 (GP) 6094 (GP)

23 Abstract by Mehra, et al from ECOG: Analysis of HPV and ERCC1 in recurrent or metastatic squamous cell carcinoma of the head and neck Ranee Mehra, Ann Marie Egloff, Shuli Li, Dong-hua Yang, Fang Zhu, Arlene Forastiere, Barbara Burtness, Athanassios Argiris

24 Mehra et al. E1395 & E3301: ERCC1 & HPV / p16 status in R/M HNSCC Overall Survival By ERCC1 status (high 18; low: 25) By HPV status (-ISH) (Pos 11; Neg: 54) By p16 status (>80% staining) (Pos 12; Neg 54) ERCC1 Low ERCC1 High p-value= HPV positive HPV negative p-value= P16 positive P16 negative p-value= Progression Free g Survival y p ERCC1 Low ERCC1 High p-value= HPV positive HPV negative p-value= P16 positive P16 negative p-value= ERCC1 HR (95% Cl) p OS 2.04 ( ) 0.15 PFS 0.80 ( ) HPV HR (95% Cl) p OS 2.66 ( ) 0.02 PFS 1.63 ( ) p16 HR (95% Cl) p OS 2.27 ( ) 0.04 PFS 1.45 ( ) 0.29 Mehra et al. Abstrsact 6006

25 Conclusions Larger prospective trials can further evaluate ERCC1 levels as it relates to survival and treatment response in SCCHN. Effectiveness of taxanes in ERCC1 high SCCHN is another potential avenue of further study. HPV+/p16+ status is associated with a significant improvement in response rate and overall survival among patients treated for R/M SCCHN. R/M clinical trials should consider stratification based on HPV or p16 status.

26 IDENTIFICATION OF A GENE EXPRESSION PROFILE ASSOCIATED TO PROGRESSION-FREE SURVIVAL IN RELAPSED OR METASTATIC HEAD AND NECK SQUAMOUS CELL CANCER PATIENTS TREATED WITH FIRST LINE CETUXIMAB AND PLATINUM THERAPY Paolo Bossi*, Loris De Cecco, Federica Perrone, Barbara Cortelazzi, Maria Cossu Rocca, Marco Siano, Andrea Sponghini, Cristiana Bergamini, Laura D. Locati, Aurora Mirabile, Roberta Granata, Carlo Resteghini, Silvana Pilotti, Silvana Canevari, Lisa F. Licitra *Head and Neck Medical Oncology Fondazione IRCCS Istituto Nazionale Tumori Milano

27 RESULTS Class Comparison: identification of genes differentially expressed p-value FDR n. genes Up Long PFS Down Long PFS 1.10E Volcano plot Heatmap Down Up Long PFS Short PFS Blue: genes DE at FDR<0.1 Bossi et al, abstract 6027

28 Conclusions To our knowledge, the present study is the first attempt to analyze expression patterns associated to response after platinum/cetuximab first line chemotherapy in RM-HNSCC A significant pattern of differentially expressed genes between long and short PFS pts was identified. These genes belong to networks related to EGFR, AKT, NFK-b signaling In silico analysis on GDS project data confirms the association of Cetuximab response to sensitivity to EGFR-pathway inhibitors and suggests potential alternative treatments for Cet-ShortPFS pts. Next steps: validation in independent sets of patients from different institutions analysis of drug sensitivity in preclinical in vitro and in vivo models development of a clinical grade predictive tool Presented by:

29 Conclusions EXTREME has been a breakthrough Interaction taxanes and cetuximab needs further study HPV (p16) is also important in the R/M-SCCHN setting Resistence issue important both with respect to DNA damaging agents and with respect to cetuximab: - biological markers - expression patterns - new drugs

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31 Why More Efficacy in HPV - SCCHN Reasons not fully understood, however HPV-(p16-) tumors are genetically more aberrant 1 HPV-(p16-) tumors are more likely to be EGFR positive 2 Increased EGFR gene copy number has been found largely restricted to p16 INK4a negative OPC 3 Association between EGFR expression and OS, PFS or best ORR has not been tested in the HPV (p16)-negative cohort 1 Stransky N et al. Science 2011:333: Kong CS et al. Int J Radiot Oncol Bio Phys 2009:74: Young RJ et al. Cancer Epidemiol Biomarkers Prev. 2011:20: