Metastatic Head Neck Cancer and Immunotherapy Jerome D. Winegarden, M.D. IHA Hematology Oncology St Joseph Mercy Ann Arbor

Scope of Problem Head and Neck Cancer survivors based on current US data is estimated at greater than 500,000 - decreased tobacco - improved treatment - HPV associated HNC associated with better prognosis

Prognosis Stage 1 and 2 associated with 5 year overall survival of between 70- 90 % Stage 3 and 4 associated with poorer 5 year overall survival Despite aggressive therapy a significant proportion (40- 50 % in larynx cancers for example) will develop recurrence Recurrence 60% with local failure and up to 30% with distant failure Those with Recurrent/Metastatic (R/M) typically have disease that is no longer amenable to curative therapy - high morbidity - dismal survival

Palliative Chemotherapy Typically platinum doublet therapy or single agent Until recently platinum/5FU doublet most active regimen with 30% response rate, PFS 3-4 months and overall survival of 6-8 months Targeted therapy most notably monoclonal antibodies to EGFR have improved upon this significantly EXTREME-Erbitux in First Line Treatment of Recurrent and Metastatic Head and Neck Cancer

EXTREME TRIAL DESIGN

EXTREME-RESULTS Overall Survival (primary end point of study) was 7.4 mos with chemo only arm vs. 10.1 mos with addition of cetuximab PFS improved with cetuximab from 3.3 to 5.6 mos Toxicity greater in cetuximab arm but the clinical benefits were not associated with adverse quality of life

NCCN Guidelines

Other Regimens

Immunology and Cancer Coordinated Innate and Adaptive response in cancer development Function to protect the host from foreign insults and are able to differentiate between ‘self’ and ‘non-self’ antigens Believed that the immune system has the capacity to perceive and eliminate many tumors early on in their development Immunoediting vs immunoserveillane causing these silent occurrences to become clinically apparent Tumor microenvironment-inhibits this typical immune response

HNSCC Immune Escape Mechanism Disruption of the antigen-presenting machinery Development of cancer-permissive tumor microenvironment Immune effector cells

HNSCC Immune Escape Mechanism

PD1 (Programmed Death Receptor 1) Check point receptor Immune system’s breaks protecting against overactive immune system Tumors exploit this system by altering the tumor microenvironment to escape detection The ligand for PD1, PD-L1, is upregulated in HNSCC (many others as well) This results in loss of function of CTLs Anti PD-1 drugs inhibit the above process- “removes the breaks”

Ongoing Studies Exploiting Immune Pathways

Two Landmark Immunotherapy Trials in HNSCC Checkmate-141 and Keynote-012 Both utilized patient populations refractory to platinum containing regimens Checkmate utilized Nivolumab (Opdivo) and Keynote utilized Pembrolizumab (Keytruda) both Anti PD-1 drugs

CheckMate-141

Check Mate -141 361 patients randomized to Nivolumab vs IC 30% reduction in risk of death Median Overall Survival of 7.5 vs 5.1 mos PD-L1 expression associated with increase OS HPV+ OS 9.1 mos vs. 4.4 mos HPV- OS 7.5 mos vs. 5.8 mos Stopped early due to results and Nivolumab granted “Breakthrough Designation” by the FDA

Keynote-012

Keynote-012 192 patients with R/M refractory to platinum 18% response rate (8 CR and 26 PR), additional 33 with stable disease Duration of response lasted from 2.4 mos to 30+ mos (responses are ongoing with median duration not yet reached) Responses irrespective of HPV status and PD- L1 status Granted FDA Approval August 5th, 2016

Conclusion Despite advances in treatment a significant proportion of patients with HNSCC will develop recurrent and metastatic disease Standard cytotoxic therapy combined with targeted agents does improve survival Cancers alter the body’s immune response to avoid detection Immunotherapy acts to restore the natural immune response allowing for detection and destruction of “non-self” PD-1 inhibitor Pembrolizumab now FDA approved for treatment