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

2. 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

3. Prognosis
Stage 1 and 2 associated with 5 year overall survival of between %
Stage 3 and 4 associated with poorer 5 year overall survival
Despite aggressive therapy a significant proportion ( % 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

4. 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

5. EXTREME TRIAL DESIGN

6. EXTREME-RESULTS
Overall Survival (primary end point of study) was 7.4 mos with chemo only arm vs 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

7. NCCN Guidelines

8. Other Regimens

9. 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

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

12. HNSCC Immune Escape Mechanism

13. 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”

15. Ongoing Studies Exploiting Immune Pathways

16. 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

17. CheckMate-141

18. 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

19. Keynote-012

20. 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

21. 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