1. Management of metastatic and recurrent head and neck cancer
Erin Alesi, MD
Medical Oncology, Palliative Medicine

2. Objectives
Define clinical scenarios for palliative chemotherapy in head and neck cancer
Discuss 1st line therapy
Discuss immunotherapy
Discuss subsequent treatment options

3. Metastatic and recurrent settings
Stage IVC
Recurrent
Relapse of malignancy in an area not amenable to further surgery or radiation therapy
Treatment = Palliative Systemic Therapy + Best Supportive Care
Poor Prognosis
Average OS 6-9 months

4. Metastatic and recurrent settings
FACTORS Associated with Longer Survival
Factors associated with Shorter Survival
ECOG PS 0-1
Poorly differentiated histology
Response to chemotherapy
HPV-associated OP SCCa
Poor ECOG PS
Weight Loss
Prior radiation therapy
Active smoking
Significant comorbidity

5. Metastatic and recurrent settings
Age
Elderly = age >70
Elderly patients generally have more comorbidities
Healthy elderly patients have similar survival to younger counterparts but often experience increased treatment-related toxicity

6. 1st line therapy Factors influencing choice of therapy Prior treatment
Type
Timing
Patient characteristics
Performance status
Comorbidities

7. 1st line therapy Molecularly Targeted Agents Combination therapy
Cytotoxic Agents
Platinum-based
Molecularly Targeted Agents
Single Agent Therapy
Immunotherapy (select cases)

8. 1st line therapy Cytotoxic Chemotherapy Platinum Agents
Cisplatin, Carboplatin
Taxanes
Docetaxel, Paclitaxel, Nab-Paclitaxel
5-Fluorouracil
Methotrexate

9. 1st line therapy Molecularly Targeted Agent Cetuximab
EGFR Receptor Antagonist
Immunotherapy
Pembrolizumab, Nivolumab
Immune checkpoint inhibitors of PD-1
Within 6 months of having received platinum in adjuvant or definitive setting

10. 1st Line Therapy Cisplatin vs. Carboplatin
Cisplatin thought to be more effective, yet very little data to support
Carboplatin
Less neurotoxic, nephrotoxic, and emetogenic
More myelosuppressive
Cisplatin
Generally reserved for patients with excellent performance status and organ function

11. 1st Line Therapy – Previously untreated patients

12. 1st Line Therapy – Previously untreated patients
EXTREME Trial
Phase III, 442 patients, Cisplatin or Carboplatin + 5FU with or without Cetuximab
Cisplatin 100mg/m2 D1 or Carboplatin 5 AUC D1 every 21 D x 6 cycles
5FU 1000mg/m2/day x 4 D every 21 D x 6 cycles
+/- Cetuximab 400mg/m2 loading dose, followed by weekly 250mg/m2 until disease progression

13. First Line Therapy – Previously untreated patients
EXTREME Trial – 2008
Chemo + Cetuximab = significantly prolonged survival compared to chemo alone
Median OS 10.1 vs 7.4 months
HR for death 0.8 (95% CI )
Similar in HPV+ and HPV- patients, though low numbers of HPV+ (HPV+ trended toward better PFS, OS, ORR)
Similar overall incidence of severe AE in chemo + cetuximab vs. chemo alone (82 vs 76%)

14. 1st Line Therapy – Previously untreated patients
EXTREME Trial
Cetuximab patients more likely to experience:
Severe hypomagnesemia (5 vs 1%)
Severe skin reactions (9 vs <1%)
Sepsis (4 vs <1%)
Severe infusion-related cetuximab reactions 3%

15. 1st Line Therapy – Previously untreated patients
Combination Cytotoxic Chemotherapy
Typically platinum-based doublet therapy
Better response rates, but no improved survival compared to single-agent chemotherapy
Platinum + 5FU
30% RR (better than single agent cisplatin or methotrexate)

16. 1st Line Therapy – Previously untreated patients

17. 1st Line Therapy – Previously untreated patients
SWOG Trial 1992
Phase III, 261 patients
Cis + 5FU vs. Carbo + 5FU vs. Methotrexate
Cisplatin 100mg/m2 D1, 5FU 1000mg/m2/d x 4D every 21 D
Carboplatin 300mg/m2 D1, 5FU 1000mg/m2/d x 4D every 28 D
Methotrexate 40mg/m2 weekly
ORR 32 vs. 21 vs. 10% (combination chemo significantly better)
OS 6.6 vs. 5.0 vs. 5.6 mo (no statistical significance)
Grade 3-4 toxicity 33 vs. 26 vs. 16%

18. 1st Line Therapy – Previously untreated patients
Platinum + Taxane
Cisplatin or Carboplatin + Paclitaxel or Docetaxel
Similar efficacy to Cisplatin + 5FU
ECOG 2005, Phase III, 204 patients
Cis + 5FU vs. Cis (75mg/m2) + Paclitaxel (175mg/m2) every 21 D
OS 8.7 vs. 8.1 mo (not statistically significant)
ORR 27 vs. 26%
GI and hematologic toxicity worse in Cis + 5FU group

19. 1st Line Therapy – Previously untreated patients
Platinum + Taxane
Phase II studies: Cisplatin (70-75mg/m2) + Docetaxel mg/m2) every 21 D
25-44 patients
ORR 32-55%, higher RR associated with more severe AE
OS 11 mo in one trial
No Phase III trial comparisons with Cis + 5FU
Weekly schedule (Cis 25mg/m2 + D 35mg/m2 x 3 weeks every 28 D) may have similar efficacy with improved toxicity

20. 1st Line Therapy – Previously untreated patients
Platinum + Taxane
Phase II studies: Carboplatin (6-7 AUC) + Paclitaxel (200mg/m2) or Docetaxel (65mg/m2) every 21 D
24-68 patients
ORR 25-43%
OS mo in 1 trial (C+P), 7.4 mo in 1 trial (C+D)
No randomized trials

21. 1st Line Therapy – Previously untreated patients
3 or 4 cytotoxic drug combinations
Phase II trials
Cis + 5FU + Taxane or Cis/Carbo + Ifosfamide + Paclitaxel
Cis + MTX + Vinblastine + Doxorubicin
Greater toxicity, no evidence of superiority to doublet or single- agent cytotoxic chemo

22. 1st Line Therapy – Previously untreated patients
Non-platinum Regimens
Phase II studies, patients
Gemcitabine 3000mg/m2 + Paclitaxel 150mg/m2 D1 and 15 every 28 D (GEMTAX)
ORR 28%, PFS 4 mo, OS 8 mo
Unclear if superior to single-agent taxane therapy
Weekly Paclitaxel (80mg/m2) + Cetuximab (400/250mg/m2)
ORR 54%, PFS 4 mo, OS 8 mo
Poor prognosis patients, unfit for platinum therapy

23. 1st Line Therapy – Previously treated patients
Pts who have received induction chemotherapy or concurrent chemoRT in the definitive setting
Choice of therapy depends on:
Original chemotherapy agents used
Response to prior therapy
Interval between initial treatment and disease progression
Performance status, comorbidities of patient

24. 1st Line Therapy – Previously treated patients
EXTREME Trial
39% of patients had received prior induction chemo and/or concurrent chemoradiotherapy at least 6 months prior to trial
No significant difference in PFS between pts who had received prior therapy and those who did not
Patients without response to initial therapy or relapse within 6 months of therapy are presumed refractory and should be considered for 2nd line therapy

25. 1st Line Therapy Single-agent therapy Poor performance status
Cisplatin
Carboplatin
Paclitaxel
Cetuximab

26. 2nd line therapy Immunotherapy Cytotoxic chemotherapy Targeted therapy
Consider
Prior treatments
PS and comorbidities
Potential toxicities of available regimens

27. 2nd line therapy PD-1 Inhibitor Immunotherapy
Pembrolizumab – FDA approval 8/2016
Nivolumab –FDA approval 11/2016

28. 2nd line therapy

29. 2nd line therapy Pembrolizumab
Accelerated approval for pts with progression on or after Platinum-based therapy
Conditional upon completion of randomized Phase III trials
KEYNOTE-040 (pembro vs. MTX, docetaxel or cetuximab)
KEYNOTE-012
Phase Ib, international, open-label, multi-center trial
174 patients with recurrent or metastatic HNSCCa with progression on or after platinum-based therapy
Pembrolizumab 200mg (flat dose) every 3 weeks
Recommended dose and schedule (vs. 10mg/kg every 2 weeks)

30. 2nd Line Therapy KEYNOTE-012 ORR 16%, CR in 8 pts (5%)
Median duration of response not reached (range mo), 82% of pts with response >6 months
HPV positive 33% - no effect on response rate
Toxicity similar to pembro in other trials, except higher incidence of hypothyroidism (15%)
Most common AE: fatigue, anorexia, dyspnea

31. 2nd Line Therapy KEYNOTE-012 Update at ASCO 2016
Treatment at 10mg/kg IV every 2 weeks
OS 8 mo
6 mo survival 58%
12 mo survival 38%

32. 2nd line therapy

33. 2nd line therapy CheckMate-141
Phase III RCT, 361 patients with recurrent HNSCCa progressed within 6 months after platinum-based therapy (in any setting)
Nivolumab 3mg/kg every 2 weeks vs. single agent cytotoxic chemotherapy
MTX 40-60mg/m2 weekly
Docetaxel 30-40mg/m2 weekly
Cetuximab 400/250mg/m2 weekly

34. 2nd Line therapy
CheckMate-141: Nivolumab vs. single agent weekly cytotoxic chemotherapy
OS 7.5 vs 5.1 mo (HR 0.7, 98% CI )
Significantly increased with PD-L1 expression >1% (8.7 vs. 4.6 mo; HR 0.55, 95%CI ), not significant with PD-L1 <1%
Better in HPV+ (9.1 vs 4.4 mo; HR 0.56, 95%CI ), not significant in HPV- patients (7.5 vs 5.8 mo, HR 0.73, 95% CI ).
1y survival 36 vs. 16.6%
ORR 13.3 vs. 5.8%

35. 2nd line Therapy Cytotoxic Chemotherapy
ORR are uncommon after 1st line therapy
No evidence of prolonged survival
MTX 40-60mg/m2 weekly
Docetaxel 30-40mg/m2 weekly
Gemcitabine 1250mg/m2 D1 and 8 every 15 D

36. 2nd Line Therapy Molecularly Targeted Therapy Cetuximab
Phase II trials, ORR 10%, OS 7.5 mo
Alternative dosing 500mg/m2 every 2 weeks has similar efficacy (ORR 11%)

37. 2nd Line Therapy Molecularly Targeted Therapy Small molecule TKIs
Some positive data but no clear clinical role established yet

38. 2nd Line Therapy Molecularly Targeted Therapy – Small molecule TKIs
Afatinib (EGFR inhibitor)
Phase III RCT, 483 pts, Afatinib vs. weekly MTX – LUX-Head & Neck 1
Improved PFS 2.6 vs. 1.7mo (HR 0.8, 95% CI )
No improvement in OS (6.8 vs 6.0 mo)
Afatinib = increased toxicity but fewer treatment discontinuations and delay in deterioration of EORTC global health status (QOL indicator)
Better PFS if no prior EGFR MoAb inhibitor therapy, HPV -, locally recurrent disease, non-oropharyngeal primary

39. 2nd Line Therapy Molecularly Targeted Therapy – Small molecule TKIs
Gefitinib (EGFR inhibitor)
Phase III RCT, 482 pts, gefitinib vs. weekly MTX
No difference in OS – approx. 6 months
No difference in ORR – 3-8%
Phase III RCT, 278 pts, gefitinib + weekly docetaxel vs. placebo + weekly docetaxel
No difference in OS (7.3 vs. 6.0 mo)
Gefitinib + docetaxel = increased grade 3-4 diarrhea

40. Upcoming studies 1st Line Therapy
KEYNOTE-048 – Phase III, Pembrolizumab vs. Pembro + Platinum + 5FU vs. Cetuximab + Platinum + 5FU in R/M HNSCCa
2nd Line Therapy
KEYNOTE-040 – Phase III, Pembro vs. SOC (docetaxel, MTX, or Cetuximab) in R/M HNSCCa after platinum therapy
AZ Eagle – Phase III, Durvalumab monotx vs. Durvalumab + Tremelimumab vs. SOC in R/M HNSCCa after platinum therapy
LUX-Head & Neck 3 – Phase III, Afatinib vs. MTX in R/M HNSCCa after platinum therapy in pts without prior EGFR inhibitor therapy

41. Summary Recurrent and metastatic HNSCCa generally has a poor prognosis
1st line combination therapy reserved for patients with good PS
Platinum + 5FU + Cetuximab improves survival over Platinum + 5FU alone
Excellent PS and organ function
Doublet cytotoxic chemotherapy (without cetuximab) improves RR but not OS compared to single-agent cytotoxic chemotherapy
Platinum + Paclitaxel has similar efficacy and decreased toxicity compared to Platinum + 5FU
1st line single agent therapy is best for patients with poor PS
Platinum, Taxane, Cetuximab
*If within 6 months of platinum therapy in adjuvant or definitive setting, can use immunotherapy*

42. Summary 2nd line therapy
Immunotherapy (nivolumab) improves RR and OS compared to single- agent cytotoxic chemotherapy
Response rates are still low overall at 13-16% with immunotherapy
Single agent cytotoxic chemotherapy
Very low response rates
No evidence of improved survival
Single agent Cetuximab
Low response rate (10%) but potentially better than cytotoxic chemo; phase II data only
Single agent EGFR TKIs
No defined role
No difference in survival compared to single-agent MTX