3. Role of Afatinib in Head and Neck cancer.pptx

role of afatinib in advance and metastatic head and neck cancers refractory to platinum based treatment

1. Role of EGFR TKIs in Head & Neck Cancer Dr. Ashok Kumar Singh Assistant Professor Surgical Oncology KSSSCI Lucknow

2. What is head and neck cancer? 1. Stewart BW and Wild CP. 2014 ( eds ). World Cancer Report. Lyon: WHO IARC Press, 2014. pp. 423; 2. Ferrarotto R, Gold K A. Expert Opin Investig Drugs 2014;23(1):135–43; 3. Mountzio G, et al Ann Oncol 2014;25(10):1889–900; Image from: https://www.cancer.gov/types/head-and-neck/head-neck-fact-sheet. HNSCC- Head and neck Squamous cell carcinoma

3. Epidemiology Head and neck cancer in India has distinct demographic profile, risks factors, food habits, and personal and family history. Overall, 57.5% of global head and neck cancers occur in Asia especially in India. Head and neck cancers in India accounted for 30% of all cancers. 60 to 80% of patients present with advanced disease as compared to 40% in developed countries. Globocan 2020

4. EGFR as a molecular target in HNSCC EGFR is overexpressed in 80–90% of HNSCCs, playing a key role in carcinogenesis and tumor evolution. Prognosis of relapsed or metastatic HNSCCs is poor with mOS of less than an year. Two different anti-EGFR therapeutic strategies have been developed: Target the extracellular domain : monoclonal antibodies such as Cituximab or Panitumumab Target the intracellular domain: tyrosine kinase inhibitors (TKIs) such as Afatinib or Erlotinib 4 Ther Adv Med Oncol 2021, Vol. 13: 1–15

5. EGFR TKIs in recurrent Head & Neck cancer

6. Afatinib Clinical Evidences 6

7. LUX Head & Neck 1 A randomised open-label Phase III study evaluating the efficacy and safety of afatinib vs methotrexate, as a second line treatment in recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) after failure of previous platinum-based chemotherapies 7 Patients with recurrent/metastatic HNSCC who progressed on or after first-line platinum-based therapy R A N D O M I Z E D Afatinib – 40 mg oral, once daily Methotrexate – 40 mg/m 2 IV, weekly 2 1 n=483 n=161 n=322 Primary endpoint : PFS Key Secondary endpoints: OS Lancet Oncol . 2015 May;16(5):583-94 PFS, progression-free survival; OS, overall survival

8. LUX-Head & Neck 1: Progression free survival 8 Afatinib significantly prolong the progression free survival as compared to Methotrexate Lancet Oncol . 2015 May;16(5):583-94

9. Emerging biomarkers in Head & Neck SCC in era of immunotherapy and targeted therapy 9

10. Tumor response in biomarker-defined subgroups 10 Subgroups of patients with p16-negative, EGFR-amplified, HER3-low or PTEN-high tumors achieved higher PFS benefit with second-line Afatinib Vs Methotrexate

11. LUX Head & Neck 3 A Randomised , Open-label, Phase III Study to Evaluate the Efficacy and Safety of Afatinib Vs Methotrexate in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma Who Have Progressed After Platinum-based Therapy 11 Patients with recurrent/metastatic HNSCC who progressed on or after first-line platinum-based therapy R A N D O M I Z E D Afatinib – 40 mg oral, once daily Methotrexate – 40 mg/m 2 IV, weekly 2 1 n=340 n=112 n=228 Primary endpoint : PFS by independent review Key Secondary endpoints: OS, ORR & PROs Other endpoints: Tumor shrinkage, DCR (PR+CR+SD) Ann Oncol. 2019 Nov 1;30(11):1831-1839 ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, PROs, patient-reported outcomes, DCR, Disease control rate

12. LUX-Head & Neck 3: Progression free survival 12 Estimated PFS probability Ann Oncol. 2019 Nov 1;30(11):1831-1839 Afatinib significantly prolong the progression free survival as compared to Methotrexate

13. LUX-Head & Neck 3: ORR & DCR 13 Significantly more patients in the afatinib arm had an objective response, p=0.0016 p=0.0016 Ann Oncol. 2019 Nov 1;30(11):1831-1839

14. LUX-Head & Neck 3: Health-Related Quality of Life ( HRQoL ) 14 More patients had clinically relevant improvements with afatinib versus MTX GHS/QoL: 40% vs 23% (p<0.01); Swallowing: 34% vs 18% (p=0.01); Pain: 34% vs 25% (p=0.22) Ann Oncol. 2019 Nov 1;30(11):1831-1839

15. LUX-Head & Neck 3: Safety Most common TRAEs (≥10%) with afatinib 15 Any grade Grade≥3 Any TRAE, n (%) 202 (89) 37 (16) Diarrhea 153 (67) 8 (4) Rash/acne 126 (55) 10(4) Stomatitis 86 (38) 7 (3) Paronychia 42 (18) 2 (<1) Dermatitis acneiform 28 (12) 1 (<1) Mouth ulceration 24 (11) 1 (<1) The most common grade ≥3 TRAEs were rash/acne (4%), diarrhea (4%), and stomatitis (3%) with afatinib, and anemia , leukopenia, and fatigue (all 5%) with MTX Ann Oncol. 2019 Nov 1;30(11):1831-1839

16. Afatinib vs Cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) 16 An open-label, randomized, phase II trial; 124 patients were randomized (1 : 1) to either afatinib (50 mg/day) or cetuximab (250 mg/m 2 /week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II) Primary end point Tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR)

17. Afatinib vs Cetuximab An open-label, randomized, phase II trial; 124 patients were randomized (1 : 1) to either afatinib (50 mg/day) or cetuximab (250 mg/m 2 /week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II) 17 Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC Sequential EGFR/ ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance

18. Treatment of recurrent, unresectable or metastatic HNSCC: NCCN guidelines 18 NCCN guidelines for Head and Neck Cancers V1.2021

19. Summary Second-line treatment options are limited for patients with recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (HNSCC), particularly in Asian countries. Afatinib significantly improved PFS and ORR versus MTX in two phase III studies, with a manageable safety profile. LUX Head & Neck 1: Subgroups of patients with p16-negative, EGFR-amplified, HER3-low or PTEN-high tumors achieved higher PFS benefit with second-line Afatinib as compared to MTX LUX-Head & Neck 3: Efficacy benefits with afatinib were complemented by improved QoL versus MTX. In phase II study, Afatinib demonstrated comparable antitumor activity vs cetuximab in R/M HNSCC The tolerability profile of afatinib was in line with previous studies and experience; there were no new safety signals. 19