Recent advances in RM Head & Neck cancer (1) (2).pptx

Recent advances in RM Head & Neck cancer

1. Recent advances in R/M Head & Neck cancer Dr. Vipul Nautiyal Associate Professor, Department of Radiation Oncology Swami Rama Himalayan University, Dehradun.

2. Incidences & Mortality Head & Neck Cancer 2020 – As per site Globocan 2020 1/3 rd of Lip, oral cavity cancer patients are in India

3. Tumor characteristics in India In a retrospective analysis of 5595 HNC patients at TATA Memorial Hospital in Mumbai 1 : The TNM staging indicated that 80-90% of cases presented with Stage III or Stage IV* malignancies Average age varied from 49.4 years (Ant. Tongue) to 54.1 years (hard palate cancer) * Stage classification as per the study stage I : T1 N0 M0 status, stage II: T2 N0 M0 stage III: T3 N0 M0, T3 N1 M0, T1 N1 M0 and T2 N1 M0 stage IV : T4 N0 M0, T4 N1 M0, and any T, N2 or N3 MO and any T any N M1 1. Rao, D. N., Shroff, P. D., Chattopadhyay, G., & Dinshaw, K. A. (1998). Survival analysis of 5595 head and neck cancers--results of conventional treatment in a high-risk population. British journal of cancer , 77 (9), 1514. Large and advanced stage tumors need a therapy that has rapid debulking and early relief features

4. HNSCC in developing world differ from those in the Western world in terms of age, site of disease, etiology and molecular biology 1 Oral cavity cancer more common in patients below 40 years of age group, whereas oropharynx and larynx common in patients above 40 years of age 2 1. Francis et al. EJC March 2018, Vol 92, 2. Alam MS, et al. J Can Res Ther 2017;13:430-5. Tumor characteristics in India

5. Globocan 2020 Oral cavity is the most common however incidence in India is higher than western population

6. 1. Argiris A, et al. Front Oncol 2017;7:72; 2. Fluorouracil EU SmPC, May 2019; 3. Guigay J, et al. Front Oncol 2019;9:668; 4. Ahn MJ, et al. Oral Oncol 2016;53:10–16; 5. Oliveira KG, et al. BMC Cancer 2014;14:39. Patients need a treatment that prolongs survival 1 Patients with R/M SCCHN have different needs and abilities to tolerate treatment Patients may not be able to tolerate 5-FU 1–3 Some patients may be unable to tolerate cisplatin 4 Patients may have a heavy tumor burden, causing symptoms and requiring a rapid response 5 Each patient is unique and personalizing care for each patient is important

7. Key clinical trials

8. Patients with recurrent and/or metastatic SCCHN KPS ≥70 Cetuximab until PD Chemotherapy + Cetuximab Primary endpoint: OS Secondary endpoints: PFS, ORR, DCR, DoR, TTF, QoL, safety Chemotherapy Chemotherapy (CT) Cisplatin (100 mg/m 2 intravenous [IV], day 1) [or Carboplatin (AUC 5 mg/mL/min, day 1)] + 5-FU (1000 mg/m 2 IV, days 1–4) Every 3 weeks, up to six cycles Cetuximab Cetuximab initial dose 400 mg/m 2 IV, then 250 mg/m 2 IV weekly until disease progression (PD) DCR, disease-control rate; DoR, duration of response; KPS, Karnofsky performance score; ORR, overall response rate; OS, overall survival; QoL, quality of life; TTF, time to treatment failure Vermorken JB, et al. N Engl J Med. 2008;359(11):1116–1127. EXTREME design: Phase III trial of CT ± cetuximab in 1st line treatment of R/M SCCHN N=442

9. Adding Cetuximab to platinum-based CT significantly improved survival 5-Year Follow-Up Vermorken JB, et al. N Engl J Med. 2008;359(11):1116–1127. Vermorken JB, et al. J Clin Oncol. 2014;32(Suppl): Abstract 6021. 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Months CT + cetuximab 221 183 152 117 81 62 46 38 31 23 18 16 14 14 13 10 9 8 7 7 6 CT alone 220 173 127 83 65 52 34 29 25 21 14 12 9 8 8 8 8 6 5 4 2 0.2 0.1 0.0 0.3 0.5 0.4 0.6 0.7 0.8 0.9 1.0 Probability of OS CT + cetuximab CT alone ITT median OS, months (95% CI) CT + cetuximab: 10.1 (8.6-11.2) CT alone: 7.4 (6.4-8.3) Long-term survival HR: 0.80 (95% CI: 0.64-0.99) P value =0.04 CT+ Cetuximab (n=222) CT alone (n=220)

10. 1L R/M SCCHN (N=539) TPEx: Cetuximab 400 mg/m 2 then 250 mg/m 2 QW + cisplatin 75 mg/m 2 Q3W + docetaxel* 75 mg/m 2 Q3W + mandatory G-CSF after each cycle 4 cycles of CT (n=271) EXTREME: Cetuximab 400 mg/m 2 then 250 mg/m 2 QW + cisplatin 100 mg/m 2 Q3W + 5-FU 4000 mg/m 2 6 cycles of CT (n=270) Cetuximab 250 mg/m 2 QW Cetuximab 500 mg/m 2 Q2W † EXTREME Cetuximab+Cisplatin+5FU 6 cycles of chemotherapy Weekly cetuximab maintenance Cisplatin dose 100 mg/m 2 No prior systemic CT for R/M SCCHN except if completed >6 months prior if given as part of multimodal treatment for LA disease ECOG PS 0–1 TPExtreme: A large randomized study comparing TPEx (cetuximab + platinum + taxane) with EXTREME TP-EXTREME Cetuximab+Cisplatin+Taxane 4 cycles of chemotherapy 2 weekly cetuximab maintain ance Cisplatin dose 75 mg/m 2 Guigay J, et al. Lancet oncology 2021; 10.1016/ S1470-2045(20)30755-5

11. The TPEx* and EXTREME regimens showed similar OS and ORR in 1L R/M SCCHN Note: median OS in the EXTREME arm was higher than previously reported 1–4 EXTREME TPEx 13.4 14.5 Median OS 1 months ORR at 12 weeks 1 Guigay J, et al. Lancet oncology 2021; 10.1016/ S1470-2045(20)30755-5

12. Keynote-048

13. Pembro monotherapy has not shown superior OS over EXTREME in ITT population, however it was superior in CPS>1 and CPS>20 subgroup CPS>20 CPS>1 Burtness B, et al. Lancet 2019. pii:S0140-6736(19)32591–7.

14. Pembro+CT has shown superior OS over EXTREME in CPS>1, CPS>20 subgroup and ITT population CPS>20 CPS>1 OS (ITT population) OS (%) 12-mo rate 53% 44 % 24-mo rate 29 % 19% Median OS HR Pembro + chemo 13.0 (10.9–14.7) HR 0.77 EXTREME 10.7 (9.3-11.7) P=0.0034 5 10 15 20 25 30 35 Months 281 227 169 122 75 40 10 1 278 227 147 100 51 20 5 1 20 40 60 80 100 No. at Risk Burtness B, et al. Lancet 2019. pii:S0140-6736(19)32591–7.

15. EXTREME regimen has shown superior ORR and significantly lesser rate of disease progression than Pembro mono and Pembro+CT CPS ≥20 CPS ≥1 CPS <20-1 ITT Pembro mono (133) Extreme (122) Pembro mono (257) Extreme (255) Pembro mono (124) Extreme (133) Pembro mono (301) Extreme (300) ORR 23 36 19 35 14.5 34 17 36 PD 32 10 39 13 NR NR 41 12 Pembro + CT (126) Extreme (110) Pembro + CT (242) Extreme (235) Pembro + CT (116) Extreme (125) Pembro + CT (281) Extreme (300) ORR 43 38 36 36 29 34 36 36 PD 15 8 17 12 NR NR 17 12 NR, not reported; ORR, overall response rate; PD, progressive disease. 1. Burtness B, et al. Keynote – 048, Lancet October 2019.

16. Real world evidences

17. Wang et al 2020, PeerJ 2020

18. (n=106) After 3 months Variable N(%) Age 55.1+/-9.9 Alcohol 71 (67%) Betel nuts 76 (71%) Smoking 79 (75%) Oral Cavity 68 (64%) Hypopharynx 21 (20%) Oropharyngeal 17 (16%) Stage I-II 15 (14) Stage III 11 (10%) Stage IV 80 (76%) Baseline characteristic: Treatment modality: Variable N(%) Cetuximab cycle, median (range) 11 (2-24) <11 46 (43%) ≥11 60 (57%) CRT refractory* 34 (32%) Non-CRT refractory 72 (68%) Wang et al 2020, PeerJ 2020 *CRT refractory: Disease progression during or within 3 months of the end of CRT

19. Cetuximab administration beyond 11 cycles resulted in superior OS and PFS compared to less than 11 cycles Wang et al 2020, PeerJ 2020

20. Summary 80-90% of Indian cases are diagnosed in stage III-IV HNSCC in Indian patients differ from those in the Western world Patients with R/M SCCHN have different needs and abilities to tolerate treatment Obtaining tumor response in patients with high tumor burden is of paramount importance Pembrolizumab +CT has shown OS advantage over EXTREME in all population however ORR is similar and rate of disease progression is higher even in CPS>20 subgroup Multiple real world evidences support Cetuximab+CT in 1L R/M SCCHN From a real-world study, Cetuximab administration beyond 11 cycles resulted in higher median OS and PFS

21. Case based discussion Dr. Vipul Nautiyal Associate Professor, Department of Radiation Oncology Swami Rama Himalayan University, Dehradun. Choosing right treatment for right patient in RM SCCHN

22. The R/M SCCHN treatment landscape is evolving Throughout the 1970s, 80s and 90s chemotherapy was the only treatment for R/M SCCHN 1–3 In 2008, the EXTREME trial demonstrated an improvement in outcomes when Cetuximab was added to CT 4 10 months In 2016–18, ICI therapy demonstrated improved outcomes in platinum-refractory disease or 2L 5,6 11 months In 2019, multiple new treatment options entered the 1L landscape 7,8 1L, first line; 2L, second line; 5-FU, 5-fluorouracil; CT, chemotherapy; ICI, immune checkpoint inhibitor; OS, overall survival; TPEx, taxane + platinum + Cetuximab. 1. Grose WE, et al. Cancer Treat Rep 1985;69:577–581; 2. Forastiere AA, et al. J Clin Oncol 1992;10:1245–1251; 3. Kish JA, et al. Cancer 1985;56:2740–2744; 4. Vermorken JB, et al. N Engl J Med 2008;359:1116–1127; 5. Ferris RL, et al. N Engl J Med 2016;375:1856–1867; 6. Cohen E, et al. Lancet 2018;393:156–157; 7. Guigay J, et al. ASCO 2019 Abstract No. 6002); 8. Burtness B, et al. Lancet 2019;394:1915–1928; 9. Guigay J, et al. ASCO 2020 (Abstract No. 6507 – presentation). 1980s 1970s 2008 2016–18 2019 6 months 14 months OS: 2020 In 2020, long OS was seen using the TPEx regimen followed by ICI therapy 9 21 months Single-agent CT 1 CT The EXTREME ICIs in 2L 5,6 TPEx 7 TPEx combinations 2,3 regimen 4 and ICI ± platinum + 5-FU 8 followed by ICI 9 2L OS

23. Do we consider following factors in deciding treatment of R/M SCCHN patients? CPS, combined positive score; TPS, tumor proportion score. 1. Modified from Szturz P, Vermorken JB. Ann Transl Med 2020;8:doi:10.21037/atm.2020.03.164. Factor Critical for R/M SCCHN treatment decision? 1 Need for response Performance status Biomarkers ✔ ✔ Biological age/co-morbidites CPS/TPS Burden/pace of disease, symptoms ✔

24. We have increasing options for the treatment of SCCHN – and must consider patient, tumor and therapy characteristics 1 Efficacy Convenience Treatment sequence Tumor biology Toxicity and pharmacokinetics Fitness/ biological age Tumor burden Pace of disease Biomarkers 1. Szturz P, Vermorken JB. Ann Transl Med 2020;8:doi:10.21037/atm.2020.03.164. Patient Therapy Tumor

25. 64-year-old male Presented with swelling on the right hand side of face and weight loss Examination: Necrotic lesion located in the mandibular body, with extension to the retromolar trigone, right amygdala and soft palate Adenopathy in the right cervical level II 15 cigarettes per day ECOG PS 1 Weight 56 KG PDL-1 testing was not available Case- 1

26. Head and neck MRI: Infiltrative lesion (6 cm) located in the right, with involvement of the retromolar trigone (destruction of the mandibular bone) and extension to the floor of the mouth and to the lateral oropharyngeal wall Also involves the right masticator space, including the masseter muscle, the pterygoid plate and the medial pterygoid muscle Metastatic lymph node in ipsilateral levels IB and II (the biggest with 5.5 cm). Possible involvement of the submandibular glandule Thorax CT scan: Lung metastasis Epidermoid carcinoma of the oral cavity/oropharynx (cT4bN2bM1 – Stage IVC) Case Analysis Tumor Burden High Age and Fitness 64 years and fit Pace of disease progression Not available PDL-1 testing Not available

27. Response is an important treatment goal in R/M SCCHN due to the impact of tumors on symptoms and quality of life 2,3 P atients with symptomatic disease require response to reduce their tumor burden, relieve symptoms and improve survival 1,2 Speaking difficulties Breathing difficulties Swallowing difficulties Pain Bleeding Impact of a growing tumor: 3,4 Symptom burden is greater with bulky tumors than smaller tumors 2 Controlled prospective study in 127 patients with SCCHN before antineoplastic treatment Mean EORTC QLQ-C30 score Note: p-values not reported T1 n=25 T4 n=48 Symptom burden was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ‑C30) EORTC, European Organization for Research and Treatment of Cancer; QLQ-C30, Quality of Life Questionnaire Core‑30. 1. Vermorken JB, Specenier P. Ann Oncol 2010;21:vii252–vii261. 2. Oliveira KG, et al. BMC Cancer 2014;14:39. 3. National Cancer Institute. 2013. Available from http://www.cancer.gov/types/head-and-neck/head-neck-fact-sheet ; Last accessed February 2020. 4. Gandhi AK et al. Indian J Palliat Care 2014;20:189–193.

28. ~80% Indian RM SCCHN patients are symptomatic IPSOS PRIMARY MARKET RESEARCH ON SCCHN- AUG 2020

29. Please choose the option that most closely resembles your preferred treatment : Cetuximab + platinum + taxane (TP-Ex regimen) Cetuximab + platinum + 5-FU (EXTREME regimen) Pembrolizumab monotherapy Pembrolizumab+ platinum +5FU Chemotherapy alone Metronomic chemotherapy How would you treat this patient?

30. Due to the distinct pharmacodynamic features of immune checkpoint inhibitors, there are several factors impacting on the decision-making process in the recurrent and/or metastatic setting 

31. What we need for Indian patients? ORR Progression Free Survival Symptom relief OS

32. Can we replace EXTREME regimen with TP-EXTREME? For which set of patients? EXTREME Cetuximab Cisplatin/ Carboplatin 5FU E TPEXTREME Cetuximab Cisplatin/ Carboplatin Taxane

33. Comparison of EXTREME with TP-EXTREME Parameters EXTREME 1 TP-EXTREME 2 Convenience 4 days of FU infusion (Requires hospitalization) Single day taxane infusion Grade 4 AE or worse 52% 36% OS 13.4 months 14.5 months ORR 59% 57% CT exposure 6 cycles 4 cycles Major Contraindications Cardiotoxicity/GI toxicity GI toxicity Maintenance Weekly Cetuximab Bi-weekly Cetuximab Mandatory G-CSF support in each cycle Not required (Used in 43% of patients) Required Guigay J, et al. Lancet oncology 2021; 10.1016/ S1470-2045(20)30755-5

34. Multiple studies support the efficacy of Cetuximab + CT in 1L R/M SCCHN irrespective of biomarker ORR and mOS are consistently high across studies with Cetuximab + CT* CET-INT 2017 (N=191) ††5 Cetuximab + cis + pac* 11 52 ORR, % mOS, months CET-MET 2018 (N=85) ‡‡7 Cetuximab + car + pac* ¶ 10.2 63 ORR, % mOS, months CSPOR-HN02 2018 (N=47)** 6 Cetuximab + car + pac* 14.7 40 ORR, % mOS, months GORTEC 2008-03 2012 (N=54) §4 Cetuximab + cis + doc* ¶ 14 44 ORR, % mOS, months EXTREME † 2008 (n=222) ‡1 Cetuximab + cis/car + 5-FU 10.1 36 ORR, % mOS, months TPExtreme 2021 (n=269) §§3 Cetuximab + cis + doc* ¶ 14.5 mOS, months 57 ORR, % CHANGE-2 2019 (N=163) ‡‡2 Cetuximab + cis/car + 5-FU 10.2 50 ORR, % mOS, months Extreme are of TPExtre me † 2021 (n=270) §§3 Cetuximab + cis + 5-FU 13.4 59 ORR, % mOS, months 1. Vermorken JB, et al. N Engl J Med 2008;359:1116–1127; 2 Guo Y, et al. ASCO 2019 (Abstract No. 6018 – Presentation); 3. Guigay J, et al. Lancet oncology 2021; 10.1016/ S1470-2045(20)30755-5 . 4. Guigay J, et al. Ann Oncol 2015;26:1941–1947; 5. Bossi P, et al. Ann Oncol 2017;28:2820–2826; 6. Tahara M, et al. Ann Oncol 2018;29:1004–1009; 7. Friesland S, et al. ASCO 2018 (Abstract 6032).

35. Case-1 December 2014 Started treatment with the TP-EXTREME regimen Good clinical response Very good partial response both on the main lesion and lymph node. Orofacial fistula which causes discomfort when eating February 2015 April–November 2015 Cetuximab maintenance therapy COMPLETE RESPONSE

36. Case-1 (Relapse) Relapsing aphthous ulcer located in the right side of the tongue Physical examination showed solid ulcerative lesion located in the right side of the tongue December 2016 Head and neck MRI scan: Nodule of 15x18 mm located in the right side of the tongue (posterior half of its mobile portion), contacting with the genioglossus muscle – does not cross the median line No involvement of the base of the tongue nor the mouth pavement

37. Please choose the option that most closely resembles your preferred treatment : Cetuximab monotherapy Nivolumab Oral Metronomic Pembro monotherapy or Pembro+CT Other How would you treat this patient in 2L?

38. Slide 11 Presented By Joel Guigay at TBD

39. 2nd line treatment: Overall Survival since randomization <br />in each arm according to Chemo +/- Cetux vs IO Presented By Joel Guigay at TBD

40. Presented in ESMO ASIA 2020 Paclitaxel, Carboplatin and Cetuximab (PCC) (n=54)- Platinum sensitive patients For upto maximum 12 weeks followed by Cetuximab maintenance Median age: 56.5 years Male 48, Female 6 ECOG PS 1/2 (32/22) Local disease/distant metastasis 30/34 Oral/Non-oral primaries: 30/24 Treatment Naïve: 16 Median treatment free interval of 10 months: 38 ORR: 79.7% PFS-1: 7 months Patients on 2 nd line treatment (n=33) Nivolumab (n=19) OMCT (n=10) Progression Continued on next slide

41. Patients on 2 nd line treatment (n=33)* Nivolumab (n=19) OMCT (n=10) ORR : 37% Median OS : 20.4 months Median PFS2 : 6.5 months ORR : 10% Median PFS2 : 2 months Median OS of entire cohort: 15 months Side effect profile (Grade III/IV) Neutropenia 31.4% Anemia 35.1% Thrombocytopenia 7.4% Febrile neutropenia 11.1% Skin reactions 16.6% Conclusion : First line weekly PCC is an effective regimen for palliative therapy for platinum sensitive R/M SCCHN patients with acceptable toxicity profile. Addition of 2 nd line Nivolumab progression further improves outcomes. *best supportive care was received by 4 patients Presented in ESMO ASIA 2020

42. Metronomic chemotherapy in Recurrent Head and Neck Cancer R.P.S. Banipal and M.K. Mahajan Failed earlier attempts of radical treatment with Surgery, Radiotherapy ± chemotherapy and have residual or recurrent tumours, were treated with single agent Injection Methotrexate 50 mg/m2 weekly 38.8% good response decrease in the tumour bulk in > 50% 39% stable Disease Overall 83.3% patient improvement in QOL. After 6 weekly treatments with injection methotrexate 63% - pain free Grade 3 toxicity Neutropenia (11.1%), anaemia (11.1%) and Mucositis (16.6%) M S with good QOL - 5.4 months

43. Conclusion Each patient with R/M SCCHN is unique : Treatment decisions should consider the variety of patients’ needs Obtaining tumor response in patients with high tumor burden is of paramount importance Cetuximab + CT is flexible option allowing treatment to be tailored to the patient (platins + 5-FU/taxane ) Appropriate patients with R/M SCCHN should benefit from both Cetuximab and ICIs at some point in their treatment journey With ASCO 2020 TPExtreme , Cetuximab based regimen in 1 st line followed by Immunotherapy in 2 nd line, with OS reaching 21.9 months