the present & future of hnc treatment in locally and very

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The Present & Future of HNC treatment in Locally and Very advanced disease

Panel Discussion

Dr.Lalit Mohan Sharma

Any correlation of Biomarkers and histologiocal progression of disease ?

• No screening strategy has proved to be effective• Careful physical examination remains the primary approach

for early detection

Biomarkers and histological progression of disease

Johnson, D.E., Burtness, B., Leemans, C.R. et al. Head and neck squamous cell carcinoma. Nat Rev Dis Primers 6, 92 (2020). https://doi.org/10.1038/s41572-020-00224-3

Artificial Intelligence-based methods in head and neck cancer diagnosis Carcinogen exposure and HPV-ve HNSCC

Johnson, D.E., Burtness, B., Leemans, C.R. et al. Head and neck squamous cell carcinoma. Nat Rev Dis Primers 6, 92 (2020). https://doi.org/10.1038/s41572-020-00224-3

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What are current treatment strategies in management of LASCCHN and their outcomes?

Current treatment options in locally advanced SCCHN

Locally advances SCCHN ( Stage III-IVa,b)

Surgery- based treatment

RT- based treatment

Concomitant therapy Sequential therapy RT alone

CRT RT CRT BioCRT BioRT RTBioRTCRT

TPF

Mesia, R., et al. "SEOM clinical guidelines for the treatment of head and neck cancer (2020)." Clinical and Translational Oncology 23.5 (2021): 913-921.Adapted from Indian consensus head and neck cancer guidelines

BMC cancer 20.1 (2020): 1-9.

HPV in Oropharynx

oWestern studies report HPV + in Ca Oropharynx 28-68%

o Indian Studies- 15-22%

o CAP Guidelines Diffuse cytoplasmic and nuclear staining in >70%

tumour cells

o Discordance in P16 and PCR positivity in India is attributed to tobacco

burden and P16 hypermethylation

HPV testing methods

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Who should be tested for HPV? Treatment for LAHNCC

Characteristics of treatment modalities in patients withLA-HNSCC

Overall Survival in Treatment

intent, CCRT group, Primary tumor location

and Oropharynx vs

Non-Oropharynx

Patients and tumor characteristics related to progression-free survival and overall survival according to multivariate analysis Points to Ponder

• The regimen for definitive CCRT was

• Weekly cisplatin in 58%

• 3-weekly cisplatin in 28%

• Cetuximab in 3%

• The preferred regimen for NACT was

• Docetaxel with cisplatin in 49%

• Docetaxel, cisplatin plus fluorouracil in 27%.

• With a median follow-up of 39 months, one-year and two-year survival rates were

89 and 80%, respectively

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Induction chemotherapy in locally advancedsquamous cell carcinoma of the head and neck: role, controversy, and future directions

Role of induction chemotherapy in LASCCHN

Controversies associated with induction chemotherapy in LASCCHN

Shabani M, Larizadeh M H. A Review of Chemotherapy for Locally Advanced Head and Neck Cancers, Rep Radiother Oncol. 2015 ; 2(1):e2261. doi: 10.5812/rro.2(1)2015.2261

Taxane based induction chemotherapies in LASCCHN


Place of induction chemotherapy in LASCCHN

Conclusions: TPF is an evidence-based ICT regimen of choice in LA SCCHN and confers benefits in suitable patients when it is administered safely by an experienced multidisciplinary team and paired with the optimal post-ICT regimen, for which, however, no consensus currently exists.

Concurrent chemoradiotherapy or radiotherapy alone in LASCCHN?

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In your practice what percentage of patients are able to receive radical chemo -radiotherapy in current challenging times ?

Treatment Delivered By Treatment Type

Floros, Peter, et al. "Altered presentation of oropharyngeal cancer, a 6‐year review." ANZ Journal of Surgery.

Various chemotherapeutic agents used in HNSCCConcurrent chemoradiotherapy or radiotherapy alone in LASCCHN


100 pts, HNSCCstage III/IV

RT alone

CCRT

RT: 66-72Gy, conventional, 1.8-2Gy/fx

5yr OS RFSDist. Mets-free survival

OS with primary site preserve

Local control without resection

RT 48% 51% 75% 34% 45%

CCRT 50% 62% 84% 42% 77%

p value 0.55 0.04 0.09 0.004 <0.001

Subsite RT CRT

Oral cavity,% 0 4

Oropharynx, % 22 22

Hypopharynx, % 9 7

Larynx, % 19 17

Cancer 2000; 88: 876-883

Cisplatin: 20mg/m2/d

5FU: 1000mg/m2/d

Infusion, D1-D4D22-D25

Primary site resection +/- neck dissection

Residual dz or recurrence

Survival benefit from better local control

Aldelstein DJ et alPhase III Randomized Trial Comparing Concurrent Chemoradiotherapy with Radiation Therapy Alone in Patients with Stage III and IV

Squamous Cell Carcinoma of the Head and Neck

Adelstein DJ et alPhase III Randomized Trial Comparing Concurrent Chemoradiotherapy with Radiation Therapy Alone in Patients with Stage III and IV

Squamous Cell Carcinoma of the Head and Neck

Cancer 2000; 88: 876-883

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What beyond CTRT for improving outcomes in LASCCHN?

What beyond CT & CTRT in HNC treatment ?

Kozakiewicz P and Kozakiewicz P: Application of molecular targeted therapies in the treatment of head and neck squamous cell carcinoma (Review). Oncol Lett 15: 7497-7505, 2018

Gao W, Li JZ, Chan JY, Ho WK, Wong TS. mTOR Pathway and mTOR Inhibitors in Head and Neck Cancer. ISRN Otolaryngol. 2012 Oct 18;2012:953089.

• Do you see benefit of adding anti-EGFR to concurrent chemoradiation in LASCCHN?

• If yes which anti-EGFR?

• Why?

• Patient criteria ?

Nimotuzumab with concurrent CTRT or CTRT in patients with SCCHN stage III/IVA (BEST Trial-2014)

Reddy BK, Lokesh V, Vidyasagar MS, et al. Nimotuzumab provides survival benefit to patients with inoperable advanced squamous cell carcinoma of the head and neck: a randomized, open-label, phase IIb, 5-year study in Indian patients. Oral Oncol. 2014 May;50(5):498-505.

70%

100%

0

20

40

60

80

100

120

CT+RT CT+RT+BIOMAb

ORR at 24 weeks

CT+RT+Nimotuzumab

Median overall survival not yet reached at 60 months in the Nimotuzumab +CTRT arm vs. 21.9 months in the CTRT alone arm(p-value= 0.0078, Hazard ratio =0.356 {0.161, 0.787})

Nimotuzumab with concurrent CTRT or CTRT (TMH Trial-2020)

Primary endpoint

CRT NCRT P value

2 yrs. PFS (%) 50.1 61.8 0.004

2 yrs. DFS (%) 48.5 60.2 0.008

Secondary endpoint

CRT NCRT P value

2 yrs. LRC (%) 57.6 67.5 P=0.006

Secondaryendpoint

CRT NCRT P value

2-year OS (%) 57.7 63.8 P=0.163

Patil VM, Noronha V, Joshi A, Agarwal J, Ghosh-Laskar S, et al. A randomized phase 3 trial comparing nimotuzumab plus cisplatin chemoradiotherapy versus cisplatin chemoradiotherapy alone in locally advanced head and neck cancer. Cancer 2019;125:3184-97.

Veitnam; Combined Nimotuzumab with CTRT for LASCCHN (N=87)

Nimo+CRT CRT Alone

Tumor Response Rate

90.6% 70.4%

mOS (months) 20 13

1 year OS 75.1% 54.4%

2 year OS 48% 29%

Thai Hoa NT, Quang Huy H. Combined Nimotuzumab with Chemoradiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma. Cureus. 2020 May 13;12(5):e8105..

1 year PFS 64.2% 39.5%

2 year PFS 37.4% 21.3%

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Singapore & Thailand; phase II study of Nimotuzumab concurrent with CTRT in patients with LASCCHN (N=37)

Ang MK, Montoya JE, Tharavichitkul E, et al. A phase II study of nimotuzumab (TheraCim-hR3) concurrent with cisplatin/radiotherapy in patients with locally advanced head and neck squamous cell carcinoma. Head Neck. 2021 Feb 5.

China; Nimotuzumab with Induction CT and concurrent CTRT in LA-HPC (N=36)

NimoGroup

WithoutNimogroup

P Value

ORR after induction CT 91.7% 58.3% 0.029

ORR after concurrent CTRT

95.8 % 83.3% 0.0253

2 year OS 62.5% 51.8% < 0.05

mPFS (months) 23 18 < 0.05

Tian X, Xuan Y, Wu R, Gao S. Nimotuzumab Combined with Induction Chemotherapy and Concurrent Chemoradiotherapy in Unresectable Locally Advanced Hypopharyngeal Carcinoma: A Single Institution Experience in China. Cancer Manag Res. 2020 May 11;12:3323-3329.

Nimotuzumab +CTRT in advanced NPC

Compared to CTRT alone, CTRT with Nimotuzumab increased response ratesRR=1.11, 95%CI 1.01-1.22

Along with decreased occurrence of Erythropenia (RR=0.11, 95%CI: 0.05-0.28)Neutropenia (RR=0.12, 95% CI:0.05-0.27)

Li Z, Li Y, Yan S, Fu J, et al. Nimotuzumab combined with concurrent chemoradiotherapy benefits patients with advanced nasopharyngeal carcinoma. Onco Targets Ther. 2017 Nov 14;10:5445-5458. doi: 10.2147/OTT.S141538.

Addition of Nimo to CTRT in LA-NPC improved survival rate

Endpoint NimoGroup

Non-Nimogroup

P Value

3 year OS 98% 91% 0.032

The survival curves of OS for nimotuzumab group versus non-nimotuzumab group after Propensity score-matching (PSM)

Fei Z, Xu T, Li M, et al. Effectiveness and cost-effectiveness analysis of nimotuzumab for the radiotherapy of locoregionally advanced nasopharyngeal carcinoma. Radiat Oncol. 2020 Oct 2;15(1):230.

Improving outcomes by addition of Nimotuzumab to CTRT in LA-NPC

Liang R, Yang L, Zhu X. Nimotuzumab, an Anti-EGFR Monoclonal Antibody, in the Treatment of Nasopharyngeal Carcinoma. Cancer Control. 2021 Jan-Dec;28:1073274821989301.

Long term survival with Nimotuzumab with IMRT and concurrent cisplatin-based CT

Zhi-Qiang W, Qi M, Ji-Bin L, et al. The long-term survival of patients with III-IVb stage nasopharyngeal carcinoma treated with IMRT with or without Nimotuzumab: a propensity score-matched analysis. BMC Cancer. 2019 Nov 19;19(1):1122.

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Study Outcomes of addition Nimotuzumab to IMRT in LA-NPC

Liang R, Yang L, Zhu X. Nimotuzumab, an Anti-EGFR Monoclonal Antibody, in the Treatment of Nasopharyngeal Carcinoma. Cancer Control. 2021 Jan-Dec;28:1073274821989301.

HPV –ve Versus HPV +ve disease ;is there higher mortality risk ?

Short-Term Mortality Risks Appear Higher in HPV-Negative Oropharyngeal Cancer

Mortality HPV +ve HPV –ve

Two-year cumulative all-cause mortality 10.4% 33.3% (P<.0001)

head and neck cancer-specific mortality 5.6% 16.3% (p<.0001)

competing-cause mortality 5.6% 17.0% (p<.0001)

mortality from second primary malignancies 42.9% 63.5%

• Patients with HPV-positive and HPV-negative OPC are distinct populations with significantly different risks of both HNC-specific and competing-cause mortalities

• Effective identification of risk factors for competing second-cancer and noncancer mortality can also inform medical management and survivorship screening for patients with OPC.

Fullerton, Zoe H., et al. "Short‐term mortality risks among patients with oropharynx cancer by human papillomavirus status." Cancer 126.7 (2020): 1424-1433.

HPV-positive disease had lower rates of cardiovascular death, chronic obstructive pulmonary disease, pneumonia, and chronic liver disease, all of which underscore “the importance of smoking-cessation counseling and lung cancer screening for HPV-negative patients.”

Currently any role of OTHER anti-EGFRs or immune check point inhibitors in HPV negative locally advanced oropharyngeal cancer?

Radiotherapy plus cisplatin or cetuximab in low-risk HPV +veOPC (De-ESCALaTE HPV)

Verma, Subodh, Peter Jüni, and C. David Mazer. "De-intensified treatment in human papillomavirus-positive oropharyngeal cancer." (2018).

Radiotherapy plus cetuximab or cisplatin for human papillomavirus (HPV)-positive oropharyngeal cancer: (RTOG 1016)

Gillison ML, Trotti AM, Harris J, Eisbruch A, Harari PM, Adelstein DJ, Jordan RC, Zhao W, Sturgis EM, Burtness B, Ridge JA. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal

cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. The Lancet. 2019 Jan 5;393(10166):40-50.

Patients with HPV-positive OPC, radiotherapy plus cetuximab demonstrated inferior OS and PFS compared to radiotherapy plus cisplatin; toxicity rates were similar

Overall Survival Progression-free survival Loco regional Failure

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Pembrolizumab with CRT: Overall Survival : HPV +ve & HPV -ve

The combination did not improve overall survival in HPV – ve patients compared to HPV +ve

Powell, Steven F., et al. "Safety and efficacy of pembrolizumab with chemoradiotherapy in locally advanced head and neck squamous cell carcinoma: a phase IB study." Journal of Clinical Oncology 38.21 (2020): 2427.

Pembrolizumab with CRTProgression free survival : HPV +ve & HPV -ve

The combination did not improve progression free survival in HPV – ve patients compared to HPV +ve

Powell, Steven F., et al. "Safety and efficacy of pembrolizumab with chemoradiotherapy in locally advanced head and neck squamous cell carcinoma: a phase IB study." Journal of Clinical Oncology 38.21 (2020): 2427.

• 187 HPV negative oropharyngeal cancers• 91 in the CRT arm • 96 in NCRT arm.

Conclusions: The addition of nimotuzumab to weekly cisplatin-radiation improves outcomes inclusive of OS in HPV negative oropharyngeal cancers.

HPV –ve OPC: Nimotuzumab with concurrent CTRT or CTRT alone

CRT NCRT P value

mPFS, mo 12.9 35.3 P=0.0015

CRT NCRT P value

mLRC, mo 17.3 60.3 P=0.023

CRT NCRT P value

mOS, mo 19 35.9 P=0.017

Noronha V, Patil VM, Joshi A, Mahimkar M, Patel U ,Pandey MK, et al. Nimotuzumab-cisplatin-radiation versus cisplatin-radiation in HPV negative oropharyngeal cancer. Oncotarget. 2020 Jan 28; 11(4): 399–408

HPV-ve OPC: OS Benefit with Nimotuzumab

In the subgroup analysis of HPV negative oropharyngeal carcinoma, addition of nimotuzumab to CRT shown

2-year PFS benefit by 25.7% with decrease in the hazard of disease progression by 46%

2-year LRC was increased by 19% with decrease in relative risk of local regional failure by 39%

2-year OS benefit by 18.6% with reduction in the hazard to death by 37%

Noronha V., Patil V. Maruti, Joshi A., Mahimkar M., Patel U., Pandey M. Kumar, Chandrasekharan A., Dsouza H., Bhattacharjee A., Mahajan A., Sabale N., Agarwal J. Prakash, Ghosh-Laskar S., et al Nimotuzumab-cisplatin-radiation versus cisplatin-radiation in HPV negative oropharyngeal cancer. Oncotarget. 2020; 11: 399-408.

Are cisplatin associated toxicities different in weekly versus three weekly regimens ?

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Cisplatin associated irreversible toxicities are lower in weekly regimens

What are absolute contraindications OR borderline unsuitability for cisplatin ?

Absolute contraindications Vs high risk group for cisplatin

Alvarado-Muñoz, Juan F., et al. "Platinum ineligibility in squamous cell carcinoma of the head and neck: consensus from Central America and the Caribbean." Future Oncology 17.15 (2021): 1963-1971.

Treatment choices in cisplatin ineligible patients ?

Treatment choices for cisplatin ineligible LASCCHN

Carbo+ 5FU+RT Cetuximab +RT

Nimotuzumab +RT

Nimotuzumab +RT

Pembrolizumab+RT

Treatment decision making in very advanced disease ?

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Systemic treatment algorithm for recurrent and/or metastatic HNSCC outside clinical trials

Szturz, Petr, and Jan B. Vermorken. "Translating KEYNOTE-048 into practice recommendations for head and neck cancer." Annals of Translational Medicine 8.15 (2020).

Very advanced disease and treatment decisions

Prabhash K, Babu G, Chaturvedi P, et al. Indian clinical practice consensus guidelines for the management of squamous cell carcinoma of head and neck. Indian J Cancer. 2020;57(Supplement):S1-S5. doi:10.4103/0019-509X.278971

Nimotuzumab with platinum based CT in Recurrent/Metastatic NPC

CT NTZ+CT P Value

mPFS (months) 7.5 8.5 0.424

CT NTZ+CT P Value

mOS (months) 25.6 48.6 0.017

3 year OS 36.7% 76.2%

5 year OS 25.5% 42.9%

Zhu Y, Yang S, Zhou S, et al .Nimotuzumab plus platinum-based chemotherapy versus platinum-based chemotherapy alone in patients with recurrent or metastatic nasopharyngeal carcinoma. Ther Adv Med Oncol. 2020 Sep 16;12:1758835920953738.

Efficacy of Cetuximab vs Panitumumab vs Nimotuzumab in R/M HNC

Clinical trials of anti-EGFR monoclonal antibody plus chemotherapy in R/M SCCHN

Trial Monoclonalantibody

Chemotherapyregime

Responserate (%)

Median PFS

Vermorken et al. (EXTREME trial) Cetuximab Platinum/5 FU 36.0 vs. 20.0 5.6 vs. 3.3 months (P<0.001)

Vermorken et al. (SPECTRUM trial) Panitumumab Platinum/5 FU 37.0 vs. 26.0 5.8 vs. 4.6 months (P=0.0036)

Yadav A et al. Nimotuzumab Platinum/taxane 38.2 vs. 19.0 5.2 vs. 3.2 months (P=0.009)

ORR and mPFS with nimotuzumab was similar to cetuximab (in EXTREME trial) and panitumumab (in SPECTRUM trial)

Yadav A, Goyal P, Agrawal CR, et al. Efficacy and tolerability of nimotuzumab in combination with chemotherapy in recurrent and metastatic s quamous cell carcinoma of head and neck at a cancer center in Northern India. Indian J Cancer. 2020;57(1):76-83. doi:10.4103/ijc.IJC_469_18

Safety of Cetuximab vs Panitumumab vs Nimotuzumab in R/M HNC

Grade 3-4 toxicity EXTREME trial(Cetuximab + CT)

SPECTRUM trial(Panitumumab + CT)

Yadav A et al. (Nimotuzumab+ CT)

Skin 9% 19% 0%

Cardiac 7% 8% 1.8%

Hypomagnesemia 5% 12% 1.8%

Hypokalemia 7% 10% 3.6%

However, Nimotuzumab showed a better safety profile compared to both cetuximab and panitumumab with Chemotherapy

Yadav A, Goyal P, Agrawal CR, et al. Efficacy and tolerability of nimotuzumab in combination with chemotherapy in recurrent and metastatic s quamous cell carcinoma of head and neck at a cancer center in Northern India. Indian J Cancer. 2020;57(1):76-83. doi:10.4103/ijc.IJC_469_18

Newer Evidences and Future of the management of Locally Advanced and Very advanced HNC

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Major pathways dysregulated in HNSCC with approved and investigational therapeutic agents and their sites of activity

Muzaffar, Jameel, et al. "Recent Advances and Future Directions in Clinical Management of Head and Neck Squamous Cell Carcinoma." Cancers 13.2 (2021): 338.

Immune checkpoint inhibitor trials in head and neck squamous cell carcinoma (HNSCC)


Chemotherapy and radiotherapy in locally advanced headand neck cancer: an individual patient data networkmeta-analysis

Petit C, Lacas B, Pignon JP, Le QT, Grégoire V, Grau C, Hackshaw A, Zackrisson B, Parmar MK, Lee JW, Ghi MG. Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis. The Lancet Oncology. 2021 May 1;22(5):727-36

The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, usingHFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally

advanced head and neck cancer.

Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT); induction chemotherapy with taxane, cisplatin, andfluorouracil followed by locoregional therapy (ICTaxPF-CLRT)

HIF1α as a prognostic and predictive biomarker in HPV- LA HNSCC

Patel U, Pandey M, Kannan S, et al. Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab. Br J Cancer. 2020 Dec;123(12):1757-1766\

HIF1α as a prognostic and predictive biomarker in HPV- LA HNSCC Ongoing clinical trials in HNSCC


the present & future of hnc treatment in locally and very

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